ES2366058T3 - 8-AZABICICLO COMPOUNDS [3.2.1] OCTANO AS ANTAGONISTS OF OPIOID RECEPTORS MU. - Google Patents

Abstract

A compound of formula (I): ** Formula ** where: R1 is chosen from-ORa, -C (O) NRaRb, -NHS (O) 2Rc, -NRaRb, -C (O) ORa and -CH2OH; A is C1-4 alkylenyl; R2 is C3-12 cycloalkyl or C6-10 aryl, so that C3-12 cycloalkyl and C6-10 aryl are each optionally substituted with a -ORa, with one or two halogens, with one or two C1-3 alkyls substituted with two or three halogens, or with one, two, three or four C1-3 alkyls; G is C1-4 alkylenyl; R3 is selected from hydrogen, -C (O) R4, -C (O) NHR5, -S (O) 2Rc and -S (O) 2NRaRb; R4 is C3-6 cycloalkyl or C1-6 alkyl, where the C3-6 cycloalkyl is optionally substituted with a -ORa and C1-6 alkyl is optionally substituted with one or two substituents chosen from -ORa, -C (O) ORa , -S (O) 2R6, -C (O) NRaRb, -NRaRb, -NHC (O) NRaRb, -CN, C3-6 cycloalkyl and phenyl, or with a D- (CH2) JR7, where D is where j is 1, 2, or 3, n is 1 or 2 and p is 1 or 2, R6 is C1-6 alkyl optionally substituted with R7, R7 is -C (O) ORa, -C (O) NRaRb, -NRaRb or - NHC (O) NRaRb, R5 is C1-6 alkyl, benzo [1.3] dioxol or - (CH2) q-phenyl, where the phenyl is optionally substituted with one or two substituents chosen from halogen, -ORa, C1-3 alkyl and C1-3 alkoxy, where C1-3 alkyl and C1-3 alkoxy are optionally substituted with 2 or 3 halogens, and q is 0, 1 or 2, Ra and Rb are independently hydrogen or C1-4 alkyl, and Rc it is C1-3 alkyl, with the proviso that, when R2 is phenyl substituted in the 4 position R3 is not -C (O) R4, where R4 is C1-4 alkyl substituted with -C ( O) ORa; or a pharmaceutically acceptable salt or solvate thereof.

Description

5 BACKGROUND OF THE PRESENT INVENTION

Scope of the present invention

The present invention relates to 8-azabicyclo [3.2.1octane compounds that serve as antagonists of

10 opioid receptors mu. The present invention also relates to pharmaceutical compositions comprising such compounds and has its application in those methods where these compounds are used to treat or improve disorders mediated by the activity of mu opioid receptors. Processes and intermediates useful for the preparation of said compounds are included.

15 Current technical status

It is now generally known that endogenous opioids play a complex role in gastrointestinal physiology. Opioid receptors are expressed throughout the body, both in the central nervous system and in the peripheral regions, including the gastrointestinal (GI) tract.

20 Compounds that act as agonists of opioid receptors, of which morphine is a prototypical example, are the pillars of analgesic therapy in the treatment of moderate to severe pain. Unfortunately, the use of opioid analgesics is often related to adverse effects on the GI tract, collectively designated as opioid-induced intestinal dysfunction (DIO). DIO includes symptoms such as

25 constipation, decreased gastric emptying, abdominal pain and discomfort, bloating, nausea and gastroesophageal reflux. Both central and peripheral opioid receptors are probably involved in the deceleration of gastrointestinal transit after the use of opioids. However, evidence indicates that peripheral opioid receptors of the gastrointestinal tract are primarily responsible for the adverse effects of opioids on GI function.

30 Since the side effects of opioids are predominantly mediated by peripheral receptors and instead analgesia is of central origin, a peripherally selective antagonist could block unwanted side effects related to the GI tract, without interfering with the beneficial central effects. of analgesia or precipitate withdrawal symptoms in the central nervous system.

35 Of the three main subtypes of opioid receptors, called mu, delta and kappa, opioid analgesics of greater clinical use allegedly act by activating opioid receptors mu exerting their analgesic effect and altering GI motility. Therefore it is expected that peripherally selective antagonists of the opioid receptors mu are useful for treating opioid-induced intestinal dysfunction. Preferred agents

40 will bind significantly in vitro to mu opioid receptors and will be active in vivo in animal GI models.

Postoperative ileus (IPO) is a disorder of reduced motility of the GI tract that occurs after abdominal or other surgery. The symptoms of IPO are similar to those of DIO. In addition, as surgical patients are usually treated with opioid analgesics during and after surgery, the duration of the IPO can be seen.

45 increased by the reduction of GI motility associated with the use of opioids. Opioid receptor antagonists mu are useful for treating DIO and therefore are also expected to be beneficial in IPO treatment.

WO 2004/089908 discloses 3-azabicyclo derivatives [3.2.1] for treating diseases mediated by 50 opioid receptors.

SUMMARY OF THE PRESENT INVENTION

The present invention provides new compounds that are active as antagonists of the opioid receptors mu. Correspondingly the present invention provides a compound of formula (I):

image 1

R1 is chosen from-ORa, -C (O) NRaRb, -NHS (O) 2Rc, -NRaRb, -C (O) ORa and -CH2OH; A is C1-4 alkylenyl; R2 is C3-12 cycloalkyl or C6-10 aryl, so that C3-12 cycloalkyl and C6-10 aryl are each optionally substituted with a -ORa, with one or two halogens, with one or two C1-3 alkyls substituted with two or three halogens, or with one, two, three or four C1-3 alkyls; G is C1-4 alkylenyl; R3 is selected from hydrogen, -C (O) R4, -C (O) NHR5, -S (O) 2Rc and -S (O) 2NRaRb; R4 is C3-6 cycloalkyl or C1-6 alkyl, where

C3-6 cycloalkyl is optionally substituted with a -ORa and C1-6 alkyl is optionally substituted with one or two substituents chosen from -ORa, -C (O) ORa, -S (O) 2R6, -C (O) NRaRb, -NRaRb, -NHC (O) NRaRb, -CN, C3-6 cycloalkyl and phenyl, or with a D- (CH2) JR7,

where D is

image2

Where j is 1.2, or 3, n is 1 or 2 and p is 1, 2, R6 is C1-6 alkyl optionally substituted with R7, R7 is -C (O) ORa, -C (O) NRaRb, -NRaRb or -NHC (O) NRaRb, R5 is C1-6 alkyl, benzo [1.3] dioxol or - (CH2) q-phenyl, where the phenyl is optionally substituted with one or two substituents chosen from halogen, -ORa, C1-3 alkyl and C1-3 alkoxy, where C1-3 alkyl and C1-3 alkoxy are optionally substituted with 2 or 3 halogens, and q is 0.1, Ra and Rb are independently hydrogen or C1-4 alkyl, and Rc is C1-3 alkyl,

With the proviso that, when R2 is phenyl substituted at position 4 R3 is not -C (O) R4, where R4 is C1-4 alkyl substituted with -C (O) ORa;

or a pharmaceutically acceptable salt or solvate thereof.

The present invention also provides a pharmaceutical composition bearing a compound of the present invention and a pharmaceutically acceptable carrier.

The present invention is applicable to a method for treating a disease or condition related to the activity of mu opioid receptors, eg a reduced motility disorder of the gastrointestinal tract such as opioid-induced intestinal dysfunction and postoperative ileus. The method is to administer to the mammal

A therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.

The compounds of the present invention can also be used as research means, that is, to study biological samples or systems or the activity of other chemical compounds. Therefore, in another of its aspects, the present invention is applicable to a method for using a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as a means of investigation to study a biological sample or system.

or to find new active compounds against the opioid receptors mu. Said method consists in contacting a sample or biological system with a compound of the present invention and determining the effects produced by the compound in the sample or biological system.

In separate and distinct aspects the present invention also offers synthesis processes and intermediates described herein, which are useful for preparing compounds according to the present invention.

The present invention also provides a compound according to the present invention, as described herein, for use in medical therapy, as well as the use of a compound of the present invention in the preparation of a formulation or a medicament for the treatment of a disease or condition related to the activity of mu opioid receptors, eg a reduced motility disorder of the gastrointestinal tract in a mammal.

55 BRIEF DESCRIPTION OF THE GRAPHICS

Figure 1 shows a powder X-ray diffraction pattern of 3-endo- (8- {2- [cyclohexylmethyl - ((S) -2,3-dihydroxypropionyl) amino] ethyl} -8-azabicyclo [3.2.1 ] oct-3-yl) benzamide crystalline glycolate of the present invention.

Figure 2 shows a powder X-ray diffraction pattern of 3-endo- (8- {2- [cyclohexylmethyl - ((S) -2,3-dihydroxypropionyl) amino] ethyl} -8-azabicyclo [3.2.1 ] oct-3-yl) benzamide crystalline oxalate of the present invention.

Figure 3 shows a powder X-ray diffraction pattern of 3-endo- (8- {2 - [(4,4-difluorocyclohexylmethyl) - (2-hydroxyacetyl) amino] ethyl} -8-azabicyclo [3.2.1] oct -3-yl) benzamide crystalline phosphate of the present invention.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention provides 8-azabicyclo [3.2.1] octane compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, as antagonists of the opioid receptors mu. The substituents and the following values are intended to provide representative examples of the various aspects of this invention. These representative values serve to define these aspects in greater detail and are not intended to exclude other values or limit the scope of the present invention.

In a specific aspect of the present invention R1 is chosen from -ORa, -C (O) NR3Rb, -NHS (O) 2Rc, -NRaRb,

-C (O) ORa and -CH2OH. In other specific aspects R1 is chosen from -ORa, -C (O) NRaRb and -NHS (O) 2Rc, or R1 is -ORa or -C (O) NRaRb, or R1 is –OH or -C (O) NRaRb.

In another more specific aspect R1 is -OH or -C (O) NH2. In another specific aspect R1 is -C (O) NH2. In a specific aspect A is C1-4 alkylenyl. In other specific aspects A is - (CH2) 2-, -CH (CH3) -o –CH2-, or A is - (CH2) 2-or –CH2-, or A is –CH2-. In a specific aspect G is C1-4 alkylenyl. In other specific aspects G is - (CH2) 3-, - (CH2) 2-or –CH2-, or G is –CH2-. In a specific aspect R2 is C3-12 cycloalkyl or C6-10 aryl, where C3-12 cycloalkyl and C6-10 aryl are each

one optionally substituted with a -ORa, with one or two halogens, with one or two C1-3 alkyls substituted with

two or three halogens, or with one, two, three or four C1-3 alkyls. In another specific aspect R2 is C3-12 cycloalkyl or C6-10 aryl, where C3-12 cycloalkyl and C6-10 aryl are each one optionally substituted with a -ORa, with one or two halogens or with one or two C1-3 alkyls optionally substituted with two or three halogens.

In another specific aspect R2 is C3-12 cycloalkyl or C6-10 aryl, where C3-12 cycloalkyl and C6-10 aryl are each one optionally substituted with one or two halogens or with one or two C1-3 alkyls optionally substituted with 2 or 3 halogens. As representative R2 groups of this aspect it is possible to mention, without limitation, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, phenyl and naphthyl, where cyclohexyl, phenyl and naphthyl are each optionally substituted with one or two halogens or with C1-3 alkyl substituted with two or three halogens.

In another specific aspect R2 is cyclobutyl, cyclopentyl, cyclohexyl, adamantyl or phenyl, where cyclohexyl and phenyl are each optionally substituted with one or two halogens or with C1-3 alkyl substituted with two or three halogens

In another specific aspect R2 is cyclohexyl or phenyl, each optionally substituted with one or two halogens or with C1-3 alkyl substituted with two or three halogens, or R2 is cyclohexyl or phenyl, each optionally substituted with one or two halogens.

In another specific aspect R2 is cyclohexyl optionally substituted with one or two halogens. In another specific aspect R2 is cyclohexyl. In another specific aspect R2 is phenyl optionally substituted with one or two halogens. In another specific aspect R2 is phenyl. In a specific aspect R3 is chosen from hydrogen, -C (O) R4, -C (O) NHR5, -S (O) 2Rc and -S (O) 2NRaRb. In another specific aspect R3 is chosen from hydrogen, -C (O) R4, -S (O) 2Rc and -S (O) 2 NRaRb. In a specific aspect R3 is chosen from hydrogen, -C (O) R4 and -C (O) NHR5.

In other specific aspects R3 is -C (O) R4 or -C (O) NHR5, or R3 is -C (O) R4.

In another specific aspect R3 is -C (O) R4, where R4 is C3-6 cycloalkyl or C1-6 alkyl, and where C1-6 alkyl is optionally substituted with one or two -ORa or with a substituent chosen from -C (O) ORa, -S (O) 2R6, - C (O) NRaRb, -NRaRb and C3-6 cycloalkyl, and R6 is C1-3 alkyl optionally substituted with R7, where R7 is -C (O) ORa.

In another specific aspect R3 is -C (O) R4, where R4 is C3-6 cycloalkyl or C1-6 alkyl, and where C3-6 cycloalkyl is optionally substituted with a -ORa and C1-6 alkyl is optionally substituted with one or two substituents chosen from -ORa, -C (O) ORa, -S (O) 2R6, -C (O) NRaRb, -NRaRb, -CN, C3-6 cycloalkyl and phenyl, where R6 is alkyl C1-3 optionally substituted with R7, where R7 is –C (O) ORa.

In another specific aspect R3 is -C (O) R4, where R4 is C5-6 cycloalkyl optionally substituted with a -OH.

In other specific aspects R3 is -C (O) R4, where R4 is C1-4 alkyl optionally substituted with one or two substituents chosen from -ORa, -S (O) 2R6, -NRaRb, -CN, C3-6 cycloalkyl and phenyl, where R6 is C1-3 alkyl, or R4 is C1-4 alkyl optionally substituted with one or two substituents selected from -OH, -OCH3, -S (O) 2CH3, -NH2, -NHCH3, -NH (CH3) 2 and phenyl. As representative values of R4 in this aspect, without limitation, -CH2OH, -CH (OH) CH2OH, -CH2SO2CH3, -CH2SO2CH2C (O) OH, -CH2CN, -CH2OCH3, -C (CH3) 2OH, -CH ( CH3) OH, -CH (OH) CH (CH3) OH, -CH (OH) CH3, - (CH2) N (CH3) 2 and CH (NHCH3) CH2OH.

In another specific aspect R3 is -C (O) R4, where R4 is selected from -CH2OH, -CH (OH) CH2OH, -CH (OH) CH3 and -CH2SO2CH3.

In another specific aspect R3 is -C (O) NHR5.

In another specific aspect R3 is -C (O) NHR5, where R5 is C1-6 alkyl, benzo [1,3] dioxol or - (CH2) q-phenyl, where q is 0 or 1 and the phenyl is optionally substituted with one or two substituents chosen from chlorine, fluorine, -OH and -OCF2.

In other specific aspects R3 is C (O) NHR5, where R5 is C1-6 alkyl or benzo [1,3] dioxol, or R5 is -CH (CH3) 2 or benzo [1,3] dioxol, or R5 is - CH (CH3) 2.

The present invention further provides a compound of formula (I) in which: R1 is -ORa or -C (O) NRaRb; A is - (CH2) 2-or -CH2-; G is - (CH2) 2-or -CH2-; R2 is chosen from cyclobutyl, cyclopentyl, cyclohexyl, adamantyl and phenyl, where cyclohexyl and phenyl are each optionally substituted with 1 or 2 halogens or with C1-3 alkyl substituted with 2 or 3 halogens; R3 is chosen from -C (O) R4, -S (O) 2Rc, -S (O) 2NRaRb and -C (O) NHR5; R4 is C3-6 cycloalkyl or C1-6 alkyl, where C3-6 cycloalkyl is optionally substituted with a -ORa and C1-6 alkyl is optionally substituted with one or two substituents chosen from -ORa, -C (O) OR3, - S (O) 2R6, -C (O) NRaRb, -NRaRb, -CN, C3-6 cycloalkyl and phenyl, where R6 is C1-3 alkyl optionally substituted with R7, where R7 is -C (O) ORa; R5 is C1-4 alkyl, benzo [1.3] dioxol or - (CH2) q-phenyl, where q is 0 or 1 and the phenyl is optionally substituted with one or two substituents chosen from chlorine, fluorine, -OH and -OCF2; Ra and Rb are independently hydrogen or C1-3alkyl, and Rc is C1-3alkyl, with the proviso that when R2 is phenyl substituted at position 4 R3 is not –C (O) R4, where R4 is C1-4 alkyl substituted with -C (O) OH;

or a pharmaceutically acceptable salt or solvate thereof.

In yet another aspect the present invention provides a compound of formula (I) in which: R1 is -OH or -C (O) NH2; A is - (CH2) 2-or -CH2-; G is - (CH2) 2-or -CH2-; R2 is cyclohexyl or phenyl, where the cyclohexyl is optionally substituted with 1 or 2 halogens; R3 is chosen from -C (O) R4 or -C (O) NHR5; R4 is chosen from -CH2OH, -CH (OH) CH2OH, -CH (OH) CH3 and -CH2SO2CH3, and R5 is -CH (CH3) 2 or benzo [1,3] dioxol;

or a pharmaceutically acceptable salt or solvate thereof.

The present invention further provides a compound of formula (I ’):

image 1

where: R2 is cyclohexyl or phenyl, where cyclohexyl and phenyl are each optionally substituted with one or two halogens, and

R4 is C3-6 cycloalkyl or C1-4 alkyl,

wherein the C3-6 cycloalkyl is optionally substituted with a -ORa, and the C1-4 alkyl is optionally substituted with one or two substituents chosen from -ORa, -S (O) 2R6, -NRaRb, -CN and C3-6 cycloalkyl , Ra and Rb are, independently, hydrogen or C1-3 alkyl, and R6 is C1-3 alkyl,

or a pharmaceutically acceptable salt or solvate thereof.

In this aspect the present invention provides a compound of formula (I ') wherein R 4 is C 1-4 alkyl optionally substituted with one or two substituents chosen from -OH, -OCH3, -S (O) 2CH3, -NH2, -NHCH3 , and NH (CH3) 2.

Also in this aspect the present invention provides a compound of formula (I ′) wherein R2 is cyclohexyl or 4.4 difluorocyclohexyl and R4 is C1-4 alkyl substituted with one or two-OH.

In addition the present invention provides the compounds of examples 1-204 of this document.

The chemical nomenclature convention employed here is illustrated by the compound of example 1:

image3

25

which is N-benzyl-2-hydroxy-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} acetamide. Alternatively, using the IUPAC conventions implemented in the AutoNom program (MDL Information Systems, GmbH, Frankfurt, Germany), the compound is called N-benzyl-2-hydroxy-N- {2 - [(1R, 3R, 5S) -3- (3-hydroxyphenyl) -8azabicyclo [3.2.1] oct-8-yl] ethyl} acetamide. The names used here therefore correspond to the IUPAC notation with the endo orientation of the substituted phenyl group with respect to the 8-azabicyclo [3.2.1] octane group explicitly indicated. All compounds of the present invention have endo orientation. As used herein for convenience, the term "8-azabicyclooctane" means 8-azabicyclo [3.2.1] octane.

Apart from the endo stereochemistry with respect to the bicyclo group, the compounds of the present invention may contain a chiral center at the R4, R5 or A substituents. Therefore the present invention includes racemic mixtures, pure stereoisomers and mixtures of said isomers. enriched with stereoisomers, unless otherwise indicated. When the stereochemistry of a compound is specified, including the orientation with respect to the group 8azabicyclooctane and the chirality of the R4, R5 or A substituents, those skilled in the art will understand that the compositions of the present invention may contain small amounts of other stereoisomers, to unless otherwise indicated, and provided that the presence of these other isomers does not rule out the general utility of the composition.

Definitions

In the description of the compounds, compositions and methods of the present invention the following terms have the following meanings, unless otherwise indicated.

The term "alkyl" means a monovalent saturated hydrocarbon group, which may be linear or branched or combinations thereof. Unless otherwise defined, these alkyl groups normally contain 1 to 10 carbon atoms. Representative examples of alkyl groups include methyl, ethyl, n-propyl (n-Pr), isopropyl (i-Pr), n-butyl (n-Bu), sec-butyl, isobutyl, tert-butyl, n-pentyl , n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

The term "alkylenyl" means a divalent saturated hydrocarbon group, which may be linear or branched or combinations thereof. Unless otherwise defined, these alkylene groups usually carry 1 to 10 carbon atoms. Representative examples of alkylenyl groups include methylene, ethylene, n-propylene, n-butylene, propane-1,2-diyl (1-methylethylene), 2-methyl-propane-1,2-diyl (1,1-dimethylethylene ) and the like.

The term "alkoxy" means a group -O-monovalent alkyl, where alkyl is defined as above. Representative examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy and the like.

The term "cycloalkyl" means a monovalent saturated carbocyclic group, which may be monocyclic or multicyclic. Unless defined otherwise, these cycloalkyl groups typically contain 3 to 10 carbon atoms. Representative examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl and the like.

The term "aryl" means a monovalent aromatic hydrocarbon having a single ring (ie, phenyl) or condensed rings (eg naphthalene). Unless defined otherwise, these aryl groups usually have between 6 and 10 carbon atoms in the ring. Representative examples of groups include phenyl, naphthalen-1-yl, naphthalen-2-yl and the like.

The term "halo" means fluorine, chlorine, bromine or iodine.

The term "compound" means prepared by synthesis or otherwise, for example as a metabolic product.

The term "therapeutically effective amount" means an amount sufficient to produce effect when administered to a patient in need of treatment.

As used herein, the term "treatment" means the therapy of a disease, disorder or medical condition of a patient such as a mammal (in particular a human), which includes:

(TO)

prevent the occurrence of disease, disorder or medical condition, that is, the prophylactic treatment of a patient;

(B)

improve the disease, disorder or medical condition, that is, eliminate or cause the regression of a patient's disease, disorder or medical condition, even counteracting the effects of other therapeutic agents;

(C)

suppress the disease, disorder or medical condition, that is to stop or stop the development of a patient's disease, disorder or medical condition, or

(D)

relieve the symptoms of a patient's disease, disorder or medical condition.

The term "pharmaceutically acceptable salt" means a salt prepared from an acid or base that is tolerable for administration to a patient such as a mammal. These salts may be derived from pharmaceutically acceptable inorganic or organic acids and pharmaceutically acceptable bases. Pharmaceutically acceptable salts of the compounds of the present invention are normally prepared from acids.

Salts derived from pharmaceutically acceptable acids include, but are not limited to, adipic, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, glycolic, hydrobromic, hydrochloric, lactic, maleic, malic, mandelic acids, methanesulfonic, mucic, nitric, oxalic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, xinafoic (1-hydroxy-2-naphthoic), naphthalen-1,5-disulfonic and the like.

The term "solvate" means a complex or aggregate formed by one or more molecules of a solute, that is, a compound of the invention or a pharmaceutically acceptable salt thereof, and one or more solvent molecules. Such solvates are generally crystalline solids with a fundamentally fixed molar ratio of solute and solvent. Representative examples of solvents include water, methanol, ethanol, isopropanol, acetic acid, and the like. When the solvent is water, the solvate formed is a hydrate.

It will be appreciated that the term "or a pharmaceutically acceptable salt or solvate thereof" is intended to include all combinations of salts and solvates, such as a solvate of a pharmaceutically acceptable salt of a compound of the formula (I).

The term "amino protecting group" means a suitable group to avoid unwanted reactions in an amine nitrogen. As representative examples of amino protecting groups, formal, but not limited to, may be mentioned; acyl groups, for example, alkanoyl groups such as acetyl and trifluoroacetyl; alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr) and 1,1-di- (4'-methoxyphenyl) methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS), and the like.

General Synthesis Procedures

The compounds of the present invention can be prepared from readily available materials with the following general methods and procedures. Although the schemes indicated below illustrate a particular aspect of the present invention, those skilled in the art will note that all variants of the present invention can be prepared using the methods described herein or using other known methods, reagents and starting materials of the specialists. It will also be appreciated that where typical or preferred process conditions (ie, temperatures and reaction times, molar proportions of reagents, solvents, pressures, etc.) are indicated, other process conditions can also be used, unless the opposite is established. The

The optimal reaction conditions may vary according to the reagents or solvents used in particular, but they can be established by the specialist by routine optimization procedures.

Also, as is evident to specialists, conventional protecting groups may be needed to prevent certain functional groups from experiencing unwanted reactions. The choice of a protective group

15 suitable for a specific functional group, as well as suitable conditions for protection and deprotection, are well known in the technical state. For example, in T.W. Greene and G.M. Wuts, Protecting Groups in Organic Synthesis, third edition, Wiley, New York, 1999, and the references cited there describe numerous protection groups, as well as their introduction and extraction.

According to a synthesis method the compounds of the present invention are prepared as shown in Scheme A. (The substituents and variables that appear in the following schemes have the definitions provided above, unless otherwise indicated).

Scheme A

In Scheme A R4a represents R4 or a protected form of R4 and L a leaving group, such as chlorine or bromine, or R4aC (O) -L represents a carboxylic acid group or a carboxylate salt. For example, a reagent useful for

image 1

30 preparing a compound in which R4 is -CH2OH is acetoxyacetyl chloride, where R4a is -CH2OC (O) CH3 and L is chlorine. When R4a is a protected form of R4 the reaction (i) also includes a deprotection step, not shown here. To prepare a compound in which R1 represents amino, intermediate (II) preferably uses a protected amino group for R1 and the reaction sequence includes a final deprotection step.

The optimum reaction conditions (i) of scheme A to prepare the compounds of the formula (Ia) may vary depending on the chemical properties of the R4aC (O) -L reagent, as is well known to specialists. For example, when L is a leaving halogen, such as chlorine, the reaction of (i) is usually carried out by contacting intermediate (II) with approximately 1 to 2 equivalents of a compound of formula R4aC (O) -L in an inert diluent such as dichloromethane, in the presence of an excess of base, for example, between

About 3 and 6 equivalents of bases such as N, N-diisopropylethylamine or triethylamine. Suitable inert diluents are also 1,1,2,2-tetrachloroethane, tetrahydrofuran, dimethylacetamide, and the like. The reaction is usually carried out at a temperature between about -50 ° C and 30 ° C for about a quarter of an hour to about 16 hours, or until the reaction is almost complete.

When the R4aC (O) -L reagent is a carboxylic acid or a carboxylate salt, the reaction of (i) is usually carried out by contacting intermediate (II) with approximately 1 to 5 equivalents of R4aC (O) acid OH or the carboxylate salt, for example R4aC (O) OLi in a diluent and in the presence of an excess of base, as described above, and in the presence of about 1 to 6 equivalents of an activating agent such as N, Ncarbonyldiimidazole (CDI), N, N, N ', N'-tetramethyl-O- (7-azabenzotriazol-l-yl) uronium hexafluorophosphate (HATU) or 1- (3-dimethyl

50 aminopropyl) -3-ethylcarbodiimide (EDC). The reaction is usually carried out at a temperature between about 25 ° C and 100 ° C, for about 2 to 16 hours, or until the reaction is almost complete.

As described in the following examples, specific compounds of formula (Ia) can be prepared by coupling an intermediate of formula (II) with alternative reagents such as cyclic anhydrides or a dioxolancarboxylic acid.

The preparation of urea compounds of formula (Ib) is represented in reaction (ii) of scheme A. The reaction is usually carried out by contacting intermediate (II) with approximately 1 to 2 equivalents of an isocyanate compound R1- N = C = O in the presence of approximately 3 to 6 equivalents

10 of a base such as N, N-diisopropylethylamine. The reaction is usually conducted at room temperature for approximately one hour to 16 hours, or until the reaction is almost complete.

Scheme B1 indicates a general procedure for preparing an intermediate of formula (II), where P1 represents an amino-protecting group. fifteen

Scheme B1

An intermediate of formula (III), designated herein as "phenyltropane", is reacted by reductive N-alkylation with an aldehyde of formula (IV) to give a protected intermediate (V) that is deprotected by usual procedures to give the intermediate (II).

The initial reaction is usually carried out by contacting intermediate (III) with approximately between

1 and 2 equivalents of an aldehyde of formula (IV) in a suitable diluent, usually an inert diluent, in the presence of about 0.9 to 2 equivalents of a reducing agent. The reaction is usually carried out at a temperature between about 0 ° C and room temperature, for half an hour to about 3 hours, or until the reaction is almost complete. Dichloromethane and those listed above serve as inert diluent. Likewise, alcohols such as methanol or ethanol can be used.

Typical reducing agents include sodium triacetoxyborohydride, sodium borohydride and sodium cyanoborohydride. The product (V) is isolated by common methods. Deprotection of (V) is performed by standard procedures. For example, when the protective group P1 is Boc, (V) is usually treated with an acid such as trifluoroacetic acid to obtain intermediate (II). In the reaction of Scheme B1 the intermediate (III) may be presented as a free base or salt. In the latter case, approximately 1 base equivalent can be used in the reaction.

In Scheme B2, another general procedure for preparing an intermediate of formula (II) is indicated.

B2 scheme

image4

where L 'represents a leaving sulfonate group such as mesylate or tosylate. The reaction is usually carried out by contacting intermediate (IIa) with approximately 1 to 2 equivalents of the R2-G-NH2 amine in an inert diluent such as dimethylformamide or an alcohol, in the presence of approximately 1 to 2 equivalents of a base such as N, N-diisopropylethylamine or the like. The reaction is usually carried out at a temperature

between about 25 ° C and 80 ° C, for about half an hour to about 2 hours, or until the reaction is almost complete.

The intermediates of formula (IIa) can be prepared by standard procedure. For example, an intermediate

5 of formula (IIa) in which L 'is mesylate can be prepared in the manner described in example 130. A halogen-substituted alcohol of formula HO-A-CH2-X, where X is a halogen, is reacted with phenyltropane ( III) to give an intermediate alcohol, coupling the HO-A-CH2-X to the tropane nitrogen, and then with methanesulfonyl chloride to obtain the intermediate (IIa).

10 Scheme B3 indicates a third procedure for preparing intermediates (II).

Scheme B3

image5

where Ga is defined such that Ga-CH2 corresponds to the variable G, that is, Ga is C1-3 alkylenyl or a covalent bond. Intermediate (IIb) is reacted by reductive N-alkylation with aldehyde R2-Ga-C (O) H to give intermediate (II). The reaction is normally carried out under the conditions described above for N-alkylation.

20 of (III) in scheme B1. Intermediate (lIb) can be prepared by phenyltropane (III) reductive N-alkylation with an amino-protected aldehyde of the formula N (HP1) -A-C (O) H, followed by a deprotection step.

In another alternative method for the preparation of intermediate (II) a carboxylic acid reagent is coupled with phenyltropane (III) in the presence of an amide coupling agent, to form an intermediate amide which is then reduced to obtain intermediate (II ), as described below, for example, in preparation 22.

In another alternative process, an intermediate of formula (II) in which the variable A is methylene is prepared by the process of scheme C.

30 Scheme C

image6

As indicated in Scheme C, intermediate (III) is reacted by reductive N-alkylation with

Dimethoxyacetaldehyde, under the reaction conditions described above, to give the acetal intermediate (VI). Then the acetal intermediate (VI) is hydrolyzed in an aqueous solution of strong acid, for example 3N or 6N HCl, to give intermediate (VII) as hydrochloride. This reaction is usually carried out at a temperature between about 20 ° C and 40 ° C for about 3 to 72, until the reaction is almost complete.

Finally, the reductive amination of intermediate (VII) with an amine of formula R2-G-NH2 provides the intermediate of formula (II ’). Normally the aldehyde (VII), in an inert diluent, is contacted with approximately 1 to 2 equivalents of amine, in the presence of approximately 1 to 2 equivalents of a reducing agent and a base equivalent. The reaction is usually carried out at room temperature for a time between 15 minutes and 2 hours, or until the reaction is almost complete.

Intermediates (III) and (IV) can be prepared from readily available materials. For example, scheme D indicates a process for preparing phenyltropane (III ’) in which R1 is hydroxyl.

Scheme D

image 1

10 where Bn means the benzyl amino-protecting group. Protected tropanone (VIII) can be prepared by reacting 2,5-dimethoxytetrahydrofuran with benzylamine and 1,3-acetondicarboxylic acid in an acidic aqueous solution, in the presence of a buffering agent, as described in US Patent 2005/0228014 . (See also patent 5,753,673).

Tropanone (VIII) is first added to a solution of between 1 and 2 equivalents of the Grignard reagent 3-methoxyphenyl magnesium bromide in an inert diluent. The reaction is normally carried out at a temperature between approximately 0 ° C and 10 ° C and for an approximate time of 1 to 3 hours, or until the reaction is practically complete. Transmetalation of Grignard reagent, from magnesium to cerium by reaction

20 with an equivalent amount of waxy chloride before use, it is convenient to obtain a good yield of intermediate (IX). The hydroxyl substituent of intermediate (IX) was removed by treatment with 6N aqueous HCl solution, to give the hydrochloride of intermediate (X). This reaction is normally carried out at a temperature between approximately 50 ° C and 100 ° C, for an approximate time of 1 to 3 hours, or until the reaction is practically complete.

The hydrogenation of intermediate (X) saturates the double bond of the alkene fragment and removes the benzyl protecting group, giving intermediate (XI). In general, the reaction is carried out by exposing the HCl salt of (X) in ethanol to a hydrogen atmosphere in the presence of a transition metal catalyst. Finally, the intermediate methyl group (XI) was removed by contacting a cooled solution of intermediate (XI) in an inert diluent with

About 1 to 2 equivalents of boron tribromide, hydrogen bromide or boron trichloride. The reaction is usually carried out at a temperature between approximately -80 ° C and 0 ° C, for about 12 to 36 hours, or until the reaction is almost complete. Alternatively, intermediate (XI) can be isolated as a hydrochloride salt, which was treated with approximately 1 to 2 equivalents of aqueous hydrobromic acid to give intermediate phenyltropane (III ’).

35 Intermediate (III ’) can be isolated as a free base or as a hydrobromide, using standard procedures. The crystallization of the hydrobromide produces intermediate (III ’) with great stereospecificity in endo configuration (endo to exo ratio greater than 99.1: 0.8).

40 As described in the following examples, certain variations of the above process can be made to prepare the intermediate (III ’). For example, different reagents can be used to remove hydroxyl from (IX) and obtain intermediate (X), which can be isolated as a free base or salt. In another alternative sequence of the process the treatment of intermediate (IX) with boron tribromide or HBr removes the methyl group, since it eliminates the hydroxyl substituent.

45 Scheme E indicates a process for preparing intermediate (III), in which the variable R1 is -C (O) NH2 and as a starting material is used (III ’).

Scheme E

where-OTf represents trifluoromethanesulfonate (commonly triflate) and P2 an amino-protecting group.

For example, when Boc is used as a protecting group, phenyltropane (III ’) is first reacted, usually with 1 equivalent of di-tert-butyl dicarbonate (commonly Boc2O), to give the intermediate protected with Boc (XII). The reactants are usually cooled to approximately 0 ° C and then allowed to warm to room temperature for a period of about 12 to 24 hours. When trifluoroacetyl is used as the protecting group, (III ’) is usually reacted with about 2 equivalents of trifluoroacetyl anhydride, to form the protected intermediate (XII). Then intermediate (XII), in an inert diluent, is contacted with a slight excess, for example 1.1 equivalents, of trifluoromethanesulfonyl chloride, in the presence of approximately 1 to 2 equivalents of base, to give the intermediate (XIII), which can be isolated by current methods. The reaction (XIV) is obtained by reacting (XIII) with zinc cyanide in the presence of a transition metal catalyst. This reaction is normally carried out at a temperature between about 60 ° C and 120 ° C, under an inert atmosphere, for about 2 to 12 hours or until the reaction is practically complete.

