RU2795521C2 - Azabicyclic and diazepine derivatives for the treatment of ophthalmic disorders - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: invention relates to a heterocyclic compound

or

to a pharmaceutical composition based on the said compound.

EFFECT: effective modulation of muscarinic receptors by the said compound useful for the treatment of ophthalmic diseases.

7 cl, 52 dwg, 1 tbl, 25 ex

Description

The field of technology to which the invention belongs

The present invention relates to azabicyclic and diazepine derivatives used as muscarinic receptor modulators and to methods of treating diseases using them.

BACKGROUND OF THE INVENTION

The muscarinic receptor is a target for the excitatory neurotransmitter acetylcholine and was named because of the selective activation of the receptor by muscarine. The muscarinic receptor is widely distributed in human tissues and is further classified into subtypes M1 to M5. Muscarinic receptor modulation has been considered a therapeutic target for disorders ranging from overactive bladder to cognitive disorders (Abrams et al., Br. J Pharmacol 2006 July; 148(5): 565-578).

Myopia is a refractive error of the eye caused by excessive longitudinal growth of the eye. This elongation of the eye causes the visual image to be focused in front of the retina and tends to cause blurry vision of distant objects. The non-selective muscarinic receptor antagonist atropine has been reported to be effective as a 1% topical drop in the treatment of myopia. (Chua et al., Ophthalmology 2006 Dec; 113(12):2285-91). However, numerous side effects have been reported, including mydriasis (dilated pupil) and blurred vision at close range due to cycloplegia (inability to accommodate). Currently, corrective lenses are the main means to reduce the intensity of the manifestation of disorders associated with the long eye, such as myopia. However, lenses optically correct refractive errors without removing the cause, which is overgrowth of the eye. Thus, there remains a need for methods of treating ocular overgrowth disorders.

Brief description of the invention

There remains a need for new treatments and therapies for eye overgrowth. The present invention provides compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof, which are muscarinic receptor modulators. The present invention further provides methods for treating, preventing or ameliorating an eye overgrowth disorder, comprising administering to a subject in need thereof an effective amount of a muscarinic receptor modulator. This document describes various embodiments of the present invention.

In some aspects, this document provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof:

Where

Me=CH ₃ ;

A=O or NR ₅ ;

W=N or CH;

X = -OH, -OYZ, -SYZ or -NR ₅ -YZ;

R ₁ and R ₂ independently represent substituents in the form of H, D, hydroxyl, alkoxy, nitrile, halogen atoms, straight, branched or cyclic C ₁ -C ₂₀ (preferably C ₁ -C ₁₀ )-alkyl groups, optionally substituted with halogen atoms ; or

R ₁ and R ₂ independently represent substituents in the form of phenyl or benzyl groups, optionally substituted with one or more substituents selected from straight, branched or cyclic C ₁ -C ₂₀ (preferably C ₁ -C ₁₀ )-alkyl groups, -haloalkyl groups , hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide, sulfonamide, and halogen atoms; or

R ₁ and R ₂ are independently substituted with a heterocyclic saturated, unsaturated or aromatic 5- or 6-membered ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur and optionally substituted with one or more substituents selected from straight, branched or cyclic C ₁ -C ₂₀ (preferably C ₁ -C ₁₀ )-alkyl, -haloalkyl groups, hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide or halogen atoms;

R ₃ and R ₄ are independently substituted with hydrogen, straight or branched or cyclic C ₁ -C ₁₀ -alkyl or -haloalkyl groups, or

R ₃ and R ₄ can be combined to form 3-6 membered rings;

R ₅ =H or straight or branched C ₁ -C ₂₀ alkyl groups, preferably C ₁ -C ₁₀ straight or branched C ₁ -C ₁₀ haloalkyl groups;

Y is a divalent radical having the following meaning:

straight or branched C ₁ -C ₂₀ (preferably C ₁ -C ₁₀ )-alkyl optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxyl atoms;

-C(O)(C ₁ -C ₁₀ alkyl)- or -C(O)(CH ₂ ) _n C(O)O-(C ₁ -C ₁₀ alkyl)- or -(C ₁ -C ₁₀ alkyl) -;

where n is an integer from 0 to 20;

R ⁶ and R ⁷ independently represent H or straight or branched C ₁ -C ₁₀ alkyl groups, straight or branched C ₁ -C ₁₀ haloalkyl groups; or

R ⁶ and R ⁷ can be combined to form 3-6 membered rings; And

Z is H, -OH, C _1-6 alkoxy, -COOH, -NR ⁸ R ⁹ ;

R ⁸ and R ⁹ independently represent substituents in the form of C ₁ -C ₂₀ -alkyl, preferably C ₁ -C ₁₀ optionally substituted with one or more substituents selected from hydroxyl, amino, ester, carboxylic acid and halogen atoms; or

R ⁸ and R ⁹ may be combined to form 3-6 membered rings containing one or more heteroatoms selected from the group consisting of:

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

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

Specific preferred embodiments of the present invention will become apparent from the following more detailed description of some preferred embodiments and the claims.

Brief description of the DRAWINGS

The figure 1 shows ¹ H NMR spectrum of ethyl-2-fluoro-2-phenylacetate;

figure 2 shows ¹ H NMR spectrum of 2-fluoro-2-phenylacetic acid;

figure 3 shows ¹ H NMR spectrum of 2-fluoro-2-phenylacetyl chloride;

Figure 4 shows ^{the 1} H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-fluoro-2-phenylacetate;

Figure 5 shows ^{the 1} H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-fluoro-3-hydroxy-2-phenylpropanoate;

Figure 6 shows the ¹³ C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-fluoro-3-hydroxy-2-phenylpropanoate;

Figure 7 shows ^{the 1} H NMR spectrum of 2-methyl-2-phenylacetyl chloride;

Figure 8 shows the ¹ H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-methyl-2-phenylacetate;

Figure 9 shows ^{the 1} H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-methyl-3-hydroxy-2-phenylpropanoate;

Figure 10 shows the ¹³ C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-methyl-3-hydroxy-2-phenylpropanoate;

figure 11 shows ¹ H NMR spectrum of 2,3-diphenylpropanoyl chloride;

Figure 12 shows ^{the 1} H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2,3-diphenylpropanoate;

Figure 13 shows ^{the 1} H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-benzyl-3-hydroxy-2-phenylpropanoate; And

Figure 14 shows the ¹³ C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-benzyl-3-hydroxy-2-phenylpropanoate.

Figure 15A shows ^{the 1} H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-methyl-2-(thiophene-2- yl) propanoate. Figure 15B shows the ¹³ C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-methyl-2-(thiophene-2- yl) propanoate.

Figure 16A shows the ¹ H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(hydroxymethyl)-2-phenylpropanoate. Figure 16B shows the ¹³ C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(hydroxymethyl)-2-phenylpropanoate.

Figure 17A shows ^{the 1} H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(hydroxymethyl)-2-phenylbutanoate. Figure 17B shows the ¹³ C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(hydroxymethyl)-2-phenylbutanoate.

Figure 18A shows the ¹ H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-cyclopropyl-2-(hydroxymethyl)-2-phenylpropanoate. Figure 18B shows the ¹³ C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-cyclopropyl-2-(hydroxymethyl)-2-phenylpropanoate.

Figure 19A shows the ¹ H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-fluoro-2-methyl-2-phenylpropanoate. Figure 19B shows the ¹³ C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-fluoro-2-methyl-2-phenylpropanoate.

Figure 20A shows ^{the 1} H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-4,4,4-trifluoro-2-(hydroxymethyl)-2 -phenylbutanoate. Figure 20B shows the ¹³ C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-4,4,4-trifluoro-2-(hydroxymethyl)-2 -phenylbutanoate.

Figure 21A shows ^{the 1} H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2,3-dihydroxy-2-phenylpropanoate. Figure 21B shows the ¹³ C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2,3-dihydroxy-2-phenylpropanoate.

Figure 22A shows the ¹ H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-methoxy-2-methyl-2-phenylpropanoate. Figure 22B shows the ¹³ C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-methoxy-2-methyl-2-phenylpropanoate.

Figure 23A shows ^{the 1} H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropanoate . Figure 23B shows the ¹³ C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropanoate .

Figure 24A shows ^{the 1} H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-chlorobenzyl)-2-phenylpropanoate . Figure 24B shows the ¹³ C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-chlorobenzyl)-2-phenylpropanoate .

Figure 25A shows ^{the 1} H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(2-chlorobenzyl)-2-phenylpropanoate . Figure 25B shows the ¹³ C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(2-chlorobenzyl)-2-phenylpropanoate .

Figure 26A shows the ¹ H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-hydroxybenzyl)-2-phenylpropanoate salts of formic acid. Figure 26B shows the ¹³ C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-hydroxybenzyl)-2-phenylpropanoate salts of formic acid.

Figure 27A shows ^{the 1} H NMR spectrum of 2-fluoro-3-hydroxy-N-((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2-phenylpropanamide . Figure 27B shows the ¹³ C NMR spectrum of 2-fluoro-3-hydroxy-N-((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2-phenylpropanamide .

Figure 28A shows ^{the 1} H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(4-fluorobenzyl)-3-hydroxy-2-phenylpropanoate . Figure 28B shows the ¹³ C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(4-fluorobenzyl)-3-hydroxy-2-phenylpropanoate .

Figure 29A shows ^{the 1} H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-methylbenzyl)-2-phenylpropanoate . Figure 29B shows the ¹³ C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-methylbenzyl)-2-phenylpropanoate .

Figure 30A shows ^{the 1} H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(3-chlorobenzyl)-3-hydroxy-2-phenylpropanoate . Figure 30B shows the ¹³ C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(3-chlorobenzyl)-3-hydroxy-2-phenylpropanoate .

Figure 31A shows ^{the 1} H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(3-chlorophenyl)-3-hydroxy-2-methylpropanoate . Figure 31B shows the ¹³ C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(3-chlorophenyl)-3-hydroxy-2-methylpropanoate .

Figure 32A shows ^{the 1} H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(4-chlorophenyl)-3-hydroxy-2-methylpropanoate . Figure 32B shows the ¹³ C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(4-chlorophenyl)-3-hydroxy-2-methylpropanoate .

Figure 33A shows ^{the 1} H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-hydroxyphenyl)-2-methylpropanoate . Figure 33B shows the ¹³ C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-hydroxyphenyl)-2-methylpropanoate .

Detailed description of the invention

The present invention relates to classes of compounds, each of which has an atropine or pirenzepine residue, and their pharmaceutically acceptable salts. In preferred embodiments, the present invention provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof:

Where

Me=CH ₃ ;

A=O or NR ₅ ;

W=N or CH;

X = -OH, -OYZ, -SYZ or -NR ₅ -YZ;

R ₁ and R ₂ independently represent substituents in the form of H, D, hydroxyl, alkoxy, nitrile, halogen atoms, straight, branched or cyclic C ₁ -C ₂₀ (preferably C ₁ -C ₁₀ )-alkyl groups, optionally substituted with halogen atoms ; or

R ₁ and R ₂ independently represent substituents in the form of phenyl or benzyl groups, optionally substituted with one or more substituents selected from straight, branched or cyclic C ₁ -C ₂₀ (preferably C ₁ -C ₁₀ )-alkyl groups, -haloalkyl groups , hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide, sulfonamide, and halogen atoms; or

R ₁ and R ₂ are independently substituted with a heterocyclic saturated, unsaturated or aromatic 5- or 6-membered ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur and optionally substituted with one or more substituents selected from straight, branched or cyclic C ₁ -C ₂₀ (preferably C ₁ -C ₁₀ )-alkyl, -haloalkyl groups, hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide or halogen atoms;

R ₃ and R ₄ are independently substituted with hydrogen, straight or branched or cyclic C ₁ -C ₁₀ -alkyl or -haloalkyl groups, or

R ₃ and R ₄ can be combined to form 3-6 membered rings;

R ₅ =H or straight or branched C ₁ -C ₂₀ alkyl groups, preferably C ₁ -C ₁₀ straight or branched C ₁ -C ₁₀ haloalkyl groups;

Y is a divalent radical having the following meaning:

straight or branched C ₁ -C ₂₀ (preferably C ₁ -C ₁₀ )-alkyl optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxyl atoms;

-C(O)(C ₁ -C ₁₀ alkyl)- or -C(O)(CH ₂ ) _n C(O)O-(C ₁ -C ₁₀ alkyl)- or -(C ₁ -C ₁₀ alkyl) -;

where n is an integer from 0 to 20;

R ⁶ and R ⁷ independently represent H or straight or branched C ₁ -C ₁₀ alkyl groups, straight or branched C ₁ -C ₁₀ haloalkyl groups; or

R ⁶ and R ⁷ can be combined to form 3-6 membered rings; And

Z is H, -OH, C _1-6 alkoxy, -COOH, -NR ⁸ R ⁹ ;

R ⁸ and R ⁹ independently represent substituents in the form of C ₁ -C ₂₀ -alkyl, preferably C ₁ -C ₁₀ optionally substituted with one or more substituents selected from hydroxyl, amino, ester, carboxylic acid and halogen atoms; or

R ⁸ and R ⁹ may be combined to form 3-6 membered rings containing one or more heteroatoms selected from the group consisting of:

In some embodiments, the compound of formula (I) is an atropine of formula (IA),

where Me, R ₁ and X are described above.

DEFINITIONS

Unless otherwise indicated, the term "compounds of the present invention" or "compound of the present invention" refers to compounds of formula (I) or its subformulas and illustrative compounds and their salts, as well as all stereoisomers (including diastereoisomers and enantiomers) , rotamers, tautomers, and isotopically labeled compounds (including deuterium substitutions), as well as initially formed fragments.

The expression "effective amount" of the compounds of the present invention, described below, refers to that amount of a therapeutic compound that is necessary or sufficient to carry out its intended function in a mammal, for example, treatment of a muscarinic receptor associated condition or disease state in a mammal. The effective amount of the therapeutic compound may vary according to factors such as the amount of the causative factor already present in the mammal, the age, sex and weight of the mammal, and the ability of the therapeutic compounds of the present invention to affect a muscarinic receptor-associated disorder in the mammal. One of ordinary skill in the art will be able to study the aforementioned factors and decide on an effective amount of a therapeutic compound without undue experimentation. An in vitro or in vivo assay may also be used to determine an "effective amount" of the therapeutic compounds described below. One skilled in the art will be able to select the appropriate amount of therapeutic compound to be used in the above assay or as a therapy.

The phrase "ophthalmologically compatible" is recognized in the art and refers to formulations, polymers, and other materials and/or dosage forms that are suitable for use in contact with human and animal ocular tissues without undue toxicity, irritation, allergic reaction, or other problems or complications. commensurate with a reasonable benefit/risk ratio as determined by a person skilled in the art.

Used in this document, the pharmaceutical composition is a composition suitable for use in pharmacy. A composition suitable for pharmaceutical use may be sterile, homogeneous and/or isotonic. Pharmaceutical compositions may be provided in certain embodiments in aqueous form, such as in a pre-filled syringe or other single or multiple dose container. In some embodiments, the pharmaceutical compositions of the present invention are ophthalmologically compatible and suitable for ophthalmic administration to a human subject, for example, via 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 administration by intravitreal infusion. In yet another embodiment, the pharmaceutical compositions are administered orally.

