Azabicyclo and diazepine derivatives for the treatment of ocular disorders

Abstract

In one aspect, the present application provides azabicyclo and diazepine derivatives useful as muscarinic receptor modulators. In another aspect, the present application provides pharmaceutical compositions for the treatment of ocular diseases, the compositions comprising at least one muscarinic receptor modulator. Formulas (I) and (II):

Description

Technical Field

[0001] This invention relates to azabicyclic and diazacyclic hepttriene derivatives that can be used as muscarinic receptor modulators, and to methods of treating diseases using said derivatives. Background Technology

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

[0003] Myopia is a refractive error of the eye caused by excessive longitudinal growth of the eye. This elongation of the eye causes visual images to focus in front of the retina and often results in blurred vision of distant objects. Atropine, a non-selective muscarinic antagonist, has been reported to be effective in treating myopia as a 1% topical eye drop (Chua et al., Ophthalmology, Dec 2006; 113(12):2285-91). However, numerous side effects have been reported, including mydriasis (pupil dilation) and myopic blurring due to ciliary muscle paralysis (inability to adapt). Currently, corrective lenses represent the primary means of improving eye length conditions such as myopia. However, lenses optically correct the refractive error but do not treat the underlying cause, namely eye overgrowth. Therefore, methods to treat conditions related to eye overgrowth are still needed. Summary of the Invention

[0004] No new treatments and therapies are still needed for eye overgrowth. This invention provides compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof, these compounds being muscarinic modifiers. This invention further provides a method for treating, preventing, or improving conditions associated with eye overgrowth, the method comprising administering an effective amount of a muscarinic modifier to a subject in need. Various embodiments of the invention are described herein.

[0005] In some respects, this article provides compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof:

[0006]

[0007] in

[0008] Me = CH3;

[0009] A = 0 or NR5;

[0010] W = N or CH;

[0011] X=-OH, -OYZ, -SYZ or -NR5-YZ;

[0012] R1 and R2 are independently substituted with H, D, hydroxyl, alkoxy, nitrile, halogen atom, or C1-C optionally substituted with halogen atom. 20 (Preferred C1-C) 10 Straight-chain, branched, or cyclic alkyl groups; or

[0013] R1 and R2 are independently substituted with phenyl or benzyl groups, which are optionally substituted by one or more substituents selected from the group consisting of C1-C2. 20 (Preferred C1-C) 10 Straight-chain, branched or cyclic alkyl, haloalkyl, hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide, sulfonamide, and halogen atom; or

[0014] R1 and R2 are independently substituted by heterocyclic saturated, unsaturated, or aromatic 5- or 6-membered rings, said rings containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and optionally substituted by one or more substituents selected from C1-C2. 20 (Preferred C1-C) 10 Straight-chain, branched or cyclic alkyl, haloalkyl, hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide or halogen atom;

[0015] R3 and R4 are independently converted by hydrogen, C1-C 10 Straight-chain or branched or cyclic alkyl or haloalkyl substitution, or

[0016] R3 and R4 can be combined to form 3 to 6-membered rings;

[0017] R5 = H or C1-C 20 Preferred C1-C 10 Straight-chain or branched alkyl groups, C1-C 10 Straight-chain or branched haloalkyl groups;

[0018] Y is a divalent group with the following meanings:

[0019] a) Straight chain or branched chain C1-C 20 (Preferred C1-C) 10 )alkyl group, which is optionally substituted by one or more substituents selected from the group consisting of halogen atoms and hydroxyl groups;

[0020] b)-C(O)(C1-C 10 Alkyl group or -C(O)(CH2) nC(O)O-(C1-C 10 alkyl)- or -(C1-C 10 alkyl)-;

[0021] c)

[0022] d)

[0023] e) or

[0024] f)

[0025] Where n is an integer from 0 to 20;

[0026] R 6 and R 7 Independently, it is H or Cl-C 10 Straight-chain or branched alkyl groups, C1-C 10 Straight-chain or branched haloalkyl groups; or

[0027] R 6 and R 7 They can be combined to form 3 to 6-membered rings; and

[0028] Z represents H, -OH, or C. 1-6 Alkoxy, -COOH, -NR 8 R 9 ;

[0029] R 8 and R 9 Independently replaced by C1-C 20 Alkyl groups, preferably C1-C 10 It may optionally be substituted with one or more substituents selected from hydroxyl, amino, ester, carboxylic acid, and halogen atoms; or

[0030] R 8 and R 9 These rings can be combined to form 3- to 6-membered rings containing one or more heteroatoms, wherein the rings are selected from the group consisting of:

[0031]

[0032] In another aspect, the present invention provides a pharmaceutical composition comprising: (1) a therapeutically effective amount (preferably from about 0.01 wt% to about 10.0 wt%, more preferably from about 0.01 wt% to about 5 wt% or about 0.1 wt% to 5.0 wt%) 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.

[0033] In another aspect, the present invention provides a combination, particularly a pharmaceutical combination, comprising: (1) a therapeutically effective amount (preferably from about 0.01 wt% to about 10.0 wt%, more preferably from about 0.01 wt% to about 5 wt% or about 0.1 wt% to 5.0 wt%) 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.

[0034] Specific preferred embodiments of the present invention will become apparent from the following description of certain preferred embodiments and the claims in greater detail. Attached Figure Description

[0035] Figure 1 It is ethyl 2-fluoro-2-phenylacetate. 1 H NMR spectrum;

[0036] Figure 2 It is 2-fluoro-2-phenylacetic acid. 1 H NMR spectrum;

[0037] Figure 3 It is 2-fluoro-2-phenylacetyl chloride. 1 H NMR spectrum;

[0038] Figure 4 It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-fluoro-2-phenylacetic acid ester. 1 H NMR spectrum;

[0039] Figure 5 It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-fluoro-3-hydroxy-2-phenylpropionate. 1 H NMR spectrum;

[0040] Figure 6 It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-fluoro-3-hydroxy-2-phenylpropionate. 13 C NMR spectrum;

[0041] Figure 7 It is 2-methyl-2-phenylacetyl chloride. 1 H NMR spectrum;

[0042] Figure 8 It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-methyl-2-phenylacetic acid ester. 1 H NMR spectrum;

[0043] Figure 9 It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-methyl-3-hydroxy-2-phenylpropionate. 1 H NMR spectrum;

[0044] Figure 10 It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-methyl-3-hydroxy-2-phenylpropionate. 13 C NMR spectrum;

[0045] Figure 11 It is 2,3-diphenylpropionyl chloride. 1 H NMR spectrum;

[0046] Figure 12 It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2,3-diphenylpropionate. 1 H NMR spectrum;

[0047] Figure 13 It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-benzyl-3-hydroxy-2-phenylpropionate. 1 H NMR spectrum; and

[0048] Figure 14 It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-benzyl-3-hydroxy-2-phenylpropionate. 13 C NMR spectrum.

[0049] Figure 15AIt is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-methyl-2-(thiophen-2-yl)propionate. 1 H NMR spectrum. Figure 15B It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-methyl-2-(thiophen-2-yl)propionate. 13 C NMR spectrum.

[0050] Figure 16A It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(hydroxymethyl)-2-phenylpropionate. 1 H NMR spectrum. Figure 16B It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(hydroxymethyl)-2-phenylpropionate. 13 C NMR spectrum.

[0051] Figure 17A It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-(hydroxymethyl)-2-phenylbutyrate. 1 H NMR spectrum. Figure 17B It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-(hydroxymethyl)-2-phenylbutyrate. 13 C NMR spectrum.

[0052] Figure 18A It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-cyclopropyl-2-(hydroxymethyl)-2-phenylpropionate. 1 H NMR spectrum. Figure 18B It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-cyclopropyl-2-(hydroxymethyl)-2-phenylpropionate. 13 C NMR spectrum.

[0053] Figure 19A It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-fluoro-2-methyl-2-phenylpropionate. 1 H NMR spectrum. Figure 19B It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-fluoro-2-methyl-2-phenylpropionate. 13 C NMR spectrum.

[0054] Figure 20A It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 4,4,4-trifluoro-2-(hydroxymethyl)-2-phenylbutyrate. 1 H NMR spectrum. Figure 20B It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 4,4,4-trifluoro-2-(hydroxymethyl)-2-phenylbutyrate. 13 C NMR spectrum.

[0055] Figure 21A It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2,3-dihydroxy-2-phenylpropionate. 1 H NMR spectrum. Figure 21B It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2,3-dihydroxy-2-phenylpropionate. 13 C NMR spectrum.

[0056] Figure 22A It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-methoxy-2-methyl-2-phenylpropionate. 1 H NMR spectrum. Figure 22B It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-methoxy-2-methyl-2-phenylpropionate. 13 C NMR spectrum.

[0057] Figure 23A It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropionate. 1 H NMR spectrum. Figure 23B It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropionate. 13 C NMR spectrum.

[0058] Figure 24A It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-chlorobenzyl)-2-phenylpropionate. 1 H NMR spectrum. Figure 24BIt is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-chlorobenzyl)-2-phenylpropionate. 13 C NMR spectrum.

[0059] Figure 25A It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(2-chlorobenzyl)-2-phenylpropionate. 1 H NMR spectrum. Figure 25B It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(2-chlorobenzyl)-2-phenylpropionate. 13 C NMR spectrum.

[0060] Figure 26A It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-hydroxybenzyl)-2-phenylpropionate formate. 1 H NMR spectrum. Figure 26B It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-hydroxybenzyl)-2-phenylpropionate formate. 13 C NMR spectrum.

[0061] Figure 27A It is 2-fluoro-3-hydroxy-N-((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-2-phenylpropionamide. 1 H NMR spectrum. Figure 27B It is 2-fluoro-3-hydroxy-N-((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-2-phenylpropionamide. 13 C NMR spectrum.

[0062] Figure 28A It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2-(4-fluorobenzyl)-3-hydroxy-2-phenylpropionate. 1 H NMR spectrum. Figure 28B It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2-(4-fluorobenzyl)-3-hydroxy-2-phenylpropionate. 13 C NMR spectrum.

[0063] Figure 29AIt is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-methylbenzyl)-2-phenylpropionate. 1 H NMR spectrum. Figure 29B It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-methylbenzyl)-2-phenylpropionate. 13 C NMR spectrum.

[0064] Figure 30A It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2-(3-chlorobenzyl)-3-hydroxy-2-phenylpropionate. 1 H NMR spectrum. Figure 30B It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2-(3-chlorobenzyl)-3-hydroxy-2-phenylpropionate. 13 C NMR spectrum.

[0065] Figure 31A It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2-(3-chlorophenyl)-3-hydroxy-2-methylpropionate. 1 H NMR spectrum. Figure 31B It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2-(3-chlorophenyl)-3-hydroxy-2-methylpropionate. 13 C NMR spectrum.

[0066] Figure 32A It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2-(4-chlorophenyl)-3-hydroxy-2-methylpropionate. 1 H NMR spectrum. Figure 32B It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2-(4-chlorophenyl)-3-hydroxy-2-methylpropionate. 13 C NMR spectrum.

[0067] Figure 33A It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-hydroxyphenyl)-2-methylpropionate. 1 H NMR spectrum. Figure 33B It is (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-hydroxyphenyl)-2-methylpropionate.13 C NMR spectrum. Detailed Implementation

[0068] This invention relates to classes of compounds each having atropine or pirenzepine residues and their pharmaceutically acceptable salts. In preferred embodiments, the invention provides compounds of formula (I) or (II) or their pharmaceutically acceptable salts:

[0069]

[0070] in

[0071] Me = CH3;

[0072] A = 0 or NR5;

[0073] W = N or CH;

[0074] X=-OH, -OYZ, -SYZ or -NR5-YZ;

[0075] R1 and R2 are independently substituted with H, D, hydroxyl, alkoxy, nitrile, halogen atom, or C1-C optionally substituted with halogen atom. 20 (Preferred C1-C) 10 Straight-chain, branched, or cyclic alkyl groups; or

[0076] R1 and R2 are independently substituted with phenyl or benzyl groups, which are optionally substituted by one or more substituents selected from the group consisting of C1-C2. 20 (Preferred C1-C) 10 Straight-chain, branched or cyclic alkyl, haloalkyl, hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide, sulfonamide, and halogen atom; or

[0077] R1 and R2 are independently substituted by heterocyclic saturated, unsaturated, or aromatic 5- or 6-membered rings, said rings containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and optionally substituted by one or more substituents selected from C1-C2. 20 (Preferred C1-C) 10 Straight-chain, branched or cyclic alkyl, haloalkyl, hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide or halogen atom;

[0078] R3 and R4 are independently converted by hydrogen, C1-C 10 Straight-chain or branched or cyclic alkyl or haloalkyl substitution, or

[0079] R3 and R4 can be combined to form 3 to 6-membered rings;

[0080] R5 = H or C1-C 20Preferred C1-C 10 Straight-chain or branched alkyl groups, C1-C 10 Straight-chain or branched haloalkyl groups;

[0081] Y is a divalent group with the following meanings:

[0082] g) Straight chain or branched chain C1-C 20 (Preferred C1-C) 10 )alkyl group, which is optionally substituted by one or more substituents selected from the group consisting of halogen atoms and hydroxyl groups;

[0083] h)-C(O)(C1-C 10 Alkyl group or -C(O)(CH2) n C(O)O-(C1-C 10 alkyl)- or -(C1-C 10 alkyl)-;

[0084] i)

[0085] j)

[0086] k) or

[0087] l)

[0088] Where n is an integer from 0 to 20;

[0089] R 6 and R 7 Independently, it is H or Cl-C 10 Straight-chain or branched alkyl groups, C1-C 10 Straight-chain or branched haloalkyl groups; or

[0090] R 6 and R 7 They can be combined to form 3 to 6-membered rings; and

[0091] Z represents H, -OH, or C. 1-6 Alkoxy, -COOH, -NR 8 R 9 ;

[0092] R 8 and R 9 Independently replaced by C1-C 20 Alkyl groups, preferably C1-C 10 It may optionally be substituted with one or more substituents selected from hydroxyl, amino, ester, carboxylic acid, and halogen atoms; or

[0093] R 8 and R9 These rings can be combined to form 3- to 6-membered rings containing one or more heteroatoms, wherein the rings are selected from the group consisting of:

[0094] In some embodiments, the compound of formula (I) is atropine of formula (IA).