Finally, the intermediate nitrile (XIV) is hydrolyzed and deprotected to obtain the intermediate carboxamide (III ”). Usually in this reaction, when P2 is Boc, intermediate (XIV) is contacted in an acid solvent, such as, for example, trifluoroacetic acid, with about 4 to 6 equivalents of concentrated sulfuric acid. Normally the reaction is carried out at a temperature between about 50 ° C and 80 ° C for about 8 to 24 hours or until the reaction is practically complete. The product is usually isolated as a free base. Alternatively, the conversion of (XIV) to (III ”) is carried out in two steps, first hydrolyzing the nitrile substituent of intermediate (XIV) to carboxamide by reaction with potassium carbonate and hydrogen peroxide and then removing the Boc protecting group by treatment with acid, for example with trifluoroacetic acid.

When a trifluoroacetyl protecting group is used, the intermediate nitrile is first hydrolyzed to carboxamide in concentrated sulfinic acid, as described above. The extinction of the hydrolysis reaction by the addition of a base also eliminates the protective group. The product is usually isolated in the form of hydrochloride. However, in the following examples another alternative reaction sequence is described, in which a protected cyanophenyltropane intermediate is used.

An intermediate of formula (III) in which R1 is NHS (O) 2Rc can be prepared from intermediate (XIII) of scheme E. As described, for example, in preparation 23 below, an intermediate of formula (III) in which R1 represents NHS (O) 2CH3 can be prepared by reacting intermediate (XIII) with benzophenonimine in the presence of a palladium catalyst to obtain an 8-azabicyclooctane intermediate with protected 3aminophenyl substitution, which, at its instead, it is reacted with methanesulfonium chloride to prepare a protected intermediate in which R1 is -NHS (O) 2CH3. The protective group was then removed by conventional methods, to obtain the intermediate of formula (III).

The substituted intermediate triflate (XIII) also serves as a starting material in the preparation of other key intermediates for the compounds of the present invention. An intermediate of formula (III) in which R1 is the ester -C (O) ORa -where Ra is C1-3 alkyl-can be prepared by the carbonylation of (XIII) catalyzed by palladium in the presence of an alcoholic solvent RaOH, followed by a checkout stage. Intermediate (III) in which R1 is -C (O) OH acid can be obtained by hydrolysis of the protected form of intermediate (III) in which R1 is the ester, in the presence of an inorganic base, and subsequent deprotection. Reduction of the protected acid intermediate, using for example a reducing agent such as sodium borohydride, can give the intermediate of formula (III) in which R1 is -CH2OH after deprotection.

The intermediates of formula (IV) used in scheme B1 can be prepared from an alcohol of formula (XV), as indicated in scheme F.

Scheme F

image 1

5 where Ga is defined so that G is Ga-CH2 and L is a leaving group. The alcohol (XV) can be prepared by the reaction process (i) in which an alcohol of formula H2N-A-CH2-OH is reacted with a substituted alkyl halide of formula R2-GL under conditions similar to those described for the reaction of scheme B2. The alcohol

(XV) can also be prepared by the reaction process (ii) under typically acidic coupling conditions,

10 as described above, to form the intermediate amide, which is reduced, for example, by a borane reducing process, to give an intermediate alcohol of formula (XV). Then, by adding an amino-protecting group by conventional procedures, intermediate (XVI) is formed, which is oxidized to obtain an intermediate of formula (IV). Intermediate (IV) can be prepared and preserved as a bisulfite adduct, from which the aldehyde is released before use.

In an alternative process to prepare the compounds of the present invention of formula (Ia) the phenyltropane intermediate (III) is reacted with an intermediate of formula (XVII)

Scheme G

20 under conditions similar to those described for the initial reaction of scheme B1. When R4a is a protected form of R4 a final deprotection step takes place to give the compound (Ia). Intermediate (XVII) can be prepared

image 1

25 by reacting the alcohol (XV) with the reagent R4aC (O) -L, to add add-C (O) R4a to the nitrogen of (XV), then oxidizing the resulting alcohol to the aldehyde (XVII). The urea compounds of the present invention of formula (Ib) can be prepared by processes analogous to those indicated in Scheme G.

The following examples describe more details about the specific reaction conditions and others

30 processes for preparing representative compounds of the present invention or their corresponding intermediates.

Therefore, in one aspect of the method, the present invention provides a process for preparing a compound of formula (I), or a protected salt or derivative thereof, which consists in (a) reacting a compound of formula

35 (II) with (i) a compound of formula R4aC (O) -L or with (ii) a compound of formula R5-N = C = O, or (b) reacting a compound of formula (III) with a compound of formula (XVII), optionally removing the protecting group or groups of R4a, to obtain a compound of formula (I), or a protected salt or derivative thereof.

In different aspects the present invention also provides a compound of formula (II) and a compound of

Formula (III) in which the variables R1, R2, G and A take any of the values described in aspects of the present invention disclosed above. Specifically, the present invention provides a compound of formula (II) in which R1 is cyclohexyl or phenyl, each optionally substituted with one or two halogens, G is -CH2- and A is -CH2-. In addition, in another specific aspect, the present invention provides a compound of formula (III) in which R1 is -ORa or -C (O) NRaRb or in which R1 is -OH or -C (O) NH2.

Four. Five

Pharmaceutical compositions

The 8-azabicyclooctane compounds of the present invention are normally administered to a patient in the form of a pharmaceutical composition or formulation. These pharmaceutical compositions can be administered to the patient by any acceptable route of administration, including without limitation, the oral, rectal, vaginal, nasal, inhalative, topical (including transdermal) routes and parenteral administration forms.

Therefore, in one of its compositional aspects, the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. If desired, these pharmaceutical compositions may optionally contain other therapeutic and / or formulation agents. When talking about compositions, the "compound of the present invention" can also be referred to herein as an "active agent". As used herein, the term "compound of the present invention" is intended to include the compounds of the formula (I) and also the species comprised in the formula (I ’). In addition, "compound of the present invention" includes the pharmaceutically acceptable salts and solvates of the compound, unless otherwise indicated.

The pharmaceutical compositions of the present invention normally contain a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. Generally, said pharmaceutical compositions will contain approximately 0.1 to 95% by weight of the active agent, preferably approximately 5 to 70% by weight, and more preferably 10 to 60% by weight of the active agent.

Any conventional vehicle or excipient can be used in the pharmaceutical compositions of the present invention. The specific choice of a vehicle or excipient, or combinations of vehicles or excipients, will depend on the form of administration employed to treat a particular patient or the type of medical condition or disease. In this sense, the preparation of a pharmaceutical composition suitable for a particular mode of administration falls within the scope of specialists in pharmaceutical techniques. In addition, the vehicles or excipients used in the pharmaceutical compositions of the present invention are commercially available. By way of illustration, conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20th edition, Lippincott Williams & White, Baltimore, Mariland (2000), and in HC Ansel and others, Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition, Lippincott Williams & White, Baltimore, Mariland (1999).

Examples of substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, the following: sugars such as lactose, glucose and sucrose; starches such as corn and potato; celluloses such as macrocrystalline cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth powder; malt; jelly; talcum powder; excipients such as cocoa butter and suppository waxes, oils such as peanut, cottonseed, safflower, sesame, olive, corn, soybeans; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen free water; isotonic saline solution; Ringer's solution; ethyl alcohol; buffer solutions of phosphate and other compatible non-toxic substances used in pharmaceutical compositions.

Pharmaceutical compositions are usually prepared by thoroughly and intimately mixing, or combining, the active agent with a pharmaceutically acceptable carrier and with one or more optional ingredients. Then the resulting uniform mixture can be shaped or loaded into tablets, capsules, pills and the like, using conventional procedures and equipment.

The pharmaceutical compositions of the present invention are preferably packaged in unit dosage form. The term "unit dose form" refers to a physically discrete unit, appropriate for dosing a patient, that is, each unit contains a predetermined amount of active agent calculated to produce the desired therapeutic effect, either alone or in combination. with one or more additional units. For example, these unit dose forms may be capsules, tablets, pills and the like, or unit packages suitable for parenteral administration.

In one embodiment, the pharmaceutical compositions of the present invention are suitable for oral administration. Pharmaceutical compositions suitable for oral administration may be in the form of capsules, tablets, pills, pills, tablets, dragees, powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-liquid emulsion. water or water-in-oil, or as an elixir or syrup, and the like; so that each of these forms contains a predetermined amount of a compound of the present invention as an active ingredient.

The pharmaceutical compositions of the present invention formulated as solid doses for oral administration (ie in the form of capsules, tablets, pills and the like) will normally comprise the active agent and one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate. Optionally or alternatively these solid dosage forms may also include: fillers or diluents such as starches, microcrystalline cellulose, lactose, sucrose, glucose, mannitol and / or silicic acid; binders such as carboxymethyl cellulose, alginates, gelatin, poly (vinyl pyrrolidone), sucrose and / or acacia gum; humectants such as glycerin; disintegrants such as agar-agar, calcium carbonate, tapioca or potato starch, alginic acid, certain silicates and / or sodium carbonate; dissolution retardants such as paraffin; absorption accelerators such as quaternary ammonium compounds; moisturizing agents such as cetyl alcohol and / or glycerin monostearate; absorbents such as kaolin and / or bentonite; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and / or mixtures thereof; dyes, and buffering agents.

The pharmaceutical compositions of the present invention may also contain release agents, humectants, coating agents, sweeteners, flavorings and flavorings, preservatives and antioxidants. Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfate, sodium sulphite and the like; Fat-soluble antioxidants such as ascorbyl palmitate, butylhydroxyanisole, butylhydroxytoluene, lecithin, propyl gallate, alfatocoferol and the like and metal chelators such as citric acid, ethylenediaminetetraacetic acid, sorbitol, tartaric acid, phosphoric acid and the like. Coating agents for tablets, capsules, pills and the like include those used for enteric coatings, such as cellulose acetate phthalate, polyvinyl phthalate acetate, hydroxypropylmethyl cellulose phthalate, methacrylic acid methacrylate copolymers, cellulose acetatotrimelitate, carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate and the like.

The pharmaceutical compositions of the present invention can also be formulated so that the active agent is released slowly or in a controlled manner, using, for example, hydroxypropyl methylcellulose in varying proportions or other polymeric matrices, liposomes and / or microspheres. In addition, the pharmaceutical compositions of the present invention may optionally contain opacifying agents and may be formulated so that they release the active ingredient only, or preferably, in a certain portion of the gastrointestinal tract, optionally delayed. Examples of usable inclusive compositions include polymeric substances and waxes. The active agent can also be found in microencapsulated form, if necessary, with one or more of the excipients described above.

Liquid dosage forms suitable for oral administration include, for example, pharmaceutically acceptable emulsions, rnicroemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms normally comprise the active agent and an inert diluent, such as water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate , propylene glycol, 1,3-butylene glycol, oils (especially cotton, peanut, corn, wheat germ, olive, castor and sesame), glycerin, tetrahydrofuryl alcohol, polyethylene glycols and sorbitan fatty acid esters and mixtures thereof. The suspensions, in addition to the active ingredient, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

The compounds of the present invention can also be administered parenterally (eg by intravenous, subcutaneous, intramuscular or intraperitoneal injection). For parenteral administration, the active agent is normally mixed with a vehicle suitable for parenteral administration, including, for example, sterile aqueous solutions, physiological serum, low molecular weight alcohols such as propylene glycol, polyethylene glycol, vegetable oils, gelatin, esters of fatty acids such as ethyl oleate and the like. Parenteral formulations may also contain one or more antioxidants, solubilizers, stabilizers, preservatives, humectants, emulsifiers, buffering agents or dispersants. These formulations can be sterilized by using a sterile injectable medium, a sterilizing agent, filtration, irradiation or heat.

Alternatively, the pharmaceutical compositions of the present invention are formulated to be administered by inhalation. Pharmaceutical compositions suitable for inhalation administration will normally be in aerosol or powder form. In general, said compositions are administered by well known devices, such as a graduated dose inhaler, a dry powder inhaler, a nebulizer or a similar delivery device.

For administration by inhalation through a pressurized container, the pharmaceutical compositions of the present invention will normally comprise the active ingredient and a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other appropriate gas. In addition, the pharmaceutical composition may be in the form of a capsule or cartridge (for example of gelatin) bearing a compound of the present invention and a powder suitable for use with a powder inhaler. Suitable powder bases include, for example, lactose or starch.

The compounds of the present invention can also be administered transdermally using known transdermal delivery systems and excipients. For example, the active agent may be mixed with penetration enhancers, such as propylene glycol, polyethylene glycol monolaurate, azacycloalkane-2-ones and the like, and incorporated into a patch or similar delivery system. If desired, additional excipients such as gelling agents, emulsifiers and buffers can be used in said transdermal compositions.

If desired, the compounds of the present invention can be administered in combination with one or more additional therapeutic agents. In this embodiment, a compound of the present invention is physically mixed with the other therapeutic agent, to form a composition containing both agents, or each agent is in separate and distinct compositions that are administered simultaneously or successively to the patient. .

For example, a compound of formula I can be combined with the second therapeutic agent using conventional procedures and equipment to form a composition comprising a compound of formula I and a second therapeutic agent. Also the therapeutic agents may be combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition comprising a compound of formula I, a second therapeutic agent and a pharmaceutically acceptable carrier. In this embodiment, the components of the composition are often mixed or combined to create a physical mixture. The physical mixture is then administered in a therapeutically effective amount by any of the routes described herein. Alternatively, therapeutic agents may remain separate and distinct before administration to the patient. In this embodiment the agents are not physically mixed before administration, but are administered simultaneously or at different times as separate compositions. Said compositions can be packaged separately, or together in kit form. The two therapeutic agents of the kit can be administered by the same route

or by different routes of administration.

As a second therapeutic agent, any that is compatible with the compounds of the present invention can be used. In combination with the compounds of the present invention, prokinetic agents that act by mechanisms other than antagonism of the opioid mu receptors can be employed. For example, 5-HT4 receptor agonists such as tegaserod, renzapride, mosapride, prucalopride, 1-isopropyl-1H-indazol-3carboxyl - {(1S, 3R, 5R) -8- [2- (4-acetylpiperazin-1- il) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} amide, 1-isopropyl-2-oxo-1,2-dihydroquinolin-3-carboxyl - {(1S, 3R, 5R) -8- [(R) -2-hydroxy-3- (methanesulfonyl-methyl-amino) propyl] -8-azabicyclo [3,2.1] oct-3-yl} amide

or 4- (4 - {[(2-isopropyl-1 H -benzoimidazol-4-carbonyl) amino] methyl} -piperidin-1-ylmethyl) piperidine-1-carboxylic acid methyl ester can be used as the second therapeutic agent.

Other useful prokinetic agents include, but are not limited to, 5-HT3 receptor agonists (eg pumosetrag), 5-HT1A receptor antagonists (eg AGI 001), alpha-2-delta ligands (eg. PD-217014), chloride channel openers (eg lubiprostone), dopamine antagonists (eg itoprida, metoclopramide, domperidone), GABA-B agonists (eg baclofen, AGI 006) , Kappa opioid agonists (eg, assadolin), M1 and M2 muscarinic antagonists (eg acotiamide), motilin agonists (eg mitemcinal), guanylate cyclase activators (eg MD-1100 ) and ghrelin agonists (eg Tzp 101, RC 1139).

In addition, the compounds of the present invention can be combined with opioid therapeutic agents. Such opioid agents include, but are not limited to, morphine, pethidine, codeine, dihydrocodeine, oxycodine, oxycodone, hydrocodone, sufentanil, fentanyl, remifentanil, buprenorphine, methadone and heroin.

Numerous examples of such therapeutic agents are known in the technical state, which can be used in combination with the compounds of the present invention. The secondary agent (s), when included, are present in therapeutically effective amounts, that is, in any amount capable of producing a beneficial therapeutic effect when co-administered with a compound of the present invention. Suitable doses of the other therapeutic agents administered in combination with a compound of the present invention are usually in the range of about 0.05 µg / day to about 100 mg / day.

Accordingly, the pharmaceutical compositions of the present invention optionally include a second therapeutic agent, as described above.

The following examples describe representative pharmaceutical compositions of the present invention:

Formulation example A: hard gelatin capsules for oral administration

A compound of the present invention (50 g) is thoroughly mixed with spray dried lactose (200 g) and magnesium stearate (10 g). The resulting composition is introduced into a hard gelatin capsule (260 mg of composition per capsule).

Formulation example B: hard gelatin capsules for oral administration

A compound of the present invention (20 g), starch (89 mg), microcrystalline cellulose (89 mg) and magnesium stearate (2 mg) is thoroughly mixed and then passed through a U.S. mesh screen. No. 45. The resulting composition is introduced into a hard gelatin capsule (200 mg of composition per capsule).

Formulation example C: gelatin capsules for oral administration

A compound of the present invention (10 g) is thoroughly mixed with polyoxyethylene sorbitan monooleate (50 mg) and powdered starch (250 mg) and then introduced into a gelatin capsule (310 mg of composition per capsule). 5

Formulation example D: tablets for oral administration

A compound of the present invention (5 mg), starch (50 mg) and microcrystalline cellulose (35 mg) are passed through a U.S. sieve. No. 45 mesh and thoroughly mixed. The resulting powder is mixed with a solution of polyvinylpyrrolidone

10 (10% by weight in water, 4 mg) and this mixture is passed through a U.S. sieve No. 14 mesh. The resulting granulate is dried at 50-60 ° C and passed through a U.S. sieve. No. 18 mesh. Then sodium carboxymethyl starch (4.5 mg), magnesium stearate (0.5 mg) and talc (1 mg), previously passed through a U.S. sieve, are added to the granulate. 60 mesh. After mixing, the mixture is compressed in a tabletting machine to produce a 100 mg weight tablet.

fifteen

Formulation example E: tablets for oral administration

A compound of the present invention (25 mg), microcrystalline cellulose (400 mg), pyrogenic silicon dioxide (10 mg) and stearic acid (5 mg) is thoroughly mixed and then compressed to form tablets (440 mg of composition 20 per tablet)

Formulation example F: mono-screened tablets for oral administration

A compound of the present invention (15 mg), corn starch (50 mg), croscarmellose sodium 25 (25 mg), lactose (120 mg) and magnesium stearate (5 mg) is thoroughly mixed and then compressed to form tablets mono-screened (215 mg of composition per tablet).

Formulation example G: suspension for oral administration

The following ingredients are mixed to form an oral administration suspension containing 100 mg of active ingredient per 10 ml of suspension:

Ingredients Amount Compound of the present invention 0.1g Fumaric acid 0.5 g Sodium chloride 2.0 g Methylparaben 0.15 g Propylparaben 0.05 g Granulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum k (Vanderbilt Co.) 1.0 g Flavoring 0.035 ml Dyes 0.5 mg Distilled water cs up to 100 ml

Formulation example H: dry powder suspension

A micronized compound of the present invention (1 mg) is mixed with lactose (25 mg) and then introduced into a gelatin inhalation cartridge. The contents of the cartridge are administered with a powder inhaler.

Formulation example J: injectable formulation

A compound of the present invention (0.1 g) is mixed with 0.1 M sodium citrate buffer solution (15 ml). The pH of the resulting solution is adjusted to 6 with 1 N aqueous hydrochloric acid or with sodium hydroxide 1 N aqueous. Sterile physiological serum is then added in citrate buffer to reach a total volume of 20 ml.

It is understood that any form of the compounds of the present invention (ie free base, pharmaceutical salt or solvate) suitable for the particular mode of administration is usable in the pharmaceutical compositions mentioned above.

Utility

The 8-azabicyclooctane compounds of the present invention are antagonists of the opioid mu receptors and therefore can be expected to be useful for treating medical conditions mediated by mu opioid receptors or related to their activity, ie medical conditions that improve by treatment with an opioid receptor antagonist mu. Specifically, it is expected that the compounds of the present invention will be useful for the treatment of adverse effects associated with the use of opioid analgesics, that is, symptoms such as constipation, decreased gastric emptying, abdominal pain, swelling, nausea, and gastroesophageal reflux. , collectively designated as opioid-induced intestinal dysfunction. It is also expected that the opioid receptor antagonists mu of the present invention will be used to treat postoperative ileus, a disorder of reduced motility of the gastrointestinal tract that occurs after abdominal surgery or other interventions. It has also been indicated that opioid receptor antagonist compounds mu can be used to counteract opioid-induced nausea and vomiting. Likewise, opioid mu receptor antagonists with some central penetration capacity may be useful in the treatment of dependence or addiction to narcotic drugs, alcohol or gambling, or in the prevention, treatment and / or improvement of obesity.

As the compounds of the present invention increase the motility of the gastrointestinal (GI) tract in animal models, they are expected to be useful for the treatment of GI tract disorders caused by reduced motility in mammals, including humans. GI motility disorders include, for example, chronic constipation, irritable bowel syndrome with predominant constipation (C-IBS), diabetic and idiopathic gastroparesis and functional dyspepsia.

In one aspect, therefore, the present invention is applicable to a method for increasing the motility of the gastrointestinal tract in a mammal, which consists in administering to the mammal a therapeutically effective amount of a pharmaceutical composition containing a pharmaceutically acceptable carrier and a compound of The present invention.

When used to treat reduced motility disorders of the GI tract or other states mediated by mu opioid receptors, the compounds of the present invention will normally be administered orally in a single dose.

or in several doses a day, although other forms of administration can also be used. For example, if they are used specifically to treat postoperative ileus, the compounds of the invention can be administered parenterally. The amount of active agent administered per dose or the total daily amount administered will normally be established by a physician under the important circumstances, including the condition to be treated, the route of administration chosen, the particular compound administered and its relative activity, age. , the weight and response of each patient, the severity of the patient's symptoms and the like.

Suitable doses for the treatment of reduced motility disorders of the GI tract or other opioid receptor mediated disorders will vary from about 0.0007 to 20 mg / kg / day of active agent, including from about 0.0007 to 1, 4 mg / kg / day. For an average human weighing 70 kg they would be approximately 0.05 to 100 mg daily of active agent.

In one aspect of the present invention the compounds thereof are used to treat opioid-induced intestinal dysfunction. When used to treat opioid-induced intestinal dysfunction the compounds of the present invention will normally be administered orally in a single dose or in several doses per day. The doses to treat opioid-induced intestinal dysfunction will preferably be about 0.05 to 100 mg daily.

In another aspect of the present invention the compounds thereof are used to treat postoperative ileus. When used to treat postoperative ileus, the compounds of the present invention will normally be administered orally or intravenously in a single dose or in several doses per day. Doses for treating postoperative ileus will preferably be about 0.05 to 100 mg daily.

The present invention is also applicable to a method for treating a mammal having a disease or condition related to the activity of mu opioid receptors, which consists in administering to the mammal a therapeutically effective amount of a compound of the present invention or of a pharmaceutical composition containing a compound of the present invention.

As described above the compounds of the present invention are antagonists of the opioid receptors mu. Therefore the present invention is also applicable to a method for antagonizing a mu opioid receptor in a mammal, which consists in administering a compound of the present invention to the mammal.

The opioid mu receptor antagonists of the present invention are optionally administered in combination with another therapeutic agent or agents, especially in combination with prokinetic agents that act through mu non-opioid mechanisms. Accordingly, in another aspect, the methods and compositions described herein comprise a therapeutically effective amount of another prokinetic agent.

In addition, the compounds of the present invention are also useful as tools for research or study of biological systems or samples that have mu opioid receptors or to discover new compounds that have mu opioid receptor activity. Any suitable biological system or sample that has mu opioid receptors can be used in these studies, which can be carried out in vitro or in vivo. Representative biological systems or samples, appropriate for such studies, include, not exclusively, cells, cell extracts, plasma membranes, tissue samples, mammals (such as mice, rats, guinea pigs, rabbits, dogs, pigs, etc.) and the like The effects of contacting a biological system or sample comprising a mu opioid receptor with a compound of the present invention are determined by conventional procedures and equipment, such as the radioligand binding assay and the functional analysis described herein or other functional assays. known from the technical state. These functional assays include, but are not limited to, changes in ligand-mediated intracellular cyclic adenosine monophosphate (cAMP), changes in ligand-mediated adenylyl cyclase enzyme activity, changes in the incorporation of guanosyntriphosphate (GTP) analogs mediated by ligands, such as [S35] GTPγS (guanosine-5'-O- (γ-thio) triphosphate) or GTP-Eu, in isolated membranes, by exchange of GTP analogs with receptor-catalyzed GDP analogs, and changes in free intracellular calcium ions mediated by ligands. A concentration of a compound of the present invention suitable for these studies generally ranges from about 1 nanomolar to about 500 nanomolar.

When compounds of the present invention are employed as a research medium to discover new compounds that have activity as mu opioid receptors, binding data or functional data of a test compound or a group of test compounds are compared with the data. binding to the opioid receptor mu or with the functional data of a compound of the present invention to identify test compounds that have the highest binding or functional activity, if applicable. This aspect of the present invention includes as separate embodiments both the generation of comparative data (using the appropriate assays), and the analysis of the test data, in order to identify the test compounds of interest.

Among other properties it has been found that the compounds of the present invention show a potent binding to mu opioid receptors and little or no agonism in the functional analyzes of mu receptors. Therefore the compounds of the present invention are potent antagonists of the opioid receptors mu. Furthermore, it has been shown in animal models that the compounds of the present invention have a predominantly peripheral activity, compared to the activity in the central nervous system. Therefore, these compounds can be expected to reverse the reduction of opioid-induced gastrointestinal motility, without interfering with the central beneficial effects of analgesia. These properties, as well as the utility of the compounds of the present invention, can be demonstrated with several well-known in vitro and in vivo assays of the specialists. Representative examples are described in detail in the following examples.

EXAMPLES

The following synthetic and biological examples are offered to illustrate the present invention, and in no way should they be construed as limiting its scope. In the following examples the following abbreviations have the following meanings, unless otherwise indicated. Abbreviations not defined below have the generally accepted meaning.

Boc = tert-butoxycarbonyl (Boc) 2O = di-tert-butyl dicarbonate DABCO = 1,4-diazabicyclo [2,2-2] octane, triethylenediamine DCM = dichloromethane DIPEA = N, N-diisopropylethylamine DMA = dimethylacetamide DMAP = dimethylaminopyridine DMF = N, N-dimethylformamide DMSO = dimethylsulfoxide EtOAc = ethyl acetate EtOH = ethanol HATU = N, N, N ', N'-tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate MeCN = acetonitrile MeOH = methanol MeTHF = 2-methyltetrahydrofuran MTBE = tert-butylmethyl ether PyBop = benzotriazol-1-yloxytripyrrolidine-phosphonium hexafluorophosphate TFA = trifluoroacetic acid THF = tetrahydrofuran

Reagents (including secondary amines) and solvents were purchased from commercial suppliers (Aldrich, Fluka, Sigma, etc.) and were used without further purification. The reactions were carried out under a nitrogen atmosphere, if not indicated otherwise. The reactive mixtures were monitored by thin layer chromatography (TLC), high resolution analytical liquid chromatography (analogous to HPLC) and mass spectrometry, the details of which are indicated separately below in the specific reaction examples. Reactive mixtures were treated in the manner specifically described in each reaction; They were normally purified by extraction and other methods such as temperature and solvent dependent crystallization, and precipitation. In addition, the reaction mixtures were routinely purified by preparative HPLC: a general protocol is described below. Reaction products were routinely identified by mass spectrometry and 1 H-NMR. For NMR measurement, samples were dissolved in deuterated solvent (CD3OD, CDCI3 or DMSO-d6) and NMR-H1 spectra were obtained with a Varian Gemini 2000 apparatus (300 MHz) under standard observation conditions. The identification of the compounds by mass spectrometry was carried out by an electrospray ionization method (ESMS), with an Applied Biosystems (Foster City, CA) model API 150 EX or with an Agilent device (Palo Alto, CA) Model 1100 LC / MSD.

Preparation 1: Synthesis of 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -phenol

to. Preparation of 8-benzyl-8-azabicyclo [3.2.1] octan-3-one

A mixture of 2,5-dimethoxytetrahydrofuran (20.5 g, 155.1 mmol), water (42.5 ml) and concentrated HCl (30 ml) was stirred at room temperature for about 30 minutes. To this stirring mixture was added successively water (62.5 ml), a premixed solution of benzylamine (17.9 ml, 162.9 mmol), water (87.5 ml) and concentrated HCl (23 ml), a solution premixed 1,3-acetondicarboxylic acid (25 g) and water (100 ml) and a solution of Na2HPO4 (16.5 g) in water (50 ml). The resulting mixture was adjusted to a pH of 4 to 5 with 40% aqueous NaOH and stirred overnight at room temperature. The mixture was acidified to pH 3 with concentrated HCl and heated at 85 ° C for 3 hours. After cooling to room temperature the mixture was made alkaline with 20% aqueous NaOH, saturated with solid sodium chloride and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give a dark oil that was purified by flash column chromatography. The product was eluted with 20% ethyl acetate / hexanes. The desired fractions were combined and concentrated to give the intermediate of the title as a yellowish oil (16.17 g).

b. Preparation of 8-benzyl-3-exo- (3-methoxy-phenyl) -8-azabicyclo [3.2.1] octan-3-ol

A solution of 8-benzyl-8-azabicyclo [3.2.1] octan-3-one (7.28 g, 33.8 mmol) in dry THF (113 ml) was cooled to -78 ° C under a nitrogen atmosphere. To this cold solution was added a 1.0 M solution of 3-methoxyphenylmagnesium bromide in THF (44 ml) through a dosing funnel. The resulting mixture was heated to room temperature and stirred for about 20 minutes. The reaction was cooled to 0 ° C and more 3-methoxyphenylmagnesium bromide (30 ml, 30.0 mmol) in THF was added. The reaction was heated again to room temperature after the addition and stirred for 30 minutes. The reaction was stopped with saturated ammonium chloride and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography and eluted with 5% (200 ml), 10% (200 ml), 15% (200 ml), 20% (200 ml), 30% (200 ml) and 100% of ethyl acetate hexanes. The desired fractions were combined and concentrated to give the intermediate of the title as a light yellowish oil (4.0 g). Starting material (3.87 g) was recovered. (m / z): [M + H] + calculated for C21H25NO2: 324.20; Found: 324.5.

C. Preparation of 3- (8-benzyl-8-azabicyclo [3.2.1] oct-2-en-3-yl) -phenol

To a solution of 8-benzyl-3-endo- (3-methoxy-phenyl) -8-azabicyclo [3.2.1] octan-3-ol (4.65 g, 14.4 mmol) in dichloromethane (70 ml) at 0 ° C, 1.0 M boron tribromide in dichloromethane (28 ml) was added. The resulting mixture was stirred one hour at 0 ° C and then allowed to rise to room temperature and stirred at that temperature overnight. The reaction mixture was concentrated and coevaporated with methanol three times. The resulting residue was dissolved in 50% acetic acid in water (20 ml), filtered and purified by reverse phase HPLC, to give the TFA salt of the title compound (4.6 g). (m / z): [M + H] + calculated for C20H21NO: 292.17; Found: 292.3.

d. Synthesis of 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -phenol

To a solution of the TFA salt of 3- (8-benzyl-8-azabicyclo [3.2.1] oct-2-en-3-yl) -phenol (2.0 g) in ethanol (200 ml) at temperature ambient was added palladium hydroxide on carbon (50% by weight of water, 20% w / w carbon, 800 mg). The resulting suspension was degassed and treated overnight under a hydrogen atmosphere. The reaction mixture was filtered through Celite and washed with ethanol. The filtrate was concentrated to give the TFA salt of the title compound (1.2 g). (m / z): [M + H] + calculated for C13H17NO: 204.14; found, 204.3.

Preparation 2: Synthesis of 3-endo- [8- (2-benzylamino-ethyl) -8-azabicyclo [3.2.1] oct-3-yl] -phenol

to. Preparation of 3-endo- [8- (2,2-dimethoxyethyl) -8-azabicyclo [3.2.1] oct-3-yl] -phenol

To a stirred suspension of 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -phenol (2.0 g, 6.3 mmol) in CH2Cl2 (25 ml) at room temperature was added successively N, N-diisopropylethylamine (814 mg, 6.3 mmol), 2,2-dimethoxyacetaldehyde (1.31 g, 12.6 mmol) and sodium triacetoxyborohydride (1.73 g, 8.19 mmol). The resulting mixture was subjected to ultrasound to facilitate dissolution and stirred at room temperature for 30 minutes. The reaction was diluted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate followed by brine, dried over sodium sulfate, filtered and concentrated to give a yellowish oil, which was used directly in the next step without purification. (m / z): [M + H] + calculated for C17H25NO3: 292.19; found:

292.3.

b. Preparation of [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] -acetaldehyde

The oily product from the previous step was treated with 6 N aqueous HCl (30 ml) at room temperature for two days. The solvents were removed in vacuo. The residue was then dissolved in water and lyophilized to give intermediate of the title as its HCl salt (1.3 g). (m / z): [M + H] + calculated for C15H19NO2: 246.15; Found: 246.1.

C. Synthesis of 3-endo- [8- (2-benzylaminoethyl) -8-azabicyclo [3.2.1] oct-3-yl] -phenol

To a stirred solution of the HCl salt of [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] -acetaldehyde (384 mg, 1.36 mmol) in dichloromethane (4 , 5 ml) at room temperature sodium triacetoxyborohydride (374 mg, 1.76 mmol) was added, followed by N, N-diisopropylethylamine (176 mg, 1.36 mmol) and benzylamine (175 mg, 1.63 mmol). The solution was stirred at room temperature for 30 minutes and the reaction was stopped with saturated sodium bicarbonate. The aqueous layer was extracted with dichloromethane. The resulting organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give an oily residue. The residue was redissolved in 50% acetic acid in water, filtered and purified by preparative reverse phase HPLC to give the title compound as its bis-TFA salt (191 mg). (m / z): [M + H] + calculated for C22H28N2O: 337.23; Found: 337.3.

Preparation 3:

Following step c of preparation method 2 and substituting benzylamine for the appropriate amine reagent,

for, bis-TFA salts of the following compounds were prepared:

3-endo- {8- [2- (cyclohexylmethylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} phenol; (m / z): [M + H] + calculated for

C22H34N2O 343.28; Found: 343.5.

3-endo- {8- [2- (3-fluorobenzylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} phenol; (m / z): [M + H] + calculated for

C22H27FN2O: 355.22; Found: 355.5.

3-endo- {8- [2- (2,6-difluorobenzylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} phenol; (m / z): [M + H] + calculated for

C22H26F2N2O: 373.21; Found: 373.3.

3-endo- {8- [2- (4-fluorobenzylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} phenol; (m / z): [M + H] + calculated for

C22H27FN2O: 355.22; Found: 355.3.

3-endo- {8- [2- (4-chlorobenzylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} phenol; (m / z): [M + H] + calculated for

C22H27ClN2O: 371.19; Found: 371.4.