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 from about 1 to about 24 carbon atoms ("C ₁ -C ₂₄ "), from about 7 to about 24 carbon atoms ("C ₇ -C ₂₄ "), from about 8 to about 24 carbon atoms (" C ₈ -C ₂₄ ") or from about 9 to about 24 carbon atoms ("C ₉ -C ₂₄ "). Alkyl groups may also contain from about 1 to about 8 carbon atoms ("C ₁ -C ₈ "), from about 1 to about 6 carbon atoms ("C ₁ -C ₆ "), or from about 1 to about 3 carbon atoms ( "C ₁ -C ₃ "). Examples of C ₁ -C ₆ alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, and n-hexyl radicals.

As used herein, the term "C _2-6 alkenyl" refers to a group that is a straight or branched chain hydrocarbon radical, consisting only of carbon and hydrogen atoms, containing at least one double bond having two to six carbon atoms. , and which is attached to the rest of the molecule via a single bond. The terms "C ₂ -C ₂₀ alkenyl" and "C ₂ -C ₁₀ alkenyl" should be understood accordingly. Examples of C _2-6 alkenyl include, without limitation, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-4-enyl, and penta-1,4-dienyl.

As used herein, the term "C _2-6 alkynyl" refers to a group that is a straight or branched hydrocarbon chain radical, consisting only of carbon and hydrogen atoms, containing at least one triple bond having two to six carbon atoms. , and which is attached to the rest of the molecule via a single bond. The term "C _2-4 alkynyl" should be understood accordingly. Examples of C _2-6 alkynyl include, without limitation, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-4-ynyl, and penta-1,4-diynyl.

As used herein, the term "C _1-6 alkoxy" refers to a radical of the formula -OR _a , where R _a is a C _1-6 alkyl radical as defined above. Examples of C _1-6 alkoxy include, without limitation, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy.

"Halogen" refers to bromine, chlorine, fluorine or iodine.

As used herein, the term "heterocyclyl" or "heterocyclic" refers to a stable radical that is a 5- or 6-membered non-aromatic monocyclic ring that contains 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The heterocyclyl radical may be linked via a carbon atom or a heteroatom. Examples of heterocyclyl include, without limitation, azetidinyl, oxetanyl, pyrrolinyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, piperazinyl, tetrahydropyranyl, morpholinyl, or perhydroazepinyl.

As used herein, the term "heteroaryl" refers to a 5- or 6-membered aromatic monocyclic ring radical which contains 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The heteroaryl radical may be linked via a carbon atom or a heteroatom. Examples of heteroaryl include, without limitation, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl, or pyridyl.

In some embodiments, the present invention provides new pharmaceutical compositions, in particular, new pharmaceutical compositions, in which the active ingredient contains a muscarinic receptor modulator of general formula (I) or (II) and/or pharmaceutically acceptable salts thereof:

Where

Me=CH ₃ ;

A=O or NR ₅ ;

W=N or CH;

X = -OH, -OYZ, -SYZ or -NR ₅ -YZ;

R ₁ and R ₂ independently represent substituents in the form of H, D, hydroxyl, alkoxy, nitrile, halogen atoms, straight, branched or cyclic C ₁ -C ₂₀ (preferably C ₁ -C ₁₀ )-alkyl groups, optionally substituted with halogen atoms ; or

R ₁ and R ₂ independently represent substituents in the form of phenyl or benzyl groups, optionally substituted with one or more substituents selected from straight, branched or cyclic C ₁ -C ₂₀ (preferably C ₁ -C ₁₀ )-alkyl groups, -haloalkyl groups , hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide, sulfonamide, and halogen atoms; or

R ₁ and R ₂ are independently substituted with a heterocyclic saturated, unsaturated or aromatic 5- or 6-membered ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur and optionally substituted with one or more substituents selected from straight, branched or cyclic C ₁ -C ₂₀ (preferably C ₁ -C ₁₀ )-alkyl, -haloalkyl groups, hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide or halogen atoms;

R ₃ and R ₄ are independently substituted with hydrogen, straight or branched or cyclic C ₁ -C ₁₀ -alkyl or -haloalkyl groups, or

R ₃ and R ₄ can be combined to form 3-6 membered rings;

R ₅ =H or straight or branched C ₁ -C ₂₀ alkyl groups, preferably C ₁ -C ₁₀ straight or branched C ₁ -C ₁₀ haloalkyl groups;

Y is a divalent radical having the following meaning:

straight or branched C ₁ -C ₂₀ (preferably C ₁ -C ₁₀ )-alkyl optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxyl atoms;

-C(O)(C ₁ -C ₁₀ alkyl)- or -C(O)(CH ₂ ) _n C(O)O-(C ₁ -C ₁₀ alkyl)- or -(C ₁ -C ₁₀ alkyl) -;

where n is an integer from 0 to 20;

R ⁶ and R ⁷ independently represent H or straight or branched C ₁ -C ₁₀ alkyl groups, straight or branched C ₁ -C ₁₀ haloalkyl groups; or

R ⁶ and R ⁷ can be combined to form 3-6 membered rings; And

Z is H, -OH, C _1-6 alkoxy, -COOH, -NR ⁸ R ⁹ ;

R ⁸ and R ⁹ independently represent substituents in the form of C ₁ -C ₂₀ -alkyl, preferably C ₁ -C ₁₀ optionally substituted with one or more substituents selected from hydroxyl, amino, ester, carboxylic acid and halogen atoms; or

R ⁸ and R ⁹ may be combined to form 3-6 membered rings containing one or more heteroatoms selected from the group consisting of:

In some embodiments, the compound of formula (I) is an atropine of formula (IA),

where Me, R ₁ and X are described above.

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

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

(1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-methyl-3-hydroxy-2-phenylpropanoate,

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

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

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

(1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(hydroxymethyl)-2-phenylbutanoate,

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

(1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-fluoro-2-methyl-2-phenylpropanoate,

(1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-4,4,4-trifluoro-2-(hydroxymethyl)-2-phenylbutanoate,

(1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2,3-dihydroxy-2-phenylpropanoate,

(1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-methoxy-2-methyl-2-phenylpropanoate,

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

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

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

(1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-hydroxybenzyl)-2-phenylpropanoate salt of formic acid,

2-fluoro-3-hydroxy-N-((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2-phenylpropanamide,

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

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

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

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

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

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

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

Additional compounds of the present invention include the following:

The following paragraphs provide examples of compounds in accordance with the present invention.

Examples

Examples 1-3

NMR spectra were obtained on a Bruker 400 MHz spectrometer or a Bruker 300 MHz spectrometer.

The LCMS methods are detailed below (unless otherwise noted):

Standard LCMS way

Equipment Acquity H-Class (quaternary pump/PDA detector) + QDa mass spectrometer Column Acquity UPLC CSH C18 1.7 µm, 50 x 2.1 mm at 40°C Mobile phase A 0.1% aqueous formic acid (v/v) Mobile phase B 0.1% formic acid in acetonitrile (v/v) Consumption 1.0 ml/min. gradient program Time (minutes) %A %B 0.0 97 03 1.5 01 99 1.9 01 99 2.0 97 03 2.5 97 03 Sample Sample injection 1 µl (free access) Detectors UV detector with diode array 190-400 nm MS, mass detector 160-800 (or 60-800 for LM method or 300-1200 for HM method) in ES+ & ES-

QC LCMS method

Equipment Acquity UPLC (two-component pump/PDA detector) + ZQ mass spectrometer Column ACQUITY UPLC BEH C ₁₈ 1.7 µm, 100 x 2.1 mm maintained at 40°C Mobile phase A 0.1% aqueous formic acid (v/v) Mobile phase B 0.1% formic acid in acetonitrile (v/v) Consumption 0.4 ml/min. gradient program Time (minutes) %A %B 0.0 95 05 0.4 95 05 6.0 05 95 6.8 05 95 7.0 95 05 8.0 95 05 Sample Injection of 1 µl of a 0.2-0.5 mg/ml solution in a suitable solvent at 20°C Detectors UV detector with diode array 200-500 nm MS, mass detector 100-800 (or -1500 for the HM method) in ES+ & ES- (no MS split) Analysis data Peak area percentage (APCT) with 0.2% integration threshold (relative)

Abbreviations

DAST Diethylaminosulfur trifluoride

DCM Dichloromethane

DMF Dimethylformamide

k.t. Room temperature

Synthesis scheme according to example 1: ( 1R,3r,5S )-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-fluoro-3-hydroxy-2-phenylpropanoate

Ethyl 2-fluoro-2-phenylacetate

To a solution of ethyl mandelate (93 g, 0.52 mol) in DCM (1.5 L) at -78°C was added DAST (81.8 ml, 0.62 mol) at such a rate that T≤-60°C. The reaction mixture was stirred while warming to 0°C. After 1 h, the basicity of the reaction mixture was slowly raised with 1N HCl. NaOH to pH~7. The mixture was extracted with DCM. The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as a straw colored oil (62.4 g, 66%). The material was used without purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54-7.36 (5H, m), 5.77 (1H, d, J =47.3 Hz), 4.32-4.16 (2H, m), 1.26 (3H, t, J = 7.2 Hz). ¹ H NMR spectrum is shown in figure 1.

2-Fluoro-2-phenylacetic acid

To a solution of ethyl 2-fluoro-2-phenylacetate (32.4 g, 0.18 mol) in MeOH (100 ml) was added LiOH.H ₂ O (11.2 g, 0.27 mol) in water (15 ml ) and the reaction mixture was stirred at rt for 1 h (a slight exothermic effect was noted). The reaction mixture was diluted with ethyl acetate and acidified to ~pH 3 with 1N HCl. HCl. The product was extracted with ethyl acetate and the combined organics washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as a white solid (27.4 g, 100%). The material was used without purification.

¹ H NMR (400 MHz, d ₆ -DMSO) δ 13.47 (1H, br s), 7.48-7.37 (5H, m), 5.95 (1H, d, J =47.6 Hz ). ¹ H NMR spectrum is shown in figure 2.

2-Fluoro-2-phenylacetyl chloride

To a solution of 2-fluoro-2-phenylacetic acid (27.4 g, 0.18 mol) in DCM (250 ml) at RT was added 1 drop of DMF. Oxalyl chloride (23.3 mL, 0.27 mol) was added resulting in the evolution of gas bubbles. The reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated in vacuo to give the title compound as a straw-colored oil (30.1 g, 100%). The material was used without purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54-7.43 (5H, m), 5.90 (1H, d, 47.6 Hz). ¹ H NMR spectrum is shown in figure 3.

( 1R,3r,5S )-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-fluoro-2-phenylacetate

To a solution of tropine (27.1 g, 0.19 mol) in toluene (450 ml) was added 2-fluoro-2-phenylacetyl chloride (30.1 g, 0.17 mol) resulting in a precipitate. The reaction mixture was stirred at reflux for 1.5 hours. The reaction mixture was diluted with ethyl acetate and extracted with 1N HCl. HCl. Raise the basicity of the combined aqueous fractions to ~ pH 13 with 1N. NaOH and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as a straw colored oil which solidified on standing (33.5 g, 69%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.51-7.37 (5H, m), 5.73 (1H, d, J =47.9 Hz), 5.08 (1H, t, J = 5.3 Hz), 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 H NMR spectrum is shown in figure 4.

LCMS (ESI) [M+H] ⁺²⁷⁸ , _Rt =0.70 min.

( 1R,3r,5S )-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-fluoro-3-hydroxy-2-phenylpropanoate

To a solution of ( 1R,3r,5S )-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-fluoro-2-phenylacetate (33.5 g, 0.12 mol) in DMF (120 ml) paraformaldehyde (5.45 g, 0.18 mol) was added. To this suspension was added freshly prepared sodium ethoxide (140 mg sodium in 3.6 ml ethanol) which caused the solids to dissolve. The reaction mixture was stirred at 40°C for 5 min. The reaction mixture was diluted with ethyl acetate and extracted with 1N HCl. HCl and basified the combined aqueous fractions to ~pH 13 with 1N HCl. NaOH and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to ~ 1/5 of the volume at which the crystallization point of the product was reached. The solid was collected by filtration and dried in vacuo to give the title compound as a white solid (25.0 g, 67%). The stock solutions were concentrated in vacuo and triturated with ethyl acetate to give a second crop similar in purity to the first (2.92 g, 8%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54-7.48 (2H, m), 7.45-7.35 (3H, m), 5.09 (1H, t, J =5.2 Hz), 4.36 (1H, dd, J =29.2, 13.2 Hz), 4.04 (1H, dd, J =15.3, 12.9 Hz), 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 H NMR spectrum is shown in figure 5.

¹³ C NMR (400 MHz, CDCl ₃ ) δ 168.4, 134.8, 129.0, 128.7, 124.7, 97.5 (d, J =189 Hz), 69.8, 67.1 , 59.6, 40.4, 36.3, 25.3. ¹³ C NMR spectrum is shown in figure 6.

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

QC LCMS (ESI) [M+H] ^+308.2 , _Rt =2.28 min. (94.2%), purity > 99% according to NMR.

Synthesis scheme according to example 2: ( 1R,3r,5S )-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-methyl-3-hydroxy-2-phenylpropanoate

2-Methyl-2-phenylacetyl chloride

To a solution of 2-methyl-2-phenylacetic acid (7.65 g, 50.94 mmol) in DCM (60 ml) at RT was added 1 drop of DMF. Oxalyl chloride (8.9 ml, 0.102 mol) was added resulting in the evolution of gas bubbles. The reaction mixture was stirred at rt for 18 h, then concentrated in vacuo to give the title compound as a straw-colored oil (8.6 g, 100%). The material was used without purification.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.43-7.26 (5H, m), 4.12 (1H, quartet, J =7.1 Hz), 1.60 (3H, d, J = 7.1 Hz). ¹ H NMR spectrum is shown in figure 7.

( 1R,3r,5S )-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-methyl-2-phenylacetate

To a solution of tropine (6.5 g, 45.9 mmol) in toluene (40 ml) was added 2-methyl-2-phenylacetyl chloride (8.6 g, 51.0 mmol) resulting in a precipitate. The reaction mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated in vacuo and the residue triturated with diethyl ether, then the solids were filtered off to give a white solid. These solids were partitioned between H ₂ O and DCM, then raised basic to pH >10 using 1N HCl. NaOH and the product was extracted into DCM. The combined DCM extracts were washed with H ₂ O and brine, then passed through a phase separation cartridge and concentrated in vacuo to give the title compound as a straw colored oil (11.43 g, 81%).

¹ H NMR (300 MHz, CDCl ₃ ) 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 H NMR spectrum is shown in figure 8.