[0095]

[0096] Me, R1, and X are as defined above.

[0097] definition

[0098] Unless otherwise specified, the term "compound of the present invention" refers to compounds of formula (I), compounds of its subforms and example compounds, and their salts, as well as all stereoisomers (including diastereomers and enantiomers), rotational isomers, tautomers and isotopically labeled compounds (including deuterated derivatives) and the inherently formed portions.

[0099] The term "effective amount" in the description of the compounds of the present invention below refers to the amount of a therapeutic compound necessary or sufficient to achieve its intended function in a mammal (e.g., treating muscarinic receptor-related symptoms or disease states in mammals). The effective amount of a therapeutic compound can vary depending on factors such as the amount of pathogen 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 muscarinic receptor-related symptoms in mammals. Those skilled in the art will be able to investigate the foregoing factors and determine the effective amount of the therapeutic compound without excessive experimentation. In vitro or in vivo assays can also be used to determine the "effective amount" of the therapeutic compound described below. Those skilled in the art will select appropriate amounts of the therapeutic compound for the above assays or as a therapeutic treatment.

[0100] The phrase “ophthalmologically compatible” is recognized in the art and refers to formulations, polymers and other materials and / or dosage forms suitable for contact with ocular tissues in humans and animals without excessive toxicity, irritation, allergic reactions or other problems or complications (in proportion to a reasonable benefit / risk ratio determined by a person skilled in the art).

[0101] 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 some embodiments, the pharmaceutical composition can be prepared in an aqueous form, for example in a pre-filled syringe or other single-dose or multi-dose container. In some embodiments, the pharmaceutical compositions of the present invention are ophthalmologically compatible and suitable for ophthalmic administration to human subjects by, for example, topical or other known delivery methods. In another embodiment, the pharmaceutical compositions of the present invention are suitable for intravitreal administration. In yet another embodiment, the pharmaceutical compositions of the present invention are suitable for intravitreal infusion administration. In yet another embodiment, the pharmaceutical compositions are administered orally.

[0102] As used herein, the term "alkyl" is intended to include branched, straight-chain, and cyclic substituted or unsubstituted saturated aliphatic hydrocarbon groups. Alkyl groups may contain about 1 to about 24 carbon atoms ("C1-C2"). 24 ("C7-C") approximately 7 to approximately 24 carbon atoms 24 ("C8-C") approximately 8 to approximately 24 carbon atoms 24 ("C9-C") or approximately 9 to approximately 24 carbon atoms ("C9-C") 24 Alkyl groups may also contain about 1 to about 8 carbon atoms (“C1-C8”), about 1 to about 6 carbon atoms (“C1-C6”), or 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.

[0103] As used in this article, the term "C" 2-6 "Alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one double bond and having two to six carbon atoms attached to the rest of the molecule by single bonds. The term "C2-C" is also used. 20 "Alkenyl" and "C2-C" 10 The term "alkenyl" is explained accordingly. C 2-6 Examples of alkenyl groups include, but are not limited to, vinyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-4-enyl, and pent-1,4-dienyl.

[0104] As used in this article, the term "C" 2-6 "Alkyne group" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one triple bond, having two to six carbon atoms, and attached to the rest of the molecule by single bonds. The term "C"... 2-4 The "alkynyl group" should be interpreted accordingly. C 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, prop-1-alkynyl, but-1-alkynyl, pent-1-alkynyl, pent-4-alkynyl, and pent-1,4-dialkynyl.

[0105] As used in this article, the term "C" 1-6 "Alkoxy" refers to the formula -OR a The group, wherein R a It is as C is generally defined above. 1-6 Alkyl group. C 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy.

[0106] "Halogen" refers to bromine, chlorine, fluorine, or iodine.

[0107] As used herein, the term "heterocyclic group" or "heterocyclic" refers to a stable 5- or 6-membered non-aromatic monocyclic group comprising one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur. Heterocyclic groups can be bonded via carbon atoms or heteroatoms. Examples of heterocyclic groups include, but are not limited to, azo-heterocyclic butyl, oxo-heterocyclic butyl, pyrrolinyl, pyrrolylyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or perhydroazepinyl.

[0108] As used herein, the term "heteroaryl" refers to a 5- or 6-membered aromatic monocyclic ring group comprising 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Heteroaryl groups can be bonded via carbon atoms or heteroatoms. Examples of heteroaryl groups include, but are not limited to, furanyl, pyrroleyl, thiopheneyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, or pyridinyl.

[0109] In some embodiments, the present invention provides novel pharmaceutical formulations, particularly novel pharmaceutical formulations wherein the active ingredient comprises a muscarinic modifier of general formula (I) or (II) and / or a pharmaceutically acceptable salt thereof:

[0110]

[0111] in

[0112] Me = CH3;

[0113] A = 0 or NR5;

[0114] W = N or CH;

[0115] X=-OH, -OYZ, -SYZ or -NR5-YZ;

[0116] R1 and R2 are independently substituted with H, D, hydroxyl, alkoxy, nitrile, halogen atom, or C1-C optionally substituted with halogen atom. 20 (Preferred C1-C)10 Straight-chain, branched, or cyclic alkyl groups; or

[0117] R1 and R2 are independently substituted with phenyl or benzyl groups, which are optionally substituted by one or more substituents selected from the group consisting of C1-C2. 20 (Preferred C1-C) 10 Straight-chain, branched or cyclic alkyl, haloalkyl, hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide, sulfonamide, and halogen atom; or

[0118] R1 and R2 are independently substituted by heterocyclic saturated, unsaturated, or aromatic 5- or 6-membered rings, said rings containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and optionally substituted by one or more substituents selected from C1-C2. 20 (Preferred C1-C) 10 Straight-chain, branched or cyclic alkyl, haloalkyl, hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide or halogen atom;

[0119] R3 and R4 are independently converted by hydrogen, C1-C 10 Straight-chain or branched or cyclic alkyl or haloalkyl substitution, or

[0120] R3 and R4 can be combined to form 3 to 6-membered rings;

[0121] R5 = H or C1-C 20 Preferred C1-C 10 Straight-chain or branched alkyl groups, C1-C 10 Straight-chain or branched haloalkyl groups;

[0122] Y is a divalent group with the following meanings:

[0123] a) Straight chain or branched chain C1-C 20 (Preferred C1-C) 10 )alkyl group, which is optionally substituted by one or more substituents selected from the group consisting of halogen atoms and hydroxyl groups;

[0124] b)-C(O)(C1-C 10 Alkyl group or -C(O)(CH2) n C(O)O-(C1-C 10 alkyl)- or -(C1-C 10 alkyl)-;

[0125] c)

[0126] d)

[0127] e) or

[0128] f)

[0129] Where n is an integer from 0 to 20;

[0130] R 6 and R 7 Independently, it is H or Cl-C 10 Straight-chain or branched alkyl groups, C1-C 10 Straight-chain or branched haloalkyl groups; or

[0131] R 6 and R 7 They can be combined to form 3 to 6-membered rings; and

[0132] Z represents H, -OH, or C. 1-6 Alkoxy, -COOH, -NR 8 R 9 ;

[0133] R 8 and R 9 Independently replaced by C1-C 20 Alkyl groups, preferably C1-C 10 It may optionally be substituted with one or more substituents selected from hydroxyl, amino, ester, carboxylic acid, and halogen atoms; or

[0134] R 8 and R 9 These rings can be combined to form 3- to 6-membered rings containing one or more heteroatoms, wherein the rings are selected from the group consisting of:

[0135] In some embodiments, the compound of formula (I) is atropine of formula (IA).

[0136]

[0137] Me, R1, and X are as defined above.

[0138] In some embodiments, the compounds of formula (I) and formula (II) are selected from the group consisting of:

[0139] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-fluoro-3-hydroxy-2-phenylpropionate,

[0140] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-methyl-3-hydroxy-2-phenylpropionate,

[0141] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octyl-3-yl-2-benzyl-3-hydroxy-2-phenylpropionate,

[0142] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-methyl-2-(thiophen-2-yl)propionate,

[0143] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(hydroxymethyl)-2-phenylpropionate,

[0144] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-(hydroxymethyl)-2-phenylbutyrate,

[0145] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-cyclopropyl-2-(hydroxymethyl)-2-phenylpropionate,

[0146] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-fluoro-2-methyl-2-phenylpropionate,

[0147] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl4,4,4-trifluoro-2-(hydroxymethyl)-2-phenylbutyrate,

[0148] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2,3-dihydroxy-2-phenylpropionate,

[0149] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-methoxy-2-methyl-2-phenylpropionate,

[0150] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropionate,

[0151] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-chlorobenzyl)-2-phenylpropionate,

[0152] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(2-chlorobenzyl)-2-phenylpropionate,

[0153] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-hydroxybenzyl)-2-phenylpropionate carboxylate,

[0154] 2-Fluoro-3-hydroxy-N-((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-2-phenylpropionamide,

[0155] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2-(4-fluorobenzyl)-3-hydroxy-2-phenylpropionate,

[0156] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-methylbenzyl)-2-phenylpropionate,

[0157] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-(3-chlorobenzyl)-3-hydroxy-2-phenylpropionate,

[0158] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropionate,

[0159] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropionate,

[0160] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-(4-(benzyloxy)phenyl)propionate, and

[0161] 6-((11-(2-(4-methylpiperazin-1-yl)acetyl)-11H-benzo[e]pyrido[3,2-b][1,4]diazacycloheptatrien-6-yl)oxy)hexyl nitrate.

[0162] Other compounds of the present invention include the following:

[0163]

[0164]

[0165] The following paragraphs provide examples of compounds according to the present invention:

[0166] Example

[0167] Example 1-3

[0168]

[0169] NMR spectra were obtained using a Bruker 400MHz spectrometer or a Bruker 300MHz spectrometer.

[0170] The LCMS method is described in detail below (unless otherwise stated):

[0171] Standard LCMS method:

[0172]

[0173]

[0174] QC LCMS Method:

[0175]

[0176] abbreviation:

[0177] DAST diethylaminosulfur trifluoride

[0178] DCM dichloromethane

[0179] DMF (dimethylformamide)

[0180] RT room temperature

[0181] Synthetic scheme of Example 1: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-fluoro-3-hydroxy-2-phenylpropionate

[0182]

[0183] ethyl 2-fluoro-2-phenylacetate

[0184] DAST (81.8 mL, 0.62 mol) was added at a rate of -78 °C to a solution of ethyl mandelate (93 g, 0.52 mol) in DCM (1.5 L) at a rate of T ≤ -60 °C. The reaction mixture was stirred while being warmed to 0 °C. After 1 hour, the reactants were slowly brought to an alkaline pH of ~7 with 1N NaOH. The mixture was extracted with DCM. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated under vacuum to give the title compound (62.4 g, 66%) as a straw-colored oil. This substance was ready for use without purification.

[0185] 1H NMR (400MHz, CDCl3) δ7.54-7.36 (5H, m), 5.77 (1H, d, J = 47.3Hz), 4.32-4.16 (2H, m), 1.26 (3H, t, J = 7.2Hz). 1 The H NMR spectrum shows Figure 1 .

[0186]

[0187] 2-Fluoro-2-phenylacetic acid

[0188] A solution of LiOH·H₂O (11.2 g, 0.27 mol) in water (15 mL) was added to a solution of ethyl 2-fluoro-2-phenylacetate (32.4 g, 0.18 mol) in MeOH (100 mL), and the reaction mixture was stirred at room temperature for 1 hour (note the slight exothermic reaction). The reaction mixture was diluted with ethyl acetate and acidified to ~ pH 3 with 1 N HCl. The product was extracted with ethyl acetate, and the combined organic fractions were washed with brine, dried (MgSO₄), and concentrated under vacuum to give the title compound (27.4 g, 100%) as a white solid. This substance can be used without purification.

[0189] 1 H NMR (400MHz, d6-DMSO) δ13.47 (1H, br s), 7.48-7.37 (5H, m), 5.95 (1H, d, J = 47.6Hz). 1 The H NMR spectrum shows Figure 2 .

[0190]

[0191] 2-Fluoro-2-phenylacetyl chloride

[0192] One drop of DMF was added to a solution of 2-fluoro-2-phenylacetic acid (27.4 g, 0.18 mol) in DCM (250 mL) at room temperature. Oxaloyl chloride (23.3 mL, 0.27 mol) was then added, causing foaming. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum to give the title compound (30.1 g, 100%) as a straw-colored oil. The substance was ready for use without purification.

[0193] 1 H NMR (400MHz, CDCl3) δ7.54-7.43 (5H, m), 5.90 (1H, d, 47.6Hz). 1 The H NMR spectrum shows Figure 3 .

[0194]

[0195] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-fluoro-2-phenylacetic acid ester

[0196] Adding 2-fluoro-2-phenylacetyl chloride (30.1 g, 0.17 mol) to a solution of tropine (27.1 g, 0.19 mol) in toluene (450 mL) resulted in precipitation. The reaction mixture was stirred under reflux for 1.5 h. The reaction mixture was diluted with ethyl acetate and extracted with 1N HCl. The combined aqueous fractions were alkalized to ~pH 13 with 1N NaOH and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated under vacuum to give the title compound (33.5 g, 69%) as a straw-colored oil, which solidified upon standing.

[0197] 1 H NMR (400MHz, CDCl3) δ7.51-7.37(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 H NMR spectrum shows Figure 4 .

[0198] LCMS(ESI)[M+H] + 278,R t =0.70min.

[0199]

[0200] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-fluoro-3-hydroxy-2-phenylpropionate

[0201] Paraformaldehyde (5.45 g, 0.18 mol) was added to a solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-fluoro-2-phenylacetic acid ester (33.5 g, 0.12 mol) in DMF (120 mL). Freshly prepared sodium ethoxide (140 mg sodium in 3.6 mL ethanol) was added to the suspension to dissolve the solid. The reaction mixture was stirred at 40 °C for 5 min. The reaction mixture was diluted with ethyl acetate and extracted with 1N HCl. The combined aqueous fractions were alkalized to ~pH 13 with 1N NaOH and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated under vacuum to ~1 / 5 volume, at which point the product crystallized. The solid was collected by filtration and dried under vacuum to give the title compound (25.0 g, 67%) as a white solid. The mother liquor was concentrated under vacuum and ground with ethyl acetate to obtain a second harvest (2.92 g, 8%) with a purity similar to that of the first harvest.