Preparation 4: Synthesis of 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -phenol

to. Preparation of 8-benzyl-8-azabicyclo [3.2.1] oct-2-en-3-yl trifluoromethanesulfonate

To a solution of 8-benzyl-8-azabicyclo [3.2.1] octan-3-one (12.8 g, 59.5 mmol) in anhydrous tetrahydrofuran (200 ml) at -78 ° C was added dropwise a solution of sodium hexamethyldisilazane (77 ml, 77.4 mmol) 1.0 M in THF. The resulting mixture was stirred at -78 ° C for thirty minutes before adding a solution of N-phenyltrifluoromethanesulfonimide (PhNHTf2) (25 g, 69.9 mmol) in THF (100 ml). After about forty minutes thin layer chromatography indicated that the reaction was not complete. More PhNHTf2 (2.0 g) in THF was added. After 30 minutes the reaction was stopped with saturated ammonium chloride. The layers were separated and the organic layer was washed twice with saturated ammonium chloride, followed by brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography and eluted with 0% (500 ml), 5% (500 ml), 10% (500 ml), 15% (500 ml), 20% (100 ml) of ethyl acetate / hexanes The desired fractions were combined and concentrated to give a yellowish oil (25.6 g, contaminated with N-phenyltrifluoromethanesulfonimide (PhNHTf2)). (m / z): [M + H] + calculated for C15H16F3NO3S: 348.09; Found: 348.0.

b. Preparation of 8-benzyl-3- (3-benzyloxyphenyl) -8-azabicyclo [3.2.1] oct-2-eno

To a solution of the product from the previous step (24.6 g, contaminated with PhNHTf) in THF (120 ml) and DMA (120 ml) at room temperature was added 3-benzyloxyphenylboronic acid (16.46 g), potassium carbonate (19.9 g) and tetrakis (triphenylphosphine) palladium (0) (5.0 g). The resulting mixture was degassed, purged with nitrogen and then stirred under a nitrogen atmosphere overnight. The reaction mixture was filtered through a block of Celite and the filtrate was concentrated to give a thick, dark oil that was purified by flash chromatography (and eluted with 40% ethyl acetate in hexanes) to obtain the intermediate of the title. (6.9 g). (m / z): [M + H] + calculated for C27H27NO: 382.22; Found: 382.5.

C. Preparation of 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -phenol

The product from the previous step (6.9 g) in ethanol (50 ml) was added to palladium hydroxide (3.5 g, 20% w / w carbon). The suspension was vigorously stirred under hydrogen atmosphere for 12 hours. The reaction mixture was filtered through a plug of Celite and the filtrate was concentrated to give the title intermediate (5.6 g). (m / z): [M + H] + calculated for C13H17NO: 204.14; Found: 204.3.

d. Preparation of tert-butyl 3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] octan-8-carboxylate

The product from the previous step (5.6 g) was dissolved in tetrahydrofuran (75 ml) and then N, N-diisopropylethylamine (3.6 ml) was added. To the stirring solution was added dropwise di-tert-butyl dicarbonate (5.4 g) dissolved in THF (20 ml) and the reaction was stirred for 1 hour. The reaction was stopped with methanol, concentrated in vacuo, diluted with dichloromethane (100 ml) and washed with 1.0 N HCl (100 ml), followed by saturated aqueous sodium chloride (100 ml). The organic layer was treated with anhydrous sodium sulfate and the solvent was removed in vacuo. The crude product was purified by flash chromatography (and eluted with 20% ethyl acetate in hexanes) to obtain the crude intermediate of the title (3.4 g). The resulting solid was dissolved in ethyl acetate (10 ml) and heated to 50 ° C, followed by the addition of heptane (50 ml). The solution was allowed to cool to room temperature for 2 hours. The resulting crystals were filtered to give the intermediate of the title (2.2 g).

and. Synthesis of 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -phenol

3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] tert-butyl octan-8-carboxylate (2.5 g) was treated with dichloromethane (10 ml) and TFA (10 ml) at room temperature 10 minutes. The reaction mixture was concentrated and coevaporated with ethyl acetate four times to give a white solid, and dried in vacuo to give the title compound as its TFA salt (3.5 g). (m / z): [M + H] + calculated for C13H17NO: 204.14; Found: 204.3.

Preparation 5: Synthesis of 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) benzamide

to. Preparation of 8-benzyl-exo- (3-bromophenyl) -8-azabicyclo [3.2.1] octan-3-ol

To a solution of 1,3-dibromobenzene (7.4 g, 31.3 mmol) in anhydrous THF (80 ml) at -78 ° C under a nitrogen atmosphere was added dropwise a solution of n-butyllithium 1, 6 M in hexanes (20 ml, 31.4 mmol). The resulting mixture was stirred at -78 ° C for 30 minutes before adding a solution of 8-benzyl-8azabicyclo [3.2.1] -octan-3-one (4.5 g, 20.9 mmol) in anhydrous THF dropwise (20 ml). The reaction mixture was allowed to rise slowly to -40 ° C for one hour and then at room temperature for 30 minutes. The reaction was stopped with saturated aqueous NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated and purified by flash chromatography. The product was eluted with 20% (300 ml) to 30% (600 ml) of ethyl acetate / hexanes. The desired fractions were combined and concentrated to give the intermediate of the title as a yellowish oil (6.1 g). (m / z): [M + H] + calculated for C20H22BrNO: 372.10; Found: 372.3, 374.2 (isotope).

b. Preparation of 2-exo- (8-benzyl-3-hydroxy-8-azabicyclo [3.2.1] oct-3-yl) benzonitrile.

To a solution of the product from the previous step (6.1 g, 16.4 mmol) in anhydrous DMF (82 ml) was added zinc cyanide (2.89 g, 24.6 mmol). The suspension was degassed and purged with nitrogen before adding tetrakis (triphenylphosphine) palladium (0) (2.84 g, 2.5 mmol). The resulting reaction mixture was then heated at 85 ° C under a nitrogen atmosphere overnight. The reaction mixture was cooled to room temperature, filtered through Celite and washed with ethyl acetate. The organic layer was washed three times with water. The aqueous layer was reextracted with ethyl acetate. The organic layers were combined and concentrated to about 25 ml and then extracted four times with an aqueous solution of 1 N HCl. The combined aqueous layers were again extracted twice with diethyl ether and then alkalized to pH 10 with NaOH (tablet). ). The basic solution was extracted three times with ethyl acetate. The organic layers were combined and washed with brine, dried over Na2SO4, filtered and concentrated to give the intermediate of the title as a yellowish oil (4.0 g). (m / z): [M + H] + calculated for C21H22N2O: 319.18; Found: 319.3.

C. Preparation of 3-exo- (8-benzyl-3-hydroxy-8-azabicyclo [3.2.1] oct-3-yl) benzamide

To a solution of 3-exo- (8-benzyl-3-hydroxy-8-azabicyclo [3.2.1] oct-3-yl) -benzonitrile (3.74 g, 11.76 mmol) in DMSO (80 ml) at room temperature potassium carbonate (243 mg) was added, followed by 30% hydrogen peroxide in water (6 ml) dropwise. The reaction development was followed by mass spectrometry. After about 2.5 hours the reaction was complete. The reaction was stopped with water (140 ml). The aqueous layer was extracted three times with ethyl acetate. The organic layers were combined and washed with semi-saturated brine (5 x 40 ml) or until an iodine-starch test strip indicated no peroxide residues. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give the intermediate of the title as a white solid (3.15 g). (m / z): [M + H] + calculated for C21H24N2O2: 337.19; Found: 337.3.

d. Preparation of 3- (8-benzyl-8-azabicyclo [3.2.1] oct-2-en-3-yl) benzamide

The product from the previous step (3.15 g) was treated with TFA (30 ml) at 75 ° C for four hours. After concentrating, the residue was dissolved in 50% acetic acid in water (15 ml), filtered and purified by preparative reverse phase HPLC to give the TFA salt of the title intermediate as a white solid. (m / z): [M + H] + calculated for C21H22N2O: 319.18; Found: 319.3.

and. Synthesis of 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) benzamide

The TFA salt of 3-endo- (8-benzyl-8-azabicyclo [3.2.1] oct-2-en-3-yl) benzamide (3.0 g) was dissolved in ethanol (50 ml) at room temperature and treated with palladium hydroxide on carbon (50% by weight of water, 20% of Pd on dry basis, 300 mg). The resulting suspension was degassed and purged three times with nitrogen and then exposed to a hydrogen atmosphere overnight. The reaction mixture was filtered through Celite and washed with ethanol. The filtrate was concentrated to give a slightly yellowish oil that became a foam when dried under vacuum to obtain the title compound as TFA salt (2.2 g). (m / z): [M + H] + calculated for C14H18N2O: 231.15; found 231.3.

Preparation 6: Synthesis of 3-endo- [8- (2-benzylaminoethyl) -8-azabicyclo [3.2.1] oct-3-yl) benzamide

to. Preparation of 3-endo- [8- (2,2-dimethoxyethyl) -8-azabicyclo [3.2.1] oct-3-yl) benzamide

To a solution of the TFA salt of 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) benzamide prepared according to preparation method 5 (1.03 g, 2.98 mmol) in dichloromethane (15.0 ml) at room temperature was added N, N-diisopropylethylamine (385 mg, 2.98 mmol), followed by 2,2-dimethoxyacetaldehyde (621 mg, 5.96 mmol) and sodium triacetoxyborohydride (821 mg, 3.87 mmol). The resulting mixture was subjected to ultrasound to facilitate dissolution. After about 30 minutes the reaction was concentrated. The resulting residue was coevaporated twice with methanol and then dissolved in 50% acetic acid in water (10 ml), filtered and purified by preparative reverse phase HPLC to give the title intermediate as TFA salt (577 mg ). (m / z): [M + H] + calculated for C18H26N7O3: 319.20; Found: 319.3.

b. Preparation of 3-endo- [8- (2-oxoethyl) -8-azabicyclo [3.2.1] oct-3-yl] benzamide

The product from the previous step (577 mg) was treated with 6 N HCl (20 ml) at room temperature overnight. The reaction mixture was concentrated and the residue was diluted with water and lyophilized to give the title intermediate as HCl salt (554 mg). (m / z): [M + H] + calculated for C16H20N2O2: 273.16; Found: 273.1.

C. Synthesis of 3-endo- [8- (2-benzylaminoethyl) -8-azabicyclo [3.2.1] oct-3-yl) benzamide

To a suspension of the 3-endo- [8- (2-oxoethyl) -8-azabicyclo [3.2.1] oct-3-yl] benzamide hydrochloride salt (220 mg, 0.71 mmol) in a mixture of dichloromethane (3 ml) and DMF (1 ml) at room temperature sodium triacetoxyborohydride (196 mg, 0.92 mmol) was added, followed by benzylamine (91 mg, 0.85 mmol) and N, N-diisopropylethylamine (92 mg, 0.71 mmol). Thirty minutes later mass spectrometry (electrospray) indicated that the reaction was complete. The reaction mixture was diluted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate and then with brine, filtered and concentrated. The residue was dissolved in 50% acetic acid in water (10 ml), filtered and purified by preparative reverse phase HPLC to give the title compound as bis-TFA salt (27 mg). (m / z): [M + H] + calculated for C23H29N3O: 364.24; Found: 364.3.

Preparation 7: Synthesis of 3-endo- {8- [2-cyclohexylmethylamino) ethyl] -8-azabicicIo [3.2.1] oct-3-yl} benzamide

To a solution of the HCl salt of 3-endo- [8- (2-oxoethyl) -8-azabicyclo [3.2.1] oct-3-yl] benzamide (554 mg, 1.80 mmol) in dichloromethane ( 9.0 ml) at 0 ° C sodium triacetoxyborohydride (496 mg, 2.34 mmol) was added, followed by cyclohexylmethylamine (244 mg, 2.16 mmol) and N, N-diisopropylethylamine (233 mg, 1.80 mmol). The ice-water cooling bath was removed at the end of the addition and the reaction was allowed to warm to room temperature and stirred at this temperature for one hour. Then the reaction mixture was concentrated. The residue was redissolved in 50% acetic acid in water (10 ml), filtered and purified by preparative reverse phase HPLC to give the title compound as bis-TFA salt (400 mg). (m / z): [M + H] + calculated for C23H35N3O: 370.29; Found: 370.5.

Preparation 8: Synthesis of tert-butyl cyclohexyImethyl- (2-oxoethyl) carbamate

to. Preparation of 2- (cyclohexylmethylamino) ethanol

A mixture of cyclohexylmethyl bromide (23.2 g, 131 mmol) with ethanolamine (47.9 g, 786 mmol) in EtOH (131 ml) was heated at 75 ° C for 2 hours. NMR analysis of an aliquot indicated that the reaction was complete. The reaction was then concentrated to remove ethanol and the resulting residue was diluted with DCM. The organic layer was washed successively with water (3 x 100 ml) and brine (100 ml) and then dried over sodium sulfate, filtered and concentrated to give the intermediate of the title as a light yellow oil (10.57 g). (m / z): [M + H] + calculated for C9H19NO: 158.16; Found: 158.2. 1 H NMR (CDCl3, 300 MHz) δ (ppm): 3.59 (t, J = 5.4 Hz, 2H), 2.73 (t, J = 5.4 Hz, 2H), 2.42 ( d, J = 6.6 Hz, 2H), 1.6-1.77 (m, 6H), 1.36-1.6 (m, IH), 1.10-1.28 (m, 2H) , 0.82-0.95 (m, 2H).

b. Preparation of tert-butyl cyclohexylmethyl- (2-hydroxyethyl) carbamate

Let it warm slowly to room temperature overnight. The mixture was washed successively with 1 N HCl (3 x 100 ml), saturated sodium bicarbonate (100 ml) and brine (100 ml). After drying over sodium sulfate, the organic layer was filtered and concentrated to give the title compound as a light yellow oil (16.5 g). RMN-H1 (CDCl3, 300 MHz) δ (ppm): 3 , 71-3.73 (m, 2H), 3.37 (brs, 2H), 3.03-3.05 (m, 2H), 1.61-1.72 (m, 6H), 1.3 -1.5 (m, IH), 1.48 (s, 9H), 1.14-1.21 (m, 2H), 0.86-0.91 (m, 2H).

C. Synthesis of tert-butyl cyclohexymethyl- (2-oxoethyl) carbamate

To the product of the previous step (16.5 g, 64.2 mmol) in DCM (256 ml) at 0 ° C was added successively dimethylsulfoxide (7.52 g, 96.3 mmol), N, N-diisopropylethylamine (20, 74 g, 160.5 mmol) and sulfur trioxide pyridine complex (25.5 g, 160.5 mmol). Thirty minutes later the NMR analysis of an aliquot indicated that the reaction was complete. The mixture was washed successively with 1 N HCl (3 x 100 mL), saturated sodium bicarbonate and brine, filtered through a block of silica gel and eluted with DCM. After concentrating, the title compound was obtained as a light yellow oil (10.46 g). 1 H-NMR (CDCl 3, 300 MHz) δ (ppm): 9.55 (s, 1 H), 3.88 (s, 1 H), 3.79 (s, 1 H), 3.07-3.15 (m , 2H), 1.56-1.72 (m, 6H), 1.3-1.5 (m, 1H), 1.4 (s, 9H), 1.1-1.25 (m, 2H ), 0.87-0.98 (m, 2H).

Preparation 9: Synthesis of 3-endo- {8- [2- (cyclohexyImethylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} benzamide

to. Preparation of tert-butyl {2- [3-endo- (3-carbamoylfenyl) -8-azabicyclo [3.2.1] oct-8-yl] -ethyl} cyclohexylmethyl-carbamate

To a stirred solution of 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) benzamide (1.16 g, 5.0 mmol) -prepared following the preparation process 13-in DCM (20 ml ) at 0 ° C a solution of tert-butyl cyclohexylmethyl- (2-oxo-ethyl) carbamate (1.53 g, 6.0 mmol) in DCM (5 ml) was added, followed by sodium triacetoxyborohydride (1.27 g , 6.0 mmol). The resulting mixture was heated to temperature after the addition and stirred at this temperature for 30 minutes, until mass spectrometry indicated that the reaction was complete. The mixture was then diluted with DCM, washed twice with saturated sodium bicarbonate, followed by brine, dried over sodium sulfate, filtered and concentrated, to give a yellowish oil, which was used in the next step without further purification. (m / z): [M + H] + calculated for C28H43N3O3: 470.34; found. 470.6.

b. Synthesis of 3-endo- {8- [2- (cyclohexylmethylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} benzamide

The oily residue from the previous step was dissolved in DCM (12 ml) and treated with TFA (12 ml) at room temperature for about 40 minutes. The reaction was considered complete by mass spectrometry. The mixture was then concentrated and coevaporated three times with ethyl acetate, diluted with DCM and alkalized to pH 8.0 with saturated sodium bicarbonate. The layers were separated and the aqueous layer was extracted again with DCM. The combined organic layer was then washed with brine, dried over sodium sulfate, filtered and concentrated to give a brown oil. After drying under vacuum, a light brown foam (1.34 g) was obtained. (m / z): [M + H] + calculated for C23H35N3O: 370.29; Found: 370.4. 1 H-NMR (CDCl 3, 300 MHz) δ (ppm): 7.89 (s, 1 H), 7.70-7.72 (m, 1 H), 7.54-7.56 (m, 1 H), 7 , 39-7.44 (m, 1H), 3.43 (brs, 2H), 3.16-3.21 (m, 1H), 3.06-3.10 (m, 2H), 2.91 (d, J = 7.2 Hz, 2H), 2.65-2.69 (m, 2H), 2.05-2.51 (m, 2H), 2.01-2.05 (m, 2H ), 1.79-1.91 (m, 8H) 1.60-1.63 (m, 2H) 5 1.27-1.42 (m, 3H), 1.09-1.17 (m, 2H).

Preparation 10: Synthesis of tert-butyl (2-oxoethyl) - (4-trifluoromethylbenzyl) -carbamate

to. Preparation of 2- (4-trifluoromethylbenzylamino) ethanol

Following step a of preparation method 8, 4-trifluoromethylbenzyl bromide (664 mg, 2.78 mmol) was heated with ethanolamine (1.02 g, 16.7 mmol) in ethanol (3 ml) at 75 ° C overnight. The product was isolated to give the intermediate of the title as a yellowish oil (585 mg). (m / z): [M + H] + calculated for C10H12F3NO: 220.10; Found: 220.3. 1 H NMR (CDCl3, 300 MHz) δ (ppm): 7.59 (d, J = 7.8 Hz, 2H) 7.45 (d, J = 7.8 Hz, 2H), 3.88 (s , 2H), 3.66-3.70 (m, 2H), 2.80-2.83 (m, 2H).

b. Preparation of tert-butyl (2-hydroxyethyl) - (4-trifluoromethylbenzyl) carbamate

Following step b of the preparation method 8, the product of the previous step (585 mg, 2.65 mmol) was treated with di-tert-butyl dicarbonate (525 mg, 2.41 mmol) to give the intermediate of the title in form of a light yellow oil (796 mg). 1 H NMR (CDCl3, 300 MHz) δ (ppm): 7.57 (d, J = 7.8 Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H), 4.52 ( brs, 2H), 3.71 (brs, 2H), 3.40 (brs, 2H), 1.44 (brs, 9H).

C. Synthesis of tert-butyl (2-oxoethyl) - (4-trifluoromethylbenzyl) carbamate

Following step c of the preparation method 8 the product of the previous stage (796 mg, 2.49 mmol) was oxidized with sulfur trioxide-pyridine complex (990 mg, 6.22 mmol) to give the title compound as a light yellow oil (538 mg).

Preparation 11: Synthesis of 3-endo- {8- [2- (4-trifluoromethylbenzylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} phenol

to. Preparation of tert-butyl {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl- (4-trifluoromethylbenzyl) carbamate

Following step a of preparation method 9, tert-butyl (25-mg, 1.84 mmol) (2-oxo-ethyl) - (4-trifluoromethylbenzyl) carbamate was reacted with the 3-endo- TFA salt ( 8-azabicyclo [3.2.1] oct-3-yl) -phenol prepared according to the method of preparation of 4 (126 mg, 0.92 mmol) to give the intermediate of the title as a yellowish oil that was used directly in The next stage.

b. Synthesis of 3-endo- {8- [2- (4-trifluoromethylbenzylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} phenol

Following step b of preparation method 9, the product from the previous stage was treated with TFA (1.5 ml) and dichloromethane (1.5 ml) and purified by preparative reverse phase HPLC to give the title compound as bis-TFA salt (142 mg). (m / z): [M + H] + calculated for C23H27F3N2O: 405.22; Found: 405.2. 1 H NMR (CDCl3, 300 MHz) δ (ppm): 7.75 (d, J = 7.8 Hz, 2H), 7.68 (d, J = 7.8 Hz, 2H), 7.11- 7.16 (m, 1H), 6.91-6.94 (m, 1H), 6.87 (s, 1H), 6.62-6.65 (m, 1H), 4.34 (s, 2H), 4.04 (brs, 2H), 3.52 (t, J = 6.3 Hz, 2H), 3.31-3.39 (m, 2H), 3.13-3.20 (m , 1H, 2.52-2.59 (m, 4H), 2.02-2.06 (m, 2H), 1.87-1.90 (m, 2H).

Preparation 12: Synthesis of 3-endo- (8-azabicicIo [3.2.1] oct-3-yl) -benzamide

to. Preparation of 8-benciI-3- (3-methoxyphenyl) -8-azabicyclo [3.2.1] oct-2-eno

8-Benzyl-3-exo- (3-methoxyphenyl) -8azabicyclo [3.2.1] octan-3-ol (21.44 g, 66.2 mmol) was introduced into a 500 ml flask equipped with a magnetic stir bar. , followed by acetic anhydride (150 ml). Solid ytterbium triflate (20.51 g, 33.1 mmol) was added and the reaction mixture solidified. More acetic anhydride (100 ml) was added to suspend the solid. The reaction was then heated at 60 ° C for 4 hours. Stirring was stopped and the reaction was diluted with ethyl acetate and carefully stopped with NaOH. The organic layer was washed with brine and then dried over magnesium sulfate. The solvent was removed in vacuo to give the intermediate of the title as a yellow sticky oil (9.9 g, 48% yield). (m / z): [M + H] + calculated for C21H23NO: 306.19; found:

306.3.

b. Preparation of 3-endo- (3-methoxyphenyl) -8-azabicyclo [3.2.1] octane

Ethanol (70 ml) was added to a small Parr flask containing the product from the previous step (9.9 g, 32.5 mmol). The mixture was stirred at room temperature until the reagent dissolved completely. To the solution was added solid palladium hydroxide (4.45 g, 50% by weight) in portions. The reaction vessel was purged with dry nitrogen and under hydrogen atmosphere (55 psi) overnight. Once the end of the reaction was checked by HPLC, the reaction mixture was purged with nitrogen and filtered through Celite. The solvent was removed in vacuo to give the intermediate of the title as a yellow oil (6.9 g, 98% yield). (m / z): [M + H] + calculated for C14H19NO: 218.16; Found: 218.3.

C. Preparation of 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -phenol

The product from the previous stage (6.9 g, 31.79 mmol) and dichloromethane (200 ml) was introduced into a 1 l round bottom flask equipped with a magnetic stir bar. The reaction was cooled for 15 minutes in a dry ice / acetone bath at -78 ° C. To the cooled reaction, 1 M boron tribromide solution in dichloromethane (64 ml, 63.59 mmol) was quickly added. The reaction was allowed to slowly warm to room temperature for a period of 20 hours. Methanol was added carefully to stop the reaction. The magnetic stirrer was removed and the solvent removed in vacuo to give a crisp brown solid. The solid was dissolved in methanol. The solvent was removed in vacuo to give a crisp brown solid. The solid was dissolved again in methanol. The solvent was removed in vacuo to give a crisp brown solid which was then dried under vacuum. The dried solid was then dissolved in dichloromethane and the solution was washed with 1 N NaOH and saturated sodium chloride solution. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give the intermediate of the title as a yellow oil. (m / z): [M + H] + calculated for C13H17NO: 204.14; Found: 204.3.

d. Preparation of 3-endo- (3-hydroxyphene) -8-azabicyclo [3.2.1] tert-butyl octan-8-carboxylate

In a 500 ml reaction flask containing 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -phenol (2.5 g, 12.3 mmol) dichloromethane (100 ml) was introduced under atmosphere of dry nitrogen and then tetrahydrofuran (70 ml). To the suspension was added N, N-diisopropylethylamine (3 ml) and di-tert-butyl dicarbonate (3 ml, 12.3 mmol) in one portion as melted liquid. The reaction was allowed to stir at room temperature for a period of 16 hours. Once the end of the reaction was checked by HPLC, the reaction mixture was transferred to a larger flask and most of the solvent was removed. The residue was dissolved in ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give the crude intermediate of the title. The crude material was chromatographed on silica gel with 20-25% ethyl acetate / hexanes as the mobile phase. The fractions were combined and the solvent removed in vacuo to give 2.4 g of purified product. The purified material was dissolved in dichloromethane (~ 10 ml) and hexanes (150 ml) were added. Dichloromethane was removed by rotary evaporation. The solution was transferred to an Erlenmeyer flask and some seed crystals from a previous preparation by the same method were added. The solution was allowed to crystallize overnight. The crystals were filtered off and washed with hexane. Drying under vacuum gave the intermediate of the title as white needles (1.01 g, 27% yield). Crystals began to grow in the mother liquor, which were collected, collected, washed with hexanes and dried under vacuum to give the intermediate of the title as white needles (850 mg, 23% yield). (m / z): [M + H] + calculated for C18H25NO3: 304.19; Found: 304.3,

248.3 (original-tert-butyl).

and. Preparation of tert-butyl 3-endo- (3-trifluoromethanesulfonyloxy-phenyl) -8-azabicyclo [3.2.1] octan-8-carboxylate

In a 50 ml reaction flask, equipped with a magnetic stir bar and purged with dry nitrogen, 3-endo- (3-hydroxyphene) -8-azabicyclo [3.2.1] octan-8-carboxylic acid tert-butyl ester was introduced (587 mg, 1.94 mmol) and dimethylformamide (10 ml). The reaction was stirred until a solution formed; Subsequently, potassium carbonate (0.40 g, 2.90 mmol) and N-phenyltrifluoromethanesulfonimide (1.03 g, 2.90 mmol) were added together in one portion, both in solid form. The reaction was heated at 50 overnight. The reaction was diluted with 1: 1 ethyl acetate: hexanes and water and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the intermediate of the title as a colorless oil (856 mg, yield> 100%). (m / z): [M + H] + calculated for C19H24F3NO5S: 436.14; Found: 436.2, 380.3 (original-tert-butyl).

F. Preparation of 3-endo- (3-cyanophenyl) -8-azabicyclo [3.2.1] tert-butyl octan-8-carboxylate

To a 1 l round bottom flask, equipped with a magnetic stir bar and purged with dry nitrogen, 3-endo- (3-trifluoromethanesulfonyloxy-phenyl) -8-azabicyclo [3.2.1] octan-8-carboxylate was introduced tert-butyl (38.4 g, 88.3 mmol) and dimethylformamide (320 ml). The solution was stirred for 5 minutes to dissolve all the starting material and then degassed under vacuum. A dry nitrogen atmosphere was introduced again. To the degassed solution was added together, in one portion, zinc cyanide (15.5 g, 132 mmol) and tetrakis (triphenylphosphine) palladium (0) (5.1 g, 4.41 mmol), both in solid form . The reaction was degassed again in vacuo to remove the possible oxygen present and a dry nitrogen atmosphere was introduced. The reaction was heated at 80 ° C for 4 hours. The reaction was cooled to room temperature and diluted with isopropyl acetate (500 ml). The resulting cloudy solution was filtered through Celite (10 g). The resulting organic solution was transferred to a separatory funnel and washed with saturated aqueous sodium bicarbonate (400 ml) and saturated aqueous sodium chloride (400 ml). The organic layer was separated and dried over anhydrous sodium sulfate (30 g). The drying agent was removed by filtration and the solvent was removed in vacuo to give the crude intermediate of the title as brown waxy crystals (29.9 g, yield> 100%). (m / z): [M + H] + calculated for C19H24N2O2: 313.19; Found: 313.3, 257.3 (original-tert-butyl).

g. Synthesis of 3-endo- (8-azabicicIo [3.2.1] oct-3-il) -benzamide

3-endo- (3-cyanophenyl) -8-azabicyclo [3.2.1] tert-butyl octan-8-carboxylate (4.8 g, 15.36 mmol) was weighed in a 500 ml round bottom flask and diluted with DMSO (105 ml). A solid potassium carbonate (3.18 g, 23.04 mmol) antiexplosive shield was carefully added, followed by 30% hydrogen peroxide in water (8 ml). The reaction was stirred outdoors overnight at room temperature. Once the end of the reaction was checked by HPLC, water (160 ml) was added and the reaction was extracted with ethyl acetate (3 x 150 ml). The combined organic layers were washed with sodium sulphite (all aqueous layers were treated with sodium sulphite to destroy peroxide) and brine, and dried over sodium sulfate. The solvent was removed in vacuo to give the protected intermediate 3- (3-carbamoylphenyl) -8-azabicyclo [3.2.1] tert-butyl octane-8-carboxylate as a colorless oil (4.8 g, 95% of performance). (m / z): [M + H] + calculated for C19H26N2O3: 331.20; Found: 331.4, 275.0 (original ether-butyl).

The protected intermediate was treated with dichloromethane and trifluoroacetic acid according to step e of preparation method 4, to obtain the TFA salt of the title compound.

Preparation 13: Synthesis of 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -benzamide

to. Preparation of 8-benzyl-3-exo- (3-methoxyphenyl) -8-azabicyclo [3.2.1] octan-3-ol

In a 3 l flask, with 3 mouths, equipped with a top stirrer and purged with dry nitrogen, powdered waxy chloride (88.2 g, 0.35 mol) was introduced. The solid was diluted with anhydrous tetrahydrofuran (500 ml) and cooled to 0 ° C. To the suspension was added dropwise 1M 3-methoxyphenyl magnesium bromide in THF (360 ml, 0.36 mol), keeping the temperature below 10 ° C. The resulting solution was stirred at 0 ° C for 1.5 hours. A solution of 8-benzyl-8-azabicyclo [3.2.1] octan-3-one (54.5 g, 0.25 mol) in tetrahydrofuran (50 ml) was added dropwise, keeping the internal temperature below 5 ° C. The resulting solution was stirred at 0 ° C for 2 hours. The reaction was stopped with 10% aqueous acetic acid solution (400 ml) and stirred for 30 minutes at room temperature. Saturated sodium chloride solution (400 ml) was then added and the resulting suspension was stirred at room temperature for 20 hours to allow complete crystallization of the product as acetate salt. The crystals were filtered and washed with cold water (200 ml) and then with isopropyl acetate (200 ml), and dried under vacuum to give the title intermediate as a white crystalline powder (91.1 g, 93% of performance). (m / z): [M + H] + calculated for C21H25NO2: 324.20; Found: 324.5.

b. Preparation of 8-benzyl-3- (3-methoxyphenyl) -8-azabicyclo [3.2.1] oct-2-eno

In a 1L flask, equipped with a magnetic stir bar, 8-benzyl-3-exo- (3methoxyphenyl) -8-azabicyclo [3.2.1] octan-3-ol (80.4 g) acetate salt was introduced , 0.209 mol), followed by 6 M aqueous hydrochloric acid (300 ml). The reaction was heated at 70 ° C for 2 hours. Stirring was stopped and the reaction was diluted with dichloromethane (200 ml). The mixture was passed to a separatory funnel, mixing the layers, and then allowed to stand. The organic layer was removed and stored. The aqueous layer was extracted with dichloromethane (2 x 200 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (400 ml) and dried over anhydrous sodium sulfate (30 g). The solvent was removed in vacuo to give the hydrochloride salt of the intermediate of the title as a sticky yellow oil (65.4 g, 91% yield). (m / z): [M + H] + calculated for C21H23NO: 306.19; Found: 306.3.

C. Preparation of 3-endo- (3-methoxyphenyl) -8-azabicyclo [3.2.1] octane

To a 1 l round bottom flask containing the product from the previous step (65.4 g, 0.191 mol) was added ethanol (300 ml). The mixture was stirred at room temperature until the intermediate dissolved completely. Solid palladium hydroxide (6.7 g, ~ 10% by weight) was added to the solution carefully. The reaction vessel was purged with dry nitrogen and hydrogen was carefully introduced by a needle valve balloon. Hydrogen was bubbled through the solution for 10 minutes and the solution was allowed to stir overnight under a hydrogen atmosphere. Once the end of the reaction was checked by HPLC, the hydrogen was removed from the reaction mixture and the vessel was purged with dry nitrogen for 10 minutes. The reaction mixture was then filtered through Celite (5 g) and the Celite cake was washed with ethanol (100 ml). The combined ethanol solutions were evaporated in vacuo and the resulting residue was dissolved in dichloromethane (400 ml). The organic layer was washed with 3 N sodium hydroxide (300 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 200 ml). The combined organic layers were washed with aqueous sodium chloride (300 ml) and dried over potassium carbonate (30 g). The drying agent was filtered off and the solvent was removed in vacuo to give the intermediate of the title as a yellow oil (27.6 g, 66% yield). (m / z): [M + H] + calculated for C14H19NO: 218.16; Found: 218.3.

d. Preparation of 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) phenol

The product from the previous stage (27.6 g, 0.127 moles) and dichloromethane (300 ml) were added in a 1 l round bottom flask, equipped with a magnetic stir bar and a dosing funnel. The reaction was cooled to -78 ° C in a dry ice / acetone bath. To the cooled reaction was added boron tribromide (1 M solution in dichloromethane, 152 ml, 0.152 mol). The reaction was allowed to slowly warm to room temperature for a period of 20 hours. The reaction was placed in an ice bath and methanol (100 ml) was carefully added to stop the reaction. The solvent was removed in vacuo to give a beige crisp solid, which was dissolved in methanol (100 ml). The solvent was removed in vacuo to give a beige crisp solid. The solid was dissolved again in methanol (100 ml). The solvent was removed in vacuo to give a beige crisp solid which was dried under vacuum for 2 hours. The dried solid was then suspended in ethanol (110 ml) and the solution was heated in an oil bath at 80 ° C. To the hot solution was added enough methanol to dissolve all solid substances (72 ml). The solution was cooled slowly to room temperature, allowing the formation of white crystals of the hydrobromide salt of the intermediate. The solution was then cooled in the freezer for one hour to -20 ° C. The crystallization was heated to room temperature and the crystals were collected by filtration. The white crystals were washed with cold ethanol (35 ml) and dried in vacuo to give the hydrobromide salt of the title intermediate as a white powder (19.5 g, 54% yield). The mother liquor was evaporated to give a beige crisp solid. The solid was dissolved in ethanol (30 ml) and heated to 80 ° C. A light brown solution formed. The solution was cooled to room temperature and then at -20 ° C for one hour. The crystals were collected by filtration, washed with cold ethanol (10 ml) and dried in vacuo to give a second batch of crystals (5.5 g, 15% yield). (m / z): [M + H] + calculated for C13H17NO: 204.14; Found: 204.4.

and. Preparation of tert-butyl 3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] octan-8-carboxylate

In a 500 ml reaction flask containing the 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -phenoI hydrobromide salt (24.8 g, 0.087 mol) dichloromethane (200 ml) under dry nitrogen atmosphere. The suspension was cooled to 0 ° C. Then N, N-diisopropylethylamine (22.75 ml, 0.13 mol) and di-tert-butyl dicarbonate (19.03 g, 0.087 mol) solid were added in one portion. The reaction was allowed to warm to room temperature for a period of 16 hours. Once the end of the reaction was checked by HPLC, the reaction mixture (now a light brown solution) was transferred to a separatory funnel and diluted with isopropyl acetate (200 ml). The organic mixture was washed with saturated aqueous sodium bicarbonate (300 ml). The organic layer was separated and the aqueous layer was extracted with isopropyl acetate (200 ml). The combined organic layers were washed with an aqueous solution of sodium chloride (300 ml), the layers were separated and the organic layer was dried over anhydrous sodium sulfate (20 g). The solvent was removed in vacuo to obtain the intermediate of the title as a white solid (27.1 g, yield> 100%). (m / z): [M + H] + calculated for C18H25NO3: 304.19; Found: 304.3, 248.3 (original ether-butyl).