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

( 1R,3r,5S )-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-methyl-3-hydroxy-2-phenylpropanoate

To a solution of ( 1R,3r,5S )-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-methyl-2-phenylacetate (12.4 g, 45.36 mmol) in DMF (15 ml) paraformaldehyde (2.04 g, 68.04 mmol) was added. Freshly prepared sodium ethoxide (52 mg sodium in 1.0 ml ethanol) was added to this suspension, which caused the solids to dissolve. The reaction mixture was stirred at rt. for 4 hours and then divided between H ₂ O and DCM. The combined DCM extracts were washed with H ₂ O and brine, then passed through a phase separation cartridge and concentrated in vacuo . The resulting oil was triturated with diethyl ether, causing the product to crystallize. The solid was collected by filtration and dried in vacuo to give the title compound as a white solid (10.5 g, 76%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38-7.25 (5H, m), 5.06 (1H, t, J =4.1 Hz), 4.12 (1H, dd, J = 8.5, 4.2 Hz), 3.62 (1H, dd, J =8.7, 6.0 Hz), 3.04-2.89 (2H, m), 2.55 (1H, t , J = 5.2 Hz), 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 H NMR spectrum is shown in Figure 9.

¹³ C NMR (400 MHz, CDCl ₃ ) 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 ¹³ C NMR spectrum is shown in Figure 10.

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

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

Synthesis scheme according to example 3: ( 1R,3r,5S )-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-benzyl-3-hydroxy-2-phenylpropanoate

2,3-Diphenylpropanoyl chloride

DMF (0.10 ml) was added to a solution of 2,3-diphenylpropanoic acid (16.0 g, 70.71 mmol) in DCM (80 ml) at rt and the mixture was cooled in an ice bath. Oxalyl chloride (12.3 ml, 141.42 mmol) was added resulting in the evolution of gas bubbles and the cooling bath was removed. The reaction mixture was stirred at rt for 18 h, then concentrated in vacuo to give the title compound as a straw-colored oil (17.3 g, 100%). The material was used without purification.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.33-7.07 (10H, m), 3.86 (1H, dd, J =7.0, 8.4 Hz), 3.41 (1H, dd, J =13.8, 8.4 Hz), 3.03 (1H, dd, J =13.8, 7.0 Hz). ¹ H NMR spectrum is shown in Figure 11.

( 1R,3r,5S )-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2,3-diphenylpropanoate

To a solution of tropine (9.49 g, 70.71 mmol) in toluene (70 ml) was added 2,3-diphenylpropanoyl chloride (17.30 g, 70.71 mmol) resulting in a precipitate. The reaction mixture was stirred at reflux for 2 hours, then concentrated in vacuo . The residue was triturated with diethyl ether and the solids were filtered off to give a white solid. This solid was partitioned between H ₂ O and DCM, basified to pH >10 using 1N HCl. NaOH solution and the product was extracted into DCM. The DCM extracts were washed with H ₂ O and brine, then passed through a phase separation cartridge and concentrated in vacuo to give the title compound as a straw colored oil (22.4 g, 90%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.35-7.11 (10H, m), 4.90 (1H, t, J =5.4 Hz), 3.79 (1H, dd, J = 6.5, 9.0 Hz), 3.43 (1H, dd, J =13.5, 9.0 Hz), 3.03 (1H, dd, J =13.5, 6.5 Hz), 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 H NMR spectrum is shown in Figure 12.

LCMS (ESI) [M+H] ⁺³⁵⁰ , _Rt =0.98 min.

( 1R,3r,5S )-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-benzyl-3-hydroxy-2-phenylpropanoate

To a solution of ( 1R,3r,5S )-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2,3-diphenylpropanoate (22.40 g, 64.10 mmol) in DMF (30 ml) paraformaldehyde (3.27 g, 108.96 mmol) was added. To this suspension was added freshly prepared sodium ethoxide (74 mg sodium in 1.3 ml ethanol) which caused the solids to dissolve. The reaction mixture was stirred at RT for 3 hours before H ₂ O was added. The precipitate was filtered off, washed with H ₂ O and dried in vacuo to remove most of the H ₂ O. The resulting "wet" solid the material was partitioned between MeOH and DCM and the phases were separated. The DCM extract was dried (MgSO ₄ ), filtered and concentrated in vacuo resulting in product crystallization . The precipitate was filtered off and dried in vacuo to give the title compound as a white solid (18.18 g, 75%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39-7.16 (8H, m), 7.05-6.97 (2H, m), 5.09 (1H, t, J =5.3 Hz), 4.12-3.95(2H, m), 3.54-3.42(2H, m), 3.02-2.90(2H, m), 2.19(3H, s) , 2.15-2.00(2H, m), 1.84-1.58(4H, m), 1.54-1.41(2H, m), 1.28-1.19(1H, m). ¹ H NMR spectrum is shown in Figure 13.

¹³ C NMR (400 MHz, CDCl ₃ ) δ 173.3, 139.9, 136.7, 130.5, 128.7, 128.1, 127.4, 126.8, 126.7, 68.1 , 63.9, 59.5 (x2 signal), 56.5, 40.4, 38.9, 36.5, 36.4, 25.2, 25.0 rings, therefore, 20 signals are observed, and not 17). ¹³ C NMR spectrum is shown in Figure 14.

LCMS (ESI) [M+H] ⁺³⁸⁰ , _Rt =0.90 min.

QC LCMS (ESI) [M+H] ^+380.3 , _Rt =3.19 min. (99.2%)

Synthesis scheme according to example 4: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-methyl-2-(thiophen-2-yl)propanoate

Ethyl-2-(thiophen-2-yl)propanoate

To a solution of diisopropylamine (4.5 ml, 32.3 mmol) in THF (100 ml) at -40°C was added dropwise n-BuLi (12.9 ml, 2.5 M, 32.3 mmol). The reaction mixture was stirred at -40°C for 20 minutes, then cooled to -78°C. Ethyl-2-(thiophen-2-yl)acetate (5 g, 29.4 mmol) was added dropwise at such a rate that T < -60°C. The reaction mixture was stirred at -78°C for 30 min., then warmed to 0°C. Methyl iodide (2.2 ml, 35.3 mmol) was added and the reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo . The resulting residue was purified on silica (80 g, 0-50% ethyl acetate in cyclohexane) to give the title compound as a pale brown oil (3.3 g, 62%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.20 (1H, t, J =3.4 Hz), 6.95 (2H, d, J =3.4 Hz), 4.22-4.12 (2H, m), 3.99 (1H, q, J = 7.2 Hz), 1.58 (3H, d, J = 7.1 Hz), 1.30-1.19 (3H, m) .

2-(Thiophen-2-yl) propanoic acid

To a solution of ethyl 2-(thiophen-2-yl)propanoate (5.9 g, 32.39 mmol) in methanol (40 ml) and water (15 ml) was added lithium hydroxide monohydrate (2.0 g, 48.4 mmol) and the reaction mixture was stirred at room temperature. over 3 hours. The reaction mixture was concentrated in vacuo to about ¼ volume and the residue was extracted with EtOAc. The organic fractions were discarded and the aqueous layer was acidified to ~pH 3 with 1N HCl. HCl and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as a yellow oil (5.0 g, 100%). ¹ H NMR (400 MHz, d ₆ -DMSO) δ 7.26 (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).

2-(Thiophen-2-yl)propanoyl chloride

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

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(thiophen-2-yl)propanoate

To a solution of 2-(thiophen-2-yl)propanoyl chloride (2.2 g, 12.6 mmol) in toluene (20 ml) was added tropine (1.62 g, 11.5 mmol) and the reaction mixture was heated at 100°C for 2 hours. The reaction mixture was diluted with EtOAc and extracted with 1N. HCl and the organic fraction were discarded. Raise the basicity of the aqueous phase to ~ pH 12 with 6 N. NaOH and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as a brown oil which was used crude in the next reaction (2.29 g, 71%). LCMS (ESI) [M+H] ⁺ 280, R _t =0.72 min.

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-methyl-2-(thiophen-2-yl)propanoate

To a suspension of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(thiophen-2-yl)propanoate (1.3 g, 4.7 mmol) and paraformaldehyde (0.21 g, 6.9 mmol) in DMF (10 ml) was added a solution of sodium ethoxide in ethanol (0.11 ml, 21%, 0.2 mmol) and the reaction mixture was stirred at RT for 10 min. The reaction mixture was diluted with EtOAc and extracted with 1N HCl. HCl. The organic fractions were discarded. The basicity of the aqueous fraction was raised to ~pH 12 with 1N HCl. NaOH and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as an off-white solid (760 mg, 52%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.24 (1H, dd, J =4.6, 1.4 Hz), 7.02-6.98 (2H, m), 5.03 (1H, t, J = 5.54 Hz), 4.13 (1H, d, J = 11.3 Hz), 3.74 (1H, d, J = 11.3 Hz), 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 ). ¹ H NMR and ¹³ C NMR spectra for the title compound are shown in Figure 15A and Figure 15B, respectively.

LCMS (ESI) [M+H] ⁺ 310, R _t =2.40 min.

Synthesis scheme according to example 5: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(hydroxymethyl)-2-phenylpropanoate

Sodium ethoxide in ethanol (0.08 ml, 21% , 0.22 mmol) and the reaction mixture was stirred at 0°C for 5 min., then at RT for 1 h. The reaction mixture was filtered through celite and the filtrate was purified on silica (24 g, 0-40% (2N NH ₃ in MeOH) in DCM). Half of the resulting material was repurified on C18 with silica (50 g, 0-50% 0.02 M NH ₃ in MeCN) to give the title compound as an off-white solid (1.19 g, 67%). ¹ H NMR (400 MHz, d ₆ -DMSO) δ 7.35-7.27 (2H, m), 7.26-7.14 (3H, m), 4.88 (1H, t, J =5 .1 Hz), 4.74 (1H, t, J =4.62 Hz), 4.06 (2H, dd, J =10.2, 4.9 Hz), 3.97 (2H, dd, J =10.2, 4.7 Hz), 3.35(1H, s), 2.92-2.83(2H, m), 2.07(3H, s), 1.92(2H, dt, J = 14.4, 4.1 Hz), 1.75-1.60 (2H, m), 1.50-1.36 (4H, m). LCMS (ESI) [M+H] ⁺ 320, R _t =1.96 min. ¹ H NMR and ¹³ C NMR spectra for the title compound are shown in Figures 16A and 16B, respectively.

Synthesis scheme according to example 6: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(hydroxymethyl)-2-phenylbutanoate

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-phenylbutanoate

To a solution of 2-phenylbutyric acid (2.0 g, 12.2 mmol) in DCM (20 ml) at 0°C was added oxalyl chloride (2.1 ml, 24.4 mmol) and DMF (0.06 ml, 0. 7 mmol). The reaction mixture was stirred at 0° C. for 30 min., then at RT for 16 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in toluene (10 ml). This solution was added to a solution of tropine (1.7 g, 12.18 mmol) in toluene (20 mL) and the reaction mixture was stirred at rt for 10 min, then refluxed for 2 h. The reaction mixture was concentrated in vacuo and the residue was collected by filtration and washed with diethyl ether. The solid was dissolved in 1N. NaOH and extracted with DCM. The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as a colorless oil (1.76 g, 50%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35-7.21 (5H, m), 4.96 (1H, t, J =5.1 Hz), 3.41, (1H, t, J = 7.8 Hz), 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 = 7.4 Hz). LCMS (ESI) [M+H] ⁺ 288, R _t =0.84 min.

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(hydroxymethyl)-2-phenylbutanoate

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

Synthesis scheme according to example 7: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-cyclopropyl-2-(hydroxymethyl)-2-phenylpropanoate

Methyl 3-cyclopropyl-2-phenylpropanoate

To a solution of methyl 2-phenylacetate (2 g, 13.3 mmol) in THF (50 ml) at -78°C was added LDA (7.3 ml, 2 M, 14.6 mmol) at such a rate that T < -60°C. The reaction mixture was stirred at -78°C for 1 h. (iodomethyl)cyclopropane (5 g, 27.5 mmol) in THF (10 ml) was added dropwise and the reaction mixture was stirred at -78°C for 30 min. then heated to rt 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 (MgSO ₄ ) and concentrated in vacuo. The residue was purified on silica (40 g, 0-100% DCM in cyclohexane) to give the title compound as a yellow oil (2.6 g, 95%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35-7.20 (5H, m), 3.71-3.64 (4H, m), 1.94-1.84 (1H, m), 1.78-1.69 (1H, m), 0.67-0.56 (1H, m), 0.46-0.34 (2H, m), 0.13-0.00 (2H, m ).

3-Cyclopropyl-2-phenylpropanoic acid

To a solution of methyl 3-cyclopropyl-2-phenylpropanoate (2.59 g, 12.7 mmol) in methanol (100 ml) and water (15 ml) was added lithium hydroxide monohydrate (1.33 g, 31.7 mmol) and the reaction mixture was stirred at RT for 16 h. HCl to ~pH 1 and the mixture was extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as a yellow oil (2.44 g, 100%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37-7.21 (5H, m), 3.67 (1H, t, J =8.0 Hz), 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).

3-Cyclopropyl-2-phenylpropanoyl chloride

To a solution of 3-cyclopropyl-2-phenylpropanoic acid (2.44 g, 12.8 mmol) in DCM (100 ml) was added DMF (0.01 ml) and oxalyl chloride (1.7 ml, 19.2 mmol) and the reaction the mixture was stirred at RT for 3 h. The reaction mixture was concentrated in vacuo to give the title compound as a pale yellow oil (2.68 g, 100%), used without purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.27 (5H, m), 4.10 (1H, t, J =7.3 Hz), 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).

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-3-cyclopropyl-2-phenylpropanoate

To a solution of tropine (2.68 g, 18.9 mmol) in toluene (20 mL) was added 3-cyclopropyl-2-phenylpropanoyl chloride (4.36 g, 20.8 mmol) and the reaction mixture was refluxed for 1 5 hours. The reaction mixture was extracted with 1N. HCl and the organic fraction were discarded. The basicity of the aqueous fraction was raised to ~pH 12 with 6N sodium hydroxide. NaOH and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as a yellow oil (1.76 g, 50%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35-7.20 (5H, m), 4.96 (1H, t, J =5.2 Hz), 3.63 (1H, t, J = 7.4 Hz), 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).

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-3-cyclopropyl-2-(hydroxymethyl)-2-phenylpropanoate

Into a suspension of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-cyclopropyl-2-phenylpropanoate (1.76 g, 5.62 mmol) and paraformaldehyde (0 .25 g, 8.42 mmol) in DMF was added sodium ethoxide in ethanol (0.07 ml, 4 M, 1.12 mmol) and the reaction mixture was stirred at 40°C for 3 hours. An additional portion of sodium ethoxide (0 07 ml, 4 M, 1.12 mmol) and the reaction mixture was stirred at 40°C for 16 h. HCl. The organic fraction was discarded and the aqueous fraction was made basic to ~pH 12 with 6N HCl. NaOH. The mixture was extracted with EtOAc and the combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo . The resulting residue was purified on silica (40 g, 0-10% (7N NH ₃ in MeOH) in DCM) to give the title compound as an off-white solid (0.23 g, 12%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39-7.22 (5H, m), 5.08 (1H, t, J =5.48 Hz), 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. ¹ H NMR and ¹³ C NMR spectra for the title compound are shown in Figures 18A and 18B, respectively.