[0202] 1 H NMR (400MHz, CDCl3) δ7.54-7.48(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 H NMR spectrum shows Figure 5 .

[0203] 13 C NMR (400MHz, CDCl3) δ168.4, 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 .

[0204] LCMS(ESI)[M+H] + 308, R t =0.66min.

[0205] QC LCMS(ESI)[M+H] + 308.2, R t =2.28 min. (94.2%), purity >99% as determined by NMR.

[0206] Synthetic scheme of Example 2: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-methyl-3-hydroxy-2-phenylpropionate

[0207]

[0208] 2-Methyl-2-phenylacetyl chloride

[0209] One drop of DMF was added to a solution of 2-methyl-2-phenylacetic acid (7.65 g, 50.94 mmol) in DCM (60 mL) at room temperature. Oxaloyl chloride (8.9 mL, 0.102 mol) was added, causing foaming. The reaction mixture was stirred at room temperature for 18 hours. The mixture was then concentrated under vacuum to give the title compound (8.6 g, 100%) as a straw-colored oil. The substance was ready for use without purification.

[0210] 1 ¹H 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 H NMR spectrum shows Figure 7 .

[0211]

[0212] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-methyl-2-phenylacetic acid ester

[0213] Adding 2-methyl-2-phenylacetyl chloride (8.6 g, 51.0 mmol) to a solution of tropine (6.5 g, 45.9 mmol) in toluene (40 mL) resulted in the formation of a precipitate. The reaction mixture was stirred under reflux for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was ground with diethyl ether and filtered off to give a white solid. This solid was partitioned between H₂O and DCM, then alkalized to pH > 10 using 1N NaOH, and the product was extracted into DCM. The combined DCM extracts were washed with H₂O and brine, then passed through a phase separator and concentrated under vacuum to give the title compound (11.43 g, 81%) as a straw-colored oil.

[0214] 1¹H NMR (300MHz, CDCl₃) δ 7.36–7.21 (5H, m), 4.96 (1H, t, J = 5.4 Hz), 3.67 (1H, quartet, J = 7.2 Hz), 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 = 7.2 Hz), 1.40–1.28 (1H, m). 1 The H NMR spectrum shows Figure 8 .

[0215] LCMS(ESI)[M+H] + 274, R t =0.79min.

[0216]

[0217] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-methyl-3-hydroxy-2-phenylpropionate

[0218] Paraformaldehyde (2.04 g, 68.04 mmol) was added to a solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-methyl-2-phenylacetic acid ester (12.4 g, 45.36 mmol) in DMF (15 mL). Freshly prepared sodium ethoxide (52 mg sodium in 1.0 mL ethanol) was added to the suspension to dissolve the solid. The reaction mixture was stirred at room temperature for 4 hours and then partitioned between H2O and DCM. The combined DCM extracts were washed with H2O and brine, passed through a phase separator, and concentrated under vacuum. The resulting oily substance was ground with diethyl ether, at which point the product crystallized. The solid was collected by filtration and dried under vacuum to give the title compound (10.5 g, 76%) as a white solid.

[0219] 1 H NMR (400MHz, CDCl3) δ7.38-7.25(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 H NMR spectrum shows Figure 9 .

[0220] 13 C NMR (400MHz, 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 causes the carbon atoms in the tropane ring to be non-equivalent, hence 16 signals were observed instead of 13). 13 The C NMR spectrum is shown in Figure 10 .

[0221] LCMS(ESI)[M+H] + 304, R t =0.69min.

[0222] QC LCMS(ESI[M+H)) + 304.2, R t = 2.38 min. (98.9%)

[0223] Synthetic scheme of Example 3: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octyl-3-yl-2-benzyl-3-hydroxy-2-phenylpropionate

[0224]

[0225] 2,3-Diphenylpropionyl chloride

[0226] DMF (0.10 mL) was added to a solution of 2,3-diphenylpropionic acid (16.0 g, 70.71 mmol) in DCM (80 mL) at room temperature, and the mixture was cooled in an ice-water bath. Oxaloyl chloride (12.3 mL, 141.42 mmol) was added, causing foaming, and the cooling bath was removed. The reaction mixture was stirred at room temperature for 18 hours. It was then concentrated under vacuum to give the title compound (17.3 g, 100%) as a straw-colored oil. The substance was ready for use without purification.

[0227] 1 H NMR (300MHz, CDCl3) δ7.33-7.07(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 H NMR spectrum shows Figure 11 .

[0228]

[0229] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2,3-diphenylpropionate

[0230] Adding 2,3-diphenylpropionyl chloride (17.30 g, 70.71 mmol) to a solution of tropine (9.49 g, 70.71 mmol) in toluene (70 mL) resulted in the formation of a precipitate. The reaction mixture was stirred under reflux for 2 hours and then concentrated under vacuum. The residue was ground with diethyl ether and the solid was filtered off to give a white solid. This solid was partitioned between H₂O and DCM, alkalized to pH > 10 with 1N NaOH solution, and the product was extracted into DCM. The DCM extract was washed with H₂O and brine, then passed through a phase separator and concentrated under vacuum to give the title compound (22.4 g, 90%) as a straw-colored oil.

[0231] 1 H NMR (300MHz, CDCl3) δ7.35-7.11(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 H NMR spectrum shows Figure 12 .

[0232] LCMS(ESI)[M+H] + 350, R t =0.98min.

[0233]

[0234] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octyl-3-yl-2-benzyl-3-hydroxy-2-phenylpropionate

[0235] Paraformaldehyde (3.27 g, 108.96 mmol) was added to a solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2,3-diphenylpropionate (22.40 g, 64.10 mmol) in DMF (30 mL). Freshly prepared sodium ethoxide (74 mg sodium in 1.3 mL ethanol) was added to the suspension to dissolve the solid. The reaction mixture was stirred at room temperature for 3 hours, and then H2O was added. The precipitate was filtered off, washed with H2O, and dried under vacuum to remove most of the H2O. The resulting “wet” solid was partitioned between MeOH and DCM, and the phases were separated. The DCM extract was dried (MgSO4), filtered, and concentrated under vacuum to induce crystallization of the product. The precipitate was filtered off and dried under vacuum to give the title compound (18.18 g, 75%) as a white solid.

[0236] 1 H NMR (400MHz, CDCl3) δ7.39-7.16(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(2 H,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 H NMR spectrum shows Figure 13 .

[0237] 13 C NMR (400MHz, 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 (×2 signals), 56.5, 40.4, 38.9, 36.5, 36.4, 25.2, 25.0 (The chiral center causes the carbon atoms in the tropane ring to be non-equivalent, hence 20 signals were observed instead of 17). 13 The C NMR spectrum is shown in Figure 14 .

[0238] LCMS(ESI)[M+H] + 380, R t =0.90min.

[0239] QC LCMS(ESI)[M+H] + 380.3, R t = 3.19 min. (99.2%)

[0240] Synthetic scheme of Example 4: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-methyl-2-(thiophen-2-yl)propionate

[0241]

[0242] Ethyl 2-(thiophen-2-yl)propionate

[0243] n-BuLi (12.9 mL, 2.5 M, 32.3 mmol) was added dropwise to a solution of diisopropylamine (4.5 mL, 32.3 mmol) in THF (100 mL) at -40 °C. The reaction mixture was stirred at -40 °C for 20 min and then cooled to -78 °C. Ethyl 2-(thiophene-2-yl)ethyl acetate (5 g, 29.4 mmol) was added dropwise at a rate of T < -60 °C. The reaction mixture was stirred at -78 °C for 30 min and then warmed to 0 °C. Iodomethane (2.2 mL, 35.3 mmol) was added and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated under vacuum. The resulting residue was purified on silica (80 g, 0-50% ethyl acetate in cyclohexane solution) to give the title compound (3.3 g, 62%) as a light brown oil. 1 H NMR (400MHz, CDCl3) δ7.20 (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).

[0244]

[0245] 2-(thien-2-yl)propionic acid

[0246] Lithium hydroxide monohydrate (2.0 g, 48.4 mmol) was added to a solution of ethyl 2-(thiophen-2-yl)propionate (5.9 g, 32.39 mmol) in methanol (40 mL) and water (15 mL), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum to about 1 / 4 volume and the residue was extracted with EtOAc. The organic fraction was discarded, and the aqueous layer was acidified to ~pH 3 with 1N HCl and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated under vacuum to give the title compound (5.0 g, 100%) as a yellow oil. 1H NMR (400MHz, d6-DMSO) δ7.26 (1H, dd, J = 5.2, 1.6 Hz), 6.89 (1H, dd, J = 5.1, 3.5 Hz), 6.87-6.80 (1H, m), 3.74 (1H, q, J = 7.0 Hz), 1.35 (3H, d, J = 7.0 Hz).

[0247]

[0248] 2-(thien-2-yl)propionyl chloride

[0249] 2-(thien-2-yl)propionic acid (2.0 g, 12.8 mmol) was dissolved in thionyl chloride (10.0 mL, 137.1 mmol), and the reaction mixture was refluxed and heated for 2 hours. The reaction mixture was concentrated under vacuum to give the title compound (2.24 g, 100%) as a brown oil. 1 H NMR (400MHz, CDCl3) δ7.30 (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).

[0250]

[0251] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-(thiophen-2-yl)propionate

[0252] Tropine alcohol (1.62 g, 11.5 mmol) was added to a solution of 2-(thiophene-2-yl)propionyl chloride (2.2 g, 12.6 mmol) in toluene (20 mL), and the reaction mixture was heated at 100 °C for 2 hours. The reaction mixture was diluted with EtOAc and extracted with 1 N HCl, and the organic fraction was discarded. The aqueous phase was prepared to alkaline pH 12 with 6 N NaOH and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated under vacuum to give the title compound (2.29 g, 71%) as a brown oil, which was used as the crude product in the next reaction. LCMS(ESI)[M+H] + 280R t =0.72min.

[0253]

[0254] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-methyl-2-(thiophen-2-yl)propionate

[0255] A solution of sodium ethoxide in ethanol (0.11 mL, 21%, 0.2 mmol) was added to a suspension of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2-(thiophen-2-yl)propionate (1.3 g, 4.7 mmol) and paraformaldehyde (0.21 g, 6.9 mmol) in DMF (10 mL), and the reaction mixture was stirred at room temperature for 10 min. The reaction mixture was diluted with EtOAc and extracted with 1N HCl. The organic fraction was discarded. The aqueous fraction was prepared to alkaline pH 12 with 1N NaOH and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated under vacuum to give the title compound (760 mg, 52%) as a grayish-white solid. 1 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), 4.13 (¹H, d, J = 11.3Hz), 3.74 (¹H, d, J = 11.3Hz), 3.08–2.94 (²H, m), 2.58 (¹H, br s), 2.22 (³H, s), 2.16–2.01 (¹H, m), 1.98–1.87 (¹H, m), 1.86–1.70 (⁵H, m), 1.69–1.62 (¹H, m), 1.57–1.50 (¹H, m), 1.41–1.31 (¹H, m). (The title compound...) 1 H NMR and 13 The C NMR spectra are shown in the figures. Figure 15A and Figure 15B middle.

[0256] LCMS(ESI)[M+H] + 310R t =2.40min.

[0257] Synthetic scheme of Example 5: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(hydroxymethyl)-2-phenylpropionate

[0258]

[0259] An ethanolic solution of sodium ethoxide (0.08 mL, 21%, 0.22 mmol) was added 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, and the reaction mixture was stirred at 0 °C for 5 min, followed by stirring at room temperature for 1 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was purified on silica (24 g, 0–40% (MeOH solution of 2N NH3) in DCM). Half of the obtained mixture was repurified on C18 silica (50 g, 0–50% 0.02 M NH3 in MeCN solution) to give the title compound (1.19 g, 67%) as a grayish-white solid. 1 HNMR(400MHz,d6-DMSO)δ7.35-7.27(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. The title compound's 1 H NMR and 13 The C NMR spectra are shown in the figures. Figure 16A and Figure 16B

[0260] Synthetic scheme of Example 6: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-(hydroxymethyl)-2-phenylbutyrate

[0261]

[0262] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-phenylbutyrate

[0263] Oxaloyl chloride (2.1 mL, 24.4 mmol) and DMF (0.06 mL, 0.7 mmol) were added to a solution of 2-phenylbutyric acid (2.0 g, 12.2 mmol) in DCM (20 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then at room temperature for 16 h. The reaction mixture was concentrated under vacuum, and the residue was dissolved in toluene (10 mL). This solution was added to a solution of tropine alcohol (1.7 g, 12.18 mmol) in toluene (20 mL), and the reaction mixture was stirred at room temperature for 10 min, then under reflux for 2 h. The reaction mixture was concentrated under vacuum, 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 (MgSO4), and concentrated under vacuum to give the title compound (1.76 g, 50%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.35-7.21(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] + 288R t =0.84min.

[0264]

[0265] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-(hydroxymethyl)-2-phenylbutyrate

[0266] A solution of sodium ethoxide in ethanol (0.11 mL, 21%, 0.2 mmol) was added to a suspension of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-phenylbutyrate (1.8 g, 6.1 mmol) and paraformaldehyde (0.28 g, 9.2 mmol) in DMF (6 mL), and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc, extracted with 1N HCl, and the organic fraction was discarded. The aqueous fraction was prepared to alkaline pH 12 with 1N NaOH and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated under vacuum. The residue was purified on silica (50 g, 0–18% DCM solution of 2N NH3 in MeOH) to give the title compound (1.56 g, 80%) as a grayish-white solid. 1 H NMR (400MHz, CDCl3) δ7.38-7.21(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] + 318R t = 2.71 min. The title compound's 1 H NMR and 13 The C NMR spectra are shown in the figures. Figure 17A and Figure 17B .

[0267] Synthetic scheme of Example 7: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-cyclopropyl-2-(hydroxymethyl)-2-phenylpropionate

[0268]

[0269] methyl 3-cyclopropyl-2-phenylpropionate

[0270] At -78 °C, LDA (7.3 mL, 2 M, 14.6 mmol) was added to a solution of methyl 2-phenylacetate (2 g, 13.3 mmol) in THF (50 mL) at a rate of T < -60 °C. The reaction mixture was stirred at -78 °C for 1 h. A solution of (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, extracted with EtOAc, and the combined organic fractions were washed with brine, dried (MgSO4), and concentrated under vacuum. The residue was purified on silica (40 g, cyclohexane solution of 0-100% DCM) to give the title compound (2.6 g, 95%) as a yellow oil. 1 H NMR(400MHz, CDCl3)δ7.35-7.20(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).