F. Preparation of tert-butyl 3-endo- (3-trifluoromethanesulfonyloxy-phenyl) -8-azabicyclo [3.2.1] octan-8-carboxylate

In a 500 ml reaction flask equipped with a magnetic stir bar and purged with dry nitrogen, the product from the previous step (27.1 g, 0.089 mol) and dichloromethane (250 ml) was introduced. The solution was cooled to 0 ° C in an ice bath. To the cold solution was added triethylamine (12.4 ml, 0.097 mol) and trifluoromethanesulfonyl chloride (9.43 ml, 0.097 mol) dropwise, keeping the internal temperature below 10 ° C. To this reaction was added 4 -N, solid N-dimethylaminopyridine (0.544 g, 4.46 mmol) in one portion. The reaction was heated to room temperature and stirred for 30 minutes. The final solution was passed to a separatory funnel. The organic layer was washed with saturated aqueous sodium bicarbonate (200 ml) and saturated aqueous sodium chloride (200 ml). The organic layer was separated and dried over anhydrous sodium sulfate (20 g). The drying agent was removed by filtration and the solvent was removed in vacuo to obtain the intermediate of the title as a clear oil (38.4 g, 98% yield). (m / z): [M + H] + calculated for C19H24F3NO5S: 436.14; Found: 436.2, 380.3 (original-tert-butyl).

g. Preparation of 3-endo- (3-cyanophenyl) -8-azabicyclo [3.2.1] tert-butyl octan-8-carboxylate

The product from the previous stage (38.4 g, 88.3 mmol) and dimethylformamide (320 ml) was introduced into a 1 l round bottom flask, equipped with a magnetic stir bar and purged with dry nitrogen. The solution was stirred for 5 minutes to dissolve all starting material and degassed in vacuo. A dry nitrogen atmosphere was introduced again. To the degassed solution, zinc cyanide (15.5 g, 132 mmol) and tetrakis (triphenylphosphine) palladium (0) (5.1 g, 4.41 mmol) were added together in solid form in a single portion. The reaction was degassed again under vacuum and a dry nitrogen atmosphere was introduced. The reaction was heated at 80 ° C for 4 hours. The reaction was cooled to room temperature and diluted with isopropyl acetate (500 ml). The resulting cloudy solution was filtered through Celite (10 g). The resulting organic solution was washed with saturated aqueous sodium bicarbonate (400 ml) and saturated aqueous sodium chloride (400 ml). The organic layer was separated and dried over anhydrous sodium sulfate (30 g). The drying agent was removed by filtration and the solvent was removed in vacuo to give the crude intermediate of the title as brown waxy crystals (29.9 g, yield> 100%). (m / z): [M + H] + calculated for C19H24N2O2: 313.19; Found: 313.3, 257.3 (original-tert-butyl).

h. Synthesis of 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -benzamide

In a 15 ml round bottom flask, equipped with a magnetic stir bar and a reflux condenser, 3-endo- (3-cyanophenyl) -8-azabicyclo [3.2.1] octan-8-carboxylic acid tert was introduced -butyl solid (500 mg, 1.60 mmol), followed by trifluoroacetic acid (4 ml). To the solution was added concentrated sulfuric acid (440 µl, 5.0 equiv.). The reaction was heated at 65 ° C for 10 hours. The reaction mixture was poured into a saturated aqueous solution of sodium chloride (70 ml) and transferred to a separatory funnel. The aqueous layer was washed with isopropyl acetate (50 ml) to remove the remains of triphenylphosphine oxide from the previous step. 3 N aqueous sodium hydroxide was added to the aqueous layer to adjust the pH to 14. The aqueous layer was extracted with tetrahydrofuran (2 x 50 ml). The combined organic layers were dried over anhydrous sodium sulfate (3 g). The drying agent was filtered off and the solvent was removed in vacuo to give the title compound as a partially crystalline crisp foam (300 mg, 79% yield). (m / z): [M + H] + calculated for C14Hi8N2O: 231.15; Found: 231.2.

Preparation 14: Synthesis of methoxycarbonylmethanesulfonyl acetic acid

to. Preparation of tert-butyl methoxycarbonylmethanesulfanyl acetate

To a solution of mercapto-methyl acetate (1.0 g, 9.42 mmol) in dimethylformamide (10 ml) at room temperature was added potassium carbonate (1.69 g), followed by tert-butyl bromo-acetate (1.84 g, 9.42 mmol). The resulting suspension was stirred at room temperature overnight and then diluted with hexane. The organic layer was washed three times with water and once with brine, dried over sodium sulfate, filtered and concentrated, to obtain a colorless oil that was used directly in the next step without purification. 1 H NMR (CDCl 3, 300 MHz) δ (ppm): 3.72 (s, 3H), 3.37 (s, 2H), 3.27 (s, 2H), 1.45 (s, 9H).

b. Preparation of tert-butyl methoxycarbonylmethanesulfonyl acetate

To a solution of the product from the previous step (830 mg, 3.75 mmol) in dichloromethane (25 ml) at 0 ° C was added 3-chloroperoxybenzoic acid (1.94 g, 11.25 mmol). The resulting mixture was allowed to warm to room temperature after the addition and stirred at room temperature for 2.5 hours. The reaction was stopped with saturated sodium sulphite (30 ml) and the mixture was stirred at room temperature for 15 minutes. The layers were separated and the organic layer was washed successively with NaOH in aqueous solution, saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtered and concentrated, to give the title intermediate as a colorless oil (683 mg) which was used directly in the next step. 1 H NMR (CDCl 3, 300 MHz) δ (ppm): 4.32 (s, 2H), 4.21 (s, 2H), 3.81 (s, 3H), 1.48 (s, 9H).

C. Synthesis of methoxycarbonylmethanesulfonyl acetic acid

The product from the previous step (683 mg) was treated with trifluoroacetic acid (10 ml) at room temperature for two hours. The mixture was concentrated, redissolved in ethyl acetate and the organic layer was washed with water, and then with brine. The organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound as a colorless oil that became a wax when dried under vacuum (345 mg). 1 H NMR (CDCl3, 300 MHz) δ (ppm): 4.39 (s, 2H), 4.33 (s, 2H), 3.83 (s, 3H).

Preparation 15: Synthesis of (S) -2,2-dimethyl- [1,3] dioxolan-4-carboxylic acid

To a solution of methyl α, β-isopropylidene-1-glycerate (2.2 g, 13.7 mmol) in MeOH (20 ml) at room temperature was added lithium hydroxide monohydrate (1.15 g, 27, 4 mmol) in water (5.0 ml). The resulting mixture was stirred at room temperature overnight. After concentrating, the residue was acidified with 10% aqueous HCl (20 ml) and extracted three times with dichloromethane. The combined organic layer was washed twice with brine, dried over sodium sulfate, filtered and concentrated to give the title compound as a colorless oil (819 mg). 1 H NMR (CDCl3, 300 MHz) δ (ppm): 4.60 (dd, J = 4.5, 7.2 Hz, 1H), 4.28 (dd, J = 7.2, 8.7 Hz , 1H), 4.18 (dd, J = 4.5, 8.7 Hz, 1H), 1.51 (s, 3H), 1.40 (s, 3H).

Preparation 16: Synthesis of [benzyl- (2-oxoethyl) carbamoyl] -methyl acetate

to. Synthesis of [benzyl- (2-hydroxyethyl) carbamoyl] -methyl acetate

Benzyl ethanolamine (1.78 g, 11.8 mmol.) Was weighed in a 25 ml round bottom flask and diluted with dichloromethane. N, N-diisopropylethylamine (2.66 ml, 15.3 mmol) was quickly added by syringe and the reaction was cooled to 0 ° C. After stirring at 0 ° C for 10 minutes, acetoxyacetyl chloride (1.26 ml, 11.8 mmol) was added dropwise with a syringe. The reaction was stirred overnight and allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was separated and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was removed in vacuo to give the crude intermediate of the title as a yellow oil. The crude material was chromatographed on silica gel with ethyl acetate as the mobile phase. The fractions were combined and the solvent was removed in vacuo to give the intermediate of the pure title as an oil (1.75 g, 59% yield). (m / z): [M + H] + calculated for C13H17NO4: 252.13, found: 252.3.

b. Synthesis of [benzyl- (2-oxoethyl) carbamoyl] -methyl acetate

[Benzyl- (2-hydroxyethyl) carbamoyl] -methyl acetate (1.28 g, 5.10 mmol) was weighed into a 200 ml round bottom flask purged with nitrogen. Dichloromethane (50 ml) was added and the reaction was cooled to -15 ° C for 10 minutes. Then dimethylsulfoxide (3.61 ml, 51.0 mmol), N, N-diisopropylethylamine (4.43 ml, 25.5 mmol) and sulfur pyridine-trioxide complex (4.06 g) were added successively at -15 ° C , 25.5 mmol). The reaction was allowed to rise slowly to room temperature and stirred overnight. The reaction was complete by thin layer chromatography and diluted with ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was separated and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was removed in vacuo to give the crude title compound as a yellow oil. The crude material was chromatographed on silica gel with ethyl acetate: dichloromethane 1: 1 as mobile phase. The fractions were combined and the solvent was removed in vacuo to give the pure title compound as a colorless oil (0.72 g, 57% yield). (m / z): [M + H] + calculated for C13H15NO4: 250.11, found: 250.0.

Preparation 17: Synthesis of 3-endo- [8- (2-phenethylaminoethyl) -8-azabicyclo [3.2.1] oct-3-yl] benzamide

to. Preparation of 2-phenethylaminoethanol

A mixture of 2-bromoethylbenzene (2.0 g, 10.8 mmol) and ethanolamine (3.96 g, 64.8 mmol) in ethanol (11 ml) was heated at 75 ° C for 16.5 hours and at this point He checked by LC / MS that the reaction was complete. The reaction mixture was concentrated to remove ethanol and the resulting residue was diluted with DCM (100 ml). The organic layer was partitioned with water (100 ml) and the aqueous layer was extracted with DCM (50 ml). The combined organic layers were washed with water (2 x 5 ml), dried over sodium sulfate, filtered and concentrated to give the intermediate of the title as a slightly yellow oil (1.5 g). (m / z): [M + H] + calculated for C10H15NO: 166.13; Found: 166.2. 1 H NMR (DMSO-d6, 300 MHz) δ (ppm): 7.13-7.29 (m, 5H), 4.4 (br, 1H), 3.42 (t, J = 5.7 Hz , 2H), 2.61-2.76 (m, 4H), 2.55-2.59 (t, J = 5.7 Hz, 2H), 1.55 (br, 1H).

b. Preparation of tert-butyl (2-hydroxyethyl) phenethylcarbamate

Following the procedure of step b of preparation 8, the product of the previous stage (1.5 g, 9.09 mmol) was reacted with di-tert-butyl dicarbonate (1.78 g, 8.2 mmol ) in DCM (14 ml) to give the intermediate of the title (2.26 g) as a slightly yellow oil.

C. Preparation of tert-butyl (2-oxoethyl) phenethylcarbamate

Following the procedure of stage c of preparation 8, the product of the previous stage (2.26 g, 8.5 mmol) became the intermediate of the title, which was obtained as a yellowish oil (1.27 g ). 1 H NMR (DMSO-d6, 300 MHz) δ (ppm): 9.37 (s, IH), 7.21-7.28 (m, 2H), 07.17 to 07.20 (m, 3H) , 3.93 (s, 2H), 3.41 (t, 2H), 2.74 (t, 2H), 1.30 (s, 9H).

d. Preparation of tert-butyl {2- [3-endo- (3-carbamoylfenyl) -8-azabicyclo [3.2.1] oct-8-yl] -ethyl} phenethylcarbamate

Following the procedure of step a of preparation 9, 3-endo- (8-azabicyclo [3.2.1] oct-8-yl) benzamide (60 mg, 0.28 mmol), obtained by the preparation method, was reacted 13, with tert-butyl (2-oxoethyl) phenethylcarbamate (87 mg, 0.34 mmol), to give the intermediate of the title as a yellowish oil. (m / z): [M + H] + calculated for C29H39N3O3: 478.4, found, 478.30.

and. Preparation of 3-endo-8- (2-phenethylaminoethyl) -8-azabicyclo [3.2.1] oct-8-yl] -benzamide

Following the procedure of stage b of preparation 9, the product of the previous stage was treated with TFA to give the intermediate of the title as a dark oil. (m / z): [M + H] + calculated for C24H31N3O: 378.25, found, 378.2.

Preparation 18: Synthesis of 3-endo- [8- (2- (3-phenylpropylamino) ethyl) -8-azabicyclo [3.2.1] oct-3-yl] benzamide

Following the preparation procedure 17 and substituting 2-bromoethylbenzene for 1-bromo-3-phenylpropane, the following intermediates were prepared:

to.

2- (3-phenylpropylamino) ethanol. 1 H NMR (DMSO-d6, 300 MHz) δ (ppm): 7.14-7.28 (m, 5H), 4.4 (br, 1H), 3.42 (t, J = 5.7 Hz , 2H), 2.46-2.58 (m, 6H), 1.61-1.71 (p, 2H), 1.65 (br, 1H).

b.

Tert-Butyl (2-hydroxyethyl) - (3-phenylpropyl) carbamate

C.

Tert-Butyl (2-oxoethyl) - (3-phenylpropyl) carbamate. 1 H NMR (DMSO-d6, 300 MHz) δ (ppm): 9.44 (s, 1H), 7.247.39 (m, 2H), 7.15-7.19 (m, 3H), 3.97 (s, 2H), 3.24 (t, 2H), 2.49 (t, 2H), 1.69-1.74 (m, 2H), 1.34 (s, 9H).

d.

Tert-Butyl {2-ethyl- [3-endo- (3-carbamoylfenyl) -8-azabicyclo [3.2.1] oct-8-yl] -ethyl} - (3-phenylpropyl) carbamate. (m / z): [M + H] + calculated for C30H41N3O3: 492.31; Found: 492.4.

and.

3-endo- {8- [2- (3-phenylpropylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} -benzamide. (m / z): [M + H] + calculated for C25H33N3O: 392.26; Found: 392.4.

Preparation 19: Synthesis of 3-endo- [8- (2- (2-cyclohexylethylamino) ethyl) -8-azabicyclo [3.2.1] oct-3-yl] benzamide

Following the preparation procedure 17 and replacing the 2-bromoethylbenzene with 1-bromo-2-cyclohexylethane, the following intermediates were prepared:

to.

2- (2-cyclohexylethylamino) ethanol. 1 H NMR (DMSO-d6, 300 MHz) δ (ppm): 4.4 (br, 1H), 3.38-3.42 (t, J = 5.7 Hz, 2H), 2.46-2 , 54 (m, 4H), 1.58-1.65 (m, 5H), 1.06-1.29 (m, 6H), 0.82-0.89 (m, 2H).

b.

Tert-Butyl (2-cyclohexylethyl) - (2-hydroxyethyl) carbamate

C.

Tert-Butyl (2-cyclohexylethyl) - (2-oxoethyl) carbamate. 1 H NMR (DMSO-d6, 300 MHz) δ (ppm): 9.43 (s, 1H), 3.93 (s, 2H) 3.20 (t, 2H), 1.64-1.68 ( m, 4H), 1.38 (s, 9H), 1.30-1.37 (m, 4H), 1.14-1.27 (m, 3H), 0.83-0.87 (m, 2H).

d.

Tert-Butyl {2- [3-endo- (3-carbamoylfenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} - (2-cyclohexylethyl) carbamate. (m / z): [M + H] + calculated for C29H45N3O3: 484.35; Found: 484.4.

and.

3-endo- {8- [2- (2-cyclohexylethylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} -benzamide. (m / z): [M + H] + calculated for C24H37N3O: 384.29; Found: 384.4.

Preparation 20: Synthesis of 3-endo- [8- (2- (3-cyclohexylpropylamino) ethyl) -8-azabicyclo [3.2.1] oct-3-yl] benzamide

to. Preparation of 3-cyclohexylpropionaldehyde

3-Cyclohexyl-1-propanol (3.96 g, 27.8 mmol) was dissolved in DCM (90 ml) at 0 ° C and treated successively with dimethylsulfoxide (3.25 g, 41.7 mmol), N, N- diisopropylethylamine (8.98 g, 69.6 mmol) and sulfur trioxide-pyridine complex (11 g, 69.6 mmol). After one hour the reaction mixture was diluted with DCM (100 ml) and washed with aqueous HCl (3 x 50 ml), saturated sodium bicarbonate (3 x 50 ml) and brine. The organic layer was dried over MgSO4, filtered and concentrated to obtain the intermediate of the title as a light yellow oil (3.8 g). 1 H NMR (DMSO-d6, 300 MHz) δ (ppm): 9.72 (s, 1H), 3.65-3.72 (m, 2H), 2.46 (t, 2H) 1.65- 1.73 (m, 3H), 1.51-1.56 (m, 2H), 1.14-1.48 (m, 4H), 0.85-0.96 (m, 2H).

b. Preparation of 2- (3-cyclohexylpropylamino) ethanol To a solution of ethanolamine (0.44 g, 7.1 mmol) in DCM (15 RAL) at 0 ° C was added a solution of 3-cyclohexylpropionaldehyde (1.0 g, 7.1 mmol) in DCM (10 ml), followed by sodium triacetoxyborohydride (1.67 g, 7.86 mmol). The resulting mixture was heated to room temperature. After 2.5 hours the desired product was analyzed by mass spectrometry. The reaction mixture was stirred overnight, then diluted with DCM (50 ml), washed with saturated sodium bicarbonate (2 x 50 ml) and brine (50 ml), dried over sodium sulfate, filtered and concentrated to give a clear oil (1.0 g) that was used in the next step without further purification. (m / z): [M + H] + calculated for C11H23NO: 186.20; Found: 186.0).

Following steps b through e of the preparation process 17 and substituting the 2-phenethylaminoethanol from step b of preparation 17 for 2- (3-cyclohexylpropylamino) ethanol, the following intermediates were prepared:

C.

Tert-Butyl (3-hydroxyethyl) carbamate (3-cyclohexylpropyl)

d.

Tert-Butyl (3-cyclohexylpropyl) - (2-oxoethyl) carbamate. 1 H NMR (DMSO-d6, 300 MHz) δ (ppm): 9.43 (s, 1H), 3.94 (s, 2H), 3.14 (t, 2H), 1,621 (m, 4H), 1.41-1.46 (m, 5H), 1.38 (s, 9H) 1.34-1.36 (m, 4H), 0.86-0.88 (m, 2H).

and.

Tert-Butyl {2- [3-endo- (3-carbamoylfeniI) -8-azabicyclo [3.2.1] oct-8-yl] -ethyl} - (3-cyclohexylpropyl) carbamate. (m / z): [M + H] + calculated for C30H47N3O3: 498.36; Found: 498.6.

F.

3-endo- {8- [2- (3-cyclohexylpropylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} -benzamide. (m / z): [M + H] + calculated for C25H39N3O: 398.31; Found: 398.4.

Preparation 21: Synthesis of 3-endo- (8- {2 - [(4,4-difluorocyclohexylmethyl) -amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide

to. Preparation of tert-butyl (4,4-difluorocyclohexylmethyl) carbamate

To a solution of tert-butyl (4-oxocyclohexylmethyl) carbamate (2.0 g, 8.81 mmol) in dichloromethane (50 ml) at 0 ° C was added dropwise under a nitrogen atmosphere of bis- (2- trifluoride) methoxyethyl) aminosulfide (Deoxo-Fluor®) (3.90 g, 17.62 mmol). The reaction was allowed to warm to room temperature after the addition and stirred at that temperature overnight. Then the reaction was slowly stopped with saturated sodium bicarbonate. More dichloromethane (300 ml) was added and the resulting mixture was filtered through a block of Celite. The layers of the filtrate were separated and the organic layer was washed three times with saturated sodium bicarbonate and then with brine. The residue was dried over sodium sulfate, filtered and concentrated to give a brown oil that was further purified by chromatography. The compound was eluted with 25% (400 ml) to 30% (200 ml) and 40% (200 ml) of ethyl acetate / hexanes. The desired fractions were combined and concentrated to give a yellowish oil that solidified on drying under vacuum (694 mg).

b. Preparation of (4,4-difluorocyclohexyl) methylamine

The product from the previous step (694 mg) was treated with a mixture of dichloromethane and 1: 1 trifluoroacetic acid (6 ml) at room temperature for thirty minutes. The reaction mixture was concentrated and coevaporated three times with ethyl acetate. The resulting residue was dried under vacuum to give the TFA salt of the intermediate of the title as a brown oil.

C. Synthesis of 3-endo- (8- {2 - [(4,4-difluorocyclohexylmethyl) -amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide

To a solution of 3-endo- [8- (2-oxoethyl) -8-azabicyclo [3.2.1] oct-3-yl] benzamide (185 mg, 0.6 mmol) in dichloromethane (3 ml) at room temperature sodium triacetoxyborohydride (165 mg, 1.8 mmol) was added, followed by the TFA salt of (4,4-difluorocyclohexyl) methylamine (315 mg, 1.2 mmol) in dichloromethane (2 ml). The reaction mixture was stirred at room temperature for about an hour and a half and then concentrated. The resulting residue was dissolved in 50% acetic acid in water (10 ml), filtered and purified by reverse phase HPLC to give the bis-TFA salt of the title compound (73 mg). (m / z): [M + H] + calculated for C23H33F2N3O: 406.27; Found: 406.2.

Preparation 22: Synthesis of 3-endo- [8- (2-benzylamino-propiI) -8-azabicyclo [3.2.1] oct-3-yl] -phenol

to. Preparation of N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] -1-methyl-2-oxoethyl} benzamide

2-Benzoylaminopropionic acid (319 mg, 1.65 mmol) and benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (BOP) (731 mg, 1.65 mmol) was added to a stirred solution of the TFA salt of 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) phenol (obtained by method of preparation 4) (524 mg, 1.65 mmol) and N, N-diisopropylethylamine (0.86 ml , 4.96 mmol) in THF (14 ml) at room temperature, under a nitrogen atmosphere. After 90 minutes the reaction was stopped by adding water (1 ml), diluted with ethyl acetate (60 ml) and washed with 1M HCl (20 ml), saturated aqueous sodium bicarbonate (20 ml), brine (20 ml ), water (20 ml) and brine (20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc: hexanes 7: 3 to 4: 1) to obtain the intermediate of the title (597 mg) as a white solid.

b. Synthesis of 3-endo- [8- (2-benzylamino-propiI) -8-azabicyclo [3.2.1] oct-3-yl] -phenol

10-10.2 borane-dimethyl sulfide complex (2.16 ml, 21.6 mmol) was added dropwise to a stirred solution of the product from the previous step (544 mg, 1.44 mmol) in THF ( 15 ml) at -20 ° C, under a nitrogen atmosphere. At the end of the addition the reaction mixture was heated to reflux. After 3 hours the reaction mixture was cooled to -20 ° C, methanol (30 ml) was added carefully and stirred overnight. The reaction mixture was concentrated in vacuo and then diluted with 4M HCl in dioxane (10 ml) and stirred for 2 hours. The reaction mixture was concentrated again in vacuo and then diluted with methanol and potassium hydroxide (10 eq) was added. After 2 hours the reaction mixture was concentrated in vacuo, diluted with water (10 ml) and extracted with a dichloromethane: THF 3: 1 mixture (2 x 20 ml). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (509 mg) as a white solid that was used without further purification. (m / z): [M + H] + calculated for C23H30N2O: 351.25; Found: 351.5.

Preparation 23: Synthesis of N- [3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -phenyl] -methanesulfonamide

to. Preparation of 3-endo- (3-aminophenyl) -8-azabicyclo [3.2.1] tert-butyl octan-8-carboxylate

To a solution of 3-endo- (3-trifluoromethanesulfonyloxy-phenyl) -8-azabicyclo [3.2.1] tert-butyl octan-8-carboxylate (400 mg, 0.92 mmol), obtained by the preparation method 13 , in tetrahydrofuran (9.0 ml), benzophenonimine (216.7 mg, 1.2 mmol), potassium tert-butoxide (154.8 mg, 1.38 mmol) and rac-2,2'-bis ( diphenylphosphino) -1,1'binafilo (BINAP) (51.5 mg, 0.08 mmol). The resulting mixture was degassed and purged with nitrogen before adding palladium (II) acetate (19.3 mg, 0.08 mmol). The mixture was heated at 78 ° C for two hours. After cooling to room temperature, the reaction mixture was treated with 2N HCl (5.0 ml) for three hours and then alkalized to pH 8 with 5% sodium hydroxide in water. The aqueous layer was extracted with ethyl acetate. The resulting organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered, concentrated and purified by reverse phase HPLC to give the TFA salt of the title intermediate. (m / z): [M + H] + calculated for C18H26N2O2: 303.41; Found: 303.2.

b. Preparation of tert-butyl 3-endo- (3-methanesulfonylamino-phenyl) -8-azabicyclo [3.2.1] octan-8-carboxylate

To a stirred mixture of the TFA salt of 3-endo- (3-aminophenyl) -8-azabicyclo [3.2.1] tert-butyl octan-8-carboxylate (114 mg, 0.37 mmol), N, N- diisopropylethylamine (146 mg, 1.13 mmol) and 4-dimethylaminopyridine (DMAP) (9 mg, 0.075 mmol) in DCM (2.0 ml) at 0 ° C was added a solution of methanesulfonyl chloride (45 mg, 0.39 mmol) in DCM (0.2 ml). Thirty minutes later, HPLC analysis indicated that the reaction was not complete. More methanesulfonyl chloride (17 mg, 0.15 mmol) was added and the mixture was stirred at 0 ° C for another thirty minutes before stopping the reaction with saturated sodium bicarbonate. The aqueous layer was extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give the intermediate of the title as a yellowish oil (140 mg).

C. Synthesis of N- [3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -phenyl] -methanesulfonamide

The oily product from the previous step was treated with DCM (2 ml) and TFA (20 ml) at room temperature for thirty minutes and at that time of HPLC analysis indicated that the reaction was complete. The reaction mixture was concentrated and the resulting residue was coevaporated three times with ethyl acetate and dried in vacuo to give the TFA salt of the intermediate of the title as a yellowish oil, which was used without further purification.

Preparation 24: Synthesis of the adduct of benzyl N-cyclohexylmethyl- (2-oxoethyl) -carbamate

to. Preparation of N-cyclohexylmethyl- (2,2-N-cyclohexylmethyl- (2,2-diethoxyethyl) amine

To a mixture of 2,2-diethoxyethylamine (209 ml, 1.43 mol) and MeTHF (1050 ml) was added cyclohexanecarbaldehyde (107 ml, 0.89 mol). The reaction mixture was stirred for 30 minutes at room temperature and cooled to 0 ° C. Sodium triacetoxyborohydride (378 g, 1.79 mol) was added for more than 40 minutes and the reaction mixture was stirred 2 hours and cooled to 0 ° C. 1 M NaOH (1 L) was added. The organic layer was washed with brine / water (1: 1, 2 x 1 L) and the volume was reduced to ~ 20%. MeTHF (1 L) was added and the volume was reduced to ~ 20%. The crude intermediate intermediate solution was used directly in the next stage.

b. Preparation of benzyl N-cyclohexylmethyl- (2,2-diethoxyethyl) carbamate

To the product of the previous step (~ 213 g, -0.9 mol) was added MeTHF (2 L) and DIPEA (233 ml, 1.34 mol). The reaction mixture was cooled to 0 ° C and benzyl chloroformate (140 ml, 0.98 mol) was added dropwise. The reaction mixture was stirred for 30 minutes at 0 ° C, for 2 hours from 0 ° C to room temperature and then for 1 hour at room temperature. Water (1.6 L) was added and the reaction mixture was stirred for 10 min. The phases were separated and the organic layer was washed with sodium bicarbonate (1.6 L) and water (1.6 L). The layers were separated and the organic layer was reduced to 20%. MeTHF (1 L) was added and the volume was reduced to ~ 20%. The crude intermediate intermediate solution was used directly in the next stage.

C. Synthesis of the adduct of N-cyclohexylmethyl- (2-oxoethyl) -benzyl carbamate with bisulfite To the product of the previous step (~ 302 g, ~ 0.62 mol) with acetonitrile (2 L) and 1 M HCl ( 2 l) and the reaction mixture was stirred at 30 ° C for 7 h. Ethyl acetate (2 L) was added and the reaction mixture was stirred for 10 min. The phases were separated, the organic phase was washed with 1M HCl (1.5 L); The phases were separated again and the organic layer was washed with 0.5 M HCl (1 L). Sodium bisulfite (71.4 g, 0.69 mol) was added and the reaction mixture was stirred overnight and then filtered. The reactor and the filter cake were washed with ethyl acetate (1 L). The resulting solution was dried in air for 2 hours and under vacuum overnight to give the title compound as a white solid (199 g, purity> 99% by HPLC). The filtrate was treated by the same procedure to give a second batch of the title compound (30 g).

Preparation 25: Synthesis of 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -benzamide

to. Preparation of 8-benzill-3- (3-methoxyphenyl) -8-azabicyclo [3.2.1] oct-2-eno

In a 3L flask, 8-benzyl-3-exo- (3-methoxyphenyl) -8-azabicyclo [3.2.1] octan-3-ol (383.9g, 1.06 mol), HCl hydrochloride was introduced 6 M (800 ml) and MeTHF (200 ml). The resulting suspension was heated at 70 ° C for 2.5 hours under a nitrogen atmosphere. The reaction mixture was transferred to a 12 l reactor and cooled to 10 ° C. The reaction flask was washed with MeTHF (1 L) and added to the 12 L reactor. NaOH (50% by weight in water, 200 ml) and more NaOH (50% by weight, 150 ml) were added in portions until reaching pH ~ 13. The phases were separated; The aqueous layer was extracted with MeTHF (1 L) and the combined MeTHF layers were washed with brine (1 L). The solvent was reduced by rotary evaporation at 30 to 40 ° C, giving the intermediate of the title (360 g) as a thick oil. EtOH (1.5 L) was added and the volume was reduced to ~ 500 ml and then adjusted to 1.8 L.

b. Preparation of 3-endo- (3-methoxyphenyl) -azabicyclo [3.2.1] octane

To the 8-benzyl-3- (3-methoxyphenyl) -8-azabicyclo [3.2.1] oct-2-ene (in 95% EtOH, 400 ml, 0.20 mol) prepared in the previous step was added HCl 6 M (45 ml) and then MeTHF (50 ml). The reaction mixture was purged with nitrogen, heated to 40 ° C and palladium on carbon (10% by weight, 8 g) was added. The reactor was pressurized with hydrogen (3 x 20 psi) and then hydrogenated at 20 psi at 40 ° C for 18 h. The reaction mixture was filtered through Celite, concentrated, washed with MeTHF (2 x 100 ml), filtered through a thick glass filter, washed with MeTHF (10 ml) and dried over the filter to give the HCl salt of the intermediate of the title as a white solid (31 g of single isomer (exo isomer undetectable by HPLC)). 5.2 g more product was recovered from the mother liquor.

C. Preparation of 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) phenol

In a 500 ml flask, 3-endo- (3-rnethoxyphenyl) -8-azabicyclo [3.2.1] octane hydrochloride (115 g, 0.45 mol) and hydrobromic acid (48% by weight in water, 100) were introduced ml, 0.88 moles). The mixture was heated to 120 ° C and maintained at that temperature for 24 h with stirring. More hydrobromic acid solution (25 ml) was added and the reaction mixture was heated with stirring for 6 hours and then cooled to 70 ° C. Acetonitrile (200 ml) was added and the resulting suspension was cooled to 10 ° C and then filtered; The filter cake was washed with acetonitrile (50 ml) to give the HBr salt of the intermediate of the title (99 g,> 99% purity) as a white granulated solid.

d. Preparation of 2,2,2-trifluoro-1- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethanone

To a solution of 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -phenol hydrobromide (54.4 g, 0.19 mol), toluene (210 ml) and triethylamine (40 ml, 0.29 mol) trifluoroacetic anhydride (54 ml, 0.38 mol) was added in 20 minutes. The reaction mixture was stirred at 40 ° C for 2 h. Ethyl acetate (370 ml) and brine in water (1: 1, 265 ml) were added. The reaction mixture was stirred for 15 minutes and the phases were separated. Saturated sodium bicarbonate (300 ml) was added to the organic layer and the mixture was stirred vigorously overnight. The phases were separated and the organic layer was washed with brine in water (1: 1, 265 ml), dried over sodium sulfate and most of the solvent was removed by rotary evaporation. Toluene (100 ml) was added and the solvent was removed by rotary evaporation to give the crude intermediate of the title.

and. Preparation of 3-endo- [8- (2,2,2-trifluoroacetyl) -8-azabicyclo [3.2.1] oct-3-yl] phenyl trifluoromethanesulfonate

The solution of ethyl acetate (220 ml) of the intermediate of the previous step (32.8 g, 0.11 mol) and triethylamine (23 ml. 0.17 mol) was introduced into a 500 ml flask. The solution was cooled to 5 ° C and trifluoromethanesulfonyl chloride (14 ml, 0.13 mol) was added dropwise. The mixture was allowed to warm to 25 ° C and stirred at this temperature for 1 h. Saturated sodium bicarbonate (200 ml) was added, the layers were separated, brine (150 ml) was added to the organic layer, the layers were separated again and the solvent was removed from the organic layer to give the crude intermediate of the title.

F. Preparation of 3-endo- [8- (2,2,2-trifluoroacetyl) -8-azabicyclo [3.2.1] oct-3-yl] benzonitrile

ferrocene (1.01 g, 1.8 mmol) and zinc cyanide (4.2 g, 35.8 mmol). The flask was purged three times with nitrogen for 5 minutes and then placed under vacuum for 5 minutes. DMF (150 ml) and distilled water (2.5 ml) were added to the flask. The solution was purged with nitrogen, stirring for 10 minutes, heated to 120 ° C and stirred at 120 ° C under a nitrogen atmosphere for 4 hours. Upon completion of the reaction, 20 g of product from a previous batch prepared by the same procedure was added and stirred for 20 minutes. Most of the solvent was removed by distillation and the solution was cooled to 22 ° C. Ethyl acetate (445 ml) was added and the resulting solution was filtered through Celite. Sodium bicarbonate (450 ml) was added and the solution was stirred for 15 minutes. The layers were separated and the organic layer was washed with dilute brine (2 x 95 ml) and filtered through sodium sulfate. The volume was reduced to approximately 50 ml by eliminating ethyl acetate. Isopropyl alcohol (150 ml) was added and the solution was stirred at 22 ° C for 1 h. The solids were filtered off and washed with isopropyl alcohol (2 x 25 ml) to give the title intermediate (33.5 g, 100% pure by HPLC) as an off-white / slightly brown solid. More product was collected from the filtrate (6.3 g,> 98% HPLC purity).

g. Synthesis of 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -benzamide

A solution of 3-endo- [8- (2,2,2-trifluoroacetyl) -8-azabicyclo [3.2.1] oct-3-yl] benzonitrile (10 g, 32 mmol) in sulfuric acid (96%) was heated , 12 ml) at 50 ° C with stirring and kept at that temperature with stirring for 2 h. The reaction mixture was cooled to 22 ° C and slowly added to a 500 ml flask containing 5 N NaOH (90 ml) and methanol (100 ml) and cooled to 10 ° C. Saline precipitates were filtered and the filtrate was stirred at 22 ° C for 1 h. The reaction mixture was concentrated under reduced pressure. MeTHF (150 ml) was added to the residue and the reaction mixture was stirred at 22 ° C for 5 minutes. The layers were separated and MeTHF (100 ml) was added to the aqueous phase. The layers were separated and brine (150 ml) was added to the combined organic layers. The layers were separated and the organic layer was dried over potassium carbonate and filtered and the solvent removed. A mixture of EtOH (25 ml) and concentrated HCl (2.6 ml), and then MTBE (25 ml) was added to the residue, and the solution was stirred at 22 ° C. The precipitated solids were filtered and air dried to give the HCl salt of the title compound (8 g, 97% HPLC purity) as a white solid.