Synthesis scheme according to example 8: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-fluoro-2-methyl-2-phenylpropanoate

To a solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-methyl-2-phenylpropanoate (392 mg, 1.29 mmol) in DCM DAST (0.51 mL, 3.9 mmol) was added at 0° C. and the reaction mixture was stirred at rt for 48 h. The reaction mixture was diluted with sat. aq. Na ₂ CO ₃ solution and extracted with DCM. The combined organic fractions were dried (Na ₂ SO ₄ ) and concentrated in vacuo . The resulting precipitate was purified on silica (4 g, 0-12% (2N NH ₃ in MeOH) in DCM). The resulting residue was then purified with SFC (YMC Amylose-C, 15% MeOH+0.1% Et ₂ NH) to give the title compound as a pale yellow oil (26 mg, 6%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39-7.27 (5H, m), 5.06 (1H, t, J =5.4 Hz), 4.97 (1H, dd, J = 47.0, 8.7 Hz), 4.55 (1H, dd, J =47.0, 8.7 Hz), 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 =2.1 Hz), 1.66-1, 49 (4H, m). LCMS (ESI) [M+H] ⁺ 306, R _t =3.10 min. ¹ H NMR and ¹³ C NMR spectra for the title compound are shown in Figures 19A and 19B, respectively.

Synthesis scheme according to example 9: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-4,4,4-trifluoro-2-(hydroxymethyl)-2-phenylbutanoate

4,4,4-Trifluoro-2-phenylbutanoyl chloride

Oxalyl chloride (0.33 ml, 3 .8 mmol) and the reaction mixture was stirred at 0° C. for 1 h before stirring at RT for 16 h. The reaction mixture was concentrated in vacuo to give the product as a yellow oil (445 mg, 100%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47-7.36 (3H, m), 7.33-7.27 (2H, m), 4.29 (1H, dd, J =10.2 , 7.3 Hz), 3.24-3.05 (1H, m), 2.65-2.46 (1H, m).

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-4,4,4-trifluoro-2-phenylbutanoate

To a solution of tropine (236 mg, 1.7 mmol) in toluene (7 ml) was added 4,4,4-trifluoro-2-phenylbutanoyl chloride (445 mg, 1.9 mmol) in toluene (3 ml) and the reaction mixture was heated with reflux for 3 hours. The reaction mixture was concentrated in vacuo and the residue was triturated with diethyl ether. The solid was dissolved in 1N. NaOH and extracted with DCM. The combined organic fractions were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound as a yellow solid (390 mg, 61%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40-7.24 (5H, m), 4.97 (1H, t, J =5.5 Hz), 3.83 (1H, dd, J = 8.7, 5.4 Hz), 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 =0.88 min.

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-4,4,4-trifluoro-2-(hydroxymethyl)-2-phenylbutanoate

To a suspension of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-4,4,4-trifluoro-2-phenylbutanoate (390 mg, 1.1 mmol) and paraformaldehyde (51 mg, 1.7 mmol) in DMF (3 ml) was added sodium ethoxide in ethanol (0.3 ml, 0.2 M, 0.06 mmol) and the reaction mixture was stirred at rt for 2 h. More paraformaldehyde (40 mg, 1.3 mmol) and sodium ethoxide in ethanol (0.15 mL, 1.5 M, 0.2 mmol) were added and the reaction mixture was stirred at rt for 16 h. diluted with water, extracted with DCM and the combined organic fractions were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo . The resulting residue was purified on silica (12 g, 0-10% (2N NH ₃ in MeOH) in DCM) to give the title compound as a white solid (105 mg, 24%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44-7.23 (5H, m), 5.09 (1H, t, J =5.4 Hz), 4.31 (2H, br s), 3.17-3.03(2H, m), 3.02-2.93(2H, m), 2.19(3H, s), 2.12-2.03(2H, m), 1, 88-1.69(3H, m), 1.64-1.48(2H, m), 1.42-1.23(2H, m). LCMS (ESI) [M+H] ⁺ 372, R _t = 2.95 min. ¹ H NMR and ¹³ C NMR spectra for the title compound are shown in Figures 20A and 20B, respectively.

Synthesis scheme according to example 10: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2,3-dihydroxy-2-phenylpropanoate

A solution of AD-mix-alpha (1.3 g) in a mixture of water (5.0 ml) and t -butanol (5 ml) was stirred at room temperature for 15 minutes. to obtain a clear yellow solution, which was cooled with an ice bath to about 0°C. A solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-phenylacrylate (250 mg, 0.921 mmol) in t -butanol (1.0 ml) was added and the resulting the solution was stirred at 0° C. for 3 hours, then allowed to warm to rt overnight. The reaction mixture was treated with excess Na ₂ SO ₃ 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 (Na ₂ SO ₄ ) and concentrated in vacuo . The resulting residue was purified on silica (12 g, 0-10% (2N NH ₃ in MeOH) in DCM) to give enantiomerically enriched (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1] octan-3-yl-2,3-dihydroxy-2-phenylpropanoate gum (110 mg, 39%).

In a separate procedure, a solution of AD-mix-beta (1.3 g) in a mixture of water (5.0 ml) and t -butanol (5 ml) was stirred at room temperature for 15 minutes. to obtain a clear yellow solution, which was cooled with an ice bath to about 0°C. A solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-phenylacrylate (250 mg, 0.921 mmol) in t -butanol (1.0 ml) was added and the resulting the solution was stirred at 0° C. for 3 hours, then allowed to warm to rt overnight. The reaction mixture was treated with excess Na ₂ SO ₃ 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 (Na ₂ SO ₄ ) and concentrated in vacuo . The resulting residue was purified on silica (12 g, 0-10% (2N NH ₃ in MeOH) in DCM) to give enantiomerically enriched (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1] octan-3-yl-2,3-dihydroxy-2-phenylpropanoate enriched in opposite enantiomers as gum (126 mg, 45%).

A portion of the reaction product AD-mix-alpha (95 mg, 0.311 mmol) was dissolved in acetonitrile (1 ml) to give a clear solution. Similarly, part of the reaction product AD-mix-beta (95 mg, 0.311 mmol) was separately dissolved in acetonitrile (1.0 ml) also to obtain a clear solution. The two solutions enriched in opposite enantiomers were then combined, diluted with water (2.0 ml) and freeze-dried to give the racemic title compound as a white solid (190 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.60-7.53 (2H, m), 7.42-7.30 (3H, m), 5.06 (1H, t, J =5.5 Hz), 4.32 (1H, d, J =11.5 Hz), 4.16 (1H, br s), 3.82 (1H, d, J =11.5 Hz), 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. ¹ H NMR and ¹³ C NMR spectra for the title compound are shown in Figures 21A and 21B, respectively.

Synthesis scheme according to example 11: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-methoxy-2-methyl-2-phenylpropanoate

tert -Butyl-(1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate

A stirred solution of nortropine (12.72 g, 100 mmol) in DCM (150 ml) was treated with triethylamine (27.9 ml, 20.24 g, 200 mmol) and cooled on ice. Solid di- tert -butyl dicarbonate (32.74 g, 150.0 mmol) was then added over 10 minutes. and the addition vessel was washed with DCM (50 ml). Excessive gas evolution was observed and the resulting mixture was stirred for 2 h while warming to rt and then at rt for 16 h. The resulting mixture was diluted with DCM (100 mL), washed with 10% citric acid (aq.), saline (50 ml) and the layers are separated. The combined organic fractions were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a cream colored solid. The solid residue was triturated with diethyl ether (30 ml) and sonicated to give a free flowing solid which was collected by filtration, 19.67 g (86%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.29-4.06 (3H, m), 2.26-1.87 (6H, m), 1.75-1.65 (2H, m), 1.55 (1H, d, J =1.5 Hz), 1.45 (9H, s). LCMS (ESI) [M+H] ⁺ not observed, R _t =1.21 min.

tert -Butyl-(1R,3r,5S)-3-((2-phenylpropanoyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate

A solution of 2-phenylpropionyl chloride (8.20 g, 48.63 mmol) in toluene (50 ml) was added to a stirred mixture of tert -butyl-(1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane -8-carboxylate (10.05 g, 44.21 mmol) and triethylamine (12.3 ml, 8.95 g, 88.42 mmol) in toluene (50 ml). The resulting slurry was refluxed with vigorous stirring for 24 hours to give the product as an off-white slurry. The reaction mixture was cooled to rt and diluted with EtOAc (100 ml) and H ₂ O (100 ml). The aqueous layer was separated and further extracted with EtOAc (2×100 ml). The combined extracts were washed with 5% citric acid solution (aq.), sat. NaHCO ₃ (aq) and brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo . This provided the title compound (16.21 g, 102%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37-7.22 (5H, m), 5.06 (1H, t, J =5 Hz), 4.24-3.90 (2H, m) , 3.68 (1H, q, J = 7 Hz), 2.23-1.90 (2H, m), 1.86-1.57 (5H, m), 1.54-1.46 (1H , m), 1.52 (3H, d, J = 7 Hz), 1.43 (9H, s), 1.38-1.27 (1H, m). LCMS (ESI) [M+H] ⁺ not observed, R _t =1.98 min.

tert -Butyl-(1R,3r,5S)-3-((3-hydroxy-2-methyl-2-phenylpropanoyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate

A stirred suspension of tert -butyl-(1R,3r,5S)-3-((2-phenylpropanoyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (7.19 g, 20.0 mmol) in DMF (15 mL) was treated with paraformaldehyde (0.90 g, 30 mmol) followed by 21% sodium ethoxide solution (0.37 mL, 1.00 mmol) and stirred at rt for 18 h. % sodium ethoxide solution (0.37 ml, 1.00 mmol) and continued stirring for an additional 2 hours. LCMS showed a shifted peak, but no mass of the ion. The reaction mixture was diluted with DCM (200 ml), washed with water and brine. The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the crude product as a yellow oil. The residue was purified on silica (120 g, 0-50% EtOAc in cyclohexane) to give the title compound as a white solid (5.29 g, 68%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39-7.24 (5H, m), 5.16 (1H, t, J =5 Hz), 4.14 (1H, dd, J =6, 11 Hz), 4.19-3.89 (2H, m), 3.62 (1H, dd, J =8.11 Hz), 2.43 (1H, dd, J =6.8 Hz), 2 .29-1.91(2H, m), 1.84-1.70(1H, m), 1.70(3H, s), 1.70-1.46(4H, m), 1.43 (9H, s), 1.25-1.08 (1H, m). LCMS (ESI) [M+H-Boc] ⁺ 290, R _t =1.60 min.

tert -Butyl-(1R,3r,5S)-3-((3-methoxy-2-methyl-2-phenylpropanoyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate

A stirred suspension of sodium hydroxide (0.24 g, 60%, 6.01 mmol) in dry THF (10 ml) was cooled to 0°C and a solution oftert-butyl-(1R,3r,5S)-3-((3-hydroxy-2-methyl-2-phenylpropanoyl)oxy)-8-azabicyclo[3.2.1]-octane-8-carboxylate (1.95 g, 5.01 mmol) in dry THF (10 ml). The resulting mixture was stirred for 1 hour at 0° C. and then the reaction mixture was cooled to -6° C. and methyl iodide (0.34 ml, 5.5 mmol) was added. The mixture was allowed to warm slowly to rt over 3 hours. The reaction mixture was quenched by adding aq. NH₄Cl (20 ml) and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na₂SO₄) and concentratedin vacuo. The residue was purified on silica (80 g, 0-25% EtOAc in cyclohexane) to give the title compound as a colorless syrup, (1.54 g, 76%).¹H NMR (400 MHz, CDCl₃)δ 7.37-7.21(5H, m), 5.12(1H, t,J= 5.3 Hz), 4.19-3.94 (2H, m), 3.99 (1H, d,J= 8.7 Hz), 3.62 (1H, d,J= 8.7 Hz), 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=1.81 min.

(1R,3r,5S)-8-Azabicyclo[3.2.1]octan-3-yl-3-methoxy-2-methyl-2-phenylpropanoate hydrochloride

To a stirred solution of tert -butyl-(1R,3r,5S)-3-((3-methoxy-2-methyl-2-phenylpropanoyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (1, 10 g, 2.73 mmol) in dioxane (2.0 ml) was added 4N. HCl solution in dioxane (2.0 ml) and the reaction mixture was stirred at RT for 20 h. The reaction mixture was concentrated in vacuo to give the crude product as a colorless syrup (1.18 g, 100%), which was used without cleaning. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.47 (2H, br s), 7.38-7.21 (5H, m), 5.10 (1H, t, J =4.5 Hz), 3.99 (1H, d, J = 8.7 Hz), 3.93-3.83 (2H, m), 3.60 (1H, d, J = 8.7 Hz), 3.37 (3H , s), 2.59-2.45(2H, m), 2.04-1.54(6H, m), 1.64(3H, s). LCMS (ESI) [M+H] ⁺ 304, R _t =1.52 min.

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-3-methoxy-2-methyl-2-phenylpropanoate

Crude (1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl-3-methoxy-2-methyl-2-phenylpropanoate hydrochloride (1.18 g, 2.73 mmol) was dissolved in formic acid (4.0 ml) and treated with 37% formaldehyde solution (0.81 ml, 10.9 mmol) and the reaction mixture was heated under reflux for 17 hours. The reaction mixture was cooled to rt and loaded into an SCX cartridge -2 (50 g) pre-moistened with DCM. The cartridge was washed with DCM (400 ml), MeOH (200 ml) and the product was eluted with 2 M NH ₃ in MeOH (200 ml). The main eluent was concentrated in vacuo . And the residue was purified by HPLC on a Kinetix Axia C18 RP (long) column using 5-50% CH ₃ CN in H ₂ O (0.1% HCOOH) at 18 ml/min. with a linear temperature change for 10 minutes, UV radiation at 194 nm. The appropriate fractions were combined and freeze dried to give the product as a colorless syrup (415 mg, 48%) containing 0.75 eq. formate, 0.25 equiv. DCM. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37-7.24 (5H, m), 5.09 (1H, t, J =5.1 Hz), 3.99 (1H, d, J = 8.7 Hz), 3.62 (1H, d, J = 8.7 Hz), 3.49-3.42 (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. ¹ H NMR and ¹³ C NMR spectra for the title compound are shown in Figures 22A and 22B, respectively.

Synthesis scheme according to example 12: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropanoate

Methyl 3-(4-methoxyphenyl)-2-phenylpropanoate

Addedtert-potassium-butoxide (2.15 g, 19.16 mmol) to a stirred solution of methylphenylacetate (2.00 g, 13.32 mmol) in dry THF (20 ml) at 0°C. After stirring for 15 min. a solution of 4-methoxybenzyl bromide in dry THF (10 ml) was added dropwise maintaining T ≤ 5°C. The resulting mixture was stirred for 10 minutes. before providing it with heating to rt during the night. The resulting mixture was diluted with EtOAc (150 ml), washed with H₂O (50 ml) followed by brine (50 ml) and the layers were separated. The organic layer was dried (Na₂SO₄) and concentratedin vacuo. The residue was purified on silica (25 g 0-50% EtOAc in cyclohexane to give the title compound as a crude pale yellow oil (1.0 g, 27%), which was used without further purification.¹H NMR (400 MHz, CDCl₃)δ 7.30 (4H, d,J=4.2 Hz), 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).