[0271]

[0272] 3-Cyclopropyl-2-phenylpropionic acid

[0273] Lithium hydroxide monohydrate (1.33 g, 31.7 mmol) was added to a solution of methyl 3-cyclopropyl-2-phenylpropionate (2.59 g, 12.7 mmol) in methanol (100 mL) and water (15 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum to ~1 / 4 volume, diluted to ~pH 1 with 1N HCl, and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated under vacuum to give the title compound (2.44 g, 100%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ7.37-7.21 (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).

[0274]

[0275] 3-Cyclopropyl-2-phenylpropionyl chloride

[0276] A solution of 3-cyclopropyl-2-phenylpropionic acid (2.44 g, 12.8 mmol) in DCM (100 mL) was added with DMF (0.01 mL) and oxaloyl chloride (1.7 mL, 19.2 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum to give the title compound (2.68 g, 100%) as a pale yellow oil, which was ready for use without purification. 1 H NMR(400MHz, CDCl3)δ7.41-7.27(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).

[0277]

[0278] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-cyclopropyl-2-phenylpropionate

[0279] 3-Cyclopropyl-2-phenylpropionyl chloride (4.36 g, 20.8 mmol) was added to a solution of tropine (2.68 g, 18.9 mmol) in toluene (20 mL), and the reaction mixture was refluxed and heated for 1.5 h. The reaction mixture was extracted with 1 N HCl, and the organic fraction was discarded. The aqueous fraction was prepared to basic pH 12 with 6 N NaOH and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated under vacuum to give the title compound (1.76 g, 50%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ7.35-7.20(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).

[0280]

[0281] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-cyclopropyl-2-(hydroxymethyl)-2-phenylpropionate

[0282] An ethanolic solution of sodium ethoxide (0.07 mL, 4 M, 1.12 mmol) was added to a suspension of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-cyclopropyl-2-phenylpropionate (1.76 g, 5.62 mmol) and paraformaldehyde (0.25 g, 8.42 mmol) in DMF, and the reaction mixture was stirred at 40 °C for 3 h. Another 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 h. The reaction mixture was diluted with EtOAc and extracted with 1 N HCl. The organic fraction was discarded, and the aqueous fraction was prepared to alkaline pH 12 with 6 N NaOH. The mixture was extracted with EtOAc, and the combined organic fractions were washed with brine, dried (MgSO4), and concentrated under vacuum. The resulting residue was purified on silica (40 g, 0-10% (7N NH3 in MeOH solution) in DCM solution) to give the title compound (0.23 g, 12%) as a grayish-white solid. 1 H NMR (400MHz, CDCl3) δ7.39-7.22(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. The title compound's 1 H NMR and 13 The C NMR spectra are shown in the figures. Figure 18A and Figure 18B .

[0283] Synthetic scheme of Example 8: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-fluoro-2-methyl-2-phenylpropionate

[0284]

[0285] A solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-methyl-2-phenylpropionate (392 mg, 1.29 mmol) in DCM was added at 0 °C, and the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted with saturated aqueous Na₂CO₃ and extracted with DCM. The combined organic fractions were dried (Na₂SO₄) and concentrated under vacuum. The resulting residue was purified on silica (4 g, 0–12% (MeOH solution of 2N NH₃) in DCM). The obtained residue was then purified by SFC (YMC amylose-C, 15% MeOH + 0.1% Et₂NH) to give the title compound (26 mg, 6%) as a pale yellow oil. 1 H NMR (400MHz, CDCl3) δ7.39-7.27(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(2H,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. Title compound 1 H NMR and 13 The CNMR spectra are shown in... Figure 19A and Figure 19B .

[0286] Synthetic scheme of Example 9: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl4,4,4-trifluoro-2-(hydroxymethyl)-2-phenylbutyrate

[0287]

[0288]

[0289] 4,4,4-Trifluoro-2-phenylbutyryl chloride

[0290] Oxaloyl chloride (0.33 mL, 3.8 mmol) was added to a solution of 4,4,4-trifluoro-2-phenylbutyric acid (410 mg, 1.9 mmol) and DMF (0.1 mL) in DCM (25 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 1 hour, followed by stirring at room temperature for 16 hours. The reaction mixture was concentrated under vacuum to give a product (445 mg, 100%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ7.47-7.36(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).

[0291]

[0292] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl4,4,4-trifluoro-2-phenylbutyrate

[0293] A solution of 4,4,4-trifluoro-2-phenylbutyryl chloride (445 mg, 1.9 mmol) in toluene (7 mL) was added to a solution of tropinol (236 mg, 1.7 mmol) in toluene (3 mL), and the reaction mixture was refluxed and heated for 3 hours. The reaction mixture was concentrated under vacuum and the residue was ground with diethyl ether. The solid was dissolved in 1 N NaOH and extracted with DCM. The combined organic fractions were washed with brine, dried (Na₂SO₄), and concentrated under vacuum to give the title compound (390 mg, 61%) as a yellow solid. 1 HNMR (400MHz, CDCl3) δ7.40-7.24(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 R t =0.88min.

[0294]

[0295] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl4,4,4-trifluoro-2-(hydroxymethyl)-2-phenylbutyrate

[0296] An ethanolic solution of sodium ethoxide (0.3 mL, 0.2 M, 0.06 mmol) was added to a suspension of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 4,4,4-trifluoro-2-phenylbutyrate (390 mg, 1.1 mmol) and paraformaldehyde (51 mg, 1.7 mmol) in DMF (3 mL), and the reaction mixture was stirred at room temperature for 2 hours. Then, paraformaldehyde (40 mg, 1.3 mmol) and an ethanolic solution of sodium ethoxide (0.15 mL, 1.5 M, 0.2 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water, extracted with DCM, and the combined organic fractions were washed with brine, dried (Na₂SO₄), and concentrated under vacuum. The resulting residue was purified on silica (12 g, 0-10% (2N NH3 in MeOH solution) in DCM solution) to give the title compound (105 mg, 24%) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.44-7.23 (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. The title compound's 1 H NMR and 13 The C NMR spectra are shown in the figures. Figure 20A and Figure 20B .

[0297] Synthetic scheme of Example 10: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2,3-dihydroxy-2-phenylpropionate

[0298]

[0299] 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 min to obtain a clear yellow solution, which was then cooled to approximately 0 °C in an ice-water bath. A solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-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 h, then warmed to room temperature overnight. The reaction mixture was treated with excess Na₂SO₃ 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 (Na₂SO₄), and concentrated under vacuum. The resulting residue was purified on silica (12 g, 0-10% DCM solution of 2N NH3 in MeOH) to give enantiomeric enrichment of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2,3-dihydroxy-2-phenylpropionate (110 mg, 39%) as a gel.

[0300] In a separate 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 min to obtain a clear yellow solution, which was then cooled to approximately 0 °C in an ice-water bath. A solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-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 h, then warmed to room temperature overnight. The reaction mixture was treated with excess Na₂SO₃ 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 (Na₂SO₄), and concentrated under vacuum. The resulting residue was purified on silica (12 g, 0-10% DCM solution of 2N NH3 in MeOH) to give enantiomeric enrichment of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2,3-dihydroxy-2-phenylpropionate (126 mg, 45%) as a gel.

[0301] One portion of the AD-mix-α reaction product (95 mg, 0.311 mmol) was dissolved in acetonitrile (1 mL) to obtain a clear solution. Similarly, one portion of the AD-mix-β reaction product (95 mg, 0.311 mmol) was dissolved alone in acetonitrile (1.0 mL), also yielding a clear solution. The two enantiomer-enriched solutions were then combined, diluted with water (2.0 mL), and freeze-dried to give the racemic title compound (190 mg) as a white solid.1 H NMR (400MHz, CDCl3) δ7.60-7.53(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. The title compound's 1 H NMR and 13 The C NMR spectra are shown in the figures. Figure 21A and Figure 21B .

[0302] Synthetic scheme of Example 11: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-methoxy-2-methyl-2-phenylpropionate

[0303]

[0304] (1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0305] The stirred solution of nortropinol (12.72 g, 100 mmol) in DCM (150 mL) was treated with triethylamine (27.9 mL, 20.24 g, 200 mmol) and cooled on ice. Then, solid di-tert-butyl dicarbonate (32.74 g, 150.0 mmol) was added over 10 min, and the addition container was washed with DCM (50 mL). Vigorous gas escape was observed. The resulting mixture was stirred for 2 h while being warmed to room temperature, and then stirred at room temperature for 16 h. The resulting mixture was diluted with DCM (100 mL), washed with 10% citric acid (water) solution and brine (50 mL), and the layers were separated. The combined organic fractions were dried (Na₂SO₄), filtered, and concentrated under vacuum to obtain a paste-like solid. The solid residue was ground with diethyl ether (30 mL) and sonicated to obtain a free-flowing solid, 19.67 g (86%), collected by filtration. 1¹H 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] was not observed. + R t =1.21min.

[0306]

[0307] (1R,3r,5S)-3-((2-phenylpropionyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0308] A solution of 2-phenylpropionyl chloride (8.20 g, 48.63 mmol) in toluene (50 mL) was added to a stirred solution of (1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (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 refluxed under vigorous stirring for 24 hours to give a product as a grayish-white suspension. The reaction mixture was cooled to room temperature and diluted with EtOAc (100 mL) and H2O (100 mL). The aqueous layer was separated and further extracted with EtOAc (2 × 100 mL). The combined extracts were washed with 5% citric acid (water) solution, saturated NaHCO3 (water) solution, and brine, dried (Na2SO4), filtered, and concentrated under vacuum. The title compound was obtained (16.21 g, 102%). 1 ¹H 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] was not observed. + R t =1.98min.

[0309]

[0310] (1R,3r,5S)-3-((3-hydroxy-2-methyl-2-phenylpropionyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0311] A slurry of (1R,3r,5S)-3-((2-phenylpropionyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (7.19 g, 20.0 mmol) in DMF (15 mL) was treated with paraformaldehyde (0.90 g, 30 mmol), then with 21% sodium ethoxide solution (0.37 mL, 1.00 mmol) and stirred at room temperature for 18 hours. A second portion of 21% sodium ethoxide solution (0.37 mL, 1.00 mmol) was added, and stirring was continued for another 2 hours. LCMS indicated a peak shift but no mass ions. The reaction mixture was diluted with DCM (200 mL), washed with water and brine. The organic layer was separated, dried (Na2SO4), filtered, and concentrated under vacuum to give a crude product as a yellow oil. The residue was purified on silica (120 g, 0-50% EtOAc in cyclohexane solution) to give the title compound (5.29 g, 68%) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.39-7.24(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=6,8Hz),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.

[0312]

[0313] (1R,3r,5S)-3-((3-methoxy-2-methyl-2-phenylpropionyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0314] A stirred suspension of sodium hydride (0.24 g, 60%, 6.01 mmol) in anhydrous THF (10 mL) was cooled to 0 °C and a solution of (1R,3r,5S)-3-((3-hydroxy-2-methyl-2-phenylpropionyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.95 g, 5.01 mmol) in anhydrous THF (10 mL) was added dropwise. The resulting mixture was stirred at 0 °C for 1 hour, then the reaction mixture was cooled to -6 °C and iodomethane (0.34 mL, 5.5 mmol) was added. The mixture was slowly warmed to room temperature over 3 hours. The reaction mixture was quenched by adding an aqueous solution of NH4Cl (20 mL) and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated under vacuum. The residue was purified on silica (80 g, 0-25% EtOAc in cyclohexane solution) to give the title compound (1.54 g, 76%) as a colorless syrup. 1 H NMR (400MHz, CDCl3) δ7.37-7.21(5H,m),5.12(1H,t,J=5.3Hz),4.19-3.94(2H,m),3.99(1H,d,J=8.7Hz),3.62(1 H,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.

[0315]

[0316] (1R,3r,5S)-8-azabicyclo[3.2.1]octane-3-yl-3-methoxy-2-methyl-2-phenylpropionate hydrochloride

[0317] A solution of 4N HCl in dioxane (2.0 mL) was added to a stirred solution of (1R,3r,5S)-3-((3-methoxy-2-methyl-2-phenylpropionyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.10 g, 2.73 mmol) in dioxane (2.0 mL), and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under vacuum to give a crude product (1.18 g, 100%) as a colorless syrup, which could be used without purification. 1H NMR (400MHz, CDCl3) δ9.47 (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 =1.52min.

[0318]

[0319] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-methoxy-2-methyl-2-phenylpropionate

[0320] The crude product (1R,3r,5S)-8-azabicyclo[3.2.1]octane-3-yl-3-methoxy-2-methyl-2-phenylpropionate 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). The reaction mixture was refluxed and heated for 17 hours. The reaction mixture was cooled to room temperature and loaded into an SCX-2 cartridge (50 g) pre-wetted with DCM. The cartridge was washed with DCM (400 mL) and MeOH (200 mL), and the product was eluted with a solution of 2 M NH3 in MeOH (200 mL). The alkaline eluent was concentrated under vacuum. The residue was purified by HPLC using a Kinetix Axia C18 RP column (long) with 5%–50% CH3CN in H2O solution (0.1% HCOOH), ascending at a rate of 18 mL / min over 10 min, under 194 nm UV light. The fractions were combined and lyophilized to give a colorless syrup product (415 mg, 48%) containing 0.75 equivalents of formamide and 0.25 equivalents of DCM. 1 H NMR (400MHz, CDCl3) δ7.37-7.24(5H,m),5.09(1H,t,J=5.1Hz),3.99(1H,d,J=8.7Hz),3.62(1H,d,J=8.7Hz),3.4 9-3.42(2H,m),3.38(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. Title compound 1 H NMR and 13 The C NMR spectra are shown in the figures. Figure 22A and Figure 22B .