Example 1: Synthesis of N-benciI-2-hydroxy-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} acetamide

3-endo- [8- (2-benzylaminoethyl) -8-azabicyclo [3.2.1] oct-3-yl] phenol, prepared by the methods of preparations 1 and 2 (246 mg, 0,) was dissolved at room temperature 73 mmol), in dichloromethane (3.6 ml) and N, N-diisopropylethylamine (123 mg, 0.95 mmol). The resulting mixture was cooled to 0 ° C. Acetoxyacetyl chloride (119 mg, 0.87 mmol) was added and the mixture was stirred at 0 ° C for about 30 minutes. The reaction was stopped with saturated sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give a yellowish oil. The oily mixture was then dissolved in 50% acetic acid in water (10 ml), filtered and purified by preparative HPLC to give TFA salts of a monoacylated product (62 mg) and a bisacilated byproduct (160.9 mg) . The TFA salt of the bisacilated byproduct (160.9 mg) was dissolved in ethanol (2 ml) at room temperature and treated with aqueous sodium hydroxide (1.0 ml) for about 30 minutes. After concentrating, the residue was dissolved in 50% acetic acid in water (10 ml), filtered and purified by reverse phase HPLC to give the TFA salt of the title compound as a white solid (46, 5 mg) (m / z): [M + H] + calculated for C24H30N2O3: 395.24; Found: 395.3.

Example 2: Synthesis of N-benzyl-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicic [3.2.1] oct-8-yl] etiI} acetamide

To a solution of the TFA salt of 3-endo- [8- (2-benzylaminoethyl) -8-azabicyclo [3.2.1] oct-3-yl] phenol prepared by the methods of preparations 1 and 2 (25 mg , 0.044 mmol) in dichloromethane (0.2 ml) at room temperature was added N, N-diisopropylethylamine (23 mg, 0.177 mmol), followed by acetyl chloride (0.044 mmol). After 10 minutes the reaction mixture was concentrated. The residue was dissolved in 50% acetic acid in water (1.5 ml), filtered and purified by reverse phase HPLC to give the TFA salt of the title compound (10 mg). (m / z): [M + H] + calculated for C24H30N2O2: 379.23, found: 379.2.

Examples 3-5

Using processes similar to that of Example 2, but replacing acetyl chloride with 0.044 mmol of chloride of suitable acyl, the TFA salts of the compounds of examples 3-5 were prepared. Example 3 cyclopentanecarboxyl-benzyl- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} -amide (18.3 mg)

(m / z): [M + H] + calculated for C28H36N2O2: 433.29; Found: 433.2. Example 4 N-benzyl-2-ethyl-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} butyramide (15.1 mg) ( m / z):

[M + H] + calculated for C28H38N2O2: 435.30; Found: 435.2. Example 5 Methyl N-benzyl-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} succinamate (19.6 mg)

(m / z): [M + H] + calculated for C27H34N2O2: 451.26; Found: 451.2.

Example 6: Synthesis of N-benzyl-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] -ethyl} succinamic acid

To a solution of the TFA salt of 3-endo- [8- (2-benzylaminoethyl) -8-azabicyclo [3.2.1] oct-3-yl] phenoI prepared by the methods of preparations 1 and 2 (110 mg , 0.195 mmol) in dichloromethane (1.0 ml) at room temperature N, N-diisopropylethylamine (101 mg, 0.78 mmol) was added, followed by 3-carbomethoxypropionyl chloride (44 mg, 0.29 mmol). After about thirty minutes the reaction mixture was concentrated. The residue was dissolved in ethanol (2 ml), treated with lithium hydroxide monohydrate (33 mg, 0.78 mmol) in water (1 ml) for about thirty minutes and then concentrated. The residue was dissolved in 50% acetic acid in water (10 ml), filtered and purified by reverse phase HPLC to give the TFA salt of the title compound (46.5 mg). (m / z): [M + H] + calculated for C26H32N2O2: 437.25; Found: 437.12.

Example 7: Synthesis of N-cyclohexylmethyl-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} acetamide

To a solution of the TFA salt of 3-endo- {8- [2- (cyclohexylmethylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl-phenol prepared by the method of preparations 1 and 3 (25 mg, 0.044 mmol) in dichloromethane (0.2 ml) at room temperature was added N, N-diisopropylethylamine (34 mg, 0.26 mmol), followed by acetyl chloride (0.044 mmol). The reaction mixture was concentrated by rotary evaporation. The residue was dissolved in ethanol (0.2 ml) and hydrolyzed with 1 N aqueous NaOH (0.1 ml) at room temperature for 30 minutes. The solvents were removed by rotary evaporation and the resulting residue was dissolved in 50% acetic acid in water (1.5 ml), filtered and purified by preparative HPLC to give the TFA salt of the title compound (12 mg). . (m / z): [M + H] + calculated for C24H36N2O2: 385.29; Found: 385.2.

Examples 8-14

Using processes similar to that of Example 7, but replacing acetyl chloride with 0.044 mmol of chloride of suitable acyl, the TFA salts of the compounds of examples 8-14 were prepared. Example 8 N-cyclohexylmethyl-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} propionamide (7.1 mg)

(m / z): [M + H] + calculated for C25H38N2O2: 399.30; Found: 399.2. Example 9 cyclopentanecarboxyl-cyclohexylmethyl- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} amide

(16.4 mg) (m / z): [M + H] + calculated for C28H42N2O2: 439.34; Found: 439.2. Example 10 cyclohexanecarboxy-cyclohexylmethyl- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} amide

(14 mg) (m / z): [M + H] + calculated for C29H44N2O2: 453.35; Found: 453.4. Example 11 N-cyclohexylmethyl-3-cyclopentyl-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} propionamide

(11.4 mg) (m / z): [M + H] + calculated for C30H46N2O2: 467.37; Found: 467.4. Example 12 N-cyclohexylmethyl-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} -3-methylbutyramide

(14.1 mg) (m / z): [M + H] + calculated for C27H42N2O2: 427.33; Found: 427.4. Example 13 N-cyclohexylmethyl-2-hydroxy-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} acetamide

(10.8 mg) (m / z): [M + H] + calculated for C24H36N2O3: 401.28; Found: 401.2. Example 14 N-cyclohexylmethyl-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} -2-phenylacetamide (16.8 mg) (m / z): [M + H] + calculated for C30H40N2O2: 461.32; Found: 461.2.

Example 15: Synthesis of 1 - [(cyclohexylmethyl- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} carbamoyl) methyl] cyclohexyl} -acetic acid

To a solution of the TFA salt of 3-endo- {8- [2- (cyclohexylmethylamino) -ethyl] -8-azabicyclo [3.2.1] oct-3-yl-phenol prepared by the method of preparations 1 and 3 (24 mg, 0.042 mmol) in dichloromethane (0.4 ml) at room temperature was added N, N-diisopropylethylamine (22 mg, 0.17 mmol), followed by 1,1-cyclohexanediacetic anhydride (0.042 mmol). After 20 minutes the reaction was completed and the reaction mixture was concentrated. The residue was dissolved in methanol and hydrolyzed with 1 N aqueous NaOH (0.1 ml) at room temperature for 30 minutes. The solvents were removed and the resulting residue was dissolved in 50% acetic acid in water (1.5 ml), filtered and purified by preparative HPLC to give the TFA salt of the title compound. (m / z): [M + H] + calculated for C32H48N2O4: 525.37; Found: 525.2.

Examples 16-17

Using processes similar to that of example 15, but substituting 1,1-cyclohexandiacetic anhydride with 0.042 mmol of the listed anhydride, TFA salts of the compounds of examples 16 and 17 were prepared. Example 16 acid {1 - [(cyclohexylmethyl- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} carbamoyl) methyl] cycle

pentyl} reactive acetic: 3,3-tetramethyleneglutaric anhydride (m / z): [M + H] + calculated for C31H46N2O4:

511.36; Found: 511.2. Example 17 2- (Cyclohexylmethyl- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3,2.1] oct-8-yl] ethyl} carbamoyl) cyclohexan acid

reactive carboxylic: 1,2-cyclohexanedicarboxylic anhydride (m / z): [M + H] + calculated for C30H44N2O4:

497.34; Found: 497.2.

Example 18A: N-cyclohexylmethyl-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} succinamic acid

To a solution of 3-endo- {8- [2- (cyclohexylmethylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl-phenol, prepared by the method of preparations 1 and 3 and converted to Free base form (83 mg, 0.24 mmol), in dichloromethane (2.5 ml) at room temperature, N, N-diisopropylethylamine (124 mg, 0.96 mmol) was added, followed by 3-carbomethoxypropionyl chloride ( 72 mg, 0.48 mmol). The resulting mixture was stirred at room temperature for about 10 minutes and then concentrated, dissolved in ethanol (2 ml) and hydrolyzed with lithium hydroxide monohydrate (61 mg) in water (2 ml) for about 30 minutes. The reaction mixture was concentrated, dissolved in 50% acetic acid in water (10 ml), filtered and reverse phase preparative HPLC purified to give the TFA salt of the title compound, (m / z): [M + H] + calculated for C20H38N2O4: 443.29, found: 443.2.

Example 18B: N-cyclohexylmethyl-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} succinamic acid

To a solution of the TFA salt of 3-endo- {8- [2- (cyclohexylmethylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl-phenol, prepared by the method of preparation 4 and similar to that of preparation 11 (70 mg, 0.12 mmol), in dichloromethane (0.4 ml) at room temperature, N, N-diisopropylethylamine (62 mg, 0.48 mmol) was added, followed by succinic anhydride . The resulting mixture was stirred, stirred at room temperature for about 10 minutes, before concentrating. The residue was then redissolved in 50% acetic acid in water (10 ml), filtered and purified by reverse phase HPLC. The residue was lyophilized and the solid was dissolved in a mixture of MeOH (1.0 ml) and water (2.0 ml) and treated with lithium hydroxide monohydrate (30 mg) at room temperature for thirty minutes. The product was concentrated, dissolved in 50% acetic acid in water (10 ml), filtered and purified by preparative reverse phase HPLC to give the TFA salt of the title compound (28.9 mg). (m / z): [M + H] + calculated for C26H38N2O4: 443.29; Found: 443.5. 1 H NMR (CD3OD, 300 MHz) δ (ppm): 7.10-7.155 (m, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.85 (s, 1H), 6.63 (d, J = 8.1 Hz, 1H), 4.01 (brs, 2H), 3.71-3.79 (m, 2H), 3.26-3.28 (m, dark 2H ), 3.10-3.12 (m, 3H), 2.67 (s, 4H), 2.48-2.52 (m, 4H), 2.04-2.08 (m, 2H), 1,706-1,875 (m, 8H), 1,238-1,30 (m, 3H), 0.98-1.03 (m, 2H).

Example 19: Synthesis of 4- (cyclohexyImetiI- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} -carbamoyl) -3,3-dimethibutyric acid

To a solution of the TFA salt of 3-endo- {8- [2- (cyclohexylmethylamino) -ethyl] -8-azabicyclo [3.2.1] oct-3-yl-phenol prepared by the method of preparations 1 and 3 (25 mg, 0.044 mmol) in dichloromethane (0.4 ml) at room temperature was added N, N-diisopropylethylamine (23 mg, 0.18 mmol) and then 3,3-dimethylglutaric anhydride (9 mg, 0.07 mmoles). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated by rotary evaporation, dissolved in 50% acetic acid in water (1.5 ml), filtered and purified by preparative HPLC to give the TFA salt of the title compound (13.3 mg). . (m / z): [M + H] + calculated for C29H44N2O4: 485.34; Found: 485.4.

Example 20: Synthesis of [(cyclohexylmethyl- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} carbamoyl) methanesulfonyl] acetic acid

To a solution of methoxycarbonylmethanesulfonylacetic acid (10 mg, 0.525 mmol) in dimethylformamide (1 ml) at room temperature was added 1,1′-carbonyldiimidazole (114 mg, 0.7 mmol). Two hours later to this stirred mixture was added a solution of the TFA salt of 3-endo- {8- [2- (cyclohexylmethylamino) -ethyl] -8-azabicyclo [3.2.1] oct-3-yl- phenol prepared by the method of preparations 1 and 3 (100 mg, 0.175 mmol) and N, N-diisopropylethylamine (91 mg, 0.7 mmol) in dimethylformamide (1 ml). The reaction mixture was heated at 65 ° C for 3 hours and then stirred at room temperature overnight. The reaction mixture was diluted with ethanol (2.0 ml) and treated with a solution of lithium hydroxide monohydrate (150 mg) in water (1.5 ml) for about 30 minutes. The solvents were removed and the residue was dissolved in 50% acetic acid in water (10 ml), filtered and purified by reverse phase HPLC to give the TFA salt of the title compound as a white solid (28 , 3 mg). (m / z): [M + H] + calculated for C26H38N2O6S: 507.26, found: 507.2. 1 H NMR (CD3OD, 300 MHz) δ (ppm): 7.1-7.17 (m, IH), 6.87-6.94 (m, 2H), 6.63-6.72 (m, 1H), 4.63 (s, 2H), 4.44 (s, 2H), 4.07 (brs, 2H), 3.80 (t, J = 5.7 Hz, 2H), 3.34 ( d, J = 7.2 Hz, 2H dark), 3.13-3.2 (m, 3H), 2.51-2.53 (m, 4H), 1.69-1.88 (m, 8H ), 1.19-1.33 (m, 3H), 0.92-1.06 (m, 2H).

Example 21: Synthesis of N-cyclohexylmetiI-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicylic [3.2.1] oct-8-yl] etiI} malonic acid

To a solution of mono-tert-butyl malonate (84 mg, 0.53 mmol) in dimethylformamide (1.0 ml) at room temperature was added 1,1′-carbonyldiimidazole (114 mg, 0.7 mmol). Two hours later, a solution of the TFA salt of 3-endo- {8- [2- (cyclohexylmethylamino) -ethyl] -8-azabicyclo [3.2.1] oct-3-yl was added to this stirred mixture -phenol prepared by the method of preparations 1 and 3 (100 mg, 0.175 mmol) and N, N-diisopropylethylamine (91 mg, 0.7 mmol) in dimethylformamide (1 ml). The resulting reaction mixture was heated at 65 ° C for 3 hours and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed successively with water and brine. The reaction mixture was dried over sodium sulfate, filtered and concentrated to give a yellowish oil and then dried under vacuum for 30 minutes. The residue was treated with trifluoroacetic acid (5 ml) at room temperature for 10 minutes. The reaction mixture was diluted with water (5 ml), filtered and purified by preparative reverse phase HPLC to obtain the TFA salt of the title compound as a white solid (51.5 mg). (m / z): [M + H] + calculated for C25H36N2O4: 429.28; found 429.2. NMR-H1 (CD3OD, 300 MHz) δ (ppm): 7.11-7, 17 (m, 1H), 6.87-6.94 (m, 2H), 6.63-6.66 (m, 1H), 4.08 (brs, 2H), 3.77-3.81 (m, 2H), 3.58 (deformed s, 1H), 3.24 (d, J = 6.9 Hz, dark 2H ), 3.14-3.18 (m, 3H), 2.51-2.54 (m, 4H), 2.05-2.09 (m, 2H), 1.69-1.89 (m , 8H), 1.24-1.31 (m, 3H), 0.98-1.03 (m, 2H).

Example 22: Synthesis of 3-sec-butyl-1-cyclohexylmethyl-1- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} -urea

To a solution of the TFA salt of 3-endo- {8- [2- (cyclohexylmethylamino) -ethyl] -8-azabicyclo [3.2.1] oct-3-yl-phenol prepared by the method of preparations 1 and 3 (30 mg, 0.053 mmol) in dimethylformamide (0.2 ml) at room temperature was added N, N-diisopropylethylamine (27 mg, 0.21 mmol), followed by sec-butyl isocyanate (0.079 mmol). The resulting mixture was stirred at room temperature overnight, concentrated, dissolved in 50% acetic acid in water (1.5 ml), filtered and purified by preparative HPLC to give the TFA salt of the title compound. (17.8 mg). (m / z): [M + H] + calculated for C27H43N3O2: 442.35; Found: 442.4.

Examples 23-28

Using processes similar to that of example 22, but substituting sec-butyl isocyanate for 0.079 mmol of Listed isocyanate, TFA salts of the compounds of Examples 23 to 28 were prepared. Example 23 3-Benzyl-1-cyclohexylmethyl-1- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3,2,1] oct-8-yl] ethyl} urea (13.2 mg );

reagent: benzyl isocyanate (m / z): [M + H] + calculated for C30H41N3O2: 476.33; Found: 476.2. Example 24 3-benzo [1,3] dioxol-5-yl-1-cyclohexylmethyl-1- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3,2,1] oct-8- il] ethyl} urea

(12.0 mg); reagent: 3,4-methylenedioxyphenyl isocyanate (m / z): [M + H] + calculated for C30H39N3O4: 506.30;

Found: 506.2. Example 25 1-Cyclohexylmethyl-3- (3-fluorophenyl) -1- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3,2,1] oct-8-yl] -ethyl} urea (14.3

mg); reagent: 3-fluorophenyl isocyanate (m / z): [M + H] + calculated for C29H38FN3O2: 480.30; found:

480.2. Example 26 1-Cyclohexylmethyl-1- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3,2,1] oct-8-yl] ethyl} -3-pentylurea (14.6 mg) ;

reagent: pentyl isocyanate (m / z): [M + H] + calculated for C28H45N3O2: 456.36; Found: 456.4. Example 27 1-Cyclohexylmethyl-3- (4-fluorobenzyl) -1- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3,2,1] oct-8-yl] ethyl} urea

(13.6 mg); reagent: 4-fluorobenzyl isocyanate (m / z): [M + H] + calculated for C30H40FN3O2: 494.34;

Found: 494.2. Example 28 1-Cyclohexylmethyl-3- (4-difluoromethoxyphenyl) -1- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3,2,1] oct-8-yl] ethyl}

urea (21.8 mg); Reagent: 4-Difluoromethoxyphenyl isocyanate (m / z): [M + H] + calculated for C30H39F2N3O3:

528.31; Found: 528.2.

Example 29A: Synthesis of N-cyclohexylmethyl-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl]} ethyl methyl succinamate

To a solution of 3-endo- {8- [2- (cyclohexylmethylamino) -ethyl] -8-azabicyclo [3.2.1] oct-3-yl-phenol prepared by the method of preparations 1 and 3 (114 mg, 0.20 mmol in dichloromethane (1 ml) at room temperature was added N, Ndiisopropylethylamine (103 mg, 0.80 mmol) followed by a solution of 3-carbomethoxypropionyl chloride (0.20 mmol) in dichloromethane (0, 3 ml) The resulting mixture was stirred at room temperature for about 10 minutes, concentrated, redissolved in 50% acetic acid in water (5 ml), filtered and reverse phase preparative HPLC purified to obtain the TFA salt of the compound of the heading in the form of a white salt (46.4 mg). (m / z): [M + H] + calculated for C27H40N2O4: 457.31; Found: 457.3.

Example 29B: Synthesis of N-cyclohexylmethyl-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl]} ethiIsuccinamate methyl

To a solution of the bis TFA salt of 3-endo- {8- [2- (cyclohexylmethylamino) -ethyl] -8-azabicyclo [3.2.1] oct-3-yl-phenol prepared by the method of preparing 4 and analogously to that of preparation 11 (88 mg, 0.15 mmol) in dichloromethane (0.4 ml) at room temperature was added N, N-diisopropylethylamine (80 mg, 0.62 mmol), followed by a solution in DCM (0.15 ml) of 3-carbomethoxypropionyl chloride (0.18 mmol). The resulting mixture was stirred at room temperature for about 10 minutes. By mass spectrometry (electrospray) it was found that there was still free starting material. More 3-carbomethoxypropionyl chloride (0.05 mmol) was added. When the reaction was considered complete by analytical HPLC, the reaction mixture was concentrated, dissolved in 50% acetic acid in water (10 ml), filtered and filtered. purified preparative reverse phase HPLC to give the TFA salt of the title compound as a white solid (44.7 mg). (m / z): [M + H] + calculated for C27H40N2O4: 457.31; Found: 457.5. 1 H NMR (CD3OD, 300 MHz) δ (ppm): 7.10-7.15 (m, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.85 (s, 1H ), 6.63 (d, J = 7.8 Hz, 1H), 4.02 (brs, 2H), 3.70-3.71 (m, 2H), 3.63 (s, 3H), 3 , 26-3.28 (m, 2H dark), 3.08-3.11 (m, 3H), 2.67-2.71 (m, 4H), 2.47-2.49 (m, 4H ), 2.04-2.1 (m, 2H), 1.708-1.878 (m, 8H), 1.21-1.38 (m, 3H), 0.95-1.03 (m, 2H).

Example 30: Synthesis of N-cyclohexylmethyl-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicicIo [3.2.1] oct-8-yl] etiI} -2-methanesulfoniIacetamide

To a solution of methanesulfonylacetic acid (0.10 mmol) in dimethylformamide (0.2 ml) at room temperature was added 1,1′-carbonyldiimidazole (21 mg, 0.13 mmol). The reaction mixture was stirred for about an hour before adding a mixture of the TFA salt of 3-endo- {8- [2- (cyclohexylmethylamino) -ethyl] -8-azabicyclo [3.2.1] -oct

3-yl-phenol (prepared by the method of preparations 1 and 3) (30 mg, 0.053 mmol) and N, N-diisopropylethylamine (0.10 mmol) in dimethylformamide (0.3 ml). The resulting mixture was stirred at room temperature overnight, concentrated, diluted with 50% acetic acid in water (8 ml), filtered and purified by preparative reverse phase HPLC to give the TFA salt of the compound of the heading (7.5 mg). (m / z): [M + H] + calculated for C25H38N2O4S: 463.27, found: 463.5.

Example 31: Synthesis of N-cyclohexylmeti-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} succinamide

To a solution of N-cyclohexylmethyl-N- {2- [3- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} succinamic acid, the product of Example 18 (95 mg, 0.17 mmol), 1,1'-carbonyldiimidazole (165 mg, 1.02 mmol) was added in dimethylformamide (0.2 ml) at room temperature. An hour later, ammonium acetate (79 mg, 1.02 mmol) was added, followed by N, N-diisopropylethylamine (132 mg, 1.02 mmol). The resulting mixture was stirred at room temperature overnight, dissolved in 50% acetic acid in water (10 ml), filtered and purified by preparative reverse phase HPLC to give the TFA salt of the title compound (5 , 6 mg). (m / z): [M + H] + calculated for C26H39N3O3: 442.31; Found: 442.5.

Example 32: Synthesis of 1-cyclohexylmeti-3- (3,4-dimethoxyphenyl) -1- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl }urea

To a solution of the TFA salt of 3-endo- {8- [2- (cyclohexylmethylamino) -ethyl] -8-azabicyclo [3.2.1] oct-3-yl-phenol prepared by the method of preparations 1 and 3 (30 mg, 0.05 mmol) in dimethylformamide (0.2 ml) at room temperature was added N, N-diisopropylethylamine (27 mg, 0.21 mmol), followed by 3,4-dimethoxyphenyl isocyanate (14 mg, 0.078 mmol ). The resulting mixture was allowed to stand at room temperature overnight, concentrated by rotary evaporation, redissolved in 50% acetic acid in water (1.5 ml), filtered and purified by preparative HPLC to obtain the TFA salt. of the title compound (13.5 mg). (m / z): [M + H] + calculated for C31H43N3O4: 522.34, found: 522.2.

Examples 33-38

Using the general method of example 7, but replacing the cyclohexylamine intermediate with the suitably substituted benzylamine obtained as in preparation 3, and the intermediate 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) phenol obtained as in preparation 1 and replacing the acetyl chloride with the appropriate acyl chloride, the TFA salts of the compounds of examples 33-38 were prepared. Example 33 N- (3-fluorobenzyl) -2-hydroxy-N- {2- [3-endo- (hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} acetamide (9.6 mg )

(m / z): [M + H] + calculated for C24H29FN2O3: 413.23, found: 413.2. Example 34 N- (3-Fluorobenzyl) -2-hydroxy-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} succinamic acid (12 , 0 mg) (m / z): [M + H] + calculated for C26H31FN2O4: 455.24, found: 455.2. Example 35 N- (3-fluorobenzyl) -N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} -3-methylbutyramide (9.9 mg) (m / z): [M + H] + calculated for C27H35FN2O2: 439.28, found: 439.2. Example 36 N- (2,6-difluorobenzyl) -2-hydroxy-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} acetamide ( 9.0 mg) (m / z): [M + H] + calculated for C24H28F2N2O3: 431.22, found: 431.2. Example 37 N- (2,6-difluorobenzyl) -N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} -3-methylbutyramide (13 , 1 mg) (m / z): [M + H] + calculated for C27H34F2N2O2: 457.27; Found: 457.2. Example 38 N- (2,6-difluorobenzyl) -N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} acetamide (11.7 mg ) (m / z): [M + H] + calculated for C24H28F2N2O2: 415.22, found: 415.2.

Examples 39-42

Using the general method of Example 21, but replacing the cyclohexylamine intermediate with the suitably substituted benzylamine obtained as in preparation 3, and the intermediate 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) phenol obtained as in preparation 1 and replacing the mono-tert-butyl malonate with methanesulfonylacetic acid in examples 40 and 42, the TFA salts of the compounds of examples 39-42 were prepared. Example 39 N- (3-fluorobenzyl) -N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] -ethyl} malonic acid

(11.4 mg) (m / z): [M + H] + calculated for C25H29FN2O4: 441.22; Found: 441.2. Example 40 N- (3-fluorobenzyl) -N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} -2-methanesulfonylacetamide (25.0 mg) (m / z): [M + H] + calculated for C25H31FN2O4S: 475.21, found: 475.2. Example 41 N- (2,6-Difluorobenzyl) -N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} malonamic acid (11.1 mg) (m / z): [M + H] + calculated for C25H28F2N2O4: 459.21, found: 459.2. Example 42 N- (2,6-Difluorobenzyl) -N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} -2-methanesulfonylacetamide (11 , 1 mg) (m / z): [M + H] + calculated for C25H30F2N2O4S: 493.20, found: 493.2.

Example 43: Synthesis of N- (4-fluorobenzyl) -2-hydroxy-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} acetamide

To a solution of the bis TFA salt of 3-endo- {8- [2- (4-fluorobenzylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} phenol

prepared by the methods of preparations 4 and 3 (30 mg, 0.05 mmol) in dichloromethane (0.2 ml) at room temperature, N, N-diisopropylethylamine (26 mg, 0.2 mmol) was added and then acetoxyacetyl chloride ( 0.075 mmol). Once the end of the reaction was verified by mass spectrometry, the mixture was concentrated by rotary evaporation and the residues were dissolved in EtOH (0.2 ml) and hydrolyzed with lithium hydroxide monohydrate (17 mg) in water (0, 2 ml) at room temperature for 30 minutes. The solvents were removed by rotary evaporation and the resulting residue was dissolved in 50% acetic acid in water (1.5 ml), filtered and purified by preparative HPLC to give the TFA salt of the title compound (16.6 mg) . (m / z): [M + H] + calculated for C24H29FN2O3: 413.23, found 413.2.

Example 44: Synthesis of N- (4-cIorobenzyl) -2-hydroxy-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} acetamide

Following the procedure of Example 43 and using the suitably substituted benzylamine of Preparation 3, the TFA salt of the title compound (19.1 mg) was obtained. (m / z): [M + H] + calculated for C24H29ClN2O3: 429.20, found: 429.2.

Example 45: Synthesis of 2-hydroxy-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} -N- (4-trifluoro-methylbenzyl) ) acetamide

Following the procedure of Example 43 and using the substituted benzylamine obtained according to Preparation 3, the TFA salt of the title compound (19.5 mg) was produced. (m / z): [M + H] + calculated for C25H29F3N2O3: 463.22; Found: 463.2.

Example 46A: Synthesis of 3-endo- (8- {2- [benzyl- (2-hydroxyacetyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl] benzamide

To a solution of the bis TFA salt of 3-endo- [8- (2-benzylaminoethyl) -8-azabicyclo [3.2.1] oct-3-yl] benzamide prepared by the method of preparations 5 and 6 ( 111 mg, 0.188 mmol) in dichloromethane (0.94 ml) at -20 ° C was added N, N-diisopropylethylamine (97 mg, 0.75 mmol), followed by acetoxyacetyl chloride (27 mg, 0.29 mmol) in dichloromethane (0.5 ml). The reaction mixture was stirred from -20 ° C to -10 ° C for about 30 minutes, before stopping the reaction with saturated sodium bicarbonate and then extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give a yellowish oil that was dissolved in EtOH (1.0 ml) and treated with lithium hydroxide monohydrate (24 mg, 0.56 mmol) in water (0.5 ml) at room temperature for 30 minutes. The solvents were removed by rotary evaporation and the resulting residue was dissolved in 50% acetic acid in water (10 ml), filtered and purified by preparative HPLC to give the TFA salt of the title compound (58.7 mg) . (m / z): [M + H] + calculated for C25H31N3O3: 422.25; Found: 422.3.

Example 46B: Synthesis of 3-endo- (8- {2- [benzyl- (2-hydroxyacetyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl] benzamide

To a solution of the 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) benzamide obtained by the method of preparation of 13 (102 mg, 0.44 mmol) in dichloromethane (2 ml) at temperature A solution of methyl [benzyl- (2-oxoethyl) carbamoyl] acetate (164 mg, 0.66 mmol) in dichloromethane (2 ml) was added, followed by sodium triacetoxyborohydride (131 mg). The reaction mixture was stirred at room temperature for about thirty minutes and it was verified by mass spectrometry that the reaction was complete. The reaction was then concentrated and redissolved in EtOH (6 ml) and treated with lithium hydroxide monohydrate (111 mg) in water (4 ml) for about thirty minutes. Then, the mixture was concentrated, redissolved in 50% acetic acid in water (10 ml), filtered and purified by reverse phase HPLC to give the TFA salt of the title compound (115.7 mg). (m / z): [M + H] + calculated for C25H31N3O3: 422.25; Found: 422.4; 1 H NMR (CD3OD, 300 MHz) δ (ppm): 8.0 (s, 1H), 7.68-7.75 (m, 2H), 7.267.47 (m, 6H), 4.57 (s , 2H), 437 (8, 2H), 4.08 (brs, 2H), 3.72 (t, J = 5.7 Hz, 2H), 3.05 (t, J = 5.4 Hz, 2H ), 2.59-2.62 (m, 4H), 1.99-2.03 (m, 2H), 1.74-1.81 (m, 2H).

Example 47: Synthesis of N- {2- [3-endo- (3-carbamoylphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} -N-cyclohexylmethylsuccinamic acid

To a solution of the bis TFA salt of 3-endo- {8- [2- (cyclohexylmethylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} benzamide prepared by the method of preparations 5 and 7 (114 mg, 0.19 mmol) in dichloromethane (0.95 ml) at room temperature was added N, N-diisopropylethylamine (98 mg, 0.76 mmol). The resulting mixture was cooled to 30 ° C before adding a solution of 3-carbomethoxypropionyl chloride (30 mg, 0.20 mmol) in DCM (0.5 ml). After completion of the reaction, the mixture was concentrated. The residue was redissolved in EtOH (2 ml) and treated with lithium hydroxide monohydrate (32 mg) in water (1 ml) for about 30 minutes. The mixture was concentrated, dissolved in 50% acetic acid in water (10 ml), filtered and purified by reverse phase HPLC to give the TFA salt of the title compound (63.2 mg). (m / z): [M + H] + calculated for C27H39N3O4: 470.30; Found: 470.5.

Example 48: Synthesis of 3-endo- (8- {2- [cyclohexylmetiI- (2-hydroxyacetyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide

To a solution of the bis TFA salt of 3-endo- {8- [2-cyclohexylmethylamine) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} benzamide prepared by the method of preparations 13 and 9 (734 mg, 1.23 mmol) in dichloromethane (5 ml) at room temperature was added N, N-diisopropylethylamine (625 mg, 4.9 mmol). The resulting mixture was cooled to -20 ° C before adding a solution of acetoxyacetyl chloride (184 mg, 1.35 mmol) in DCM (2 ml). After five minutes the reaction was completed, as confirmed by mass spectrometry analysis. The reaction mixture was concentrated, dissolved in EtOH (15 ml) and treated with lithium hydroxide monohydrate (309 mg) in water (5 ml) for about 30 minutes. The reaction mixture was then concentrated, dissolved in 50% acetic acid in water (15 ml), filtered and purified by preparative reverse phase HPLC to obtain the TFA salt of the title compound (585.9 mg). (m / z): [M + H] + calculated for C25H37N3O3: 428.29; Found: 428.2. 1 H NMR (CD3OD, 300 MHz) δ (ppm): 8.0 (s, 1H), 7.68-7.74 (m, 2H), 7.42-7.47 (t, J = 8, 1 Hz, 1H), 4.27 (s, 2H), 4.09 (brs, 2H), 3.72 (t, J = 5.7 Hz, 2H), 3.2-3.35 (m, dark 1H), 3.09-3.14 (m, 4H), 2.59-2.62 (m, 4H), 2.07-2.12 (m, 2H), 1.62-1.83 (m, 8H), 1.15-1.35 (m, 3H), 0.87-1.16 (m, 2H).

Example 49: Synthesis of 3-endo- {8- [2- (cyclohexylmethyl-phenylacetylamino) -ethyl] -8-azabicyclo [3.2.1] oct-3-yl} benzamide

To a solution of the bis TFA salt of 3-endo- {8- [2-cyclohexylmethylamine) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} benzamide prepared by the method of preparations 5 and 7 (112 mg, 0.19 mmol) in dichloromethane (1 ml) at room temperature was added N, N-diisopropylethylamine (97 mg, 0.75 mmol). The resulting mixture was then cooled to -40 ° C before adding a solution of phenylacetyl chloride (32 mg, 0.21 mmol) in DCM (0.1 ml). The resulting mixture was stirred at a temperature between -40 ° C and -20 ° C for about 30 minutes. Mass spectrometry analysis confirmed that the reaction was complete. After concentrating, the residue was redissolved in 50% acetic acid in water (10 ml), filtered and purified by preparative reverse phase HPLC to give the TFA salt of the title compound (27.5 mg). (m / z): [M + H] + calculated for C31H41N3O2: 488.33; Found: 488.8.

Example 50: Synthesis of N- {2- [3-endo- (3-carbamoyl-phenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} -N-cyclohexylmethylsuccinamate methyl

To a solution of the bis TFA salt of 3-endo- {8- [2-cyclohexylmethylamine) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} benzamide prepared by the method of preparations 5 and 7 (97 mg, 0.16 mmol) in dichloromethane (0.8 ml) at room temperature was added N, N-diisopropylethylamine (83 mg, 0.64 mmol). The resulting mixture was then cooled to -20 ° C before adding a solution of 3-carbomethoxypropionyl chloride (29 mg, 0.19 mmol) in DCM (0.1 ml), followed by another portion of 3-carbomethoxypropionyl chloride (0 , 20 mmol) in DCM (0.3 ml). At 30 minutes the analysis of an aliquot by LC-MS gave the desired molecular weight. The reaction mixture was then concentrated, redissolved in 50% acetic acid in water (8 ml), filtered and purified by reverse phase preparative HPLC to give the TFA salt of the title compound as a white solid ( 46.4 mg). (m / z): [M + H] + calculated for C28H41N3O4: 484.32; Found: 484.5.