3-(4-Methoxyphenyl)-2-phenylpropanoic acid

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

3-(4-Methoxyphenyl)-2-phenylpropanoyl chloride

A stirred solution of 3-(4-methoxyphenyl)-2-phenylpropanoic acid (450 mg, 1.76 mmol) in DCM (5.0 ml) containing DMF (10 μl) was treated dropwise at 0°C with oxalyl chloride ( 200 µl, 2.29 mmol). The resulting mixture was stirred at 0°C for 10 min. and then allowed to warm to rt and stirred for 18 h. The reaction mixture was concentrated in vacuo and the crude product was azeotropically distilled with toluene (2 x 10 mL) to give the title crude compound (483 mg, 100%) . Applied directly without purification.

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-3-(4-methoxyphenyl)-2-phenylpropanoate

The crude 3-(4-methoxyphenyl)-2-phenylpropanoyl chloride (483 mg, 1.76 mmol) was stirred in dry toluene (5 ml) with tropine (248 mg, 1.76 mmol) at 100°C for 3 h. the mixture was concentratedin vacuo. The residue was treated with DCM (30 ml) and H₂O (20 ml) and increased basicity to pH 10 with 1N. NaOH (aq.). The organic layer was separated, washed with brine, dried (MgSO₄) and concentratedin vacuo. The resulting residue was purified on silica (12 g 0-10% MeOH in DCM) to give the title compound as a light brown oil (277 mg, 41%). ¹H NMR (400 MHz, 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, 5.2 Hz, 1H), 3.77-3.76 (m, 3H), 3.37 (dd,J=9.0, 13.8 Hz, 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 0.99 min, 380.1 (M+H)⁺.

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropanoate

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-3-(4-methoxyphenyl)-2-phenylpropanoate (200 mg, 0.53 mmol) in DMF (3 ml) was treated with paraformaldehyde (160 mg, 5.33 mmol), then 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 celite. The filtrate was concentrated in vacuo to volume reduction and purified on silica (12 g, 0-10% MeOH in DCM) to give the title compound as a white solid (187 mg, 86%). ¹H NMR (400 MHz, 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, 5.3 Hz), 4.08-3.96 (2H, 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 3.30 min., 410.0 (M+H) ⁺ . ¹ H NMR and ¹³ C NMR spectra for the title compound are shown in Figures 23A and 23B, respectively.

Synthesis scheme according to example 13: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-chlorobenzyl)-2-phenylpropanoate

3-(4-Chlorophenyl)-2-phenylpropanoic acid

n -Butyllithium (2.5 M solution in hexanes, 15.3 ml, 38.3 mmol) was added dropwise under nitrogen atmosphere to a cooled solution of N,N -diisopropylamine (5.6 ml, 40.0 mmol) in dry THF (20 ml) maintaining T ≤ 0°C. The resulting LDA solution was stirred for 20 minutes, then cooled with a dry ice/acetone bath to -78°C. A solution of methylphenylacetate (5.0 g, 33.3 mmol) in dry THF (20 ml) was added dropwise via syringe maintaining T ≤ -55°C. After stirring for 2 hours, a solution of 4-chlorobenzyl bromide (4.8 ml, 36.6 mmol) in dry THF (10 ml) was added and the resulting mixture was stirred overnight with warming to rt. The mixture was diluted with EtOAc ( 100 ml) and water (50 ml) and the aqueous layer was separated and further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo and the residue was dissolved in a mixture of methanol (20 ml) and THF (100 ml) and aqueous sodium hydroxide solution (2 M, 35 ml, 70 mmol). The resulting opaque solution was stirred for 22 hours then concentrated in vacuo. The residue was partitioned between hydrochloric acid (1N, 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 (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound as an off-white solid (8.62 g, 99%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.35-7.24 (5H, m), 7.21-7.15 (2H, m), 7.04-6.98 (2H, m) , 3.80 (1H, dd, J= 7.5, 8 Hz), 3.36 (1H, dd, J= 8, 13.9 Hz), 3.0 (1H, dd, J= 7, 13 .9 Hz).

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-3-(4-chlorophenyl)-2-phenylpropanoate

A stirred solution of 3-(4-chlorophenyl)-2-phenylpropanoic acid (3.30 g, 12.7 mmol) in DCM (30 ml) containing DMF (45 μl) was treated dropwise at 0°C with oxalyl chloride ( 2.2 ml, 25.3 mmol) and the resulting mixture was stirred at 0°C for 10 min., then allowed to warm to rt and stirred for 18 h. The reaction mixture was concentrated in vacuo and the crude product was subjected to azeotropic distillation with toluene (20 ml) to give crude 3-(4-chlorophenyl)-2-phenylpropanoyl chloride which was dissolved in dry toluene (50 ml). Tropin (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 rt and stirred overnight. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO ₃ , water, brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo . The residue was purified by silica chromatography (80 g, 0-10% (2 M NH ₃ in MeOH) in DCM gradient) to give the pure title compound as a viscous orange oil (2.24 g, 50%). A second crop of the crude title compound (0.54 g, 12%) was also isolated as a brown oil. ¹H NMR (400 MHz, CDCl ₃ ): δ 7.35-7.23 (5H, m), 7.22-7.16 (2H, m), 7.09-7.02 (2H, m), 4.90 (1H, t, J= 5.4 Hz), 3.73 (1H, dd, J= 6.9, 8.7 Hz), 3.39 (1H, dd, J= 8.7, 13.8 Hz), 3.00 (1H, dd, J= 6.9, 13.8 Hz), 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.

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-chlorobenzyl)-2-phenylpropanoate

A solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-(4-chlorophenyl)-2-phenylpropanoate (2.22 g, 5.78 mmol) in DMF (10 ml) was treated with paraformaldehyde (0.26 g, 8.7 mmol). A 21% solution of sodium ethoxide in ethanol (0.29 ml, 0.6 mmol) was added and the resulting mixture was stirred at rt for 14 h. The reaction mixture was diluted with water (50 ml) and EtOAc (100 ml) and the aqueous layer separated and further extracted with EtOAc. The combined organic layers were washed with 5% w/w aqueous lithium chloride solution (2×25 ml), brine, dried (Na ₂ SO ₄ ) and filtered through a pad of celite. The solution was concentrated in vacuo and the residue was purified on silica (40 g, 0.5-10% (2 M NH ₃ in MeOH) in DCM) to give the title compound as a white solid (0.86 g, 36% ). ¹H NMR (400 MHz, d ₆ -DMSO): δ 7.35-7.27 (2H, m), 7.27-7.21 (1H, m), 7.20-7.14 (2H, m ), 7.09-7.01(2H, m), 6.88-6.79(2H, m), 5.14(1H, wide t, J= 4Hz), 4.90(1H, t , J= 4.8 Hz), 3.98 (1H, dd, J= 4.2, 10 Hz), 3.74 (1H, dd, J= 3.8, 10 Hz), 3.36 (1H , d, J= 13 Hz), 3.23 (1H, d, J= 13 Hz), 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 . ¹ H NMR and ¹³ C NMR spectra for the title compound are shown in Figures 24A and 24B, respectively.

Synthesis scheme according to example 14: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(2-chlorobenzyl)-2-phenylpropanoate

3-(2-Chlorophenyl)-2-phenylpropanoic acid

n -Butyl lithium (2.5M solution in hexanes, 15.3 ml, 38.3 mmol) was added dropwise under nitrogen atmosphere to a cooled solution of N,N -diisopropylamine (5.6 ml, 39.95 mmol) in dry THF (20 ml) maintaining T ≤ 0°C. The resulting LDA solution was stirred for 20 minutes, then cooled with a dry ice/acetone bath to -74°C. A solution of methylphenylacetate (5.0 g, 33.3 mmol) in dry THF (20 ml) was added dropwise via syringe maintaining T ≤ -55°C. After stirring for 1 h, a solution of 2-chlorobenzyl bromide (4.8 ml, 36.6 mmol) in dry THF (10 ml) was added and the resulting mixture was stirred overnight with warming to rt. The mixture was diluted with EtOAc ( 50 ml) and saturated aqueous ammonium chloride solution (10 ml). The organic layer was separated and washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give crude methyl 3-(2-chlorophenyl)-2-phenylpropanoate as an orange syrup. This material 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 opaque solution was stirred for 40 hours then concentrated in vacuo to give an orange aqueous solution which was diluted with hydrochloric acid (1 M, 20 ml), water (30 ml) and EtOAc (100 ml). The aqueous layer was separated and further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound as a mixture with unreacted methyl 3-(2-chlorophenyl)-2-phenylpropanoate. The mixture was redissolved in THF (50 ml), methanol (10 ml) and aqueous sodium hydroxide solution (2 M, 17 ml, 34 mmol) and the resulting opaque solution was stirred at RT overnight. The solvents were concentrated in vacuo and the residue was partitioned between water (50 ml), hydrochloric acid (1 M, 50 ml) and EtOAc (100 ml). The aqueous layer was separated and further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound as an off-white solid (4.10 g, 94%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.35-7.24 (6H, m), 7.16-7.08 (1H, m), 7.07-7.03 (2H, m) , 4.00 (1H, dd, J = 6.7, 8.5 Hz), 3.49 (1H, dd, J = 8.5, 13.8 Hz), 3.15 (1H, dd, J = 6.7, 13.8 Hz).

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-3-(2-chlorophenyl)-2-phenylpropanoate

A stirred solution of 3-(2-chlorophenyl)-2-phenylpropanoic acid (3.30 g, 12.7 mmol) in DCM (30 ml) containing DMF (45 μl) was treated with oxalyl chloride (2.2 ml, 25 .3 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the crude product was azeotropically distilled with toluene (20 ml). The residue was dissolved in dry toluene (50 ml) and tropine (1.62 g, 11.5 mmol) and triethylamine (4.8 ml, 34.5 mmol) were added and the mixture was stirred at 110°C for 4 hours, cooled to rt and stirred overnight. The reaction mixture was diluted with EtOAc (150 ml) and washed with saturated NaHCO ₃ , water, brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo . The residue was purified on silica (120 g, 0-10% (2 M NH ₃ in MeOH) in DCM) to give the pure title compound as a viscous orange oil (3.26 g, 73%). ¹H NMR (400 MHz, CDCl ₃ ) δ 7.37-7.22 (6H, m), 7.16-7.04 (3H, m), 4.91 (1H, t, J= 5.4 Hz ), 3.95 (1H, dd, J= 6.5, 9 Hz), 3.51 (1H, dd, J= 9, 13.5 Hz), 3.16 (1H, dd, J= 6, 5, 13.5 Hz), 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.

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(2-chlorobenzyl)-2-phenylpropanoate

A solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-(2-chlorophenyl)-2-phenylpropanoate (1.92 g, 5.0 mmol) in DMF (10 ml) was treated with paraformaldehyde (0.23 g, 7.5 mmol). A 21% solution of sodium ethoxide in ethanol (0.25 ml, 0.5 mmol) was added and the resulting mixture was stirred at RT for 3 h, then heated to 45° C. overnight. Second parts of paraformaldehyde (0.23 g, 7.5 mmol) and 21% sodium ethoxide in ethanol (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 h. Heating was stopped and the reaction mixture was stirred at RT 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 aqueous lithium chloride solution (2×25 ml), brine, dried (Na ₂ SO ₄ ), filtered through celite and concentrated in vacuo . The residue was purified on silica [40 g, 0.5-10% (2 M NH ₃ in MeOH) in DCM] to give the title compound as a white solid (1.0 g, 48%). ¹H NMR (400 MHz, d ₆ -DMSO): δ 7.26-7.18 (4H, m), 7.17-7.10 (3H, m), 6.99-6.91 (2H, m ), 5.21 (1H, wide t, J= 4 Hz), 4.99 (1H, t, J= 5.2 Hz), 4.06-3.94 (2H, m), 3.51 ( 1H, d, J= 14 Hz), 3.46 (1H, d, J= 14 Hz), 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 . ¹ H NMR and ¹³ C NMR spectra for the title compound are shown in Figures 25A and 25B, respectively.

Synthesis scheme according to example 15: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-hydroxybenzyl)-2-phenylpropanoate formic acid salt

3-(4-(( tert -Butyldimethylsilyl)oxy)phenyl)-2-phenylpropanoic acid

tert -Butyldimethylchlorosilane (3.16 g, 21.0 mmol) was added to a stirred solution of 3-(4-hydroxyphenyl)-2-phenylpropanoic acid (2.42 g, 10.0 mmol) and imidazole (2.04 g, 29 .97 mmol) in dry DMF (40 mL) and the resulting mixture was stirred at RT overnight. An additional portion of tert -butyldimethylchlorosilane (0.75 g, 5.0 mmol) was added and stirring was continued for 2 h. The reaction mixture was diluted with EtOAc and washed with water, saturated aqueous lithium chloride, brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a straw colored oil. The oil was dissolved in methanol (40 ml), potassium carbonate (1.52 g, 11.0 mmol) was added and the resulting suspension was stirred at rt for 1.5 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between water and DCM and the aqueous phase were acidified to pH 3 by careful addition of 1M hydrochloric acid. The aqueous layer was separated and further extracted with DCM. The combined organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the crude title compound as a straw colored oil. This material was purified by silica chromatography (80 g, 0-20% EtOAc in DCM gradient) to give the title compound as a straw colored oil (1.58 g, 44%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.32-7.22 (5H, m), 6.95-6.89 (2H, m), 6.71-6.64 (2H, m) , 3.79 (1H, apparent t, J= 8 Hz), 3.32 (1H, dd, J = 8.2, 13.9 Hz), 2.95 (1H, dd, J= 7.2, 13.9 Hz), 0.95 (9H, s), 0.15 (6H, s).

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-3-(4-(( tert -butyldimethylsilyl)oxy)phenyl)-2-phenylpropanoate

A stirred solution of 3-(4-(( tert -butyldimethylsilyl)oxy)phenyl)-2-phenylpropanoic acid (1.30 g, 3.65 mmol) in DCM (20 ml) containing one drop of DMF (45 μl) was treated dropwise at 0°C with oxalyl chloride (0.64 ml, 7.3 mmol) and the resulting mixture was stirred at 0°C for 10 min., then the cooling bath was removed and the reaction mixture was stirred overnight with heating to r. m. The mixture was concentrated in vacuo and the crude acid chloride intermediate was azeotropically distilled with toluene (20 mL) to give 3-(4-(( tert -butyldimethylsilyl)oxy)phenyl)-2-phenylpropanoyl chloride as a straw colored oil. This material was dissolved in dry toluene (20 ml) and tropine (0.51 g, 3.7 mmol) and triethylamine (1.5 ml, 11.0 mmol) was added. The resulting mixture was stirred at 110° C. for 3 hours. The mixture was cooled to rt, diluted with EtOAc (50 ml) and washed with water, saturated NaHCO ₃ , brine, dried (Na ₂ SO ₄ ) and concentrated in vacuum . The product was purified on silica (25 g, 0-10% (2 M NH ₃ in MeOH) in DCM) to give the pure title compound as a colorless syrup (0.778 g, 44%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.34-7.21 (5H, m), 7.02-6.94 (2H, m), 6.73-6.66 (2H, m) , 4.90 (1H, t, J= 5.3 Hz), 3.73 (1H, dd, J= 6.6, 9 Hz), 3.35 (1H, dd, J =9, 13.8 Hz), 2.95 (1H, dd, J= 6.6, 13.8 Hz), 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).