[0321] Synthetic scheme of Example 12: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropionate

[0322]

[0323] Methyl 3-(4-methoxyphenyl)-2-phenylpropionate

[0324] Potassium tert-butoxide (2.15 g, 19.16 mmol) was added to a stirred solution of methyl phenylacetate (2.00 g, 13.32 mmol) in anhydrous THF (20 mL) at 0 °C. After stirring for 15 min, a solution of 4-methoxybenzyl bromide in anhydrous THF (10 mL) was added dropwise, maintaining T ≤ 5 °C. The resulting mixture was stirred for 10 min and then warmed to room temperature overnight. The resulting mixture was diluted with EtOAc (150 mL), washed with H2O (50 mL), then washed with brine (50 mL), and the layers were separated. The organic layer was dried (Na2SO4) and concentrated under vacuum. The residue was purified on silica (25 g, 0-50% EtOAc in cyclohexane solution) to give the title compound (1.0 g, 27%) as a pale yellow oil. This compound was impure but could be used 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).

[0325]

[0326] 3-(4-Methoxyphenyl)-2-phenylpropionic acid

[0327] A solution of methyl 3-(4-methoxyphenyl)-2-phenylpropionate (1.1 g, 4.07 mmol) in THF (20 mL) and MeOH (5 mL) was treated with 2N NaOH (aqueous solution) (4 mL, 8.0 mmol) and stirred for 18 hours at room temperature. The reaction mixture was concentrated under vacuum, and the residue was diluted with H₂O (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 (MgSO₄) and concentrated under vacuum to give a crude product as a colorless oil, which was allowed to crystallize upon standing (881 mg 84%). LCMS R t = 1.28 min, 255.1 (MH) - It can be used without purification. 1 H NMR (400MHz, CDCl3) δ7.32-7.26(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).

[0328]

[0329] 3-(4-methoxyphenyl)-2-phenylpropionyl chloride

[0330] A stirred solution of 3-(4-methoxyphenyl)-2-phenylpropionic acid (450 mg, 1.76 mmol) in 5.0 mL DCM containing 10 μL DMF was treated dropwise with oxalyl chloride (200 μL, 2.29 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 10 min, then warmed to room temperature and stirred for 18 h. The reaction mixture was concentrated under vacuum, and the crude product was azeotropically reacted with toluene (2 × 10 mL) to give the title crude compound (483 mg, 100%). It was used immediately without purification.

[0331]

[0332] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-(4-methoxyphenyl)-2-phenylpropionate

[0333] Crude 3-(4-methoxyphenyl)-2-phenylpropionyl chloride (483 mg, 1.76 mmol) was stirred in anhydrous toluene (5 mL) containing tropine (248 mg, 1.76 mmol) for 3 hours at 100 °C. The reaction mixture was concentrated under vacuum. The residue was treated with DCM (30 mL) and H2O (20 mL) and alkalized to pH 10 with 1N NaOH (aqueous solution). The organic layer was separated, washed with brine, dried (MgSO4), and concentrated under vacuum. The resulting residue was purified on silica (12 g, 0-10% MeOH in DCM solution) to give the title compound (277 mg, 41%) as a light brown oil. 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) + .

[0334]

[0335] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropionate

[0336] 1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-(4-methoxyphenyl)-2-phenylpropionate (200 mg, 0.53 mmol) in DMF (3 mL) was treated with paraformaldehyde (160 mg, 5.33 mmol), followed by treatment with 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 diatomaceous earth. The filtrate was concentrated under vacuum to a small volume and purified on silica (12 g, 0-10% MeOH in DCM solution) to give the title compound as a white solid (187 mg, 86%). 1H 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(2 H,m),3.76-3.76(3H,m),3.49-3.34(2H,m),3.02-2.92(2H,m),2.20(6H,s),1.76-1.58(3H,m),1.56-1.44(2H,m),1.28-1.20(1H,m). LCMS 3.30min, 410.0(M+H) + The title compound 1 H NMR and 13 The C NMR spectra are shown in the figures. Figure 23A and Figure 23B .

[0337] Synthetic scheme of Example 13: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-chlorobenzyl)-2-phenylpropionate

[0338]

[0339] 3-(4-chlorophenyl)-2-phenylpropionic acid

[0340] Under a nitrogen atmosphere, n-butyllithium (2.5 M hexane solution, 15.3 mL, 38.3 mmol) was added dropwise to a cooled solution of N,N-diisopropylamine (5.6 mL, 40.0 mmol) in anhydrous THF (20 mL), maintaining T ≤ 0 °C. The resulting LDA solution was stirred for 20 min and then cooled to -78 °C using a dry ice / acetone bath. Methyl phenylacetate (5.0 g, 33.3 mmol) in anhydrous THF (20 mL) was added dropwise using a syringe, maintaining T ≤ -55 °C. After stirring for 2 hours, a solution of 4-chlorobenzyl bromide (4.8 mL, 36.6 mmol) in anhydrous THF (10 mL) was added, and the resulting mixture was stirred overnight and warmed to room temperature. The mixture was diluted with EtOAc (100 mL) and water (50 mL), the aqueous layer was separated, and further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated under vacuum. The residue was dissolved in a mixture of methanol (20 mL) and THF (100 mL) with the addition of an aqueous sodium hydroxide solution (2 M, 35 mL, 70 mmol). The resulting turbid solution was stirred for 22 hours and then concentrated under vacuum. 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 under vacuum to give the title compound (8.62 g, 99%) as a grayish-white solid. 1 HNMR (400MHz, CDCl3): δ7.35-7.24(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).

[0341]

[0342] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-(4-chlorophenyl)-2-phenylpropionate

[0343] A stirred solution of 3-(4-chlorophenyl)-2-phenylpropionic 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 min, then warmed to room temperature and stirred for 18 h. The reaction mixture was concentrated under vacuum, and the crude product was azeotropically reacted with toluene (20 mL) to give crude 3-(4-chlorophenyl)-2-phenylpropionyl chloride, which was dissolved in anhydrous toluene (50 mL). Tropine alcohol (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 h, cooled to room temperature, and stirred overnight. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3, water, and brine, dried (Na2SO4), and concentrated under vacuum. The residue was purified by chromatography over silica (80 g, 0-10% (2 M NH3 in MeOH solution) in a DCM solution gradient) to give a pure title compound (2.24 g, 50%) as a viscous orange oil. A second batch of impure title compound (0.54 g, 12%) as a brown oil was also isolated. 1 H NMR (400MHz, CDCl3): δ7.35-7.23(5H,m),7.22-7.16(2H,m),7.09-7.02(2H,m),4.9 0(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.

[0344]

[0345] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-chlorobenzyl)-2-phenylpropionate

[0346] A solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-(4-chlorophenyl)-2-phenylpropionate (2.22 g, 5.78 mmol) in DMF (10 mL) was treated with paraformaldehyde (0.26 g, 8.7 mmol). An ethanol solution of 21% sodium ethoxide (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), the aqueous layer was separated, and further extracted with EtOAc. The combined organic layers were washed with 5% w / w lithium chloride aqueous solution (2 × 25 mL), brine, dried (Na₂SO₄), and filtered through a diatomaceous earth stopper. The solution was concentrated under vacuum, and the residue was purified in silica (40 g, 0.5%–10% DCM solution of 2 M NH3 in MeOH) to give the title compound (0.86 g, 36%) as a white solid. 1 H NMR (400MHz, d6-DMSO): δ7.35-7.27(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,width 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=13Hz),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. Title compound 1 H NMR and 13 The C NMR spectra are shown in the figures. Figure 24A and Figure 24B .

[0347] Synthetic scheme of Example 14: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(2-chlorobenzyl)-2-phenylpropionate

[0348]

[0349] 3-(2-chlorophenyl)-2-phenylpropionic acid

[0350] Under a nitrogen atmosphere, n-butyllithium (2.5M hexane solution, 15.3 mL, 38.3 mmol) was added dropwise to a cooled solution of N,N-diisopropylamine (5.6 mL, 39.95 mmol) in anhydrous THF (20 mL), maintaining T ≤ 0 °C. The resulting LDA solution was stirred for 20 min and then cooled to -74 °C using a dry ice / acetone bath. Methyl phenylacetate (5.0 g, 33.3 mmol) in anhydrous THF (20 mL) was added dropwise using a syringe, maintaining T ≤ -55 °C. After stirring for 1 hour, a solution of 2-chlorobenzyl bromide (4.8 mL, 36.6 mmol) in anhydrous THF (10 mL) was added, and the resulting mixture was stirred overnight and warmed to room temperature. The mixture was diluted with EtOAc (50 mL) and a saturated aqueous solution of ammonium chloride (10 mL). The organic layer was separated and washed with brine, dried (Na₂SO₄), and concentrated under vacuum to give crude methyl 3-(2-chlorophenyl)-2-phenylpropionate as an orange syrup. It 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 turbid solution was stirred for 40 hours and then concentrated under vacuum 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 (Na₂SO₄), and concentrated under vacuum to give the title compound as a mixture with unreacted methyl 3-(2-chlorophenyl)-2-phenylpropionate. The mixture was redissolved in THF (50 mL), methanol (10 mL), and an aqueous solution of sodium hydroxide (2 M, 17 mL, 34 mmol), and the resulting turbid solution was stirred overnight at room temperature. The solvent was concentrated under vacuum, 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 under vacuum to give the title compound (4.10 g, 94%) as a grayish-white solid. 1 H NMR (400MHz, CDCl3): δ7.35-7.24(6H,m),7.16-7.08(1H,m),7.07-7.03(2H,m),4.0 0(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).

[0351]

[0352] 1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-(2-chlorophenyl)-2-phenylpropionate

[0353] A stirred solution of 3-(2-chlorophenyl)-2-phenylpropionic 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 overnight at room temperature. The reaction mixture was concentrated under vacuum, and the crude product was azeotropically reacted with toluene (20 mL). The residue was dissolved in anhydrous toluene (50 mL), and tropine alcohol (1.62 g, 11.5 mmol) and triethylamine (4.8 mL, 34.5 mmol) were added. 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) and washed with saturated NaHCO3, water, and brine, dried (Na2SO4), and concentrated under vacuum. The residue was purified on silica (120 g, 0-10% (2 M NH3 in MeOH solution) in DCM) to give the pure title compound (3.26 g, 73%) as a viscous orange oil. 1 H NMR (400MHz, CDCl3) δ7.37-7.22(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.

[0354]

[0355] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(2-chlorobenzyl)-2-phenylpropionate

[0356] A solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-(2-chlorophenyl)-2-phenylpropionate (1.92 g, 5.0 mmol) in DMF (10 mL) was treated with paraformaldehyde (0.23 g, 7.5 mmol). An ethanol solution of 21% sodium ethoxide (0.25 mL, 0.5 mmol) was added, and the resulting mixture was stirred at room temperature for 3 hours, then heated to 45 °C overnight. A second portion of paraformaldehyde (0.23 g, 7.5 mmol) and an ethanol solution of 21% sodium ethoxide (0.25 mL, 0.5 mmol) were added, and the mixture was stirred at 45 °C for 4.5 hours, 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), the aqueous layer was separated, and further extracted with EtOAc. The combined organic layers were washed with 5% w / w lithium chloride aqueous solution (2 × 25 mL), brine, dried (Na₂SO₄), filtered through diatomaceous earth, and concentrated under vacuum. The residue was purified on silica [40 g, 0.5%–10% (2 M NH₃ in MeOH solution) in DCM solution] to give the title compound (1.0 g, 48%) as a white solid. 1 H NMR (400MHz, d6-DMSO): δ7.26-7.18(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. Title compound 1 H NMR and 13 The C NMR spectra are shown in the figures. Figure 25A and Figure 25B .

[0357] Synthetic scheme of Example 15: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-hydroxybenzyl)-2-phenylpropionate carboxylate

[0358]

[0359] 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-2-phenylpropionic acid

[0360] tert-Butyldimethylchlorosilane (3.16 g, 21.0 mmol) was added to a stirred solution of 3-(4-hydroxyphenyl)-2-phenylpropionic acid (2.42 g, 10.0 mmol) and imidazole (2.04 g, 29.97 mmol) in anhydrous DMF (40 mL), and the resulting mixture was stirred overnight at room temperature. Another portion of tert-butyldimethylchlorosilane (0.75 g, 5.0 mmol) was added, and stirring continued for 2 hours. The reaction mixture was diluted with EtOAc, washed with water, saturated lithium chloride aqueous solution, and brine, dried (Na₂SO₄), and concentrated under vacuum to obtain a straw-colored oil. This 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 hours. The reaction mixture was concentrated under vacuum, and the residue was partitioned between water and DCM. The aqueous phase was acidified to pH 3 by carefully adding 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 under vacuum to give the crude title compound as a straw-colored oil. The compound was purified by chromatography on silica (80 g, 0-20% EtOAc in DCM solution gradient) to give the title compound (1.58 g, 44%) as a straw-colored oil. 1 H NMR (400MHz, CDCl3): δ7.32-7.22(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).

[0361]

[0362] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-2-phenylpropionate

[0363] A stirred solution of 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-2-phenylpropionic acid (1.30 g, 3.65 mmol) in DCM (20 mL) containing one 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 and warmed to room temperature. The mixture was concentrated under vacuum, and the crude acyl chloride intermediate was azeotropically reacted with toluene (20 mL) to give 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-2-phenylpropionic acid chloride as a straw-colored oil. This was dissolved in anhydrous toluene (20 mL), and tropine alcohol (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 NaHCO3, and brine, dried (Na2SO4), and concentrated under vacuum. The product was purified on silica (25 g, 0-10% (2 M NH3 in MeOH solution) in DCM solution) to give the pure title compound (0.778 g, 44%) as a colorless syrup. 1 H NMR (400MHz, CDCl3): δ7.34-7.21(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),2.9 5(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).

[0364]

[0365] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-hydroxybenzyl)-2-phenylpropionate carboxylate

[0366] A solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl-3-(4-((tert-butyldimethylsilyl)oxy)-phenyl)-2-phenylpropionate (0.77 g, 1.61 mmol) in DMF (10 mL) was treated with paraformaldehyde (0.072 g, 2.4 mmol) and an ethanol solution of 21% sodium ethoxide (0.06 mL, 0.16 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 6.5 hours, then a second portion of paraformaldehyde (0.072 g, 2.4 mmol) and an ethanol solution of 21% sodium ethoxide (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 an ethanol solution of 21% sodium ethoxide (0.06 mL, 0.15 mmol) was added, and stirring was continued at room temperature for 3 days. The reaction mixture was diluted with EtOAc (100 mL) and washed with water, 5% lithium chloride aqueous solution, and brine. It was dried (Na₂SO₄) and concentrated under vacuum. The product was partially purified on 15 μm silica (4 g, 0–20% (2 M NH₃ in MeOH solution) DCM solution) to give an impure title compound as a white solid. This was achieved using Kinetix. The title compound was further purified by reversed-phase preparative HPLC using a C18 21.2 × 250 mm column with a gradient eluent of 18 mL / min of 10%–60% MeCN in water containing 0.1% HCOOH, detected by monochromatic ultraviolet light at 220 nm. The title compound was given as a white solid (0.273 g, 38%). 1 HNMR(400MHz,d6-DMSO): δ8.31(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),3.9 5(1H,d,J=10Hz),3.77(1H,d,J=10Hz),3.26(1H,d,J=13.3Hz),3.25-3.16(2H,m),3.13(1H,d,J =13.3Hz),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. Title compound 1 H NMR and 13 The C NMR spectra are shown in the figures. Figure 26A and Figure 26B.