Example 51: Synthesis of 3-endo- {8- [2- (3-sec-butyl-1-cyclohexylmethylureido) ethyl]) - 8-azabicyclo [3.2.1] oct-3-yl} benzamide

Following the method of example 32, the bis TFA salt of the 3-endo- {8- [2-cyclohexylmethylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} -benzamide prepared by the method of Preparations 5 and 9 (30 mg, 0.05 mmol) were reacted with sec-butyl isocyanate (0.075 mmol). Purification provided the TFA salt of the title compound (24.2 mg). (m / z): [M + H] + calculated for C28H44N4O2: 469.35; Found: 469.4.

Example 52: Synthesis of 3-endo- {8- [2- (1-cyclohexylmethyl-3-pentylureido) ethyl]) - 8-azabicyclo [3.2.1] oct-3-yl} benzamide

To a solution of the bis TFA salt of 3-endo- {8- [2-cyclohexylmethylamine) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} benzamide prepared by the method of preparations 5 and 9 (30 mg, 0.05 mmol) in DMF (0.4 ml) at room temperature was added N, N-diisopropylethylamine (27 mg, 0.20 mmol), followed by pentyl isocyanate (0.075 mmol). The resulting mixture was stirred at room temperature overnight, concentrated, redissolved in 50% acetic acid in water (1.5 ml), filtered and purified by preparative HPLC to give the TFA salt of the title compound. (23.3 mg). (m / z): [M + H] + calculated for C29H46N4O2: 483.37; Found: 483.4.

Examples 53-55

Using the general method of Example 52 and replacing the pentyl isocyanate with the appropriate isocyanate, TFA salts of the compounds of Examples 53-55 were prepared. Example 53 3-endo- (8- {2- [1-cyclohexylmethyl-3- (4-fluorobenzyl) -ureido] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) benzamide

(30.3 mg) (m / z): [M + H] + calculated for C31H41FN4O2: 521.33; Found: 521.2. Example 54 3-endo- {8- [2- (3-benzo [1,3] dioxol-5-yl-1-cyclohexylmethylureido) ethyl] -8-azabicyclo [3,2,1] oct-3-yl} benzamide

(24.5 mg) (m / z): [M + H] + calculated for C31H40N4O4: 533.31; Found: 533.2; 1 H-NMR (CD3OD, 300 MHz) δ (ppm): 7.97 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.42 (dd, J = 7.8 Hz,

1H), 3.90-3.99 (m, 3H), 3.60 (t, J = 4.8 Hz, 2H), 3.25-3.29 (m, 1H, solvent overlap), 3 , 02-3.09

(m, 4H), 2.55-2.58 (m, 4H), 2.03-2.07 (m, 2H), 1.63-1.78 (m, 8H), 1.07-1 , 25 (m, 9H), 0.92-1.01 (m, 2H). Example 55 3-endo- {8- [2- (1-cyclohexylmethyl-3-isopropylureido) ethyl] -8-aza-bicyclo [3,2,1] oct-3-yl} benzamide (24.5 mg)

(m / z): [M + H] + calculated for C27H42N4O2: 455.33; Found: 455.4; NMR-H1 (CD3OD, 300 MHz) δ

(ppm): 7.97 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.42 (dd , J = 7.8 Hz, 1H), 3.90

3.99 (m, 3H), 3.60 (t, J = 4.8 Hz, 2H), 3.25-3.29 (m, 1H, solvent overlap), 3.02-3.09 ( m, 4H),

2.55-2.58 (m, 4H), 2.03-2.07 (m, 2H), 1.63-1.78 (m, 8H), 1.07-1.25 (m, 9H ), 0.92-1.01 (m, 2H).

Example 56: Synthesis of 3-endo- (8- {2- [cyclohexylmethyl- (2-methanesulfonyl-acetyl) amino] ethyl} -8-azabicyclo [3.2.1] oct3-yl} -benzamide

To a solution of methanesulfonylacetic acid (90 mg, 0.65 mmol) in DMF (0.2 ml) was added 1,1′-carbonyldiimidazole (105 mg, 0.65 mmol). One hour later, 3-endo- {8- [2-cyclohexylmethylamine) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} benzamide prepared by the method of preparations 12 and 9 (30 mg, 0.05 mmol), followed by N, N-diisopropylethylamine (84 mg, 0.65 mmol). The resulting mixture was heated at 60 ° C for two hours and then cooled to room temperature for 60 hours. It was then concentrated, dissolved in 50% acetic acid in water (3 ml), filtered and purified by preparative HPLC to give the TFA salt of the title compound (35.1 mg). (m / z): [M + H] + calculated for C26H39N3O4S: 490.27; Found: 490.2. 1 H NMR (CD3OD, 300 MHz) δ (ppm): 7.98 (s, 1H), 7.66-7.74 (m, 2H), 7.41-7.46 (m, 1H), 4 , 77 (s, 2H), 4.38 (brs, 2H), 3.78-3.82 (m, 2H), 3.04-3.33 (m, dark 5H), 3.21 (s, 3H), 2.57-2.61 (m, 4H), 2.07-2.10 (m, 2H), 1.66-1.79 (m, 8H), 1.22-1.29 ( m, 3H), 0.94-1.01 (m, 2H).

Example 57: Synthesis of 3-endo- (8- {2 - [(aminoacetyl) -cyclohexylmethylamino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide

To a solution of n-tert-butoxycarbonylglycine (43 mg, 0.30 mmol) in DMF (0.2 ml) at room temperature was added 1,1′-carbonyldiimidazole (32 mg, 0.2 mmol). After stirring at room temperature for 2 hours, the bis TFA salt of 3-endo- {8- [2-cyclohexylmethylamine) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} was added to this mixture benzamide prepared by the method of preparations 12 and 9 (30 mg, 0.05 mmol) and N, N-diisopropylethylamine (26 mg, 0.2 mmol). The resulting reaction mixture was stirred at room temperature overnight. After concentrating the residue, it was treated with 50% TFA in DCM (1 ml). The mixture was concentrated and the residue was dissolved in 50% acetic acid in water (1.5 ml), filtered and purified by preparative reverse phase HPLC to give the bis TFA salt of the title compound (15.9 mg) (m / z): [M + H] + calculated for C25H38N4O2: 427.31; Found: 427.2.

Example 58A: Synthesis of 3-endo- (8- {2- [cyclohexylmethyl - ((S) -2,3-dihydroxy-propionyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide

To a solution of (S) -2,2-dimethyl- [1,3] dioxolan-4-carboxylic acid (98 mg, 0.67 mmol) in DMF (0.2 ml) at room temperature was added 1, 1'-carbonyldiimidazole (109 mg, 0.67 mmol). After stirring at room temperature for one hour, the bis TFA salt of 3-endo- {8- [2-cyclohexylmethylamine) ethyl] -8azabicyclo- [3.2.1] oct-3-yl} benzamide was added to this mixture prepared by the method of preparations 12 and 9 (100 mg, 0.167 mmol) and N, N-diisopropylethylamine (87 mg, 0.67 mmol). The reaction mixture was heated at 60 ° C for two hours and then cooled to room temperature for 72 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water (2 x 2 ml), 1 N NaOH (2 ml) and brine (2 ml), dried over sodium sulfate, filtered and concentrated. The resulting residue was then dissolved in 50% acetic acid in water (1.5 ml) and water (0.5 ml) and heated at 65 ° C overnight. The mixture was concentrated by rotary evaporation, redissolved in 50% acetic acid in water (3.0 ml), filtered and purified by preparative reverse phase HPLC to give the TFA salt of the title compound (15.9 mg) (m / z): [M + H] + calculated for C26H39N3O2: 458.30; Found: 458.2. 1 H NMR (CD3OD, 300 MHz) δ (ppm): 7.98 (s, 1H), 7.67-7.73 (m, 2H), 7.40-7.45 (m, 1H), 4 , 57 (t, J = 5.4 Hz, 1H), 3.94-4.12 (m, 3H), 3.69-3.72 (m, 2H), 3.50-3.58 (m , 1H), 3.35-3.43 (m, 1H), 3.20-3.27 (dark 2H partially overlapped with solvent), 3.12-3.15 (m, 2H), 2.52 ( brs, 4H), 1.98-2.02 (m, 2H), 1.61-1.70 (m, 8H), 1.09-1.22 (m, 3H), 0.88-0, 95 (m, 2H).

The TFA salt of the title compound (4.45 g, 7.78 mmol), prepared by the method described above using the reactants 3-endo- {8- [2-cyclohexylmethylamine) ethyl] -8-azabicyclo- [3.2 .1] oct-3-yl} benzamide, prepared by the method of preparations 13 and 9, and (4S) -2,2-dimethyl-1,3-dioxolan-4-carboxylate, was dissolved in methanol ( <10 ml) and diluted with DCM (400 ml). The organic solution was washed with 1 M NaOH (500 ml). The basic aqueous layer was extracted with DCM (2 x 150 ml). The combined organic layers were washed with saturated aqueous sodium chloride (500 ml). The organic layer was dried over potassium carbonate. The solution was filtered and the solvent removed in vacuo to give the title compound (3.09 g, 87%) as a glassy solid. (m / z): [M + H] + calculated for C26H39N3O2: 458.30; Found: 458.5. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 7.81-7.83 (s, 1H), 7.61-7.65 (br s, 1H), 7.55-7.60 (d, 1H), 7.30-7.35 (d, 1H), 7.18-7.22 (m, 2H), 4.80-4082 (d, 0.8 H), 4.62- 4.65 (d, 0.64 H), 4.50-4.60 (m, 1.1 H), 4,224.38 (m, 0.83 H), 4.10-4.20 (m, 0.65 H), 3.00-3.50 (m, 8H), 2.70-2.99 (m, 2H), 2.00-2.30 (m, 4H), 1.60-1 , 80 (m, 2H), 1.43-1.60 (m, 4H), 1.22-1.40 (m, 3H), 0.93-1.19 (m, 3H), 0.82 -0.94 (m, 2H).

Example 58B: Synthesis of 3-endo- (8- {2- [cyclohexylmethyl - ((S) -2,3-dihydroxy-propionyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide crystalline sulfate

to. Preparation of benzyl N-cyclohexylmethyl- (2-oxoethyl) -carbamate

In a 100 ml flask, an adduct of benzyl bisulfite N-cyclohexylmethyl- (2-oxoethyl) -carbamate (3.94 g, 1 mmol) and MeTHF (35 ml) was introduced, followed by water (25 ml). The resulting suspension was stirred at room temperature for 5 minutes and 1M NaOH (8 ml) was added. The reaction mixture was stirred at room temperature for 45 min. The layers were separated and the volume of the organic layer was reduced to ~ 8 ml to obtain the crude intermediate of the title.

b. Preparation of benzyl 2- [3-endo- (3-carbamoylfenyl) -8-azabicyclo [3.2.1] oct-8-yl] -ethyl-cyclohexylmethyl-carbamate

DMF (15 ml) was added to the product of the previous step, followed by 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -benzamide hydrochloride (2.67 g, 1 mmol), prepared by the preparation process 25 and then DMF (10 ml). The mixture was stirred at room temperature for 30 minutes, cooled to 10 ° C and then sodium triacetoxyborohydride (4.25 g, 2 mmol) was added. The reaction mixture was stirred at room temperature for 90 minutes and then cooled to 10 ° C. Isopropyl acetate (100 ml) was added, followed by 1 M NaOH (50 ml). The mixture was stirred for 15 minutes and the phases were separated. The organic layer was washed with brine in water (1: 1, 2 x 50 ml) and the volume of the organic layer was reduced to ~ 10 ml to provide the crude intermediate of the title.

C. Preparation of 3-endo- {8- [2- (cyclohexylmethylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} benzamide

To the product of the previous step was added EtOH (30 ml) and concentrated HCl (1.5 ml). The solution was purged with nitrogen, 10% palladium on carbon (470 mg) was added and the mixture was purged with nitrogen for 5 minutes and then hydrogenated at 30 psi overnight. After purging with nitrogen for 2 minutes, the solution was filtered through Celite and the solvent was removed to ~ 10 ml. Isopropyl acetate (40 ml) and 1 M NaOH (20 ml) were added. The layers were separated and the organic layer was washed with brine (20 ml), the phases were separated and organic solvent was removed to 5-10 ml. Isopropyl acetate (20 ml) was added and the volume was reduced to ~ 8 ml, and isopropyl acetate (20 ml) was added. The resulting suspension was stirred at room temperature for 2 h. The product was isolated by filtration, the reaction flask and the filter cake were washed with isopropyl acetate (10 ml) to obtain the intermediate of the title (2.4 g, 98% purity) as an off-white solid.

d. Preparation of 3-endo- (8- {2- [cyclohexylmethyl - ((S) -2,3-dihydroxy-propionyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide sulfate ( hydrate)

3-endo- {8- [2- (cyclohexylmethylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} benzamide (31 g, 83.9 mmol) and DMF were charged into a 500 ml flask (150 ml). The mixture was stirred for 10 minutes; then benzotriazol-1-yloxytris (pyrrolidin) -phosphonium hexafluorophosphate (56.8 g, 109 mmol) and (4S) -2,2-dimethyl-1,3-dioxolan-4-carboxylate lithium (15.6 g, 92.3 mmol) and the mixture is stirred at room temperature for 2 h. Ethyl acetate (600 ml) and 0.5 M NaOH (300 ml) were added and the phases were separated. The organic layer contained (S) -2,2-dimethyl- [1,3] dioxolan-4-carboxyl {2- [3- (3-carbamoyl-phenyl) -8-azabicyclo [3.2.1] oct-8- il] ethyl} crude cyclohexylmethyl amide (~ 84 mmol), which was not isolated.

The organic layer was washed with brine in water (1: 1, 2 x 300 ml) and the phases were separated. To the organic layer was added 2M H2SO4 (42 ml) and the reaction mixture was stirred at room temperature overnight. Acetonitrile (300 ml) was added and the resulting suspension was stirred for 2-6 h. The product was isolated by filtration, the filter cake was washed with acetonitrile (200 ml), air dried for 2 hours and then under vacuum at room temperature for 20 hours to give the title compound (40 g, 97% of HPLC purity) in the form of white powder.

and. Synthesis of 3-endo- (8- {2- [cyclohexylmethyl - ((S) -2,3-dihydroxy-propionyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide crystalline sulfate

In a 100 ml flask, 3-endo- (8- {2- [cyclohexylmethyl - ((S) -2,3-dihydroxy-propionyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3 was introduced -il) -benzamide sulfate in the form of hydrate (2 g) and methanol (40 ml). The resulting suspension was heated at 65 ° C under a nitrogen atmosphere for 20 minutes, resulting in complete dissolution. The solution was cooled to room temperature with stirring. About 20 ml of solvent was removed under slightly reduced pressure and the resulting mixture was stirred at room temperature overnight. The product was isolated by filtration and the bottle and the filter cake were washed with acetonitrile (2 x 5 ml). The filter cake was air dried for 2 hours and then under vacuum at room temperature overnight, to give the title compound (1.71 g,> 99% HPLC purity, ~ 85% yield) under white powder form.

A sample prepared according to the above procedure was analyzed by NMR-H1 (300 MHz, DMSO-d6) δ (ppm): 9.08 and 8.94 (two series of BRS, 1H), 7.99-8.04 ( m, 2H), 7.74-7.76 (m, 1H), 7.68-7.70 (m, 1H), from 7.41 to 7.45 (m, 2H), 4.81, 5 , 00 and 5.30 (three series of brs, 2H), 4.34 (deformed m, 1H), 4.00 and 4.05 (deformed m, 2H), 3.01-3.25 and 3.47 -3.55 and 3.75-3.82 y (three groups of m, 10H), 2.50-2.55 (m, 2H), 1.99 (m deformed, 2H), 1.56-1 , 70 (m, 8H), 1.15-1.19 (m, 3H), 0.89-0.99 (m, 2H).

Example 58C: Synthesis of 3-endo- (8- {2- [cyclohexylmetiI - ((S) -2,3-dihydroxy-propionyl) amino] ethyl} -8-azabicico [3.2.1] oct-3-yl) benzamide crystalline glycolate

3-endo- (8- {2- [cyclohexylmethyl - ((S) -2,3-dihydroxypropionyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide (35 mg) was dissolved in aqueous acetone (2% water, 98% acetone, 0.46 ml). To this solution was added 0.78 M glycolic acid in acetonitrile (0.10 ml). A precipitate formed quickly and after 2 h it became a birefringent material. The mother liquors were decanted and the remaining solid dried to obtain the title compound. The powder X-ray diffraction pattern (PDRXP) of the crystalline material is shown in Figure 1. Diffraction peaks were observed at 2θ values of 8.00 ± 0.2, 12.50 ± 0.2, 16.19 ± 0.2, 16.91 ± 0.2, 18.41 ± 0.2, 20 , 69 ± 0.2, 22.04 ± 0.2, 23.03 ± 0.2, 25.44 ± 0.2, 25.85 ± 0.2 and 28.76 ± 0.2.

All PDRXP data presented here were obtained with a Rigaku diffractometer using Cu Ka radiation (30.0 kV, 15.0 mA) that operates in continuous scanning mode of 3º per minute with a gradation of 0.03º.

Example 58D: Synthesis of 3-endo- (8- {2- [cyclohexylmetiI - ((S) -2,3-dihydroxy-propionyl) amino] ethyl} -8-azabicic [3.2.1] oct-3-yl) crystalline benzamide oxalate

3-endo- (8- {2- [cyclohexylmethyl - ((S) -2,3-dihydroxypropionyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide was dissolved

(25.4 mg) in acetone (0.34 ml). To this solution was added 0.4 M oxalic acid in acetonitrile (0.14 ml), followed by water (0.24 ml). The resulting dispersion was sonicated for 30 seconds and then water (0.045 ml) and DCM (0.015 ml) were added. After 4 days the title compound was collected by vacuum filtration, as a crystalline solid (19.8 mg). The PDRXP of the crystalline material is shown in Figure 2. Diffraction peaks were observed at 2θ values of 5.84 ± 0.2, 13.80 ± 0.2, 17.03 ± 0.2, 23.00 ± 0 , 2 and 28.85 ± 0.2.

Example 59: Synthesis of 3-endo- (8- {2 - [(2-hydroxyacetyl) phenethylamino] -ethyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide

The product of preparation 17 (~ 0.26 mmol) was dissolved in DCM (0.5 ml) and cooled to 0 ° C. The reaction mixture was treated with N, N-diisopropylethylamine (100 mg, 0.78 mmol) and then with acetoxyacetyl chloride (39 mg, 0.29 mmol). The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate and brine. The organic layer was dried with sodium sulfate, filtered and concentrated. The crude oil was dissolved in ethanol (1 ml) and treated with lithium hydroxide monohydrate (66 mg, 1.2 mmol) in water (0.5 ml). After one hour the reaction mixture was concentrated and the residue was dissolved in 50% acetic acid in water (1.2 ml), filtered and purified by preparative HPLC to give the TFA salt of the title compound (38 , 7 mg). (m / z): [M + H] + calculated for C26H33N3O3: 436.25; Found: 436.4.

Examples 60-62

Following the procedure of example 59 and replacing the product of preparation 17 with that of preparations 18, 19 and 20, respectively, TFA salts of the compounds of examples 60 were prepared

62. Example 60 3-endo- (8- {2 - [(2-hydroxyacetyl) - (3-phenylpropyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide (66.7 mg) (m / z): [M + H] + calculated for C27H35N3O3: 450.27; Found: 450.4. Example 61 3-endo- (8- {2 - [(2-cyclohexylethyl) - (2-hydroxyacetyl) amino] ethyl} -8-azabicyclo [3.2,1] oct-3-yl) -benzamide (68.6 mg ) (m / z): [M + H] + calculated for C26H39N3O3: 442.30; Found: 442.6.

Example 62 3-endo- (8- {2 - [(3-cyclohexylpropyl) - (2-hydroxyacetyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide (37.1 mg ) (m / z): [M + H] + calculated for C27H41N3O3: 456.31, found: 456.4.

Example 63 A: Synthesis of 3-endo- (8- {2 - [(4,4-difluorocyclohexylmethyl) - (2-hydroxyacetyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide

Following the procedure of example 48, the product of preparation 21, 3-endo- (8- {2 - [(4,4-difluorocyclohexylmethyl) -amino] ethyl} 8-azabicyclo [3.2.1] oct-3-yl ) benzamide (72.5 mg, 1 eq) was treated with acetoxyacetyl chloride (1.3 eq), hydrolyzed and purified by HPLC to provide the TFA salt of the title compound (14.4 mg). (m / z): [M + H] + calculated for C25H35F2N3O3: 464.27, found: 464.2.

Example 63B: Synthesis of 3-endo- (8- {2 - [(4,4-difluorocyclohexylmethyl) - (2-hydroxyacetyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide

To a solution of 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -benzamide prepared by preparation method 13 (2.15 g, 9.34 mmol) in DCM (45.0 ml ) at 0 ° C acetic acid (0.56 g, 9.34 mmol) was added followed by a solution of [(4,4-diphenocyclohexylmethyl) - (2-oxoethyl) -carbamoyl] methyl acetate (2.59 g, 8.9 mmol) in DCM (10.0 ml) and sodium triacetoxyborohydride (2.26 g, 10.7 mmol). The resulting mixture was stirred at 0 ° C for 30 minutes and then diluted with DCM (40.0 ml). The organic layer was washed successively with saturated sodium bicarbonate (20.0 ml) and brine (20.0 ml), dried over sodium sulfate, filtered and concentrated to give [{2- [3-endo-] acetate ( 3-Phenylcarbamoyl) -8-azabicyclo [3.2.1] oct-8-yl] -ethyl} - (4,4-difluorocyclohexylmethyl) carbamoyl] methyl in the form of a slightly yellowish foam.

The product from the previous step was dissolved in methanol (20.0 ml) at room temperature and treated with lithium hydroxide monohydrate (0.56 g, 13.4 mmol) in water (5.0 ml) for 30 minutes. The reaction mixture was concentrated. The residue was dissolved in 25% acetic acid in water (48.0 ml), filtered and purified by reverse phase preparation HPLC. The desired fractions were combined and lyophilized to give the title compound as the TFA salt (2.1 g). 1 H NMR (CD3OD, 300 MHz) δ (ppm): 8.07 (s, 1H), 7.75-7.81 (m, 2H), 7.48 (dd, J = 7.8 Hz, 1H ), 4.35 (s, 2H), 4.17 (brs, 2H), 3.81 (t, J = 6.0 Hz, 2H), 3.35-3.38 (dark 1H, solvent overlapped ), 3.25 (d, J = 6.9 Hz, 2H), 3.20 (t, J = 5.4 Hz, 2H), 2.66-2.72 (m, 4H), 2.10 -2.19 (m, 4H), 1.77-1.90 (m, 7H), 1.33-1.41 (m, 2H).

Example 63C: Synthesis of 3-endo- (8- {2 - [{4,4-difluorocyclohexylmethyl) - (2-hydroxyacetyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide phosphate crystalline

3-endo- (8- {2 - [(4,4-difluorocyclohexylmethyl) - (2-hydroxyacetyl) amino] ethyl} -8-azabicyclo [3.2.1] was dissolved in a 4 ml glass vial at room temperature oct-3-yl) benzamide (20 mg) in methanol (0.172 ml). To this solution was added 1.0 M phosphoric acid in methanol (0.043 ml) and acetone (0.228 ml). The mixture was gently stirred for 16 hours at room temperature. The title compound was collected by vacuum filtration as a crystalline powder (13.4 mg). The PDRXP of the crystalline material is shown in Figure 3. Diffraction peaks were observed at 2θ values of 5.51 ± 0.20, 7.27 ± 0.20, 17.30 ± 0.20, 18.05 ± 0 , 20, 19.94 ± 0.20, 20.39 ± 0.20, 21.89 ± 0.20, 24.62 ± 0.20, 26.66 ± 0.20, 27.38 ± 0.20 , 28.52 ± 0.20, 29.21 ± 0.20 and 32.87 ± 0.20.

Examples 64 to 74

A solution of the product of preparation 22, 3-endo- [8- (2-benzylaminopropyl) -8-azabicyclo [3.2.1] oct-3-yl] -phenol (509 mg, 1.45 mmol), and N , N-diisopropylethylamine (0.76 ml) in dichloromethane (12 ml) was distributed in 12 equal parts, in vials containing respectively an appropriate acid chloride (0.16 mmol). The jars were stirred at room temperature for 45 minutes and then concentrated in vacuo. Each residue was dissolved in ethanol (1 ml) and a solution of lithium hydroxide (6 eq) in water (0.2 ml) was added, and the vials were stirred at 40 ° C for 30 minutes. The contents of the vials were concentrated in vacuo, diluted with acetic acid: water 1: 1 (1 ml), filtered and purified by preparative HPLC to give the TFA salts of the compounds of examples 64 to 74. Example 64 cyclopropanecarboxyl- (R) -benzyl- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] -1-methyl} amide

(7.9 mg) (m / z): [M + H] + calculated for C27H34N2O2, 419.26; found 419.2. Example 65 N-benzyl-3-cyclopentyl-N - {(R) -2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] -1-methyl} propionamide (1.9 mg) (m / z): [M + H] + calculated for C31H42N2O2: 475.32, found: 475.2. Example 66 N-benzyl-N - {(R) -2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] -1-methyl-ethyl} -2- feniIacetamide (3.9 mg) (m / z): [M + H] + calculated for C31H36N2O2: 469.28; Found: 469.2. Example 67 N-benzyl-N - {(R) -2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] -1-methyl-ethyl} -3- methylbutyramide (6.5 mg) (m / z): [M + H] + calculated for C28H38N2O2: 435.29; Found: 435.2. Example 68 N-benzyl-N - {(R) -2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] -1-methyl-ethyl} -3- methylbutyramide (3.5 mg) (m / z): [M + H] + calculated for C25H32N2O3: 409.24; Found: 409.2. Example 69 N-benzyl-2-cyclopentyl-N - {(R) -2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] -1-methyl} acetamide (2.6 mg) (m / z): [M + H] + calculated for C30H40N2O2: 461.31; Found: 461.2. Example 70 cyclohexanecarboxyl- (R) -benzyl- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] -1-methyl-ethyl} -amide

(3.8 mg) (m / z): [M + H] + calculated for C30H40N2O2: 461.31; Found: 461.2. Example 71 N-benzyl-2-ethyl-N - {(R) -2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] -1-methylethyl} butyramide (3.8 mg) (m / z): [M + H] + calculated for C29H40N2O2: 449.31; Found: 449.2.

Example 72 N-benzyl-N - {(R) -2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] -1-methyl ethyl} succinamic acid (5, 7 mg) (m / z): [M + H] + calculated for C27H34N2O4: 451.25, found: 451.2. Example 73 cyclopentanecarboxyl- (R) -benzyl- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] -1-methylethylamide (5.2 mg) (m / z): [M + H] + (calculated for C29H38N2O2: 447.29; found: 447.2. Example 74 N-benzyl-N - {(R) -2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] -1-methyl} acetamide (4.6 mg) (m / z): [M + H] + calculated for C25H32N2O2: 393.25; found: 393 ,2.

Example 75: Synthesis of N-cyclohexylmethyl-2-hydroxy-N- {2- [3-endo- (3-methanesulfonylamino-phenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} acetamide

to. Preparation of cyclohexylmethyl- {2- [3-endo- (3-phenylmethanesulfonylamino) -8-azabicyclo [3.2.1] oct-8-yl] -ethyl} tert-butyl carbamate

To a solution of the TFA salt of N- [3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -phenyl] -methanesulfonamide, the product of preparation 23 (140 mg, 0.35 mmoles), in DCM (2 ml) at room temperature a solution of tert-butyl cyclohexylmethyl- (2-oxoethyl) carbamate (116 mg, 0.455 mmol) and then sodium triacetoxyborohydride (96 mg, 0.455 mmol) was added. The resulting mixture was stirred at room temperature overnight and then diluted with DCM. The organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated to give the title intermediate as an oily residue that was used directly in the next step. (m / z): [M + H] + calculated for C28H45N3O4S: 520.31; Found: 520.4.

b. Preparation of N- (3-endo- {8- [2- (cyclohexylmethylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} -phenyl) -methanesulfonamide

The oily product from the previous step was treated with DCM (1.5 ml) and TFA (1.5 ml) at room temperature for thirty minutes. It was then concentrated, redissolved in a 1: 1 mixture of acetic acid and water (6 ml), filtered and purified by preparative reverse phase HPLC to give the intermediate of the title as its bis TFA salt (38 , 9 mg). (m / z): [M + H] + calculated for C23H37N3O2S: 420.26; Found: 420.4.

C. Synthesis of N-cyclohexylmethyl-2-hydroxy-N- {2- [3-endo- (3-methanesulfonylamino-phenyl) -8-azabicyclo [3.2.1] -8-yl] -ethyl} acetamide

To a solution of the product from the previous step (39 mg, 0.06 mmol) in DCM (0.2 ml) at room temperature was added N, N-diisopropylethylamine (31 mg, 0.24 mmol), followed by acetoxychloride of acetyl (12 mg, 0.09 mmol). Five minutes later, the reaction was concentrated, redissolved in ethanol (0.2 ml) and treated with lithium hydroxide monohydrate (15 mg, 0.36 mmol) in water (0.2 ml) at room temperature for thirty minutes The reaction mixture was then reconcentrated and the resulting residue was dissolved in a 1: 1 mixture of acetic acid and water (1.5 ml), filtered and purified by preparative reverse phase HPLC to give the title compound as a your TFA salt (16.9 mg). (m / z): [M + H] + calculated for C25H39N3O4S: 478.27; Found: 478.2.

Examples 76-204

In the following examples, the 8-azabicyclooctane-phenol or 8-azabicyclooctane-benzamide intermediate was prepared according to the preparation process 13 with the following exceptions: preparation 1: example 137; preparation 12, steps a to c: examples 106-108 and 112; Preparation 12: Examples 91, 101, 109-111 and 131.

Example 76: Synthesis of N-cyclohexylmethyl-2-hydroxy-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} -2- (S ) -phenylacetamide

To a solution of 3-endo- {8- [2- (cyclohexylmethylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} phenol (30 mg, 0.087 mmol) in DMF (0.4 ml) HATU (39.6 mg, 0.10 mmol) and (S) -hydroxyphenylacetic acid (15.2 mg, 0.1 mmol) were added. The reaction mixture was concentrated by rotary evaporation and the residue was dissolved in 50% acetic acid in water (1.2 ml), filtered and purified by preparative HPLC to give the title product as a TFA salt ( 8.6 mg). (m / z): [M + H] + calculated for C30H40N2O3: 477.30; Found: 477.4.

Examples 77-84

Using processes similar to that of Example 76, but substituting (S) -hydroxyphenylacetic acid for the appropriate carboxylic acid, TFA salts of the compounds of Examples 77-84 were prepared. Example 77: (S) -N-Cyclohexylmethyl-2-hydroxy-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] etill} -3- phenyl

propionamide (15.9 mg) (m / z): [M + H] + calculated for C31H42N2O3: 491.68, found: 491.4. Example 78: (R) -N-Cyclohexylmethyl-2-hydroxy-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-iI] ethyl} -4- phenylbutyramide (17.8 mg) (m / z): [M + H] + calculated for C32H44N2O3: 505.34; Found: 505.4. Example 79: 1-hydroxy-cyclopropancarboxyl-cyclohexylmethyl- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl}

amide (5.7 mg) (m / z): [M + H] + calculated for C26H38N2O3: 427.29; Found: 427.4. Example 80: (S) -2-hydroxy-4-methyl-pentan-cyclohexylmethyl- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} amide (12.7 mg) (m / z): [M + H] + calculated for C28H44N2O3: 457.34; Found: 457.4.

Example 81: (S) -N-Cyclohexylmethyl-2-dimethylamino-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} -3- phenylpropionamide (9.4 mg) (m / z): [M + H] + calculated for C33H47N3O2: 518.37; Found: 518.6. Example 82: 2-hydroxy-hexane-cyclohexylmethyl- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} amide (10.6 mg) (m / z): [M + H] + calculated for C28H44N2O3: 457.34; Found: 457.5. Example 83: (R) -2-cyclohexyl-N-cyclohexylmethyl-2-hydroxy-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] - ethyl} acetamide (9.8 mg) (m / z): [M + H] + calculated for C30H46N2O3: 483.35; Found: 483.2. Example 84: (S) -2-cyclohexyl-N-cyclohexylmethyl-2-hydroxy-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] - ethyl} acetamide (14.5 mg) (m / z): [M + H] + calculated for C30H46N2O3: 483.35; Found: 483.4.

Examples 85-89

Using processes similar to that of Example 76, but replacing azabicyclooctane-phenol with 3-endo- {8- [2 (cyclohexylmethylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} benzamide and using carboxylic acid As appropriate, TFA salts of the compounds of Examples 85-89 were prepared. Example 85: 3-endo- (8- {2- [cyclohexylmethyl - ((S) -2-hydroxy-3-phenylpropionyl) -amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl)

benzamide (15.2 mg) (m / z): [M + H] + calculated for C32H43N3O3: 518.33; Found: 518.4. Example 86: 3-endo- (8- {2- [cyclohexylmethyl - ((S) -2-hydroxy-4-methylpentanoyl) -amino] etill-8-azabicyclo [3.2.1] oct-3-yl) benzamide ( 19 mg) (m / z): [M + H] + calculated for C29H45N3O3: 484.35; Found: 484.4. Example 87: 3-endo- (8- {2- [cyclohexylmethyl- (1-hydroxy-cyclopropancarbonyl) -amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl)

benzamide (15.5 mg) (m / z): [M + H] + calculated for C27H39N3O3: 454.30; found. 454.4. Example 88: 3-endo- (8- {2- [cyclohexylmethyl - ((S) -2-dimethylamino-3-phenyl-propionyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl)

benzamide (17.4 mg) (m / z): [M + H] + calculated for C34H48N4O2: 545.38; Found: 545.4. Example 89: 3-endo- (8- {2- [cyclohexylmethyl- (3-hydroxy-2,2-dimethyl-propionyl) -amino] -ethyl} -8-azabicyclo [3.2.1] oct-3-yl)

benzamide (5.3 mg) (m / z): [M + H] + calculated for C28H43N3O3: 470.33; Found: 470.4.

Example 90: Synthesis of 3-endo- (8- {2- [cyclohexylmethyl- (4-dimethylamino-butyryl) amino] etill-8-azabicyclo [3.2.1] oct3-yl) benzamide

To a vial loaded with 4-dimethylaminobutyric acid HCl salt (19.7 mg, 0.15 mmol) was added DMF (0.3 ml), followed by HATU (57.0 mg, 0.15 mmol). After stirring for 1 h, the reaction mixture was treated with DIPEA (25.8 mg, 0.2 mmol) and bis TFA salt of 3-endo- {8- [2- (cyclohexylmethylamino) ethyl] -8-azabicyclo [ 3.2.1] oct-3-yl} benzamide (30.0 mg, 0.05 mmol). The resulting mixture was stirred at room temperature for 4 hours and then heated at 65 overnight. After concentrating, the resulting residue was dissolved in 50% acetic acid in water (1.5 ml) and purified by preparative reverse phase HPLC to give the title compound as a bis TFA salt (4.9 mg). (m / z): [M + H] + calculated for C29H46N4O2: 483.36; Found: 483.4.

Examples 91-92

Using processes similar to that of Example 90, but substituting 4-dimethylaminobutyric acid for the appropriate carboxylic acid, the compounds of Examples 91-92 were prepared. Example 91: 3-endo- (8- {2- [cyclohexylmethyl- (1-hydroxycyclopropancarbonyl) -amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl)

benzamide TFA salt (18.8 mg). (m / z): [M + H] + calculated for C27H39N3O3: 454.30; found:

454.2. Example 92: 3-endo- (8- {2- [cyclohexylmethyl - ((S) -3-hydroxy-2-methylamino-propionyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3

il) -benzamide bis TFA salt (24. mg). (m / z): [M + H] + calculated for C27H42N4O3: 471.33; found:

471.4.