Formic acid (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-hydroxybenzyl)-2-phenylpropanoate salt

A solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-(4-(( tert- butyldimethylsilyl)oxy)-phenyl)-2-phenylpropanoate (0, 77 g, 1.61 mmol) in DMF (10 mL) was treated with paraformaldehyde (0.072 g, 2.4 mmol) and 21% sodium ethoxide in ethanol (0.06 mL, 0.16 mmol) was added at rt. The resulting mixture was stirred at RT for 6.5 hours, then the second parts of paraformaldehyde (0.072 g, 2.4 mmol) and a 21% solution of sodium ethoxide in ethanol (0.06 ml, 0.15 mmol) were added. ) and the mixture was stirred overnight. A third of paraformaldehyde (0.072 g, 2.4 mmol) and 21% sodium ethoxide in ethanol (0.06 ml, 0.15 mmol) were added and stirring continued at rt for 3 days. The reaction mixture was diluted with EtOAc (100 ml) and washed with water, 5% aqueous lithium chloride, brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo . The product was partially purified on 15 μm silica (4 g, 0-20% (2 M NH ₃ in MeOH) in DCM) to give the crude title compound as a white solid, which was further purified by reverse phase preparative HPLC. using a Kinetix Axia ^® C18 21.2×250 mm column, 18 ml/min. with a gradient eluent of 10-60% MeCN in water with 0.1% HCOOH with monochromatic UV detection at 220 nm. This provided the title compound as a white solid (0.273 g, 38%). ¹H NMR (400 MHz, d ₆ -DMSO): δ 8.31 (1H, s), 7.34-7.26 (2H, m), 7.26-7.19 (1H, m), 7, 10-7.02(2H, m), 6.63(2H, dm, J= 8.5Hz), 6.49(2H, dm, J= 8.5Hz), 4.91(1H, t , J= 4.9 Hz), 4.48-3.60 (3H, bs), 3.95 (1H, d, J= 10 Hz), 3.77 (1H, d, J= 10 Hz), 3.26 (1H, d, J= 13.3 Hz), 3.25-3.16 (2H, m), 3.13 (1H, d, J= 13.3 Hz), 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. ¹ H NMR and ¹³ C NMR spectra for the title compound are shown in Figures 26A and 26B, respectively.

Synthesis scheme according to example 16: 2-fluoro-3-hydroxy-N-((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2-phenylpropanamide

2-Fluoro-3-hydroxy-2-phenylpropanoic acid

A stirred mixture of methyl 2-fluoro-2-phenylpropanoate (1.49 g, 7.62 mmol) and paraformaldehyde (0.55 g, 18.3 mmol) in DMF (5 mL) was treated with 21% sodium ethoxide in ethanol (0.43 ml, 1.14 mmol) and the resulting orange suspension was stirred at RT for 3.5 hours. The mixture was diluted with EtOAc and washed with hydrochloric acid, 5% aqueous lithium chloride, saline solution, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give crude methyl 2-fluoro-3-hydroxy-2-phenylpropanoate as an orange oil (1.82 g). This substance was dissolved in a mixture of water (9 ml) and methanol (20 ml), then lithium hydroxide (0.44 g, 18.3 mmol) was added and the resulting mixture was stirred at RT for 4 h. 1,4-dioxane (4N, 5 mL, 20 mmol) and the mixture was concentrated in vacuo to give the title crude compound as a dark cream solid (2.21 g, quantitatively). This material was used without purification. ¹ H NMR (400 MHz, d ₆ -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, wide s).

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

HATU (3.77 g, 9.9 mmol) was added in three parts to a stirred ice-cold solution of crude 2-fluoro-3-hydroxy-2-phenylpropanoic acid (2.21 g, 7.6 mmol), 8-methyl-8- azabicyclo[3.2.1]octane-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 heated to rt and stirred for 40 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between water and EtOAc. The aqueous layer was separated and further extracted with EtOAc. The combined organic layers were washed with 5% aqueous lithium chloride, brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give an orange gum. The product was purified on silica (40 g, 15 μm silica, 5-20% (2 M NH ₃ in MeOH) in DCM) to give the title compound as a pale yellow solid (0.631 g, 27 %). ¹ H NMR (400 MHz, d ₆ -DMSO): δ 7.84 (1H, bs), 7.63-7.47 (2H, m), 7.44-7.33 (3H, m), 5 .45 (1H, t, J= 5.8 Hz), 4.12 (1H, ddd, J= 6.3, 12.3, 33 Hz), 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. ¹ H NMR and ¹³ C NMR spectra for the title compound are shown in Figures 37A and 37B, respectively.

Synthesis scheme according to example 17: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(4-fluorobenzyl)-3-hydroxy-2-phenylpropanoate

Methyl 3-(4-fluorophenyl)-2-phenylpropanoate

2 M lithium diisopropylamine in THF/heptane/ethylbenzene (10 ml, 20 mmol) was added to a stirred solution of methylphenylacetate (3.00 g, 20.0 mmol) in dry THF (40 ml) under argon at -30°C. After stirring for 15 min. the reaction mixture was heated to 0°C and stirred for 30 min. The reaction mixture was cooled to -30°C and a solution of 4-fluorobenzyl bromide (4.10 g, 21.7 mmol) in dry THF (10 ml) was added dropwise while maintaining T ≤ -25°C. The resulting mixture was stirred for 10 minutes. before allowing it to warm to rt for 16 hours. The solvent was removed in vacuo and the residue was diluted with EtOAc, washed with water and brine, and the layers were separated. The organic fraction was dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified on silica (40 g, 0-10% MTBE in cyclohexane) to give the title compound as a crude pale yellow oil (1.51 g, 29%), which was used without further purification. ¹H NMR (400 MHz, CDCl ₃ ): δ 7.33-7.26 (5H, m), 7.08-7.03 (2H, m), 6.93-6.88 (2H, m), 3.81-3.77 (1H, m), 3.37 (1H, dd, J= 8.7, 13.8 Hz), 2.99 (1H, ddd, J= 4.1, 6.7 , 13.5 Hz).

3-(4-Fluorophenyl)-2-phenylpropanoic acid

Methyl 3-(4-fluorophenyl)-2-phenylpropanoate (1.51 g, 5.9 mmol) was stirred in THF (30 ml) and MeOH (3 ml) and treated with 2 M NaOH (aq) (12 ml, 24.0 mmol). The reaction mixture was stirred at RT for 18 hours. The solvent was removed in vacuo , the residue was diluted with H ₂ O and washed with EtOAc. The aqueous fraction was acidified with 1M HCl to pH 1.0 and extracted with EtOAc. The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as a light brown oil which crystallized on standing (1.13 g, 79%). The material was used without purification. ¹H NMR (400 MHz, CDCl ₃ ): δ 7.34-7.27 (5H, m), 7.06 (2H, ddd, J= 3.1, 5.3, 11.8 Hz), 6.93- 6.88 (2H, m), 3.81 (1H, dd, J= 7.1, 8.4 Hz), 3.37 (1H, dd, J= 8.4, 13.9 Hz), 3 .01 (1H, dd, J= 7.1, 13.9 Hz); LCMS (ESI) [MH] ^- 243.

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-3-(4-fluorophenyl)-2-phenylpropanoate

A stirred solution of 3-(4-fluorophenyl)-2-phenylpropanoic acid (1.13 g, 4.6 mmol) in DCM (10 ml) containing DMF (200 μl) under argon was treated dropwise at 0° C. with using oxalyl chloride (573 µl, 6.6 mmol). The resulting mixture was stirred at 0° C. for 10 minutes, then warmed to rt and stirred for 18 hours. Solvents were removed in vacuo and the residue was azeotropically distilled with toluene (2 x 15 ml) to give the crude acid chloride , which was stirred in dry toluene (10 ml) with (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-ol (790 mg, 5.6 mmol) under argon at 100 °C for 4 h. The reaction mixture was concentrated in vacuo and the residue was treated with DCM (60 ml) and H ₂ O (40 ml) and raised to pH 10 with 1 M NaOH (aq.). The organic fractions were separated, washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the crude product as a pale yellow oil (1.27 g). This material was used crude without purification. ¹H NMR (400 MHz, CDCl ₃ ): δ 7.26 (4H, s), 7.19-7.07 (3H, m), 6.94-6.89 (2H, m), 4.99- 4.89 (1H, m), 3.73 (1H, dd, J= 6.8, 8.8 Hz), 3.40 (1H, dd, J= 8.8, 13.8 Hz), 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.

( 1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(4-fluorobenzyl)-3-hydroxy-2-phenylpropanoate

( 1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-3-(4-fluorophenyl)-2-phenylpropanoate (154 mg, 0.4 mmol) in DMF (3 ml) was treated with paraformaldehyde (160 mg, 5.3 mmol), then 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 celite. The filtrate was concentrated in vacuo to volume reduction and purified on silica (4 g, 0-10% 2 M NH ₃ /MeOH in DCM) to give the title compound as 108 mg of a white solid. This material was further purified by HPLC on a Kinetix Axia C18 RP (long) column using 10-60% CH ₃ CN in H ₂ O [0.1% HCOOH] with a temperature ramp over 10 minutes. at 18 ml/min. (UV at 200 nm) to give the title compound as a white solid (64 mg, 38%). ¹H NMR (400 MHz, CDCl ₃ ): δ 7.38-7.27 (3H, m), 7.16-7.12 (2H, m), 6.90-6.85 (4H, m), 5.15 (1H, t, J= 5.1 Hz), 4.12-4.08 (1H, m), 3.98 (1H, d, J= 10.6 Hz,), 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= 16.4 Hz), 1.62-1.48 (2H, m); LCMS (ESI) [M+H] ⁺ 398.3. ¹ H NMR and ¹³ C NMR spectra for the title compound are shown in Figures 28A and 28B, respectively.

Synthesis scheme according to example 18: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-methylbenzyl)-2-phenylpropanoate

Methyl 2-phenyl-3-(p-tolyl)propanoate

Potassium tert- Butoxide (4.08 g, 22.1 mmol) was added to a stirred solution of methyl phenyl acetate (3.00 g, 20 mmol) in dry THF (30 mL) under argon at 0°C. After stirring for 15 min. a solution of 4-methylbenzyl bromide in dry THF (10 ml) was added dropwise maintaining T ≤ 5°C. The resulting mixture was stirred for 10 minutes. before allowing it to warm to RT for 16 hours. The resulting mixture was diluted with EtOAc, washed with water, then brine. The organic layer was dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the crude product as a yellow oil. This material was purified on silica (40 g, 0-25% EtOAc in cyclohexane) to give the title compound as a crude pale yellow oil (3.60 g, 70%), which was used without further purification.

2-Phenyl-3-(p-tolyl)propanoic acid

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

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-phenyl-3-(p-tolyl)propanoate

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

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-methylbenzyl)-2-phenylpropanoate

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-phenyl-3-(p-tolyl)propanoate (688 mg, 1.9 mmol) in DMF ( 10 ml) was treated with paraformaldehyde (722 mg, 24.0 mmol), then with 21% sodium ethoxide solution (20 μl, 0.054 mmol) and stirred at 50 ± 5°C for 24 h. The reaction mixture was cooled, diluted with DCM ( 50 ml) and filtered through celite. The filtrate was concentrated in vacuo and the residue was purified on silica (12 g, 0-10% 2 M NH ₃ /MeOH in DCM), the resulting residue was further purified by HPLC on a Kinetix Axia C18 RP (long) column using 10-60% CH ₃ CN in H ₂ O [0.1% HCOOH] with temperature ramp over 10 min. at 18 ml/min. (UV=200 nm) to give the title compound as a white solid (260 mg, 35%). ¹H NMR (400 MHz, CDCl ₃ ): δ 7.38-7.33 (2H, m), 7.31-7.27 (1H, m), 7.20 (2H, d, J= 7.3 Hz,), 7.01-6.97 (2H, m), 6.87-6.83 (2H, m), 5.14 (1H, t, J= 5.0 Hz), 4.04 ( 2H, q, J= 11.0 Hz), 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. ¹ H NMR and ¹³ C NMR spectra for the title compound are shown in Figures 29A and 29B, respectively.

Synthesis scheme according to example 19: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(3-chlorobenzyl)-3-hydroxy-2-phenylpropanoate

Methyl 3-(3-chlorophenyl)-2-phenylpropanoate

1 M sodium bis (trimethylsilyl)amide in THF (20 ml, 20 mmol) was added dropwise to a stirred solution of methylphenylacetate (3.00 g, 20.0 mmol) and 3-chlorobenzyl chloride (3.16 g, 19.6 mmol) in dry THF (40 ml) under argon at -78°C maintaining T ≤ -65°C. The reaction mixture was stirred for 1 h, then warmed to rt for 16 h. The reaction mixture was concentrated in vacuo and the residue was diluted with EtOAc, washed with water, then brine. The organic layer was dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the crude product as a yellow oil (5.48 g, 100%). This material was used crude without purification. ¹H NMR (400 MHz, CDCl ₃ ): δ 7.32-7.26 (6H, m), 7.16-7.14 (2H, m), 7.13-7.10 (1H, m), 3.82 (1H, dd, J= 6.7, 9.2 Hz), 3.61 (3H, s), 3.39 (1H, dd, J= 13.6, 9.6 Hz), 2 .99 (1H, dd, J= 13.6, 6.8 Hz).

3-(3-Chlorophenyl)-2-phenylpropanoic acid

Methyl 3-(3-chlorophenyl)-2-phenylpropanoate (5.48 g, 20 mmol) in a mixture of THF (70 ml) and MeOH (7 ml) was treated with 2 M NaOH (aq.) (28.5 ml , 57 mmol) and the reaction mixture was stirred at RT for 18 h. The reaction mixture was concentrated in vacuo and the residue was diluted with water and washed with EtOAc. The aqueous fraction was acidified with 1M HCl to pH 1.0 and extracted with EtOAc. The combined organic fractions were dried (MgSO ₄ ) and concentrated in vacuo to give the crude product as a yellow oil which crystallized on standing (3.82 g, 73%). Used without cleaning. ¹H NMR (400 MHz, CDCl ₃ ): δ 7.34-7.27 (5H, m), 7.16-7.11 (3H, m), 7.00-6.96 (1H, m), 3.84 (1H, dd, J= 7.0, 8.5 Hz), 3.38 (1H, dd, J= 8.5, 13.9 Hz), 3.01 (1H, dd, J= 7.0, 13.9 Hz).