[0367] Synthetic scheme of Example 16: 2-fluoro-3-hydroxy-N-((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-2-phenylpropionamide

[0368]

[0369]

[0370] 2-Fluoro-3-hydroxy-2-phenylpropionic acid

[0371] A mixture of methyl 2-fluoro-2-phenylpropionate (1.49 g, 7.62 mmol) and paraformaldehyde (0.55 g, 18.3 mmol) in DMF (5 mL) was treated with an ethanol solution of 21% sodium ethoxide (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% lithium chloride aqueous solution, and brine, dried (Na2SO4), and concentrated under vacuum to give crude methyl 2-fluoro-3-hydroxy-2-phenylpropionate (1.82 g) as an orange oil. It was dissolved in a mixture of water (9 mL) and methanol (20 mL), and then lithium hydroxide (0.44 g, 18.3 mmol) was added. 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 under vacuum to give a crude title compound (2.21 g, quantified) as a dark cream-colored solid. This substance can be used without purification. 1 ¹H NMR (400MHz, d⁶-DMSO): δ 7.58–7.29 (⁵H, m), 4.11 (¹H, dd, J = 12.3, 30.7 Hz), 3.79 (¹H, dd, J = 12.3, 17.6 Hz), 3.10–3.09 (²H+ water, broad spectrum).

[0372]

[0373] 2-Fluoro-3-hydroxy-N-((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-2-phenylpropionamide

[0374] HATU (3.77 g, 9.9 mmol) was added in three portions to an ice-cold solution of crude 2-fluoro-3-hydroxy-2-phenylpropionic acid (2.21 g, 7.6 mmol), 8-methyl-8-azabicyclo[3.2.1]oct-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 warmed to room temperature and stirred for 40 hours. The reaction mixture was concentrated under vacuum, 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% lithium chloride aqueous solution and brine, dried (Na2SO4), and concentrated under vacuum to give an orange gel. The product was purified on silica (40 g, silica with 15 μm pore size, 5%–20% DCM solution (2 M NH3 in MeOH solution)) to give the title compound (0.631 g, 27%) as a pale yellow solid. 1 H NMR (400MHz, d6-DMSO): δ7.84(1H,bs),7.63-7.47(2H,m),7.44-7.33(3H,m),5.45(1H,t,J=5.8Hz),4.12(1H,d dd,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. Title compound 1 H NMR and 13 The C NMR spectra are shown in Figures 37A and 37B, respectively.

[0375] Synthetic scheme of Example 17: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-(4-fluorobenzyl)-3-hydroxy-2-phenylpropionate

[0376]

[0377] Methyl 3-(4-fluorophenyl)-2-phenylpropionate

[0378] Under argon atmosphere and at -30°C, 2M lithium diisopropylamine in THF / heptane / ethylbenzene (10 mL, 20 mmol) was added to a stirred solution of methyl phenylacetate (3.00 g, 20.0 mmol) in anhydrous THF (40 mL). After stirring for 15 min, the reaction mixture was warmed 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 anhydrous THF (10 mL) was added dropwise, maintaining T ≤ -25°C. The resulting mixture was stirred for 10 min and then warmed to room temperature over 16 hours. The solvent was removed under vacuum, and the residue was diluted with EtOAc, washed with water and brine, and the layers were separated. The organic fraction was dried (Na₂SO₄) and concentrated under vacuum. The residue was purified on silica (40 g, 0-10% MTBE in cyclohexane solution) to give the title compound (1.51 g, 29%) as a pale yellow oil. The compound was impure but could be used without further purification. 1 H NMR (400MHz, CDCl3): δ7.33-7.26(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).

[0379]

[0380] 3-(4-fluorophenyl)-2-phenylpropionic acid

[0381] Methyl 3-(4-fluorophenyl)-2-phenylpropionate (1.51 g, 5.9 mmol) was stirred in THF (30 mL) and MeOH (3 mL) and treated with 2 M NaOH (aqueous solution) (12 mL, 24.0 mmol). The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under vacuum, and the residue was diluted with H2O 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 (MgSO4) and concentrated under vacuum to give the title compound (1.13 g, 79%) as a light brown oil, which crystallized upon standing. The substance was ready for use without purification. 1H NMR (400MHz, CDCl3): δ7.34-7.27(5H,m),7.06(2H,ddd,J=3.1,5.3,11.8Hz),6.93-6.88(2H,m),3.8 1(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.

[0382]

[0383] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-(4-fluorophenyl)-2-phenylpropionate

[0384] At 0 °C, oxalyl chloride (573 μL, 6.6 mmol) was added dropwise under argon to treat a stirred solution of 3-(4-fluorophenyl)-2-phenylpropionic acid (1.13 g, 4.6 mmol) in 10 mL of DCM containing 200 μL of DMF. The resulting mixture was stirred at 0 °C for 10 min, then warmed to room temperature and stirred for 18 h. The solvent was removed under vacuum, and the residue was azeotropically reacted with toluene (2 × 15 mL) to give crude acyl chloride. The acyl chloride was stirred under argon at 100 °C in 10 mL of anhydrous toluene containing (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ol (790 mg, 5.6 mmol) for 4 h. The reaction mixture was concentrated under vacuum, and the residue was treated with 60 mL of DCM and 40 mL of H2O and alkalized to pH 10 with 1 M NaOH (aqueous solution). The organic fraction was separated, washed with brine, dried (MgSO4), and concentrated under vacuum to obtain a crude product (1.27 g) that was a pale yellow oil. This product could be used without further purification. 1 H NMR (400MHz, CDCl3): δ7.26(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=8.8,13.8Hz),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.

[0385]

[0386] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-(4-fluorobenzyl)-3-hydroxy-2-phenylpropionate

[0387] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-(4-fluorophenyl)-2-phenylpropionate (154 mg, 0.4 mmol) in DMF (3 mL) was treated with paraformaldehyde (160 mg, 5.3 mmol), followed by treatment with 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 diatomaceous earth. The filtrate was concentrated to a small volume under vacuum and purified on silica (4 g, 0-10% 2M NH3 / MeOH in DCM solution) to give 108 mg of the title compound as a white solid. The compound was purified by HPLC using a Kinetix Axia C18 RP column (long) with 10%–60% CH3CN in H2O solution [0.1% HCOOH], ascending at a rate of 18 mL / min over 10 min (under 200 nm UV) to give the title compound (64 mg, 38%) as a white solid. 1 H NMR (400MHz, CDCl3): δ7.38-7.27(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. Title compound 1 H NMR and 13 The C NMR spectra are shown in the figures. Figure 28A and Figure 28B .

[0388] Synthetic scheme of Example 18: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-methylbenzyl)-2-phenylpropionate

[0389]

[0390] 2-Phenylacetic acid methyl ester

[0391] Under argon atmosphere and at 0 °C, potassium tert-butoxide (4.08 g, 22.1 mmol) was added to a stirred solution of methyl phenylacetate (3.00 g, 20 mmol) in anhydrous THF (30 mL). After stirring for 15 min, a solution of 4-methylbenzyl bromide in anhydrous THF (10 mL) was added dropwise, maintaining T ≤ 5 °C. The resulting mixture was stirred for 10 min and then warmed to room temperature over 16 hours. The resulting mixture was diluted with EtOAc, washed with water, and then with brine. The organic fraction was dried (Na2SO4) and concentrated under vacuum to give a crude product as a yellow oil. This product was purified on silica (40 g, 0-25% EtOAc in cyclohexane solution) to give the title compound (3.60 g, 70%) as a pale yellow oil. This compound was impure but could be used without further purification.

[0392]

[0393] 2-Phenylacetic-3-(p-Tolyl)propionic acid

[0394] 2-Phenylacetic acid methyl ester (3.60 g, 14.2 mmol) in THF (60 mL) and MeOH (6 mL) was treated with 2 M NaOH (aqueous solution) (20 mL, 40 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum, 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 under vacuum to give a crude title compound (1.67 g, 49%) as a light brown oil, which crystallized upon standing. It was ready for use without purification. 1 H NMR (400MHz, CDCl3): δ7.31 (3H, d, J = 4.3Hz), 7.29-7.27 (2H, m), 7.02 (4H, dd, J = 8.2, 12.7Hz), 3.8 4(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).

[0395]

[0396] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-phenyl-3-(p-tolyl)propionate

[0397] At 0 °C, oxalyl chloride (518 μL, 5.9 mmol) was added dropwise under argon to treat a stirred solution of 2-phenyl-3-(p-tolyl)propionic acid (1.0 g, 4.2 mmol) in 10 mL of DCM containing 200 μL of DMF. The reaction mixture was stirred at 0 °C for 10 min, then warmed to room temperature and stirred for 18 h. The reaction mixture was concentrated under vacuum, and the residue was azeotropically reacted with toluene (2 × 15 mL) to give crude acyl chloride. It was stirred at 100 °C under argon in 10 mL of anhydrous toluene containing (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ol (710 mg, 5.1 mmol) for 4 h. The reaction mixture was concentrated under vacuum. The resulting residue was treated with 60 mL of DCM and 40 mL of water, and alkalized to pH 10 with 1 M NaOH (aqueous solution). The organic fraction was separated, washed with brine, dried (MgSO4), and concentrated under vacuum. The residue was purified on silica (12 g, 0-10% DCM solution of 2MNH3 / MeOH) to give the title compound (688 mg, 45%) as a light brown oil. 1 H NMR (400MHz, CDCl3): δ7.33-7.25(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.

[0398]

[0399] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-methylbenzyl)-2-phenylpropionate

[0400] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-phenyl-3-(p-tolyl)propionate (688 mg, 1.9 mmol) in DMF (10 mL) was treated with paraformaldehyde (722 mg, 24.0 mmol), then with 21% sodium ethoxide solution (20 μL, 0.054 mmol) and stirred at 50 ± 5 °C for 24 h. The reaction mixture was diluted with DCM (50 mL) and filtered through diatomaceous earth. The filtrate was concentrated under vacuum and the residue was purified on silica (12 g, 0-10% 2M NH3 / MeOH in DCM solution) using a Kinetix Axia C18 RP column (long) with 10%-60% CH3CN in H2O solution [0.1% HCOOH], ascending at a rate of 18 mL / min over 10 min (UV = 200 nm). The residue was purified by HPLC to give the title compound (260 mg, 35%) as a white solid. 1 H NMR (400MHz, CDCl3): δ7.38-7.33(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. Title compound 1 HNMR and 13 The C NMR spectra are shown in the figures. Figure 29A and Figure 29B .

[0401] Synthetic scheme of Example 19: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-(3-chlorobenzyl)-3-hydroxy-2-phenylpropionate

[0402]

[0403] Methyl 3-(3-chlorophenyl)-2-phenylpropionate

[0404] A 1M sodium bis(trimethylsilyl)amide solution (20 mL, 20 mmol) in THF was added dropwise to a stirred solution of methyl phenylacetate (3.00 g, 20.0 mmol) and 3-chlorobenzyl chloride (3.16 g, 19.6 mmol) in anhydrous THF (40 mL) under argon atmosphere at -78 °C, maintaining T ≤ -65 °C. The reaction mixture was stirred for 1 hour and then warmed to room temperature over 16 hours. The reaction mixture was concentrated under vacuum, and the residue was diluted with EtOAc, washed with water, and then with brine. The organic fraction was dried (Na₂SO₄) and concentrated under vacuum to give a crude product (5.48 g, 100%) as a yellow oil. This crude product was ready for use without purification. 1 H NMR (400MHz, CDCl3): δ7.32-7.26(6H,m),7.16-7.14(2H,m),7.13-7.10(1H,m),3.82(1H,d d,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).

[0405]

[0406] 3-(3-Chlorophenyl)-2-phenylpropionic acid

[0407] Methyl 3-(3-chlorophenyl)-2-phenylpropionate (5.48 g, 20 mmol) in a mixture of THF (70 mL) and MeOH (7 mL) was treated with 2 M NaOH (aqueous solution) (28.5 mL, 57 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum, 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 under vacuum to give a crude product (3.82 g, 73%) as a yellow oil, which was allowed to crystallize upon standing. It was ready for use without purification. 1 H NMR (400MHz, CDCl3): δ7.34-7.27(5H,m),7.16-7.11(3H,m),7.00-6.96(1H,m),3.8 4(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).

[0408]

[0409] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-(3-chlorophenyl)-2-phenylpropionate

[0410] At 0 °C, oxalyl chloride (955 μL, 5.9 mmol) was added dropwise under argon to treat a stirred solution of 3-(3-chlorophenyl)-2-phenylpropionic acid (2.0 g, 7.7 mmol) in 20 mL of DCM containing 300 μL of DMF. The reaction mixture was stirred at 0 °C for 10 min, then warmed to room temperature and stirred for 18 h. The reaction mixture was concentrated under vacuum, and the residue was azeotropically reacted with toluene (2 × 15 mL) to give crude acyl chloride. The resulting residue was stirred at 100 °C under argon in anhydrous toluene (10 mL) containing (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ol (1.31 g, 9.3 mmol) for 3 h. The reaction mixture was concentrated under vacuum. The resulting residue was treated with DCM (60 mL) and water (40 mL) and alkalized to pH 10 with 1 M NaOH (aqueous solution). The organic fraction was separated, washed with brine, dried (MgSO4), and concentrated under vacuum. The residue was purified on silica (40 g, 0-10% DCM solution of 2M NH3 / MeOH) to give the title compound (1.06 g, 36%) as a light brown oil. 1 H NMR (400MHz, CDCl3): δ7.33-7.26(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.