Example 93: Synthesis of 3-endo- (8- {2- [cyclohexylmethyl- (3-hydroxy-2-hydroxymethyl-2-methylpropionyl) amino] ethyl} -8azabicyclo [3.2.1] oct-3-yl) -benzamide

to. Preparation of 5-methyl-2-phenyl-1,3-dioxinan-5-carboxylic acid

In a round bottom flask, 3-hydroxy-2-hydroxymethyl-2-methyl-propionic acid (10.0 g, 74.5 mmol), acetone (75.0 ml), benzaldehyde-dimethylacetal (17.02) were successively introduced g, 111.0 mmol) and para-toluenesulfonic acid monohydrate (0.71 g, 3.7 mmol). The resulting mixture was stirred at room temperature for 4 hours and then filtered. The filter cake was washed with cold acetone and dried under vacuum to give the title compound as a white solid. 1 H NMR (CDCl 3, 300 MHz) δ (ppm): 7.46-7.48 (m, 2H), 7.34-7.36 (m, 3H), 5.49 (s, 1H), 4 , 65 (d, J = 10.8 Hz, 2H), 3.70 (d, J = 11.4 Hz, 2H), 1.11 (s, 3H).

b. Synthesis of 3-endo- (8- (2- [cyclohexylmethyl- (3-hydroxy-2-hydroxymethyl-2-methylpropionyl) amino] ethyl} -8-azabicyclo [3.2.1] oct3-yl-benzamide

To a solution of the product of the previous step (55.7 mg, 0.25 mmol) in DMF (0.5 ml) at room temperature was added HATU (95.0 mg, 0.25 mmol). After stirring for 2 h the reaction was treated with 3-endo {8- [2- (cyclohexylmethylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} benzamide bis TFA salt (75.0 mg , 0.13 mmol), followed by DIPEA (64.9 mg, 0.50 mmol). The reaction was heated at 40 overnight. After concentrating, the residue was treated with a mixture of acetic acid (2.1 ml) and water (0.7 ml) at 70 ° C for 2 hours and then reconcentrated. The resulting residue was dissolved in 50% acetic acid in water (1.5 ml) and purified by reverse phase HPLC to give the TFA salt of the title compound (24.6 mg). (m / z): [M + H] + calculated for C28H43N3O4: 486.33; Found: 486.4.

Example 94: Synthesis of 3-endo- (8- {2- [cyclohexylmetiI - ((S) -4-dimethylamino-hydroxybutyryl) -amino] -ethyl} -8-azabicyclo- [3.2.1] oct-3-yl -benzamide

to. Preparation of lithium (S) -4-tert-butoxycarbonylamino-2-hydroxybutyrate

A solution of S) -4-tert-butoxycarbonylamino-hydroxybutyrate of methyl (1.52 g, 6.52 mmol) in methanol (20.0 ml) was treated with lithium hydroxide monohydrate (273.8 mg, 6.52 mmol) and water (2.0 ml) for 30 minutes, concentrated and dried in vacuo to give a white solid (1.26 g).

b. Preparation of 3-endo- (8- {2 - [((S) -4-amino-2-hydroxybutyryl) cyclohexylmethyl-amino] ethyl} -8-aza-bicyclo- [3.2.1] oct-3-ylbenzamide

After stirring for 2 h, the reaction mixture was diluted with ethyl acetate (100.0 ml), washed successively with semi-saturated sodium bicarbonate (20.0 ml), saturated sodium bicarbonate (15.0 ml) and brine (15.0 ml), dried over sodium sulfate, filtered and concentrated to give intermediate [(S) -3- (2- [3- (3-endo-carbamoylphenyl) -8-azabicyclo [3.2.1] oct-8 -yl] ethyl} -cyclohexylmethyl-carbamoyl) -3-hydroxypropyl] -carbonate tert-butyl in the form of a yellowish oil (m / z): [M + H] + calculated for C32H50N4O5: 571.4; Found: 571.6.

The intermediate product was then treated with DCM (1.5 ml) and TFA (2.5 ml) at room temperature for thirty minutes. After concentrating, the residue was dissolved in 25% acetic acid in water (8.0 ml), filtered and purified by reverse phase HPLC to give the bis TFA salt of the title compound (194.4mg). (m / z): [M + H] + calculated for C27H42N4O3: 471.3; Found: 471.6.

C. Synthesis of 3-endo- (8- {2 - [((S) -4-dimethylamino-2-hydroxybutyryl) cyclohexylmethylamino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide

To the solution of the product from the previous step (65.3 mg, 0.09 mmol) in methanol (0.3 ml) was added 37% aqueous formaldehyde solution (0.02 ml, 0.27 mmol), followed by sodium cyanoborohydride (14.0 mg, 0.27 mmol). The resulting mixture was stirred at room temperature for twenty minutes before concentrating. The residue was dissolved in 25% acetic acid in water (6.0 ml), filtered and purified by reverse phase HPLC to give the bis TFA salt of the title compound (33.0mg). 1 H NMR (CD3OD, 400 MHz) δ (ppm): 8.06 (s, 1H), 7.74-7.81 (m, 2H), 7.49-7.51 (m, 1H), 4 , 66-4.69 (m, 1H), 4.14-4.18 (m, 2H), 3.84-3.89 (m, 1H), 3.73-3.78 (m, 1H) , 5 3.37-3.44 (dark, 3H, partially overlapped with solvent), 3.28-3.30 (2H dark, partially overlapped with solvent), 3.20-3.22 (m, 2H), 2.96 (s, 6H), 2.61-2.70 (m, 4H), 2.09-2.18 (m, 4H), 1.74-1.88 (m, 8H), 1, 25-1.36 (m, 3H), 1.04-1.12 (m, 2H), (m / z): [M + H] + calculated for C29H46N4O3: 499.36; Found: 499.6.

Example 95: Synthesis of 3-endo- (8- {2 - [((S) -4-tert-butylamino-2-hydroxy-butyrill) -cyclohexylmethyl-amino] ethyl} -8azabicycIo [3.2.1] oct-3 -il) -benzamide

To a solution of bis TFA salt of 3-endo- (8- {2 - [((S) -4-amino-2-hydroxybutyryl) cyclohexylmethylamino] ethyl} -8-azabicyclo [3.2.1] oct-3- il) benzamide (29.0 mg, 0.04 mmol) in DMF (0.5 ml) was added DIPEA (20.7 mg, 0.16 mmol) and tert-butyl iodide (14.7 mg, 0 , 08 mmol). The resulting mixture was heated at 75 ° C for 2 h. After concentrating, the residue was dissolved in 25% acetic acid in water and purified by reverse phase HPLC to give the bis TFA salt of the title compound (4.5 mg). (m / z): [M + H] + calculated for C31H50N4O3: 526.38; Found: 526.6.

Example 96: Synthesis of 3-endo- (8- {2- [cyclohexylmethyl - ((S) -4-diethylamino-2-hydroxybutyryl) amino] etiI} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide

By a process similar to that of example 95, substituting the tert-butyl iodide for ethyl iodide (3.0 eq), the bis TFA salt of the title compound (m / z) was prepared: [M + H] + calculated for C31H50N4O3: 527.39; Found: 527.2.

Example 97: Synthesis of 3-endo- (8- {2- [cyclohexylmetiI- (3-dimethylamino-2-hydroxypropionyl) amino] etiI} -8-azabicyclo [3.2.1] oct-3-yl) benzamide

to. Preparation of [2- {2- [3-endo- (3-carbamoylphenyl) -8-azabicyclo [3.2.1] oct-8-yl] -ethyl} -cyclohexylmethyl-carbamoyl) -2-hydroxyethyl] -carbamate 9H -fluoren-9-ylmethyl

By a process similar to that of example 94 (b), substituting lithium (S) -4-tert-butoxycarbonylamino-2-hydroxybutyrate for 3- (9H-fluoren-9-ylmethoxycarbonylamino) -2-hydroxypropionic acid (163.7 mg, 0.5 mmol, 2.0 eq), the title compound was obtained as a yellowish oil. (m / z): [M + H] + calculated for C41H50N4O5: 679.4; Found: 679.6.

b. Preparation of 3-endo- (8- {2 - [(3-amino-2-hydroxypropionyl) -cyclohexylmethylamino] ethyl} -8-azabicyclo [3.2.1] oct-3-ylbenzamide

The product from the previous step was treated with DMF (2.0 ml) and piperidine (0.4 ml) at room temperature for 5 minutes and then concentrated. The residue was purified by preparative reverse phase HPLC to give the bis TFA salt of the title compound (93.7 mg). (m / z): [M + H] + calculated for C26H40N4O3: 457.3; Found: 457.4.

C. Synthesis of 3-endo- (8- {2- [cyclohexylmethyl- (3-dimethylamino-2-hydroxypropionyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-ylbenzamide

Following the procedure of example 94 c, the bis TFA salt of the title compound (m / z) was prepared: [M + H] + calculated for C28H44N4O3: 485.34; Found: 485.4.

Example 98: Synthesis of 3-endo- (8- {2- [cyclohexylmethyl- (4-hydroxy-butylamino] ethyl] -8-azabicyclo [3.2.1] oct-3-yl

benzamide

To a solution of γ-butyrolactone (170.0 mg, 1.98 mmol) in methanol (0.5 ml) was added water (0.2 ml) and lithium hydroxide monohydrate (83 mg, 2.0 mmol). The resulting mixture was stirred at room temperature overnight. After concentrating, the residue was dried under vacuum to give the intermediate 4-lithium hydroxybutyrate as a white solid. The intermediate (18.3 mg, 0.17 mmol) was added to a bis TFA salt mixture of 3-endo- {8- [2 (cyclohexylmethylamino) ethyl] -8-azabicyclo [3.2.1] oct-3- il} benzamide (50 mg, 0.083 mmol) and DIPEA (58.3 µl, 0.33 mmol) in DMF (0.4 ml). HATU (63.1 mg, 0.17 mmol) was then added and the resulting reaction mixture was stirred at room temperature overnight. After concentrating, the residue was dissolved in 50% acetic acid in water (6 ml), filtered and purified by preparative HPLC. The desired fractions were combined and lyophilized to give a white solid. 1 H NMR (CD3OD, 400 MHz) δ (ppm): 8.05 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.51 (dd, J = 7.6, 8.0 Hz, 1H), 4.13 (brs, 2H), 3.78 (t, J = 5.6 Hz, 2H), 3.69 (t, J = 6.0 Hz, 2H), 3.31-3.35 (dark 3H, solvent overlap), 3.17 (t, J = 5.6 Hz, 2H), 2, 43-2.53 (m, 6H), 2.01-2.05 (m, 2H), 1.61-1.84 (m, 10H), 1.12-1.26 (m, 3H), 0.89-0.98 (m, 2H), (m / z): [M + H] + calculated for C27H41N3O3: 456.31; Found: 456.4.

Examples 99-100

Using processes similar to those of example 98 and substituting γ-butyrolactone for the appropriate lactone, the compounds of examples 99 to 100 were prepared. Example 99: 3-endo- (8-2- [cyclohexylmethyl - ((S) - 2,4-dihydroxybutyryl) amino] ethyl-8-azabicyclo [3.2,1] oct-3-yl) benzamide TFA salt, (m / z): [M + H] + calculated for C27H41N3O4: 472.31; Found: 472.4. Example 100: 3-endo- (8-2- [cyclohexylmethyl - ((S) -3,4-dihydroxybutyryl) amino] ethyl-8-azabicyclo [3.2,1] oct-3-yl) benzamide TFA salt, (m / z): [M + H] + calculated for C27H41N3O4: 472.31; Found: 472.4

Example 101: Synthesis of 3-endo- (8- {2- [cyclohexylmethyl- (2-dimethylamino-acetyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide

to. Preparation of 3-endo - {(8- [2-cyclohexylmethyl-amino) ethyl] -8-azabicyclo [3.2.1] -oct-3-yl} benzamide

Following the procedure of preparations 9 and 12, 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) benzamide (1.18 g) was reacted with tert-cyclohexylmethyl- (2-oxoethyl) -carbamate -butyl (1.57 g) to give tert-butyl {2- [3-endo- (3-carbamoylphenyl) 8-azabicyclo [3.2.1] oct-8-yl] ethyl} cyclohexylmethyl carbamate, which is then dealt with DCM and TFA. The resulting crude product was dissolved in 50% acetic acid in water (15.0 ml) and purified by preparative reverse phase HPLC. The desired fractions were combined and lyophilized to give the bis TFA salt of the title compound (1.65 g). 1 H NMR (CD3OD, 300 MHz) δ (ppm): 8.03 (s, 1H), 7.71-7.77 (m, 2H), 7.44-7.50 (m, 1H), 4 , 11 (brs, 2H), 3.52 (t, J = 6.0 Hz, 2H), 3.33-3.40 (dark, 3H, solvent overlapped), 2.96 (d, J = 6 , 6 Hz, 2H), 2.67-2.67 (m, 4H), 2.05-2.12 (m, 2H), 1.70 1.84 (m, 8H), 1.20-1 , 39 (m, 3H), 1.03-1.10 (m, 2H), (m / z): [M + H] + calculated for C23H35N3O: 370.28; Found: 370.2.

b. Synthesis of 3-endo - (8- {2- [cyclohexylmethyl- (2-dimethylamino-acetyl) amino] ethyl} -8-azabicyclo [3.2.1] -oct-3-yl) -benzamide

To a solution of the product of the previous step (33.0 mg, 0.055 mmol) in DCM (0.3 ml) at room temperature was added DIPEA (28.4 mg, 0.22 mmol) and then HCl salt of dimethylaminoacetyl chloride (12.6 mg, 0.08 mmol). The reaction mixture was stirred for 10 minutes and then concentrated. The resulting residue was dissolved in 50% acetic acid in water (1.5 ml), filtered and purified by preparative reverse phase HPLC to give the bis TFA salt of the title compound (16.1mg). (m / z): [M + H] + calculated for C27H42N4O2: 455.33; Found: 455.2.

Examples 102-103

Using a process similar to that of example 101 and replacing dimethylaminoacetyl chloride with chloride

Suitable compounds of Examples 102-103 were prepared. Example 102: 3-endo- (8- (2 - ((cyclohexylmethyl) (N, N-dimethylsulfamoyl) amino) ethyl) -8-azabicyclo [3.2.1] oct-3-yl) benzamide salt

of TFA (21.2 mg). (m / z): [M + H] + calculated for C25H40N4O3S: 477.28; Found: 477.2. Example 103: 3-endo- (8- {2- [cyclohexylmethyl- (2-methoxyacetyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide salt of

TFA (m / z): [M + H] + calculated for C26H39N3O3: 442.30; Found: 442.4.

Example 104: Synthesis of 3-endo- (8- {2 - [((S) -2,3-dihydroxypropionyl) - (3-hydroxy-adamantan-1-ylmethyl) amino] ethyl} 8-azabicyclo [3.2.1 ] oct-3-yl) benzamide

to. Preparation of 3-aminomethyl-adamantan-1-ol

To a vigorously stirred mixture of concentrated sulfuric acid (22.7 ml) and 65% nitric acid (2.3 ml) at 0 ° C was added C-adamantan-1-yl-methylamine (2.0 g, 12.12 mmoles) drop by drop. The reaction mixture was stirred for 2 hours at 0 ° C, heated to room temperature and stirred at that temperature for 24 h, cooled to 0 ° C and slowly stopped with ice (10.8 g). The mixture was allowed to warm to the environment by melting ice overnight, cooled again to 0 ° C and treated with sodium hydroxide (50 g) in small portions. The resulting brown paste was filtered and the filter cake was washed with DCM (200 ml). After separation, the organic layer was washed with brine (2 x 20 ml), dried over sodium sulfate, filtered and concentrated to give a white solid (1.09 g). (m / z): [M + H] + calculated for C11H19N: 182.2; Found: 182.2.

b. Preparation of 3-endo- (8- {2 - [(3-hydroxy-adamantan-1-ylmethyl) aminoethyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide

To a solution of 3-endo- [8- (2-oxoethyl) -8-azabicyclo [3.2.1] oct-3-yl) -benzamide (108.6 mg, 0.60 mmol) HCl salt in DCM (5.0 ml) sodium triacetoxyborohydride (137.8 mg, 0.65 mmol) was added followed by the product from the previous step (190.0 mg, 0.50 mmol). The resulting mixture was stirred at room temperature for 2 hours before concentrating. The residue was dissolved in 25% acetic acid in water (6.0 ml), filtered and purified by preparative reverse phase HPLC to give the bis TFA salt of the title compound (91.0 mg). (m / z): [M + H] + calculated for C27H39N3O2 438.3; Found: 438.4.

C. Synthesis of 3-endo- (8- {2 - [((S) -2,3-dihydroxypropionyl) - (3-hydroxy-adamantan-1-ylmethyl) amino] ethyl} -8-azabicyclo [3.2.1] oct -3-il) benzamide

To a suspension (4S) -2,2-dirnetyl-1,3-dioxolan-4-carboxylate lithium (28.0 mg, 0.17 mmol) in DMF (0.5 ml) was added HATU (62, 5 mg, 0.164 mmol) at room temperature. The mixture was subjected to ultrasound to facilitate dissolution. After 1 hour DIPEA (87.9 mg, 0.68 mmol) was added, followed by the product from the previous stage (60.0 mg, 0.085 mmol). The resulting mixture was stirred for 2 hours and then concentrated. The residue was treated with a mixture of acetic acid (2.1 ml) and water (0.7 ml) at 70 ° C for 1 h. After concentrating, the oily residue was dissolved in 50% acetic acid in water (3.0 ml) and purified by preparative reverse phase HPLC to obtain the TFA salt of the title compound (6.2 mg). (m / z): [M + H] + calculated for C30H43N3O5: 526.32; Found: 526.4.

Example 105: Synthesis of 3-endo-8- {2 - [(2-hydroxyacetyl) - (3-hydroxy-adamantan-1-ylmethyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl ) benzamide, salt

To a solution of bis TFA salt of 3-endo- (8- {2 - [(3-hydroxy-adamantan-1-ylmethyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3yl) benzamide (132 , 2 mg, 0.20 mmol) in DCM (1.0 ml) DIPEA (0.14 ml, 0.79 mmol) was added, followed by acetoxyacetal chloride (54.6 mg, 0.40 mmol) at room temperature. The reaction mixture was stirred for 5 minutes and then concentrated. The resulting residue was dissolved in methanol (2.0 ml) and treated with lithium hydroxide monohydrate (50.0 mg, 1.2 mmol) for 30 minutes and reconcentrated. The residue was dissolved in 50% acetic acid in water (1.5 ml), filtered and purified by preparative reverse phase HPLC to give the TFA salt of the title compound (23.4 mg). 1 H NMR (CD3OD, 400 MHz) δ (ppm): 8.16 (s, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.60 (dd, J = 7.6, 8.0 Hz, 1H), 4.46 and 4.44 (two series of s, 2H total), 4.25 and 4.20 ( two series of brs, total 2H), 3.92 (t, J = 5.6 Hz, 2H), 3.44-3.46 (m, 1H), 3.31 (t, J = 5.6 Hz , 2H), 3.25 (s, 2H), 2.75-2.82 (m, 4H), 2.36 (brs, 2H), 2.24-2.30 (m, 2H), 1, 92-1.98 (m, 2H), 1.62-1.85 (m, 12H). (m / z): [M + H] + calculated for C29H41N3O4: 496.31; Found: 496.4.

Examples 106-112

Using processes similar to those of examples 104b and 105, as well as suitable oxoethyl-8-azabicyclooctane and chloride, the compounds of examples 106 to 112 were prepared. Example 106: N-adamantan-1-imetiI-2-hydroxy -N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} acetamide

TFA salt (m / z): [M + H] + calculated for C28H40N2O3: 453.31; found 453.2. Example 107: N-adamantan-1-ylmethyl-N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] -ethyl} acetamide TFA salt (m / z): [M + H] + calculated for C28H40N2O2: 437.31; Found: 437.2. Example 108: N-adamantan-1-ylmethyl-N- {2- [3-endo-3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] -ethyl} succinamic TFA salt (m / z): [M + H] + calculated for C30H42N2O4: 495.31; Found: 495.2. Example 109: 3-endo- (8- {2- [adamantan-1-ylmethyl- (2-hydroxyacetyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide TFA salt ( m / z): [M + H] + calculated for C29H41N3O3: 480.31; Found: 480.2. Example 110: N-adamantan-1-ylmethyl-N- {2- [3-endo- (3-carbamoylfenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} succinamic TFA salt (m / z): [M + H] + calculated for C31H43N3O4: 522.33; Found: 522.2. Example 111: 3-endo- {8- [2- (acetyl-adamantan-1-ylmethyl-amino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} benzamide TFA salt (m / z) : [M + H] + calculated for C29H41N3O2: 464.32; Found: 464.2. Example 112: N- (2,6-difluorobenciI) -N- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} succinamic acid TFA salt (m / z): [M + H] + calculated for C26H30F2N2O4: 473.22; Found: 473.2.

Example 113: Synthesis of N- (2,6-difluorobenzyl) -N- {2- [3- (3-hydroxyphenyl) -8-azabicyclo [3.2.1] oct-8-yl] -ethyl} succinamyl-3- endo- (8- {2 - [(2,6-difluorobenciI) - (2-hydroxy-acetiI) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide

to. Preparation of 2- (2,6-difluorobenzylamino) ethanol (50 ml). The organic layer was partitioned with water (75 ml) and the aqueous layer was extracted with dichloromethane (50 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow solid (3.25 g). (m / z): [M + H] + calculated for C9H11F2NO: 188.08; Found: 188.1. 1 H NMR (DMSO-d6, 300 MHz) δ (ppm): 7.37-7.34 (m, 1H), 7.10-7.05 (m, 2H), 4.47 (t, J = 5.4 Hz, 1H), 3.75 (s, 2H), 3.42 (q, J = 5.5 Hz, 2H), 2.25 (t, J = 5.7 Hz, 2H), 1 , 82 (br s, 1H).

b. Preparation of tert-butyl (2,6-difluorobenzyl) - (2-hydroxyethyl) -carbamate

To the solution of the product of the previous step (3.25 g, 17.4 mmol) in dichloromethane (20 ml) at 0 ° C, a solution of di-tert-butyl dicarbonate (drop-added) was added dropwise through a syringe ( 3.40 g, 15.6 mmol) for 5 min. The resulting mixture was slowly heated to room temperature and stirred overnight under a nitrogen atmosphere. The crude reaction mixture was diluted with DCM (50 ml) and washed successively with 1 N HCl (2 x 50 ml), saturated NaHCO3 (3 x 50 ml) and brine (50 ml). The organic layer was dried with magnesium sulfate, filtered and concentrated to give the title compound (4.46 g). (m / z): [M + H] + calculated for C14H19F2NO3: 288.13; Found: 288.2.

C. Preparation of (2,6-difluorobenzyl) - (2-oxoethyl) -carbamate tert-butyl

To the solution of the product of the previous step (4.46 g, 15.5 mmol) in DCM (50 ml) at 0 ° C., dimethylsulfoxide (1.79 g, 23 mmol), DIPEA (5.01 g, successively added) 38.9 mmol) and sulfur triridium trioxide complex (6.20 g, 38.9 mmol). After 30 minutes, the reaction was washed successively with 1 N aq HCl (3 x 100 ml), saturated NaHCO3 (100 ml) and brine (100 ml), filtered and eluted with DCM. After concentrating, the title compound was obtained as a yellow oil (2.31 g). 1 H NMR (DMSO-d6, 300 MHz) δ (ppm): 9.42 (s, 1H), 7.40 (m, 1H), 7.09 (m, 2H), 4.49 (s, 2H ), 4.00 (d, J = 24.6, 2H), 1.31 (s, 9H).

d. Preparation of tert-butyl {2- [3-endo- (3-carbamoylfenyl) -8-azabicyclo [3.2.1] oct-3-yl] ethyl} - (2,6-difluorobenzyl) carbamate

To a solution of 3-endo-8-azabicyclo [3.2.1] oct-3-yl) benzamide (120 mg, 0.56 mmol) in DCM (2 ml) at 0 ° C was added a solution of the product of the step anterior (193 mg, 0.68 mmol) in DCM (1 ml) and then sodium triacetoxyborohydride (144 mg, 0.68 mmol). The resulting mixture was heated to room temperature and allowed to react for 1 h. The reaction mixture was diluted with DCM, washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated to give a yellowish oil and used in the next step without further purification. (m / z): [M + H] + calculated for C28H35F2N3O3: 500.26; Found: 500.1.

and. Preparation of: 3-endo- {8- [2- (2,6-difluorobenzylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} -benzamide

The oily residue from the previous step was dissolved in DCM (2 ml) and treated with TFA (2 ml) at room temperature for 2 h. The mixture was concentrated and coevaporated three times with ethyl acetate, diluted with DCM and alkalized to pH = 8.0 with saturated sodium bicarbonate. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give a dark oil (200 mg). (m / z): [M + H] + calculated for C23H27F2N3O: 400.21; Found: 400.4.

F. Synthesis of 3-endo- (8- {2 - [(2,6-difluorobenzyl) -2-hydroxyacetyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide

To a solution of the mono-TFA salt of 3-endo- {8- [2- (2,6-difluorobenzylamino) -ethyl] -8-azabicyclo [3.2.1] oct-3-yl} benzamide (132 mg , 0.26 mmol) in DCM (1 ml) at 0 ° C DIPEA (132 mg, 1.0 mmol) was added. The reaction mixture was treated with acetoxyacetyl chloride (46 mg, 0.34 mmol) for 30 minutes. The reaction mixture was concentrated and the crude oil was dissolved in ethanol (0.5 ml) and treated with lithium hydroxide monohydrate (66 mg, 1.65 mmol) in water (0.2 ml). The solvent was concentrated and the residue was dissolved in 50% acetic acid in water (5 ml), filtered and purified by preparative HPLC to give the TFA salt of the title compound (30.8 mg). (m / z): [M + H] + calculated for C25H29F2N3O3: 458.22; Found: 458.2. 1 H NMR (CD3OD, 400 MHz) δ (ppm): 8.025 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.49-7.45 (m, 2H), 7.103 (t, J = 8.8 Hz, 2H), 4.67 (s, 2H), 4.52 (s, 2H), 4, 10 (br s, 2H), 3.71 (t, J = 6.0Hz, 2H), 3.4-3.3 (dark 1H, solvent overlapped), 3.08 (t, J = 5.6 , 2H), 2,632.61 (m, 4H), 2.6 -2.3 (m, 2H), 1.83-1.79 (m, 2H).

Examples 114-118

Using processes similar to that of example 113 (f) and the appropriate chloride, the compounds of examples 114-118 were prepared. Example 114: 3-endo- (8- (2 - ((2,6-difluorobenzyl) (N, N-dimethylsulfamoyl) amino) ethyl) -8-azabicyclo [3.2.1] oct-3-yl) benzamide

TFA salt (m / z): [M + H] + calculated for C25H32F2N4O3S: 507.22; Found: 507.4. Example 115: 3-endo- (8- {2 - [(2,6-difluorobenzyl) - (2-hydroxy-2-methylpropionyl) -amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl)

benzamide TFA salt (m / z): [M + H] + calculated for C27H33F2N3O3: 486.25; Found: 486.4. Example 116: 3-endo- (8- {2 - [(2,6-difluorobenzyl) - (2-methoxyacetyl) -amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide salt

TFA (m / z): [M + H] + calculated for C26H31F2N3O3: 472.23; Found: 472.4. 1 H NMR (CD3OD, 400 MHz) δ (ppm): 8.023 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.49-7.45 (m, 2H), 7.103 (t, J = 8.4 Hz, 2H), 4.72 (s, 2H), 4.45 (s, 2H), 4, 08 (br s, 2H), 3.71 (t, J = 6.0 Hz, 2H), 3.48 (s, 3H), 3.4-3.3 (dark 1H, solvent overlapped), 3 , 05 (t, J = 5.6, 2H), 2.62-2.59 (m, 4H), 2.05-2.02 (m, 2H), 1.81-1.79 (m, 2H).

Example 117: 3-endo- (8- {2 - [(2,6-difluorobenzyl) - (2,2-dimethylpropionyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide salt of TFA (m / z): [M + H] + calculated for C28H35F2N3O2: 484.27; Found: 484.4.

Example 118: 3-endo- (8- {2 - [(2,6-difluorobenzyl) -methanesulfonylamino] -ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide TFA salt (m / z): [M + H] + calculated for C24H29F2N3O2S: 478; 19; Found: 478.2. 1 H NMR (CD3OD, 400 MHz) δ (ppm): 8.00 (s, 1H), 7, 76 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.49-7.45 (m, 2H), 7.10 (t, J = 8.4 Hz, 2H), 4.67 (s, 2H), 4.10 (br s, 2H), 3.65 (t, J = 6.0Hz, 2H), 3.4-3.3 (1H dark, solvent overlapped), 3.10 (t, J = 5.6Hz, 2H), 2.99 (s, 3H), 2.62-2.59 (m, 4H), 2.04-2.02 (m, 2H), 1.83-1.81 (m, 2H).

Example 119: Synthesis of 3-endo- (8- {2 - [(2,6-difluorobenzyl) - (2-metansuIfoniIacetil) amino] ethyl} -8-azabicyclo [3.2.1] -oct-3-yl) benzamide

To a solution of methanesulfonylacetic acid (80.8 mg, 0.58 mmol) in DMF (1.0 ml) was added HATU (220 mg, 0.58 mmol). After stirring for 1 hour at room temperature, the reaction mixture was treated with the mono-TFA salt of 3-endo- {8- [2- (2,6-difluorobenzylamino) ethyl] -8-azabicyclo [3.2.1 ] oct-3-yl} benzamide (150 mg, 0.29 mmol) and DIPEA (74.8 mg, 0.58 mmol) at 45 ° C for 6 h. The solvent was concentrated and the residue was dissolved in 50% acetic acid in water (5 ml), filtered and purified by preparative HPLC to give the TFA salt of the title compound (52.4 mg). (m / z): [M + H] + calculated for C26H31F2N3O4S: 520.20; Found: 520.4. 1 H NMR (CD3OD, 400 MHz) δ (ppm): 8.01 (s, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.51-7.45 (m, 2H), 7.11 (t, J = 8.4 Hz, 2H), 4.89 (s, 2H), 4.68 (s, 2H ), 4.10 (br s, 2H), 3.78 (t, J = 6.0 Hz, 2H), 3.04-3.03 (dark 1H, solvent overlapped), 3.26 (s, 3H), 3.15 (t, J = 5.6 Hz, 2H), 2.63-2.60 (m, 4H), 2.09-2.06 (m, 2H), 1.83-1 , 80 (m, 2H).

Examples 120-129

Using compounds similar to that of Example 119 and the suitable carboxylic acid or carboxylate, the compounds of Examples 120-129 were prepared. Example 120: 3-endo- (8- {2 - [(2,6-difluorobenzyl) - ((S) -2-hydroxy-3-phenylpropionyl) -amino] ethyl} -8-azabicyclo [3.2.1] oct -3-il)

benzamide TFA salt (m / z): [M + H] + calculated for C32H35F2N3O3: 548.26; Found: 548.4. Example 121: 3-endo- (8- {2 - [(2,6-difluorobenzyl) - ((S) -2-hydroxy-4-methylpentanoyl) -amino] ethyl} -8-azabicyclo [3.2.1] oct -3-yl) benzamide TFA salt (m / z): [M + H] + calculated for C29H37F2N3O3: 514.28; Found: 514.4. Example 122: 3-endo- (8- {2 - [(2,6-difluorobenzyl) - ((R) -2,3-dihydroxypropionyl) -amino] ethyl} -8-azabicyclo [3.2.1] oct-3 -il) benzamide TFA salt (m / z): [M + H] + calculated for C26H31F2N3O4: 488.23; Found: 488.4. Example 123: 3-endo- (8- {2 - [(2,6-difluorobenzyl) - ((S) -2,3-dihydroxypropionyl) -amino] ethyl} -8-azabicyclo [3.2.1] oct-3 -il) benzamide TFA salt (m / z): [M + H] + calculated for C26H31F2N3O4: 488.23; Found: 488.2.

Example 124: 3-endo- (8- {2 - [(2,6-difluorobenzyl) - ((S) -2-hydroxypropionyl) amino] -ethyl} -8-azabicyclo [3.2.1] oct-3-yl ) benzamide TFA salt (m / z): [M + H] + calculated for C26H31F2N3O3: 472.23; Found: 472.4; NMR1 (CD3OD, 400 MHz) δ (ppm): 8.02 (s, 1H), 7.77-7.70 (m, 2H), 7.50-7.45 (m, 2H), 7.10 (t, J = 8.0 Hz, 2H), 4.91 (s, 2H), 4.08-4.00 (m, 2H), 3.87-3.83 (m, 1H), 3, 61-3.60 (m, 1H), 3.01 (t, J = 6.0 Hz, 2H), 2.63-2.61 (m, 4H), 2.04-1.99 (m, 2H), 1.81-1.79 (m, 2H), 1.40 (d, J = 6.4 Hz, 3H).

Example 125: 3-endo- (8- {2 - [(2,6-difluorobenzyl) - (3-hydroxy-2,2-dimethylpropionyl) -amino] ethyl} -8-azabicyclo [3.2.1] oct-3 -il) benzamide TFA salt (m / z): [M + H] + calculated for C28H35F2N3O3: 500.26; Found: 500.4. NMR1 (CD3OD, 400 MHz) δ (ppm): 8.01 (s, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.49 (m, 2H), 7.09 (t, J = 8.4 Hz, 2H), 5.02 (s, 2H), 4.04 (br s, 2H), 3.78 (s, 2H), 3.66 (t, J = 6.4 Hz, 2H), 3.4-3.3 (dark 1H, solvent overlapped), 2.98 (t, J = 6.0 Hz , 2H), 2.66-2.54 (m, 4H), 2.02-1.99 (m, 2H), 1.80 -1.76 (m, 2H), 1.41 (s, 6H ). Lithium 3-hydroxy-2,2-dimethylpropionate reagent was prepared by treating methyl 3-hydroxy-2,2-dimethylpropionate (5.0 g, 37.7 mmol) in methanol (45 ml) with lithium hydroxide monohydrate ( 1.6 g, 37.8 mmol).

Example 126: 3-endo- (8- {2 - [(2-cyanoacetyl) - (2,6-difluorobenzyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide salt of TFA (m / z): [M + H] + calculated for C26H28F2N4O2: 467.22; Found: 467.2. 1 H NMR (CD3OD, 400 MHz) δ (ppm): 8.02 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.50-7.48 (m, 2H), 7.12 (t, J = 8.4 Hz, 2H), 4.72 (s, 2H), 4.11 (br s, 2H), 3.70 (t, J = 6.4Hz, 2H), 3.4 to 3.3 (1H dark, solvent overlapped), 3.09 (t, J = 6Hz, 2H), 2, 65-2.59 (m, 4H), 2.06-2.05 (m, 2H), 1.82-1.79 (m, 2H).

Example 127: 3-endo- (8- {2 - [(2,6-difluorobenzyl) - (1-hydroxycyclopropancarbonyl) -amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide salt of TFA (m / z): [M + H] + calculated for C27H31F2N3O3: 484.23; found, 484.4. Example 128: 3-endo- (8- {2 - [(2-tert-butoxyacetyl) - (2,6-difluorobenzyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide salt of TFA (m / z): [M + H] + calculated for C29H37F2N3O3: 514.28; Found: 514.4. Example 129: 3-endo- (8- {2 - [(2,6-difluorobenzyl) - (trans-4-hydroxy-cyclohexanecarbonyl) amino] ethyl} -8-azabicyclo [3.2.1] oct3-yl) benzamide salt of TFA (m / z): [M + H] + calculated for C30H37F2N3O3: 526.28; Found: 526.4.