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-3-(3-chlorophenyl)-2-phenylpropanoate

A stirred solution of 3-(3-chlorophenyl)-2-phenylpropanoic acid (2.0 g, 7.7 mmol) in DCM (20 ml) containing DMF (300 μl) under argon was treated dropwise at 0°C with using oxalyl chloride (955 µl, 5.9 mmol). The reaction mixture was stirred at 0° C. for 10 min., then allowed to warm to rt and stirred for 18 h. acid chloride. The resulting residue was stirred in dry toluene (10 ml) with (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-ol (1.31 g, 9.3 mmol) under argon at 100° C. for 3 hours. The reaction mixture was concentrated in vacuo . The resulting residue was treated with DCM (60 ml) and water (40 ml) and raised basic to pH 10 with 1 M NaOH (aq.). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated in vacuo . The residue was purified on silica (40 g, 0-10% 2 M NH ₃ /MeOH in DCM) to give the title compound as a light brown oil (1.06 g, 36%). ¹H NMR (400 MHz, CDCl ₃ ): δ 7.33-7.26 (5H, m), 7.16-7.15 (3H, m), 7.03-7.00 (1H, m), 4.91 (1H, t, J= 5.4 Hz), 3.75 (1H, dd, J= 6.5, 9.0 Hz), 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.

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(3-chlorobenzyl)-3-hydroxy-2-phenylpropanoate

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-3-(3-chlorophenyl)-2-phenylpropanoate (1.10 g, 2.9 mmol) in DMF (15 ml) was treated with paraformaldehyde (1.10 g, 36.0 mmol), then 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 celite. The filtrate was concentrated in vacuo and the residue was purified on silica (24 g, 0-10% 2 M NH ₃ /MeOH in DCM). The product was further purified by HPLC on a Kinetix Axia C18 RP (long) column using 10-60% CH ₃ CN in H ₂ O [0.1% HCOOH] with a temperature ramp over 10 minutes. at 18 ml/min. (UV=200 nm) to give the product as a white solid (554 mg, 50%). ¹H NMR (400 MHz, CDCl ₃ ): δ 7.38-7.27 (3H, m), 7.16-7.06 (4H, m), 6.91 (1H, t, J= 1.7 Hz), 6.79 (1H, d, J= 7.6 Hz), 5.16 (1H, t, J= 5.0 Hz), 4.10 (1H, d, J= 10.6 Hz) , 3.98 (1H, d, J= 10.6 Hz), 3.52-3.45 (3H, m), 3.35 (1H, d, J= 13.3 Hz), 2.64- 2.55 (1H, m), 2.54 (3H, s), 1.91-1.72 (4H, m), 1.68-1.48 (2H, m); LCMS (ESI) [M+H] ^+414.2 . ¹ H NMR and ¹³ C NMR spectra for the title compound are shown in Figures 30A and 30B, respectively.

Synthesis scheme according to example 20: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropanoate

2-(3-Chlorophenyl)propanoic acid

Methyl 2-(3-chlorophenyl)propanoate (590 mg, 2.97 mmol) in THF (12 mL) and MeOH (1 mL) at rt was treated with 2N HCl. NaOH (aq.) (4.2 ml, 8.41 mmol) and stirred overnight. The reaction mixture was concentrated in vacuo and the resulting aqueous layer was acidified with 1N HCl. HCl to pH 1 and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo . The residue was purified on silica (40 g, 0-30% EtOAc in cyclohexane) to give the title compound as a pale yellow oil (229 mg, 42%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.34-7.15 (4H, m), 3.72 (1H, q, J =7.3 Hz), 1.51 (3H, d, J = 7.3 Hz).

2-(3-Chlorophenyl)propanoyl chloride

A stirred solution of 2-(3-chlorophenyl)propanoic acid (229 mg, 1.24 mmol) in DCM (3 ml) containing DMF (55 µl) was treated dropwise with oxalyl chloride (150 µl, 1.77 mmol) at 0°C in an argon atmosphere. The resulting mixture was stirred at 0°C for 30 min. before providing it with heating to rt during the night. The reaction mixture was concentrated in vacuo to give the crude title compound, which was used directly without purification.

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(3-chlorophenyl)propanoate

The crude 2-(3-chlorophenyl)propanoyl chloride was stirred in dry toluene (3 ml) with tropine (214 mg, 1.51 mmol) at 100° C. under argon for 3 h. The reaction mixture was concentratedin vacuo. The residue was diluted with aqueous saturated NaHCO₃ and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO₄) and concentratedin vacuo. The resulting precipitate was purified on silica (40 g, 0-10% 2N NH₃ MeOH in DCM) to give the title compound as a yellow oil (272 mg, 71%). LCMS (ESI) [M+H]⁺ 308.2.

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(3-chlorophenyl)-3-hydroxy-2-methylpropanoate

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(3-chlorophenyl)propanoate (337 mg, 1.09 mmol) in DMF (2.5 ml ) was treated with paraformaldehyde (49 mg, 1.64 mmol) followed by 21% sodium ethoxide solution (4.3 µl, 0.055 mmol) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with 1 n. HCl and extracted with EtOAc. The combined aqueous fractions were then made basic with 1N HCl. NaOH to pH 13 and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO₄) and concentratedin vacuo. The resulting precipitate was purified on silica (40 g, 0-10% 2N NH₃ MeOH in DCM) to give the title compound as an off-white solid (193 mg, 52%).¹H NMR (400 MHz, CDCl₃):δ7.34-7.26(3H, m), 7.23-7.17(1H, m), 5.06(1H, t,J=5.4 Hz), 4.07 (1H, d,J=11.3 Hz), 4.64 (1H, d,J=11.3 Hz), 3.06-3.00 (1H, m), 2.99-2.93 (1H, m), 2.57 (1H, br s), 2.21 (3H, m ), 2.16-2.03(2H, m), 1.93-1.82(1H, m), 1.80-1.69(1H, m), 1.67(3H, s), 1.66-1.56(2H, m), 1.51-1.44(1H, m), 1.27-1.17(1H, m); LCMS (ESI) [M+H]⁺338.12. Spectra¹H NMR and¹³C NMR for the title compound are shown in Figures 31A and 31B, respectively.

Synthesis scheme according to example 21: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropanoate

2-(4-Chlorophenyl)propanoic acid

Methyl 2-(4-chlorophenyl)propanoate (547 mg, 2.75 mmol) in THF (12 mL) and MeOH (1 mL) at RT was treated with 2N HCl. NaOH (aq.) (3.9 ml, 7.79 mmol) and stirred for 8 hours. The reaction mixture was concentrated in vacuo and the resulting aqueous layer was acidified with 1N. HCl to pH 1 and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo . The residue was purified on silica (40 g, 0-30% EtOAc in cyclohexane) to give the title compound as an off-white solid (137 mg, 27%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.35-7.16 (4H, m), 3.71 (1H, q, J =9.4 Hz), 1.49 (3H, d, J =9 .6 Hz).

2-(4-Chlorophenyl)propanoyl chloride

A stirred solution of 2-(4-chlorophenyl)propanoic acid (265 mg, 1.44 mmol) in DCM (4 ml) containing DMF (70 μl) was treated dropwise with oxalyl chloride (180 μl, 2.05 mmol) at 0°C in an argon atmosphere. The resulting mixture was stirred at 0°C for 30 min. The reaction mixture was concentrated in vacuo to give the crude title compound and used directly without purification.

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(4-chlorophenyl)propanoate

The crude 2-(4-chlorophenyl)propanoyl chloride was stirred in dry toluene (4 ml) with tropine (247 mg, 1.75 mmol) at 100° C. under argon overnight. The reaction mixture was concentrated in vacuo . The residue was diluted with EtOAc and extracted with 1N HCl. HCl. The combined aqueous fractions were then made basic with 1N HCl. NaOH to pH 13 and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as a brown oil which was used crude in the next reaction (230 mg, 52%). LCMS (ESI) [M+H] ⁺ 308.1.

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(4-chlorophenyl)-3-hydroxy-2-methylpropanoate

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(4-chlorophenyl)propanoate (230 ml, 0.75 mmol) in DMF (2 ml) was treated with paraformaldehyde (34 mg, 1.12 mmol) followed by 21% sodium ethoxide solution (3 µl, 0.037 mmol) and the reaction mixture was stirred at RT for 1 h. Additional paraformaldehyde (34 mg, 1 .12 mmol), then 21% sodium ethoxide solution (3 μl, 0.037 mmol) and continued stirring at RT for 1 h. The reaction mixture was diluted with 1 N. HCl and extracted with EtOAc. The combined aqueous fractions were then made basic with 1N HCl. NaOH to pH 13 and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO₄) and concentratedin vacuo. The resulting precipitate was purified on silica (40 g, 0-10% 2N NH₃ MeOH in DCM) to give the title compound as an off-white solid (118 mg, 47%).¹H NMR (400 MHz, CDCl₃):δ7.36-7.31(2H, m), 7.28-7.22(2H, m), 5.06(1H, t,J=5.5 Hz), 4.05 (1H, d,J=11.1 Hz), 3.62 (1H, d,J=11.1 Hz), 3.06-3.00 (1H, m), 2.99-2.92 (1H, m), 2.52 (1H, br s), 2.21 (3H, s ), 2.16-2.01(2H, m), 1.93-1.82(1H, m), 1.80(1H, m), 1.67(3H, s), 1.65- 1.56 (2H, m), 1.49-1.42 (1H, m), 1.25-1.15 (1H, m); LCMS (ESI). [M+H]⁺338.1. Spectra¹H NMR and¹³C NMR for the title compound are shown in Figures 32A and 32B, respectively.

Synthesis scheme according to example 22: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(4-(benzyloxy)phenyl)propanoate

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(4-(benzyloxy)phenyl)propanoate

To a solution of 2-(4-(benzyloxy)phenyl)propanoyl chloride (1.61 g, 5.86 mmol) in toluene (20 ml) was added tropine (750 mg, 5.33 mmol) and the reaction mixture was stirred at 90° C. for for 3 hours, then at 50°C for 16 hours. The reaction mixture was diluted with 1N. HCl and extracted with EtOAc and the organic fractions were discarded. Increased the basicity of the combined aqueous fractions with 1N. NaOH and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound (750 mg, 37%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47-7.29 (5H, m), 7.23-7.19 (2H, m), 6.97-6.90 (2H, m), 5.06 (2H, s), 4.94 (1H, t, J =5.3 Hz), 3.62 (1H, q, 7.1 Hz), 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 = 7.2 Hz), 1.43-1.35 (1H, m). LCMS (ESI) [M+H] ^+380.2 , _Rt =0.97 min. (method 2).

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(4-(benzyloxy)phenyl)-3-hydroxy-2-methylpropanoate

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(4-(benzyloxy)phenyl)propanoate (750 mg, 1.98 mmol) in DMF (8 ml) was treated with paraformaldehyde (89 mg, 2.96 mmol), then with 21% sodium ethoxide solution (37 μl, 0.10 mmol) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with EtOAc and extracted with 1N HCl. Increased the basicity of the combined aqueous fractions with 1N. NaOH and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO₄) and concentratedin vacuo. The resulting residue was purified on silica (12 g, 0-10% MeOH in DCM) to give the title compound (685 mg, 85%).¹H NMR (400 MHz, 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=5.5 Hz), 4.09 (1H, d,J=11.1 Hz), 3.59 (1H, d,J=11.2 Hz), 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=0.87 min. (method 2).

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-3-hydroxy-2-(4-hydroxyphenyl)-2-methylpropanoate

(1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-2-(4-(benzyloxy)phenyl)-3-hydroxy-2-methylpropanoate (685 mg, 1 67 mmol) in EtOAc (10 mL) and MeOH (3 mL) was treated with palladium on charcoal (10 wt%, 150 mg) and stirred at rt under hydrogen atmosphere for 16 h. The reaction mixture was filtered and the filtrate concentrated in vacuo . The residue was purified on silica (12 g, 0-10% MeOH in DCM) to give the title compound as a white solid (278 mg, 52%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.18-7.12 (2H, m), 6.77-6.71 (2H, m), 5.03 (1H, t, J =5, 1 Hz), 4.10 (1H, d, J =11.4 Hz), 3.57 (1H, d, J =11.4 Hz), 3.11-3.05 (1H, m), 3 .01-2.92 (1H, m), 2.27 (3H, s), 2.17 (1H, dt, J = 15.2, 4.1 Hz), 2.08 (1H, dt, J =15.3, 4.3 Hz), 1.92-1.78(1H, m), 1.67-1.54(6H, m), 1.41(1H, d, J =15.3 Hz), 1.18-1.07 (1H, m); LCMS (ESI) [M+H] ⁺ 320.3. ¹ H NMR and ¹³ C NMR spectra for the title compound are shown in Figures 33A and 33B, respectively.

Synthesis scheme according to example 23: 6-chloro-11 H -benzo[e]pyrido[3,2-b][1,4]diazepine

2-Nitrobenzoyl chloride

To a solution of 2-nitrobenzoic acid (5 g, 29.9 mmol) in DCM (140 ml) was added 1 drop of DMF followed by the addition of oxalyl chloride (3.7 ml, 41.9 mmol) resulting in the evolution of gas bubbles. The reaction mixture was stirred at room temperature for 20 min. The reaction mixture was concentrated in vacuo to give the title compound as a straw colored oil (5.55 g, quant.). The material was used without purification. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.13-8.07 (1H, m), 7.84-7.68 (3H, m).

N -(2-Chloropyridin-3-yl)-2-nitrobenzamide

To a solution of 2-nitrobenzoyl chloride (5.55 g, 29.9 mmol) in THF (120 ml) was added pyridine (14.5 ml, 0.18 mol) and 3-amino-2-chloropyridine (4.23 g, 32 .9 mmol), which led to the formation of a precipitate. The reaction mixture was stirred at RT for 2 hours before being diluted with 10% aqueous citric acid and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the product as a light brown solid (8.6 g, quant.). The material was used without purification. ¹ H NMR (400 MHz, d ₆ -DMSO) δ 10.61 (1H, s), 8.31 (1H, dd, J =4.3, 1.5 Hz), 8.25-8.16 ( 2H, m), 7.94-7.87 (1H, m), 7.84-7.75 (2H, m), 7.54 (1H, dd, J =8.3, 4.3 Hz) .

2-Amino- N -(2-chloropyridin-3-yl)benzamide

To a solution of N- (2-chloropyridin-3-yl)-2-nitrobenzamide (8.3 g, 29.9 mmol) in ethanol (100 ml) was added water (20 ml), iron (2.67 g, 47. 8 mmol) and ammonium chloride (16 g, 0.3 mol). The mixture was heated at reflux for 40 minutes, then diluted with water and filtered. The filtrate was extracted with ethyl acetate and the combined organics were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as a beige solid (7.4 g, quant.) The material was used without purification. ¹ H NMR (400 MHz, d ₆ -DMSO) δ 9.93 (1H, s), 8.29 (1H, dd, J =4.7, 1.8 Hz), 8.05 (1H, dd, J = 7.9, 1.8 Hz), 7.73 (1H, dd, J = 8.0, 1.5 Hz), 7.48 (1H, dd, J = 7.8, 4.7 Hz ), 7.24 (1H, ddd, J = 8.4, 7.1, 1.5 Hz), 6.78 (1H, dd, J = 8.3, 0.9 Hz), 6.61 ( 1H, ddd, J = 8.1, 7.2, 1.1 Hz), 6.48 (2H, br s).