[0411]

[0412] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-(3-chlorobenzyl)-3-hydroxy-2-phenylpropionate

[0413] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-(3-chlorophenyl)-2-phenylpropionate (1.10 g, 2.9 mmol) in DMF (15 mL) was treated with paraformaldehyde (1.10 g, 36.0 mmol), followed by treatment with 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 diatomaceous earth. The filtrate was concentrated under vacuum, and the residue was purified on silica (24 g, 0-10% 2M NH3 / MeOH in DCM solution). The product was purified by HPLC using a Kinetix Axia C18 RP column (long) with 10%-60% CH3CN in H2O solution [0.1% HCOOH], ascending at a rate of 18 mL / min over 10 min (UV = 200 nm), yielding a white solid product (554 mg, 50%). 1 H NMR (400MHz, CDCl3): δ7.38-7.27(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,J=10.6Hz),3.52-3.45(3H,m),3.35(1H,d,J=13.3Hz),2.64-2.5 5(1H,m),2.54(3H,s),1.91-1.72(4H,m),1.68-1.48(2H,m); LCMS(ESI)[M+H] + 414.2. Title compound 1 H NMR and 13 The C NMR spectra are shown in the figures. Figure 30A and Figure 30B .

[0414] Synthetic scheme of Example 20: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropionate

[0415]

[0416] 2-(3-chlorophenyl)propionic acid

[0417] A solution of methyl 2-(3-chlorophenyl)propionate (590 mg, 2.97 mmol) in THF (12 mL) and MeOH (1 mL) was treated with 2N NaOH (aqueous solution) (4.2 mL, 8.41 mmol) and stirred overnight at room temperature. The reaction mixture was concentrated under vacuum, and the resulting aqueous layer was acidified to pH 1 with 1N HCl and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated under vacuum. The residue was purified on silica (40 g, 0-30% EtOAc in cyclohexane solution) to give the title compound (229 mg, 42%) as a pale yellow oil. 1 H NMR (400MHz, CDCl3): δ7.34-7.15 (4H, m), 3.72 (1H, q, J = 7.3Hz), 1.51 (3H, d, J = 7.3Hz).

[0418]

[0419] 2-(3-Chlorophenyl)propionyl chloride

[0420] A stirred solution of 2-(3-chlorophenyl)propionic acid (229 mg, 1.24 mmol) in 3 mL of DCM containing 55 μL DMF was treated dropwise with oxalyl chloride (150 μL, 1.77 mmol) under argon atmosphere at 0 °C. The resulting mixture was stirred at 0 °C for 30 min and then warmed to room temperature overnight. The reaction mixture was concentrated under vacuum to give the crude title compound, which was ready for immediate use without purification.

[0421]

[0422] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-(3-chlorophenyl)propionate

[0423] Crude 2-(3-chlorophenyl)propionyl chloride was stirred for 3 hours at 100 °C under argon atmosphere in anhydrous toluene (3 mL) containing tropine alcohol (214 mg, 1.51 mmol). The reaction mixture was concentrated under vacuum. The residue was diluted with a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated under vacuum. The resulting residue was purified on silica (40 g 0-10% DCM solution of 2N NH3 MeOH) to give the title compound (272 mg, 71%) as a yellow oil. LCMS(ESI)[M+H] + 308.2.

[0424]

[0425] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-(3-chlorophenyl)-3-hydroxy-2-methylpropionate

[0426] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2-(3-chlorophenyl)propionate (337 mg, 1.09 mmol) in DMF (2.5 mL) was treated with paraformaldehyde (49 mg, 1.64 mmol), followed by treatment with 21% sodium ethoxide solution (4.3 μL, 0.055 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 1N HCl and extracted with EtOAc. The combined aqueous fractions were then alkalized to pH 13 with 1N NaOH and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated under vacuum. The resulting residue was purified on silica (40 g, 0-10% DCM solution of 2N NH3 MeOH) to give the title compound (193 mg, 52%) as a grayish-white solid. 1 H NMR (400MHz, CDCl3): δ7.34-7.26(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,brs),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. Title compound 1 H NMR and 13 The C NMR spectra are shown in the figures. Figure 31A and Figure 31B .

[0427] Synthetic scheme of Example 21: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropionate

[0428]

[0429] 2-(4-chlorophenyl)propionic acid

[0430] Methyl 2-(4-chlorophenyl)propionate (547 mg, 2.75 mmol) in THF (12 mL) and MeOH (1 mL) was treated with 2N NaOH (aqueous solution) (3.9 mL, 7.79 mmol) at room temperature and stirred for 8 hours. The reaction mixture was concentrated under vacuum, and the resulting aqueous layer was acidified to pH 1 with 1N HCl and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated under vacuum. The residue was purified on silica (40 g, 0-30% EtOAc in cyclohexane solution) to give the title compound (137 mg, 27%) as a grayish-white solid. 1 H NMR (400MHz, CDCl3): δ7.35-7.16 (4H, m), 3.71 (1H, q, J = 9.4Hz), 1.49 (3H, d, J = 9.6Hz).

[0431]

[0432] 2-(4-Chlorophenyl)propionyl chloride

[0433] Under argon atmosphere at 0 °C, a stirred solution of 2-(4-chlorophenyl)propionic 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). The resulting mixture was stirred at 0 °C for 30 min. The reaction mixture was concentrated under vacuum to give the crude title compound, which was ready for immediate use without purification.

[0434]

[0435] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-(4-chlorophenyl)propionate

[0436] Crude 2-(4-chlorophenyl)propionyl chloride was stirred overnight at 100 °C under argon atmosphere in anhydrous toluene (4 mL) containing tropine alcohol (247 mg, 1.75 mmol). The reaction mixture was concentrated under vacuum. The residue was diluted with EtOAc and extracted with 1N HCl. The combined aqueous fractions were then alkalized to pH 13 with 1N NaOH and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated under vacuum to give the title compound (230 mg, 52%) as a brown oil, which was used as the crude product in the next reaction. LCMS(ESI)[M+H] + 308.1.

[0437]

[0438] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-(4-chlorophenyl)-3-hydroxy-2-methylpropionate

[0439] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2-(4-chlorophenyl)propionate (230 mg, 0.75 mmol) in DMF (2 mL) was treated with paraformaldehyde (34 mg, 1.12 mmol), followed by treatment with 21% sodium ethoxide solution (3 μL, 0.037 mmol), and the reaction mixture was stirred at room temperature for 1 hour. Paraformaldehyde (34 mg, 1.12 mmol) was added again, 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 alkalized to pH 13 with 1N NaOH and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated under vacuum. The resulting residue was purified on silica (40 g, 0-10% DCM solution of 2N NH3 MeOH) to give the title compound (118 mg, 47%) as a grayish-white solid. 1 H NMR (400MHz, CDCl3): δ7.36-7.31(2H,m),7.28-7.22(2H,m),5.06(1H,t,J=5.5Hz),4.05(1 H,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(3 H,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. Title compound 1 H NMR and 13 The C NMR spectra are shown in the figures. Figure 32A and Figure 32B .

[0440] Synthetic scheme of Example 22: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-(4-(benzyloxy)phenyl)propionate

[0441]

[0442] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2-(4-(benzyloxy)phenyl)propionate was reacted with tropine alcohol (750 mg, 5.33 mmol) in a solution of 2-(4-(benzyloxy)phenyl)propionyl chloride (1.61 g, 5.86 mmol) in toluene (20 mL), and the reaction mixture was stirred at 90 °C for 3 h, followed by stirring at 50 °C for 16 h. The reaction mixture was diluted with 1N HCl and extracted with EtOAc, discarding the organic matter. The combined aqueous fractions were made alkaline with 1N NaOH and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated under vacuum to give the title compound (750 mg, 37%). 1 H NMR (400MHz, CDCl3) δ7.47-7.29(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).

[0443]

[0444] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-(4-(benzyloxy)phenyl)-3-hydroxy-2-methylpropionate

[0445] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl 2-(4-(benzyloxy)phenyl)propionate (750 mg, 1.98 mmol) in DMF (8 mL) was treated with paraformaldehyde (89 mg, 2.96 mmol), followed by treatment with 21% sodium ethoxide solution (37 μL, 0.10 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc and extracted with 1N HCl. The combined aqueous fractions were made alkaline with 1N NaOH and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated under vacuum. The resulting residue was purified on silica (12 g, DCM solution of 0-10% MeOH) to give the title compound (685 mg, 85%).1 H NMR (400MHz, CDCl3) δ7.45-7.29(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).

[0446]

[0447] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-3-hydroxy-2-(4-hydroxyphenyl)-2-methylpropionate

[0448] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl-2-(4-(benzyloxy)phenyl)-3-hydroxy-2-methylpropionate (685 mg, 1.67 mmol) in EtOAc (10 mL) and MeOH (3 mL) was treated with palladium / carbon (10 wt%, 150 mg) and stirred under hydrogen at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified on silica (12 g, 0-10% MeOH in DCM solution) to give the title compound (278 mg, 52%) as a white solid. 1H NMR (400MHz, CDCl3): δ7.18-7.12(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. Title compound 1 H NMR and 13 The C NMR spectra are shown in the figures. Figure 33A and Figure 33B .

[0449] Synthetic scheme of Example 23: 6-chloro-11H-benzo[e]pyrido[3,2-b][1,4]diazacycloheptatriene

[0450]

[0451] 2-Nitrobenzoyl chloride

[0452] One drop of DMF was added to a solution of 2-nitrobenzoic acid (5 g, 29.9 mmol) in DCM (140 mL), followed by the addition of oxaloyl chloride (3.7 mL, 41.9 mmol), which induced foaming. The reaction mixture was stirred at room temperature for 20 min. The reaction mixture was concentrated under vacuum to give the title compound (5.55 g, quantified) as a straw-colored oil. The substance was ready for use without purification. 1 H NMR (400MHz, CDCl3): δ8.13-8.07(1H,m),7.84-7.68(3H,m).

[0453]

[0454] N-(2-chloropyridin-3-yl)-2-nitrobenzamide

[0455] Adding pyridine (14.5 mL, 0.18 mol) and 3-amino-2-chloropyridine (4.23 g, 32.9 mmol) to a solution of 2-nitrobenzoyl chloride (5.55 g, 29.9 mmol) in THF (120 mL) resulted in the formation of a precipitate. The reaction mixture 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 (MgSO4), and concentrated under vacuum to give a product (8.6 g, quantitative) as a pale yellow solid. The substance was ready for use without purification. 1 H NMR(400MHz,d6-DMSO)δ10.61(1H,s),8.31(1H,dd,J=4.3,1.5Hz),8.25-8.1 6(2H,m),7.94-7.87(1H,m),7.84-7.75(2H,m),7.54(1H,dd,J=8.3,4.3Hz).

[0456]

[0457] 2-Amino-N-(2-chloropyridin-3-yl)benzamide

[0458] To a solution of N-(2-chloropyridin-3-yl)-2-nitrobenzamide (8.3 g, 29.9 mmol) in ethanol (100 mL), water (20 mL), iron (2.67 g, 47.8 mmol), and ammonium chloride (16 g, 0.3 mol) were added. The mixture was refluxed and heated for 40 min, then diluted with water and filtered. The filtrate was extracted with ethyl acetate, and the combined organic fractions were washed with brine, dried (MgSO4), and concentrated under vacuum to give the title product (7.4 g, quantitative) as a beige solid. The substance was ready for use without purification. 1 HNMR(400MHz,d6-DMSO)δ9.93(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,brs).

[0459]

[0460] 5,11-Dihydro-6H-benzo[e]pyrido[3,2-b][1,4]diaza-6-one

[0461] 2-Amino-N-(2-chloropyridinyl-3-yl)benzamide (3.5 g, 14.1 mmol) was heated at 210 °C for 5 min. Upon reaching 200 °C, the reaction mixture turned black and bubbling was observed. The reaction mixture was cooled to room temperature, and the solid residue was washed with a saturated aqueous solution of NaHCO3, followed by washing with DCM, to give the title product (2.89 g, 96%) as a gray solid. The substance can be used without purification. 1 H NMR (400MHz, d6-DMSO): δ9.94(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).

[0462]

[0463] 6-Chloro-11H-benzo[e]pyrido[3,2-b][1,4]diazacycloheptatriene

[0464] A mixture of 5,11-dihydro-6H-benzo[e]pyrido[3,2-b][1,4]diazacycloheptatrien-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 ~4 °C, isohexane (10 mL) was added, and the solid was filtered off. The solid was washed with another 10 mL of isohexane and dried under vacuum to give a product as a yellow solid (520 mg, 95%). The substance was ready for use without purification. 1 H NMR (400MHz, CDCl3): δ9.96 (1H, s), 7.72-7.59 (3H, m), 7.41 (1H, td, J = 8.0, 1.3Hz), 7.16-7.04 (3H, m).

[0465] The 6-chloro-11H-benzo[e]pyrido[3,2-b][1,4]diazacycloheptatriene obtained in Example 23 can be used to prepare pirenzepine of formula (II) of the present invention according to the following reaction scheme.

[0466]

[0467] Where R can be a hexyl group.

[0468] Example 24

[0469] Human muscarinic receptor assay

[0470] I. Measurement protocols M1-M5

[0471] M1

[0472] Cell membrane homogenate (45 μg protein) was incubated with 2 nM [3H]pirenzepine at 22 °C for 60 min in a buffer containing 50 mM Tris-HCl (pH 7.4), 120 mM NaCl, 5 mM KCl, 5 mM MgCl2, and 1 mM EDTA. Nonspecific binding was measured in the presence of 1 μM atropine. After incubation, the sample was rapidly filtered under vacuum through a glass fiber filter (GF / B, Packard) pre-soaked in 0.3% PEI and washed several times with ice-cold 50 mM Tris-HCl using a 96-compartment sample collector (Unifilter, Packard). The filter was dried and radioactivity was counted using a scintillation mixture (Microscint O, Packard) in a scintillation counter (Topcount, Packard). The results are expressed as the percentage of inhibition of specific binding of the control radioligand. The standard reference compound was pirenzepine. In each experiment, pirenzepine was tested at several concentrations to obtain competition curves, from which its K value was calculated. i and IC 50 .