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

2-Amino- N- (2-chloropyridin-3-yl)benzamide (3.5 g, 14.1 mmol) was heated at 210° C. for 5 min. After reaching 200°C, the reaction mixture turned black and gas bubbles were observed. The reaction mixture was cooled to room temperature and the solid was washed with sat. aq. NaHCO ₃ solution then DCM to give the title product as a gray solid (2.89 g, 96%). The material was used without purification. ¹ H NMR (400 MHz, d ₆ -DMSO): δ 9.94 (1H, s), 8.63 (1H, s), 7.90 (1H, dd, J =4.84, 1.6 Hz ), 7.72 (1H, dd, J = 7.9, 1.6 Hz), 7.41-7.29 (2H, m), 7.13 (1H, dd, J = 8.3, 0 .8 Hz), 6.97 (1H, dd, J =7.8, 4.8 Hz), 6.95-6.89 (1H, m).

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

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

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

,

,

in which R may represent hexyl.

Example 24

Human muscarinic receptor assay

Analysis protocol for M ₁ -M ₅

M ₁

Cell membrane homogenates (45 µg of protein) were incubated for 60 min. at 22°C with 2 nM [3H]pirenzepine in the absence or presence of test compound in buffer containing 50 mM Tris-HCl (pH 7.4), 120 mM NaCl, 5 mM KCl, 5 mM MgCl ₂ and 1 mM EDTA . Non-specific binding was determined in the presence of 1 μM atropine. After incubation, samples were quickly filtered under vacuum through glass fiber filters (GF/B, Packard) presoaked with 0.3% PEI and washed several times with ice-cold 50 mM Tris-HCl using a 96 sample cell harvester (Unifilter, Packard). The filters were dried, then the radioactivity was determined in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The results are expressed as percent inhibition of specific binding of the control radioligand. The standard reference compound was pirenzepine, which was tested in each experiment at several concentrations to obtain a competitive success curve from which its K _i and IC ₅₀ were calculated.

M ₂

Cell membrane homogenates (60 μg of protein) were incubated for 60 min. at 22°C with 2 nM [3H]AF-DX 384 in the absence or presence of test compound in a buffer containing 50 mM Tris-HCl (pH 7.4), 120 mM NaCl, 5 mM KCl, 5 mM MgCl2 and 1 mM EDTA. Non-specific binding was determined in the presence of 1 μM atropine. After incubation, samples were quickly filtered under vacuum through glass fiber filters (GF/B, Packard) presoaked with 0.3% PEI and washed several times with ice-cold 50 mM Tris-HCl using a 96 sample cell harvester (Unifilter, Packard). The filters were dried, then the radioactivity was determined in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The results are expressed as percent inhibition of specific binding of the control radioligand. The standard reference compound was methoctramine, which was tested in each experiment at several concentrations to obtain a competitive success curve from which its K _i and IC ₅₀ were calculated.

M ₃

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

M ₄

Cell membrane homogenates (16 µg of protein) were incubated for 60 min. at 22° C. with 0.2 nM [3H]4-DAMP in the absence or presence of test compound in a buffer containing 10 mM Tris-HCl (pH 7.4) and 2 mM EDTA. Non-specific binding was determined in the presence of 1 μM atropine. After incubation, samples were quickly filtered under vacuum through glass fiber filters (GF/B, Packard) presoaked with 0.3% PEI and washed several times with ice-cold 50 mM Tris-HCl using a 96 sample cell harvester (Unifilter, Packard). The filters were dried, then the radioactivity was determined in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The results are expressed as percent inhibition of specific binding of the control radioligand. The standard reference compound was 4-DAMP, which was tested in each experiment at several concentrations to obtain a competitive success curve from which its K _i and IC ₅₀ were calculated.

M ₅

Cell membrane homogenates (15 μg of protein) were incubated for 60 min. at 22° C. with 0.3 nM [3H]4-DAMP in the absence or presence of test compound in a buffer containing 10 mM Tris-HCl (pH 7.4) and 2 mM EDTA. Non-specific binding was determined in the presence of 1 μM atropine. After incubation, samples were quickly filtered under vacuum through glass fiber filters (GF/B, Packard) presoaked with 0.3% PEI and washed several times with ice-cold 50 mM Tris-HCl using a 96 sample cell harvester (Unifilter, Packard). The filters were dried, then the radioactivity was determined in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The results are expressed as percent inhibition of specific binding of the control radioligand. The standard reference compound was 4-DAMP, which was tested in each experiment at several concentrations to obtain a competitive success curve from which its K _i and IC ₅₀ were calculated.

Binding affinity M ₁ -M ₅

The results of the analysis of human muscarinic receptors of some compounds of the present invention are shown in the table below.

Connections Analysis: K _i (nM) M ₁ M ₂ M ₃ M ₄ M ₅

3.4 6.8 1 0.58 0.6

3.5 15 2.9 0.48 0.71

3.1 eleven 2 0.58 0.68

19 72 13 7.4 8.5

27 110 14 5.8 7.2

2.5 7.9 0.78 0.39 0.71

230 <50% at 1 µM 150 83 52

4.4 35 1.3 0.71 1.1

3.4 39 1.3 0.57 0.99

8.2 240 2.0 1.7 1.9

17 54 4.1 3.0 4.5

600 <50% at 1 µM <50% at 1 µM 230 280

300 <50% at 1 µM 310 200 160

570 <50% at 1 µM 610 <50% at 1 µM 320

Results showing inhibition or stimulation above 50% are considered to represent significant effects of the test compounds.

The compounds of the present invention and their pharmaceutically acceptable salts may be present in combination with one or more pharmaceutical carriers to form various types of delivery formulations. For example, topical formulations may 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 in review articles, for example, "Recent Advances in Topical Ocular Drug Delivery", by V.K. Yellepeddi and S. Palakurthi (J. Ocul. Pharmacol. Ther. 2016, 32(2):67-82), incorporated herein by reference in its entirety. Also contemplated are formulations for systemic administration (eg, orally swallowed tablets) and formulations for intraocular injection. (pharmaceutically acceptable carriers) Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company (incorporated herein by reference in its entirety), standard pharmaceutical reference text.

The particular type of composition selected will depend on various factors such as the compound or salt thereof to be used, the frequency of dosing, the location of the disease being treated, the chosen route of administration, and standard pharmaceutical practice. Ophthalmologically compatible topical aqueous solutions, suspensions, ointments and gels are the preferred dosage forms for the treatment of ophthalmic disorders in the anterior part of the eye (cornea, iris, trabecular meshwork) or ophthalmic disorders in the posterior part of the eye, if the compound can be formulated so that it can be delivered by topical application and is able to penetrate into the tissues of the anterior part of the eye. The compound according to formula (I) will typically be present in such formulations in an amount of from about 0.01 to about 10.0 w/%. Preferred concentrations for topical administration range from about 0.1 to about 5.0 w/%. Thus, for topical administration, these formulations are delivered to the surface of the eye from one to six times per day, depending on the judgment of the appropriately qualified physician. Systemic administration, eg in the form of tablets, is useful for the treatment of an ophthalmic disease, especially the back of the eye, eg the retina.

The compounds of the present invention are preferably included in ophthalmologically compatible formulations for delivery to the eye. The compounds may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride and water to form an aqueous, sterile ophthalmic suspension or solution. Ophthalmic solution formulations can be prepared by dissolving the compound in a physiologically acceptable isotonic aqueous buffer. In addition, the ophthalmic solution may include an ophthalmologically acceptable surfactant to ensure dissolution of the compound. Moreover, the ophthalmic solution may contain a viscosity increasing agent such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the composition in the conjunctival sac. Gelling agents may also be used, including but not limited to gellan and xanthan gum. To obtain sterile ophthalmic ointment formulations, the active ingredient is combined with a preservative in an appropriate carrier medium such as mineral oil, liquid lanolin or white petrolatum. Sterile ophthalmic gel formulations can be prepared by suspending the compound in a hydrophilic base derived from a combination of, for example, Carbopol-974 or the like, according to published formulations for similar ophthalmic formulations; preservatives and tonicity agents may be included.

Pharmaceutical compositions may include one or more buffering agents or pH adjusting agents to provide improved pH control. In some topical embodiments, the pharmaceutical composition of the present invention has a pH of 5.0 to 8.0, 5.0 to 7.0, 6.0 to 8.0, or 6.0 to 7.0 . In one embodiment, the pH of the pharmaceutical composition of the present invention is from about 6.3 to about 7.3. In a specific embodiment, the aqueous pharmaceutical composition of the present invention has a substantially neutral pH of approximately 6.8.

Other contemplated adjuvants that can 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 adjuvants such as serum albumin (human serum albumin), recombinant human albumin, gelatin, casein, salt-forming counterions such as sodium and the like. These and additional known pharmaceutical excipients and/or additives suitable for use in the formulations of the present invention are known in the art, for example, see "The Handbook of Pharmaceutical Excipients, ^4th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, ^21st edition, Gennaro, Ed., Lippincott Williams & Wilkins (2005).

In another aspect, the present invention provides a pharmaceutical composition comprising: (1) a compound of the present invention, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable and pharmaceutically acceptable carrier. In one embodiment, the composition contains a therapeutically effective amount, preferably from about 0.01 to about 10.0 percent by weight, more preferably from about 0.01 to about 5 percent by weight/volume, or from about 0.1 to about 5, 0 percent by weight of (a) said compound and/or (b) said pharmaceutically acceptable salt. In an additional embodiment, the composition contains at least two such pharmaceutically acceptable carriers as described herein. For the purposes of the present invention, unless otherwise indicated, solvates and hydrates generally refer to the compositions in question. Preferably, the pharmaceutically acceptable carriers are sterile. The pharmaceutical composition may be formulated for specific routes of administration such as oral administration, parenteral administration and rectal administration, etc. In addition, the pharmaceutical compositions of the present invention may be formulated into solid form (including, without limitation, capsules, tablets, pills, granules, powders or suppositories) or in liquid form (including, without limitation, solutions, suspensions or emulsions). Pharmaceutical compositions may be subjected to conventional pharmaceutical processing steps such as sterilization and/or they may contain conventional inert diluents, lubricants or buffers, as well as adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc. .

In another embodiment of the present invention, the pharmaceutical compositions are tablets or gelatin capsules containing the active ingredient together with one or more of:

a) diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;

b) lubricants, for example, silicon dioxide, talc, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; also in the case of tablets

c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if necessary

d) baking powder, for example, types of starch, agar, alginic acid or its sodium salt or effervescent mixtures; And

e) absorbents, colors, flavors and sweeteners.

Tablets can be either film-coated or enteric-coated according to methods known in the art.

Pharmaceutical compositions of the present invention may include an additional therapeutic agent in addition to the compounds of the present invention. Additional therapeutic agents may include, for example, other compounds and antibodies useful in the treatment of ophthalmic diseases.

The pharmaceutical compositions of the present invention may be administered to a patient. As used herein, the term "subject" or "patient" refers to humans and non-human mammals, including, without limitation, primates, rabbits, pigs, horses, dogs, cats, sheep, and cows. Preferably the subject or patient is a human.

Various delivery methods are contemplated for administering pharmaceutical compositions, and these may include, for example, topical, intravitreal, oral, IV, intraocular, and other methods known to those skilled in the art.

In one embodiment, administration will typically be via a syringe. Thus, the present invention provides a delivery device (eg, a syringe) containing a pharmaceutical composition of the present invention (eg, a pre-filled syringe). Patients will receive an effective amount of a compound according to formula (I) as the main active ingredient.

In yet another embodiment, ophthalmic inserts or films are used to deliver a compound of the present invention. In one such embodiment, a compound of formula (I) is formulated into a polymeric ophthalmic insert containing one or more mucoadhesive polymers that are biocompatible with the ocular surface and the tear film of the eye. In some embodiments, after insertion of the polymeric ophthalmic insert into the blind sac of the eye, the thickness of the tear film may increase for at least 30 minutes after insertion. One or more mucoadhesive polymers may be selected from the group consisting of: hyaluronic acid (acid or salt form), hydroxypropyl methylcellulose (HPMC), methylcellulose, tamarind seed polysaccharide (TSP), guar, hydroxypropyl guar (HP-guar), scleroglucan, poloxamer , poly(galacturonic) acid, sodium alginate, pectin, xanthan gum, xyloglucan gum, chitosan, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidine, carbomer, polyacrylic acid, and combinations thereof. In one embodiment of the present description, one or more mucoadhesive polymers can be HP-guar, hyaluronic acid, and sodium hyaluronate.

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

As used herein, all percentages are percentages by weight unless otherwise indicated. Unless otherwise indicated, terms in the singular mean "one", "at least one", or "one or more". Unless the context otherwise requires, singular terms used herein should include the plural, and plural terms should include the singular. For the purpose of clarity, the contents of any patents, patent applications and references cited throughout this specification are hereby incorporated by reference in their entirety.

COMPOSITION EXAMPLES

The following examples are provided to demonstrate embodiments of the present invention. Those skilled in the art will appreciate that it is possible to make changes to the specific embodiments disclosed herein and still obtain a similar result without departing from the spirit and scope of the present invention.

COMPOSITION EXAMPLE 1. Ophthalmic topical preparation

Ingredients Concentration (% w/v) Compound of formula (I) 0.01-2% Hydroxypropyl methylcellulose 0.5% Dibasic sodium phosphate (anhydrous) 0.2% Sodium chloride 0.5% Disodium EDTA (edetate disodium) 0.01% Polysorbate 80 0.05% Benzalkonium chloride 0.01% Sodium hydroxide/hydrochloric acid To bring the pH to 7.3-7.4 Purified water How much will it take to 100%

The present invention and its embodiments have been described in detail. However, specific embodiments of any process, manufacturing option, compound-based composition, compounds, means, methods and/or steps described herein are not intended to limit the scope of the present invention. Various modifications, substitutions and changes can be made in the disclosed substance without deviating from the essence and/or essential features of the present invention. Accordingly, one skilled in the art will readily appreciate upon reading the present invention that further modifications, substitutions, and/or variations that perform substantially the same function or achieve substantially the same result as the embodiments disclosed herein may be used. in accordance with such related embodiments of the present invention. Thus, the following claims are intended to cover modifications, substitutions, and variations of the processes, manufacturing options, compound-based compositions, compounds, means, methods, and/or steps disclosed herein. The claims are not to be construed as being limited to the order or elements described unless specifically indicated. It should be appreciated that various changes in form and content may be made without departing from the scope of the appended claims.

Claims (8)

1. Connection

or

2. Pharmaceutical composition used as a muscarinic receptor modulator, containing: (1) a compound according to claim 1 and/or a pharmaceutically acceptable salt thereof; and (2) one or more pharmaceutically acceptable carriers. 3. The composition of claim 2, wherein said composition is an ophthalmologically compatible composition. 4. A composition according to claim 2 or 3, wherein said composition contains a therapeutically effective amount of said compound and/or said pharmaceutically acceptable salt thereof. 5. A composition according to claim 2 or 3, wherein said composition contains from 0.01 to 10.0 percent by weight of said compound and/or said pharmaceutically acceptable salt. 6. Composition according to any one of paragraphs. 2-5, where the specified composition contains: from 0.01 percent by weight/volume to 5 percent by weight/volume of the specified compound and/or the specified pharmaceutically acceptable salt; or from 0.1 to 5.0 percent by weight of said compound and/or said pharmaceutically acceptable salt. 7. The composition according to any one of paragraphs. 2-6, where the specified composition is a composition for topical application.

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