[0473] M2

[0474] Cell membrane homogenate (60 μg protein) was incubated with 2 nM [3H]AF-DX 384 at 22 °C for 60 min in a buffer containing 50 mM Tris-HCl (pH 7.4), 120 mM NaCl, 5 mM KCl, 5 mM MgCl2, and 1 mM EDTA. Nonspecific binding was measured in the presence of 1 μM atropine. After incubation, the sample was rapidly filtered under vacuum through a glass fiber filter (GF / B, Packard) pre-soaked in 0.3% PEI and washed several times with ice-cold 50 mM Tris-HCl using a 96-compartment sampler (Unifilter, Packard). The filter was dried, and radioactivity was counted using a scintillation mixture (Microscint O, Packard) in a scintillation counter (Topcount, Packard). The results are expressed as the percentage of inhibition of specific binding of the control radioligand. The standard reference compound is mesotrimine. In each experiment, mesotrimine was tested at several concentrations to obtain competition curves, from which its K value was calculated. i and IC 50 .

[0475] M3

[0476] Cell membrane homogenate (8 μg protein) was incubated with 0.2 nM [3H]4-DAMP at 22 °C for 60 min in a buffer containing 10 mM Tris-HCl (pH 7.4) and 2 mM EDTA, with or without the test compound. Nonspecific binding was measured in the presence of 1 μM atropine. After incubation, the sample was rapidly filtered under vacuum through a glass fiber filter (GF / B, Packard) pre-soaked in 0.3% PEI and washed several times with ice-cold 50 mM Tris-HCl using a 96-compartment sample collector (Unifilter, Packard). The filter was dried and radioactivity was counted in a scintillation counter (Topcount, Packard) using a scintillation mixture (Microscint O, Packard). Results are expressed as the percentage of inhibition of specific binding of the control radioligand. The standard reference compound is 4-DAMP. In each experiment, it was tested at several concentrations to obtain competition curves, from which its K value was calculated. i and IC 50 .

[0477] M4

[0478] Cell membrane homogenate (16 μg protein) was incubated with 0.2 nM [3H]4-DAMP at 22 °C for 60 min in a buffer containing 10 mM Tris-HCl (pH 7.4) and 2 mM EDTA, with or without the test compound. Nonspecific binding was measured in the presence of 1 μM atropine. After incubation, the sample was rapidly filtered under vacuum through a glass fiber filter (GF / B, Packard) pre-soaked in 0.3% PEI and washed several times with ice-cold 50 mM Tris-HCl using a 96-compartment sampler (Unifilter, Packard). The filter was dried and radioactivity was counted in a scintillation counter (Topcount, Packard) using a scintillation mixture (Microscint O, Packard). Results are expressed as the percentage of inhibition of specific binding of the control radioligand. The standard reference compound is 4-DAMP. In each experiment, it was tested at several concentrations to obtain competition curves, from which its K value was calculated. i and IC 50 .

[0479] M5

[0480] Cell membrane homogenate (15 μg protein) was incubated with 0.3 nM [3H]4-DAMP at 22 °C for 60 min in a buffer containing 10 mM Tris-HCl (pH 7.4) and 2 mM EDTA, with or without the test compound. Nonspecific binding was measured in the presence of 1 μM atropine. After incubation, the sample was rapidly filtered under vacuum through a glass fiber filter (GF / B, Packard) pre-soaked in 0.3% PEI and washed several times with ice-cold 50 mM Tris-HCl using a 96 sample chamber collector (Unifilter, Packard). The filter was dried and radioactivity was counted in a scintillation counter (Topcount, Packard) using a scintillation mixture (Microscint O, Packard). Results are expressed as the percentage of inhibition of specific binding of the control radioligand. The standard reference compound is 4-DAMP. In each experiment, it was tested at several concentrations to obtain competition curves, from which its K value was calculated. i and IC 50 .

[0481] II. Binding Affinity M1-M5

[0482] The table below shows the results of human muscarinic receptor assays for some of the compounds of the present invention.

[0483]

[0484]

[0485] Results showing inhibition or stimulation greater than 50% are considered to represent a significant effect of the tested compound.

[0486] The compounds of the present invention and their pharmaceutically acceptable salts can be combined with one or more drug carriers to form various types of formulations for delivery. For example, topical formulations can be used and may include ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, buffers, sodium chloride, and water to form aqueous ophthalmologically compatible solutions and suspensions. Suitable topical formulations are described, for example, by reference in “Recent Advances in Topical Ocular Drug Delivery” by VKYellepeddi and S. Palakurthi, whose full text is incorporated herein by reference (J. Ocul. Pharmacol. Ther. 2016, 32(2):67-82). Systemic formulations (e.g., tablets for oral ingestion) and formulations for intraocular injection are also considered. (Pharmaceutically Acceptable Carriers) Examples of suitable pharmaceutically acceptable carriers are described in the standard reference text in the pharmaceutical field, namely Remington's Pharmaceutical Sciences by Mack Publishing Company (incorporated in its entirety by reference).

[0487] The specific type of formulation chosen will depend on various factors, such as the compound used or its salts, dosage frequency, location of the disease being treated, route of administration chosen, and standard pharmaceutical practice. Topically ophthalmologically compatible aqueous solutions, suspensions, ointments, and gels are preferred dosage forms for treating eye diseases of the anterior part of the eye (cornea, iris, trabecular meshwork) or the posterior part of the eye (if the compound can be formulated to allow for local delivery and penetration of the anterior ocular tissue). These formulations typically contain from about 0.01% by weight to about 10.0% by weight of the compound according to formula (I). Preferred concentrations for local application range from about 0.1% by weight to about 5.0% by weight. Therefore, for local application, these formulations are delivered to the ocular surface one to six times daily (depending on the routine judgment of a skilled clinician). For example, systemic administration in tablet form can be used to treat eye diseases, particularly those of the posterior part of the eye, such as the retina.

[0488] Preferably, the compounds of the present invention are incorporated into ophthalmologically compatible formulations for delivery to the eye. The compounds can be combined with ophthalmologically acceptable preservatives, cosolvents, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, or water to form an aqueous, sterile ophthalmic suspension or solution. Ophthalmic solution formulations can be prepared by dissolving the compounds in physiologically acceptable isotonic aqueous buffer solutions. Furthermore, the ophthalmic solution may include ophthalmologically acceptable surfactants to aid in the dissolution of the compounds. Additionally, the ophthalmic solution may contain viscosity-enhancing agents (such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, methylcellulose, polyvinylpyrrolidone, etc.) to improve retention of the formulation in the conjunctival sac. Gelling agents, including but not limited to gellan gum and xanthan gum, can also be used. To prepare sterile ophthalmic ointment formulations, the active ingredient is combined with a preservative in a suitable medium (such as mineral oil, liquid lanolin, or white petrolatum). Sterile ophthalmic gel formulations can be prepared by suspending compounds in a hydrophilic matrix, which, according to publicly available formulations of similar ophthalmic formulations, is prepared from a combination of, for example, carbopol-974; preservatives and tension agents may be incorporated.

[0489] The pharmaceutical composition may include one or more buffers or pH adjusters to provide improved pH control. In some partial embodiments, the pH of the pharmaceutical composition of the present invention is between 5.0 and 8.0, between 5.0 and 7.0, between 6.0 and 8.0, or between 6.0 and 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 an approximately neutral pH of about 6.8.

[0490] Other intended excipients that may be used in the pharmaceutical compositions of the present 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 other known pharmaceutical excipients and / or additives suitable for use in formulations of the present invention are known in the art, for example, as listed in: "The Handbook of Pharmaceutical Excipients," 4th edition, edited by Rowe et al., American Pharmaceutical Association (2003); and Remington: the Science and Practice of Pharmacy, 21st edition, edited by Gennaro, Lippincott Williams & Wilkins (2005).

[0491] In another aspect, the present invention provides a pharmaceutical composition comprising: (1) a compound of the present invention, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one embodiment, the composition comprises a therapeutically effective amount, preferably about 0.01 wt% to about 10.0 wt%, more preferably about 0.01 wt / volume% to about 5 wt / volume% or about 0.1 wt% to 5.0 wt% of (a) the compound and / or (b) the pharmaceutically acceptable salt. In another embodiment, the composition comprises at least two pharmaceutically acceptable carriers (as described herein). For the purposes of the present invention, unless otherwise specified, solvates and hydrates are generally considered to be part of the composition. Preferably, the pharmaceutically acceptable carrier is sterile. The pharmaceutical composition may be formulated for a specific route of administration, such as oral administration, parenteral administration, and rectal administration. Additionally, the pharmaceutical compositions of the present invention may be formulated in solid form (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including but not limited to solutions, suspensions, or emulsions). The pharmaceutical composition can be subjected to routine pharmaceutical operations, such as sterilization and / or can contain conventional inert diluents, lubricants or buffers, as well as adjuvants (such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.).

[0492] In another embodiment of the invention, the pharmaceutical composition is a tablet or gelatin capsule comprising an active ingredient and one or more of the following:

[0493] a) Diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0494] b) Lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol; in the case of tablets, also comprising...

[0495] c) Binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone; if desired

[0496] d) Disintegrants, such as starch, agar, alginate, or their sodium salts or effervescent mixtures; and

[0497] e) Adsorbents, colorants, flavoring agents and sweeteners.

[0498] Tablets can be film-coated or enteric-coated using methods known in the art.

[0499] In addition to the compounds of the present invention, the pharmaceutical compositions of the present invention may also contain other therapeutic agents. Other therapeutic agents may include, for example, other compounds and antibodies that can be used to treat eye diseases.

[0500] The pharmaceutical compositions of the present invention can be administered to patients. As used herein, the terms "subject" or "patient" refer to humans and non-human mammals, including but not limited to primates, rabbits, pigs, horses, dogs, cats, sheep, and cattle. Preferably, the subject or patient is a human.

[0501] Various delivery methods for administering the pharmaceutical composition are considered, and may include, for example, local, intravitreal, oral, intravenous (IV), intra-anterior chamber, and other methods known to those skilled in the art.

[0502] In one embodiment, administration is typically via a syringe. Therefore, the present invention provides a delivery device (e.g., a syringe) comprising the pharmaceutical composition of the present invention (e.g., a pre-filled syringe). The patient will receive an effective amount of the compound according to formula (I) as the main active ingredient.

[0503] In yet another embodiment, an ophthalmic insert or membrane is used to deliver the compounds of the present invention. In one such embodiment, the compound of formula (I) is formulated in a polymeric ophthalmic insert comprising one or more mucoadhesive polymers biocompatible with the ocular surface and tear film of the eye. In some embodiments, when the polymeric ophthalmic insert is inserted into the cul-de-sac, the thickness of the tear film may increase after insertion, lasting for at least 30 minutes. The one or more mucoadhesive polymers may be selected from the group consisting of: hyaluronic acid (in acid or salt form), hydroxypropyl methylcellulose (HPMC), methylcellulose, tamarind seed polysaccharide (TSP), guar gum, hydroxypropyl guar gum (HP guar gum), poloxamer, poly(galacturonic acid), sodium alginate, pectin, xanthan gum, xyloglucan gum, chitosan, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, carbomer, polyacrylic acid, and combinations thereof. In one embodiment of this disclosure, the one or more mucosal adhesive polymers may be HP guar gum, hyaluronic acid, and sodium hyaluronate.

[0504] The present invention further provides a method for delivering a compound according to formula (I) to a patient, the method comprising the step of administering the pharmaceutical composition of the present invention to the patient once or more daily.

[0505] Unless otherwise stated, all percentages used herein are weight percentages. Unless otherwise indicated, the term "an" means "an," "at least one," or "one or more." Unless the context otherwise requires, singular terms used herein shall include the plural, and plural terms shall include the singular. For clarity, the contents of any patents, patent applications, and references cited throughout this specification are hereby incorporated in their entirety by reference.

[0506] Preparation examples

[0507] The following examples illustrate embodiments of the invention. Those skilled in the art will understand that changes can be made to the specific embodiments described herein without departing from the spirit and scope of the invention and while still obtaining the same results.

[0508] Formulation Example 1 - Topical Ophthalmic Preparations

[0509] Element Concentration (w / v%) Compound of formula (I) 0.01％-2％ Hydroxypropyl methylcellulose 0.5％ Anhydrous disodium hydrogen phosphate 0.2％ Sodium chloride 0.5％ Disodium EDTA (Disodium ethylenediaminetetraacetate) 0.01％ Polysorbate 80 0.05％ benzalkonium chloride 0.01％ Sodium hydroxide / hydrochloric acid Used to adjust the pH to 7.3-7.4. purified water Appropriate amount up to 100%

[0510] The invention and its embodiments have been described in detail. However, the scope of the invention is not intended to be limited to any specific embodiments of the processes, articles, material 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. Therefore, those skilled in the art will readily understand from this disclosure that subsequent modifications, substitutions, and / or variations can be made to perform substantially the same function or achieve substantially the same results as the embodiments described herein, based on such relevant embodiments of the invention. Accordingly, the following claims are intended to cover within their scope any modifications, substitutions, and variations to the processes, articles, material compositions, compounds, means, methods, and / or steps disclosed herein. Unless otherwise stated, the claims should not be construed as limited to the described order or elements. It should be understood that various changes in form and detail can be made without departing from the scope of the appended claims.

Claims

1. Compound 2. A pharmaceutically acceptable salt of the compound according to claim 1.

3. A pharmaceutical composition comprising: (1) the compound of claim 1 and / or a pharmaceutically acceptable salt thereof; and (2) one or more pharmaceutically acceptable carriers.

4. The composition according to claim 3, wherein the composition is an ophthalmic compatible composition.

5. The composition according to claim 3 or 4, wherein the composition comprises a therapeutically effective amount of the compound and / or a pharmaceutically acceptable salt thereof.

6. The composition according to claim 3 or 4, wherein the composition comprises 0.01% to 10.0% by weight of the compound and / or its pharmaceutically acceptable salt.

7. The composition according to claim 3 or 4, wherein the composition comprises: 0.01 wt% to 5 wt% of the compound and / or a pharmaceutically acceptable salt thereof; or 0.1 wt% to 5.0 wt% of the compound and / or a pharmaceutically acceptable salt thereof.

8. The composition according to claim 3, wherein the composition is a topical composition.

9. The composition according to claim 4, wherein the composition is a topical composition.

10. The composition according to claim 5, wherein the composition is a topical composition.

11. The composition according to claim 6, wherein the composition is a topical composition.

12. The composition according to claim 7, wherein the composition is a topical composition.

Images