Example 130: Synthesis of 3-endo- (8- {3- [cyclohexylmetiI (2-hydroxyacetyl) amino] propiI} -8-azabicyclo [3.2.1] oct-3yl) benzamide

to. Preparation of 3-endo- [8- (3-hydroxypropyl) -8-azabicyclo [3.2.1] oct-3-yl] -benzamide

A mixture of 3- (8-azabicyclo [3.2.1] oct-3-yl) benzamide (326.7 mg, 1.42 mmol) and 3-bromo-1-propane (217.1 mg, 1.56 mmol ) in EtOH (1.0 ml) was heated at 70 ° C for one hour. After concentrating, the residue was coevaporated three times with DCM and dried under vacuum to give the title compound as a yellowish foam. (m / z): [M + H] + calculated for C17H24N2O2: 289.2; Found: 289.0.

b. Preparation of 3-endo- [3- (3-carbamoyl-phenyl) -8-azabicyclo [3.2.1] oct-8-yl] propyl methanesulfonate

The product from the previous step was dissolved in DCM (7.0 ml). DIPEA (367 mg, 2.84 mmol) was added to the resulting solution, followed by methanesulfonyl chloride (275.2 mg, 2.41 mmol) and DMAP (24.2 mg, 0.20 mmol). The reaction was stirred at room temperature for 3 hours and then stored at 4 ° C overnight. The reaction mixture was concentrated and the oily residue dried under vacuum to give an orange oil that was used directly in the next step.

C. 3-endo- {8- [3- (cyclohexylmethylamino) propyl] -8-azabicyclo [3.2.1] oct-3-yl} -benzamide

Half of the crude product from the previous stage was dissolved in DMF (0.8 ml) and treated with DIPEA (183.2 mg, 1.42 mmol) and cyclohexylmethylamine (200.6 mg, 1.77 mmol) at 75 ° C for 1 h. After concentrating, the residue was dissolved in 50% acetic acid in water (8.0 ml), filtered and purified by preparative reverse phase HPLC to give the title compound as its bis TFA salt (103 , 9 mg). (m / z): [M + H] + calculated for C24H37N3O: 384.3; Found: 384.4.

d. Synthesis of 3-endo- (8- (3- {cyclohexylmethyl- (2-hydroxyacetyl) amino] propyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide

To a solution of the product from the previous step (100.0 mg, 0.164 mmol) in DCM (0.6 ml) was added DIPEA (84.4 mg, 0.65 mmol), followed by acetoxyacetyl chloride (24, 5 mg, 0.18 mmol). After five minutes the reaction was concentrated. The residue was dissolved in methanol (0.6 ml) and treated with lithium hydroxide monohydrate (41.32 mg, 0.984 mmol) in water (0.6 ml) for thirty minutes. The reaction mixture was concentrated and the resulting residue was dissolved in a mixture of 50% acetic acid in water (6.0 ml) and water (2.0 ml), filtered and purified by preparative reverse phase HPLC to give the title compound in the form of its TFA salt (22.1 mg). (m / z): [M + H] + calculated for C26H39N3O3: 442.30; Found: 442.6. 1 H NMR (CD3OD, 400 MHz) δ (ppm): 8.08 (s, 1H), 7.76-7.80 (m, 2H), 7.48-7.55 (m, 6H), 4 , 28 (s, 2H), 4.08 (brs, 2H), 3.36-3.38 (dark 1H, partially overlapped with solvent), 3.20 (t, J = 7.2 Hz, 2H), 3.12 (t, J = 8.4 Hz, 2H), 2.62-2.78 (m, 4H), 2.21-2.29 (m, 2H), 2.09-2.12 ( m, 2H), 1.78-1.84 (m, 2H).

Example 131: Synthesis of 3-endo- {8- [3- (acetylcyclohexylmethylamino) -propyl] -8-azabicyclo [3.2.1] oct-3-yl} benzamide

To a solution of bis TFA salt of 3-endo- {8- [3- (cyclohexylmethylamino) -propyl] -8-azabicycIo [3.2.1] oct-3-yl} benzamide (30.0 mg, 0.05 mmol ) in DCM (0.2 ml) DIPEA (25.8 mg, 0.20 mmol) was added, followed by acetic anhydride (7.65 mg, 0.075 mmol). Thirty minutes later the reaction was concentrated. The residue was dissolved in ethanol (0.4 ml) and treated with lithium hydroxide monohydrate (12.6 mg, 0.30 mmol) in water (0.4 ml) for thirty minutes. The reaction mixture was concentrated and the resulting residue was dissolved in 50% acetic acid in water (1.5 ml), filtered and purified by preparative reverse phase HPLC to obtain the title compound as its TFA salt. (26.7 mg). (m / z): [M + H] + calculated for C26H39N3O2: 426.30; Found: 426.2.

Example 132: Synthesis of 3-endo- (8- [3- [cyclohexylmethyl- (2-methanesulfonylacetyl) amino] propyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide

To a solution of methanesulfonylacetic acid (20.7 mg, 0.15 mmol) in DMF (0.2 ml) was added N, N-carbonyldiimidazole (24.3 mg, 0.15 mmol) at room temperature. Thirty minutes later, DIPEA (25.8 mg, 0.20 mmol) and 3-endo- {8- [3- (cyclohexylmethylamino) -propyl] -8-azabicic [3.2.1] oct-3-yl were added to the stirred mixture } -benzamide bis TFA (30.0mg, 0.05 mmol). The resulting reaction mixture was heated at 65 ° C for 3 hours, concentrated, dissolved in 50% acetic acid in water (1.5 ml), filtered and purified by preparative reverse phase HPLC to give the title compound in form of its TFA salt (16.0 mg). (m / z): [M + H] + calculated for C27H41N3O4S: 504.28; Found: 504.2.

Example 133: Synthesis of 3-endo- (8- {3- [benzyl- (2-hydroxyacetyl) amino] -propyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide

Using the procedure of Example 130, 3-endo- [8- (3-benzylaminopropyl) -8azabicyclo [3.2.1] oct-3-yl] -benzamide (100 mg, 0.165 mmol) bis TFA salt was reacted with chloride of acetoxyacetyl (24.5 mg, 0.18 mmol) to obtain the TFA salt of the title compound (22.6 mg). 1 H-NMR (CD3OD, 400 MHz) δ (ppm): 8.08 (s, 1H), 7.777.81 (m, 2H), 7.51 (t, J = 7.6, 8.0 Hz, 1H ), 7.31-7.46 (m, 5H). (m / z): [M + H] + calculated for C26H33N3O3: 436.25; Found: 436.4.

Example 134: Synthesis of 3-endo- (8- {3- [benzyl - ((S) -2-hydroxypropionyl) -amino] propyl} -8-azabicyclo [3.2.1] oct-3yl) -benzamide

to. Preparation of tert-butyl benzyl- (3-hydroxypropyl) -carbamate

To a mixture of 3-benzylamino-1-propanol HCl salt (2.0 g, 9.9 mmol) in DCM (49.0 ml) at 0 ° C was added DIPEA (1.72 ml, 9.9 mmol) ), followed by a solution of di-tert-butyl dicarbonate (1.94 g, 8.91 mmol) in DCM (20.0 ml). After stirring 3 hours at 0 ° C, the reaction mixture was washed successively with 1N HCl (2 x 10.0 ml), saturated sodium bicarbonate (10.0 ml) and brine (10.0 ml), dried over sodium sulfate, filtered and concentrated to give a yellowish oil (2.22 g). 1 H NMR (CD3OD, 300 MHz) δ (ppm): 7.20-7.39 (m, 5H), 4.40 (s, 2H), 3.55 (brs, 2H), 3.38 (brs , 2H), 1.61 (brs, 2H), 1.44 (s, 9H).

b. Preparation of tert-butyl benzyl-3-oxo-propylcarbamate

To the solution of the product from the previous step (2.22 g, 7.38 mmol) in DCM (37.0 ml) at 0 ° C was added DIPEA (2.38 g, 18.45 mmol), followed by DMSO ( 0.86 g, 11.07 mmol) and sulfur trioxide pyridine complex (2.93 g, 18.45 mmol). After stirring for 30 minutes at 0 ° C the reaction mixture was diluted with DCM (20.0 ml) and washed successively with 1N HCl (10.0 ml), saturated sodium bicarbonate (10.0 ml) and brine (10.0 ml ), dried over sodium sulfate, filtered and concentrated to give a yellowish oil that was still purified by normal phase chromatography to give the title compound as a colorless oil (1.54 g). 1 H NMR (CDCl3, 300 MHz) δ (ppm): 9.73 (s, 1H), 7.24-7.36 (m, 5H), 4.45 (s, 2H), 3.51 (brs , 2H), 2.65 (brs, 2H), 1.46 (s, 9H).

C. Preparation of 3-endo- [8- (3-benzylamino-propyl) -8-azabicyclo [3.2.1] oct-3-yl) -benzamide

To a solution of the product from the previous step (972.6 mg, 3.25 mmol) in DCM (16.0 ml) at room temperature was added 3- (8-azabicyclo [3.2.1] oct-3-yl ) -benzamide (747.5 mg, 3.25 mmol), followed by sodium triacetoxyborohydride (826.6 mg, 3.9 mmol). The resulting mixture was stirred at room temperature for 30 minutes before diluting it with DCM (40.0 ml). The organic layer was washed with saturated sodium bicarbonate (20.0 ml) followed by brine (20.0 ml), dried over sodium sulfate, filtered and concentrated to give a yellowish oil. The oily residue was treated with a mixture of TFA (5.0 ml) and DCM (5.0 ml) at room temperature for 30 min. It was then concentrated and the resulting residue was dissolved in a mixture of water (4.0 ml) and acetonitrile (3.0 ml), filtered and purified by preparative reverse phase HPLC to give the title compound as its bis TFA salt (1.22 g). 1 H NMR (CD3OD, 400 MHz) δ (ppm): 8.06 (s, 1H), 7.74-7.78 (m, 2H), 7.46-7.53 (m, 6H), 4 , 27 (6, 2 H), 4.08 (br s, 2H), 3.35-3.38 (1H dark, partially overlapped with solvent), 3.20 (t, J = 8.0 Hz, 2H ), 3.12 (t, J = 8.4 Hz, 2H), 2.62-2.78 (m, 4H), 2.21-2.29 (m, 2H), 2.09-2, 12 (m, 2H), 1.79-1.84 (m, 2H). (m / z): [M + H] + calculated for C24H31N3O: 378.25; Found: 378.4.

d. Synthesis of 3-endo- (8- {3- [benzyl - ((S) -2-hydroxy-propionyl) amino] propyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide

DIPEA (32.4 mg, 0.24 mmol) was added to a solution of the product from the previous step (30.0 mg, 0.06 mmol) in DCM (0.5 ml), followed by acetoxyacetyl chloride ( 9.8 mg, 0.072 mmol) at room temperature. The reaction was completed instantly. After concentrating, the resulting residue was dissolved in methanol (0.5 ml) and treated with lithium hydroxide monohydrate (15.1 mg, 0.36 mmol) overnight. The reaction was concentrated and the residue was dissolved in 50% acetic acid in water (1.5 ml), filtered and purified by preparative reverse phase HPLC to give the title compound as its TFA salt (23 , 4 mg). (m / z): [M + H] + calculated for C27H35N3O3: 450.27; Found: 450.4.

Examples 135-199

Using processes described in the previous examples, the following additional compounds were prepared by reacting the corresponding intermediate of formula (II) with a suitable acid, carboxylic acid or carboxylate chloride reactant, as indicated in Scheme A (i), followed in specific cases of a Nalkylation stage. The intermediates of formula (II) were prepared by reacting an aldehyde of formula (IV) with an azabicyclooctylbenzamide, according to the process of example 134 (c), as indicated in Scheme B. The aldehydes of formula (IV) they were prepared by the general process described in scheme F, as described, for example, in example 134 (a) and (b). Example 135: 3-endo- (8- {2 - [((S) -2,3-dihydroxypropionyl) phenethylamino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide salt of

TFA (m / z): [M + H] + calculated for C27H35N3O4: 466.27; Found: 466.4. Example 136: 3-endo- (8- {2 - [(2-methanesulfonylacetyl) phenethylamino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide TFA salt

(m / z): [M + H] + calculated for C27H35N3O4S: 498.23; Found: 498.4. Example 137: (benzyl- {2- [3-endo- (3-hydroxyphenyl) -8-azabicyclo [3,2,1] oct-8-yl] -ethyl} carbamoyl) methyl acetate

TFA (m / z): [M + H] + calculated for C26H32N2O4: 437.24; Found: 437.4. Example 138: 3-endo- (8- {2- [benzyl - ((S) -2,3-dihydroxypropionyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide Get ouf of

TFA NMR-H1 (CD3OD, 400 MHz) δ (ppm): 8.05 (s, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8, 0 Hz,

1H), 7.37-7.52 (m, 6H), 4.90-4.95 (m, 1H), 4.77-4.83 (m, 1H), 4.72 (t, J = 5.2 Hz, 1H), 4.10 (brs, 2H), 3.85-3.91 (m, 3H), 3.63-3.69 (m, 1H), 3.31-3.34 (1H dark, partially overlapped with solvent), 3.09-3.12 (m, 2H), 2.64 (brs, 4H), 2.04-2.07 (m, 2H), 1.80-1 , 83 (m, 2H); (m / z): [M + H] + calculated for C26H33N3O4: 452.25; Found: 452.2.

Example 139: 3-endo- (8- {3- [benzyl - ((S) -2,3-dihydroxypropionyl) amino] propyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide TFA salt (m / z): [M + H] + calculated for C27H35N3O4: 466.26; Found: 466.4. Example 140: 3-endo- (8- {3- [benzyl - ((R) -2,3-dihydroxypropionyl) amino] propyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide TFA salt (m / z): [M + H] + calculated for C27H35N3O4: 466.26; Found: 466.4. Example 141: 3-endo- (8- {3- [benzyl- (2,3-dihydroxybutyryl) amino] propyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide TFA salt ( m / z): [M + H] + calculated for C28H37N3O4: 480.28; Found: 480.4. (continuation)

Example 142: 3-endo- (8- {3- [benzyl- (2-methanesulfonylacetyl) amino] propyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide TFA salt NMR-H1 (CD3OD, 400 MHz) δ (ppm): 8.04 (s, 1H), 7.72-7.77 (m, 2H), 7.48 (t, J = 7.6 Hz, 1H), 7 , 31-7.37 (m, 5H), 4.79 (s, 2H), 4.49 (s, 2H), 3.99 & 3.92 (two series of brs, 2H), 3.6 ( t, J = 6.4 Hz, 2H), 3.34-3.38 (m, 1H), 3.22 (s, 3H), 2.98 (t, J = 8.0 Hz, 2H), 2.53-2.72 (m, 4H), 1.96-2.11 (m, 4H), 1.74-1.80 (m, 2H), (m / z): [M + H] + calculated for C27H35N3O4S: 498.23; Found: 498.2.

Example 143: 3-endo- (8- {3- [benzyl- (2-hydroxy-2-methylpropionyl) amino] -propyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide salt of TFA (m / z): [M + H] + calculated for C28H37N3O3: 464.28; Found: 464.4.

Example 144: 3-endo- (8- {3- [benzyl- (2,2-dimethylpropionyl) amino] propyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide TFA salt ( m / z): [M + H] + calculated for C29H39N3O2: 462.30; found 462.4.

Example 145: 3-endo- (8- {2 - [(4,4-difluoro-cyclohexylmethyl) - (3-hydroxy-2-hydroxymethyl-2-methylpropionyl) amino] ethyl} -8-azabicyclo [3,2, 1] oct-3-yl) -benzamide TFA salt (m / z): [M + H] + calculated for C28H41F2N3O4: 522.31; Found: 522.2.

Example 146: 3-endo- (8- {2 - [(4,4-difluorocyclohexylmethyl) - ((S) -2,3-dihydroxy-propionyl) amino] ethyl} -8-azabicyclo [3,2,1] oct3-yl) -benzamide TFA salt (m / z): [M + H] + calculated for C26H37F2N3O4: 494.28; Found: 494.4.

Example 147: 3-endo- (8- {2 - [(4,4-difluorocyclohexylmethyl) - ((R) -2,3-dihydroxy-propionyl) amino] ethyl} -8-azabicyclo [3,2,1] oct3-yl) -benzamide TFA salt (m / z): [M + H] + calculated for C26H37F2N3O4: 494.28; Found: 494.4.

Example 148: 3-endo- (8- {2 - [(4,4-difluorocyclohexylmethyl) - (2-methanesulfonylacetyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) benzamide salt TFA NMR-H1 (CD3OD, 400 MHz) δ (ppm): 8.06 (s, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 8 , 8 Hz, 1H), 7.51 (dd, J = 7.6, 8.0 Hz, 1H), 4.51 (s, 2H), 4.18 (deformed m, 2H), 3.89 ( t, J = 6.0 Hz, 2H), 3.48 (d, J = 7.2 Hz, 2H), 3.28 (s, 3H), 3.24 (t, J = 6.0 Hz, 2H), 2.65-2.68 (m, 4H), 2.102.19 (m, 4H), 1.75-1.90 (m, 7H), 1.36-1.45 (m, 2H) , (m / z): [M + H] + calculated for C26H37F2N3O4S: 526.25; Found: 526.4.

Example 149: 3-endo- (8- {2 - [(4,4-difluorocyclohexylmethyl) - ((S) -4-dimethylamino-2-hydroxybutyryl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide bis TFA salt (m / z): [M + H] + calculated for C29H44F2N4O3: 535.34; Found: 535.4.

Example 150: 3-endo- (8-2 - [(4,4-difluorocyclohexylmethyl) - ((S) -2-hydroxypropionyl) -amino] ethyl-8-azabicyclo [3,2,1] oct-3-yl ) benzamide TFA NMR-H1 salt (CD3OD, 400 MHz) δ (ppm): 8.05 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.49 (dd, J = 7.6 Hz, 1H), 4.64 (q, J = 6.0 Hz, 1H), 4.10-4.14 ( m, 2H), 3,723.86 (m, 1H), 3.32-3.46 (dark m, 3H, partially overlapped with solvent), 3.18 (t, J = 5.6 Hz, 2H), 2 , 64-2.67 (m, 4H), 2.11-2.16 (m, 4H), 1.78-1.88 (m, 7H), 1.37-1.43 (m, 5H) ; (m / z): [M + H] + calculated for C26H37F2N3O3: 478.28; Found: 478.4.

Example 151: 3-endo- (8- {2 - [(4-fluorocyclohexylmethyl) - ((S) -2,3-dihydroxy-propionyl) amino] ethyl} -8-azabicyclo [3,2,1] oct- 3-yl) benzamide TFA salt (m / z): [M + H] + calculated for C26H38FN3O4: 476.28; Found: 476.4.

Example 152: 3-endo- (8- {2 - [(4-fluorocyclohexylmethyl) - (2-hydroxyacetyl) amino] -ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide salt TFA (m / z): [M + H] + calculated for C25H36FN3O3: 446.27; Found: 446.4.

Example 153: 3-endo- (8- {2- [cyclopentylmethyl- (3-hydroxy-2-hydroxymethyl-2-methyl-propionyl) amino] ethyl} -8azabicyclo [3,2,1] oct-3-yl) -benzamide TFA salt (m / z): [M + H] + calculated for C27H41N3O4: 472.31; Found: 472.4.

Example 154: 3-endo- (8- {2- [cyclopentihnetyl - ((S) -2,3-dihydroxypropionyl) -amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) benzamide TFA salt (m / z): [M + H] + calculated for C25H37N3O4: 444.28; Found: 444.4.

Example 155: 3-endo- (8- {2- [cyclopentylmethyl - ((R) -2,3-dihydroxypropionyl) -amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) benzamide TFA salt (m / z): [M + H] + calculated for C25H37N3O4: 444.28; Found: 444.4.

Example 156: 3-endo- (8- {2- [cyclopentylmethyl- (2-methanesulfonylacetyl) -amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide from TFA (m / z): [M + H] + calculated for C25H37N3O4S: 476.25; Found: 476.2.

Example 157: 3-endo- (8- {2- [cyclopentylmethyl- (2-hydroxyacetyl) amino] -ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide (m / z) : [M + H] + calculated for C24H35N3O3: 414.27; Found: 414.4.

Example 158: 3-endo- (8- {2- [cyclobutylmethyl- (3-hydroxy-2-hydroxymethyl-2-methyl-propionyl) -amino] ethyl} -8-azabicyclo [3,2,1] oct-3 -yl) -benzamide TFA salt (m / z): [M + H] + calculated for C26H39N3O4: 458.29; Found: 458.4.

Example 159: 3-endo- (8- {2- [cyclobutylmethyl - ((S) -2,3-dihydroxypropionyl) -amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) benzamide TFA salt (m / z): [M + H] + calculated for C24H35N3O4: 430.26; found. 430.4.

Example 160: 3-endo- (8- {2- [cyclobutylmethyl - ((R) -2,3-dihydroxypropionyl) -amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) benzamide TFA salt (m / z): [M + H] + calculated for C24H35N3O4: 430.26; Found: 430.4.

Example 161: 3-endo- (8- {2- [cyclobutylmethyl- (2-methanesulfonylacetyl) -amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide from TFA (m / z): [M + H] + calculated for C24H35N3O4S: 462.23; Found: 462.2.

Example 162: 3-endo- (8- {2- (cyclobutylmethyl- (2-methanesulfonyl-2-methyl-propionyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) benzamide salt of TFA (m / z): [M + H] + calculated for C26H39N3O4S: 490.27; found: 490.2.

Example 163: 3-endo- (8- {2- [cyclobutylmethyl- (2-hydroxyacetyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide TFA salt (m / z): [M + H] + calculated for C23H33N3O3: 400.25; Found: 400.4.

Example 164: 3-endo- (8- {2- [cyclobutylmethyl - ((S) -2-hydroxypropionyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide salt of TFA (m / z): [M + H] + calculated for C24H35N3O3: 414.27; Found: 414.4.

Example 165: 3-endo- (8- {2- [benzyl- (2-methanesulfonylacetyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide TFA salt (m / z): [M + H] + calculated for C26H33N3O4S: 484.22; Found: 484.2; 1 H NMR (CD3OD, 400 MHz) δ (ppm): 8.01 (s, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.49-7.35 (m, 6H), 4.80 (s, 2H), 4.57 (s, 2H) 4.07 (br s, 2H), 3.80 (t , J = 6.0 Hz, 2H), 3.4-3.3 (dark, 1H, solvent overlap), 3.25 (s, 3H), 3.08 (t, J = 6 Hz, 2H) , 2.61-2.60 (m, 4H), 2.03-2.00 (m, 2H), 1.82-1.79 (m, 2H).

(continued) Example 166: 3-endo- (8- {2- [benzyl- (2-hydroxy-2-methylpropionyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) - benzamide TFA salt (m / z): [M + H] + calculated for C27H35N3O3: 450.27; Found: 450.2.

Example 167: 3-endo- (8- {2- [benzyl - ((S) -2-hydroxy-1-oxopropyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide TFA salt (m / z): [M + H] + calculated for C26H33N3O3: 436.25; Found: 436.5; 1 H NMR (CD3OD, 400 MHz) δ (ppm): 8.02 (s, 1H), 7.77-7.70 (m, 2H), 7.50-7.32 (m, 6H), 4 , 83-4.71 (m, 2H), 4.07-4.01 (m, 2H), 3.81 (m, 1H), 3.64 (m, 1H), 3.03 (t, J = 6.0 Hz, 2H), 2.63-2.60 (m, 4H), 2.03-1.94 (m, 2H), 1.80-1.77 (m, 2H), 1, 40 (d, J = 6.4 Hz, 3H).

Example 168: 3-endo- (8- {2- [benzyl- (2,2-dimethylpropionyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide TFA salt ( m / z): [M + H] + calculated for C28H37N3O2: 448.29; Found: 448.

Example 169: 3-endo- {8- [2- (benzyl-methanesulfonylamino) ethyl] -8-azabicyclo [3,2,1] oct-3-yl} -benzamide TFA salt (m / z): [M + H] + calculated for C24H31N3O3S: 442.21; Found: 442.2.

Example 170: 3-endo- (8- {2- [benzyl- (2-methoxyacetyl) -amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide TFA salt (m / z): [M + H] + calculated for C26H33N3O3: 436.25; Found: 436.5.

Example 171: 3-endo- (8- {2- [benzyl- (3-hydroxy-2,2-dimethylpropionyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide TFA salt (m / z): [M + H] + calculated for C28H37N3O3: 464.28; Found: 464.2.

Example 172: 3-endo- (8- {2- [benzyl- (1-hydroxy-cyclopropancarbonyl) amino] ethyl} -8-aza-biciao [3,2,1] oct-3-yl) -benzamide from TFA (m / z): [M + H] + calculated for C27H33N3O3: 448.25; Found: 448.3.

Example 173: 3-endo- (8- {2- [benzyl- (2-cyanoacetyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide TFA salt (m / z): [M + H] + calculated for C26H30N4O2: 431.24; Found: 431.5.

Example 174: 3-endo- (8- {2- [benzyl - ((R) -3-hydroxy-2- (S) -hydroxybutyryl) amino] -ethyl} -8-azabicyclo [3,2,1] oct -3-yl) -benzamide from TFA (m / z): [M + H] + calculated for C27H35N3O4: 466.26; Found: 466.4.

Example 175: 3-endo- (8- {2- [benzyl - ((R) -2,3-dihydroxypropionyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide TFA salt (m / z): [M + H] + calculated for C26H33N3O4: 452.25; Found: 452.2.

Example 176: 3-endo- (8- {2- [cyclopentylmethyl- (3-hydroxypropionyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide TFA salt (m / z): [M + H] + calculated for C25H37N3O3: 428.28; Found: 428.4.

Example 177: 3-endo- (8- {2- [cyclopentylmethyl- (3-hydroxy-2,2-dimethylpropionyl) -amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) benzamide TFA salt (m / z): [M + H] + calculated for C27H41N3O3: 456.31; Found: 456.5.

Example 178: 3-endo- (8- {2- [cyclopentylmethyl- (trans-4-hydroxycyclohexanecarbonyl) -amino] ethyl} -8-azabicyclo [3,2,1] oct-3yl) -benzamide TFA salt (m / z): [M + H] + calculated for C29H43N3O3: 482.33; Found: 482.5.

Example 179: 3-endo- (8- {2- [cyclopentylmethyl- (2,2-dimethylpropionyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide TFA salt ( m / z): [M + H] + calculated for C27H41N3O: 440.32; Found: 440.4.

Example 180: 3-endo- {8- [2- (cyclopentihmethyl-methanesulfonylamino) ethyl] -8-azabicyclo [3,2,1] oct-3-yl} -benzamide TFA salt (m / z): [M + H] + calculated for C23H35N3O3S: 434.24; Found: 434.2.

Example 181: 3-endo- (8- {2 - [(2-hydroxyacetyl) - (4-trifluoromethylbenzyl) -amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide salde TFA (m / z): [M + H] + calculated for C26H30F3N3O3: 490.22; Found: 490.4.

Example 182: 3-endo- (8- (2 - ((4-bifluoromethylbenzyl) (N, N-dimethylsulfamoyl) amino-ethyl) -8-azabicyclo [3,2,1] oct-3-yl) benzamide salt of TFA (m / z): [M + H] + calculated for C26H33F3N4O3S: 539.22; found: 539.5.

Example 183: 3-endo- (8- {2 - [(2-methanesulfonylacetyl) - (4-trifluoromethyl-benzyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) benzamide salt of TFA (m / z): [M + H] + calculated for C27H32F3N3O4S: 552.21; Found: 552.4. NMR1 (CD3OD, 400 MHz) δ (ppm): 8.02 (s, 1H), 7.77-7.70 (m, 4H), 7.56-7.54 (m, 3H), 4.94 (s, 2H), 4.56 (s, 2H), 4.12 (br s, 2H), 3.80 (t, J = 5.6 Hz, 2H), 3.4-3.3 (dark , 1H, solvent overlapped), 3.26 (s, 3H), 3.17 (t, J = 5.6 Hz, 2H), 2.63-2.61 (m, 4H), 2.10- 2.06 (m, 2H), 1.84-1.81 (m, 2H).

Example 184: 3-endo- (8- {2 - [(4-fluorobenzyl) - (2-methanesulfonylacetyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide from TFA (m / z): [M + H] + calculated for C26H32FN3O4S: 502.21; Found: 502.4. 1 H NMR (CD3OD, 400 MHz) δ (ppm): 8.01 (s, 1H), 7.77-7.68 (m, 2H), 7.46 (t, J = 8.0 Hz, 1H ), 7.40-7.36 (m, 2H), 7.15 (t, J = 8.8 Hz, 2H), 4.79 (s, 2H) 4.10 (br s, 2H), 3 , 78 (t, J = 6.0 Hz, 2H), 3.4-3.3 (dark, 1H, solvent overlap), 3.25 (s, 3H), 3.11 (t, J = 5 , 6 Hz, 2H), 2.61-2.60 (m, 4H), 2.06-2.03 (m, 2H), 1.80-1.78 (m, 2H).

Example 185: 3-endo- (8- {2 - [(4-fluorobenzyl) - (2-hydroxyacetyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide salt of TFA ((m / z): [M + H] + calculated for C25H30FN3O3: 440.23; found: 440.4.

Example 186: 3-endo-8- (2 - ((4-fluoromethylbenzyl) (N, N-dimethylsulfamoyl) -amino) ethyl) -8-azabicyclo [3,2,1] oct-3-yl) benzamide salt of TFA (m / z): [M + H] + calculated for C25H33FN4O3S: 489.23; Found: 489.5.

Example 187: 3-endo- (8- {2 - [[2- (3-fluorophenyl) ethyl] - (2-hydroxyacetyl) amino] -ethyl} -8-azabicyclo [3,2,1] oct-3- il) -benzamide TFA salt (m / z): [M + H] + calculated for C26H32FN3O3: 454.24; Found: 454.2.

Example 188: 3-endo- (8- {2 - [[2- (4-fluorophenyl) ethyl] - (2-hydroxyacetyl) amino] -ethyl} -8-azabicyclo [3,2,1] oct-3- il) -benzamide from TFA (m / z): [M + H] + calculated for C26H32FN3O3: 454.24; Found: 454.4; 1 H NMR (CD3OD, 400 MHz) δ (ppm): 8.03 (s, 1H), 7.77-7.71 (m, 2H), 7.47 (t, J = 8.0 Hz, 1H ), 7.30-7.26 (m, 2H), 7.087.04 (m, 2H), 4.13 (br s, 2H) 4.08 (s, 2H), 3.78 (t, J = 5.2 Hz, 2H), 3.52 (t, J = 7.2 Hz, 2H), 3.4-3.3 (dark, 1H, solvent overlapped), 3.17 (t, J = 5 , 6 Hz, 2H), 2.91 (t, J = 7.6 Hz, 2H), 2.65-2.61 (m, 4H), 2.14-2.11 (m, 2H), 1 , 85-1.82 (m, 2H).

Example 189: 3-endo- (8- {2 - [[2- (4-fluorophenyl) ethyl] - (2-methanesulfonyl-acetyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3 -il) benzamide TFA salt (m / z): [M + H] + calculated for C27H34F2N3O4S: 516.23; Found: 516.4; 1 H NMR (CD3OD, 400 MHz) δ (ppm): 8.01 (s, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H) 7.49-7.45 (m, 1H), 7.32 (m, 2H), 7.08 (m, 2H), 4.21 (s, 2H), 4.11 (br s , 2H), 3.79-3.73 (m, 2H), 3.4-3.3 (dark, 1H, solvent overlap), 3.19 (s, 3H), 3.16 (t, J = 5.6 Hz, 2H), 2.97 (t, J = 7.2 Hz, 2H), 2.63-2.60 (m, 4H), 2.12-2.09 (m, 2H) , 1.83-1.80 (m, 2H).

Example 190: 3-endo- [8- (2 - {(2-hydroxyacetyl) - [2- (4-hydroxyphenyl) ethyl] -amino} ethyl) -8-azabicyclo [3,2,1] oct-3- il] -benzamide from TFA (m / z): [M + H] + calculated for C26H33N3O4: 452.25; Found: 452.2. Example 191: 3-endo- (8- {2 - [[2- (4-hydroxyphenyl) ethyl] - (2-methanesulfonyl-acetyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3 -il) benzamide TFA salt (m / z): [M + H] + calculated for C27H35N3O5S: 514.23; Found: 514.3.

Example 192: 3-endo- (8- {2 - [(3-fluorobenzyl) - (2-hydroxyacetyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide salt of TFA (m / z): [M + H] + calculated for C25H30FN3O3: 440.23; Found: 440.4; 1 H NMR (CD3OD, 400 MHz) δ (ppm): 8.03 (s, 1H), 7.77-7.71 (m, 2H), 7.49-7.43 (m, 2H), 7 , 13-7.06 (m, 3H), 4.62 (s, 2H), 4.37 (s, 2H) 4.12 (br s, 2H), 3.75 (t, J = 5.6 Hz, 2H), 3.4-3.3 (dark, 1H, solvent overlap), 3.12 (t, J = 5.6 Hz, 2H), 2.64-2.62 (m, 4H) , 2.09-2.06 (m, 2H), 1.84-1.81 (m, 2H).

Example 193: 3-endo- (8- {2 - [(3-fluorobenzyl) - (2-methanesulfonyl-acetyl) -amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) - benzamide from TFA (m / z): [M + H] + calculated for C26H32FN3O4S: 502.21; Found: 502.4; 1 H NMR (CD3OD, 400 MHz) δ (ppm): 8.02 (s, 1H), 7.77-7.70 (m, 2H), 7.49-7.45 (m, 2H), 7 , 19-7.11 (m, 3H), 4.8-4.9 (dark, 2H, solvent overlap), 4.56 (s, 2H) 4.10 (br s, 2H), 3.80 (t, J = 5.6 Hz, 2H), 3.4-3.3 (dark, 1H, solvent overlap), 3.25 (s, 3H), 3.13 (t, J = 6.0 Hz, 2H), 2.63-2.60 (m, 4H), 2,082.05 (m, 2H), 1.83-1.80 (m, 2H).

Example 194: 3-endo- (8- {2 - [(2,2-difluoro-2-phenylethyl) - ((S) -2,3-dihydroxy-propionyl) amino] ethyl} -8-azabicyclo [3, 2,1] oct-3-yl) benzamide TFA salt (m / z): [M + H] + calculated for C21H33F2N3O4: 502.24; Found: 502.4. Example 195: 3-endo- (8- {2 - [(2-methanesulfonylacetyl) - (4-methyl-cyclohexylmethyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) benzamide salt of TFA (m / z): [M + H] + calculated for C27H41N3O4S: 504.28; Found: 504.4. Example 196: 3-endo- (8- {2 - [((S) -2,3-dihydroxypropionyl) - (4-methyl-cyclohexyl-methyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) benzamide TFA salt (m / z): [M + H] + calculated for C27H41N3O4: 472.31; Found: 472.4. Example 197: 3-endo- (8- {2 - [(2-hydroxy-acetyl) (4-trifluoromethyl-cyclohexylmethyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl ) benzamide TFA salt (m / z): [M + H] + calculated for C26H36F3N3O3: 496.27; Found: 496.4. Example 198: 3-endo- (8- {2 - [(2-methanesulfonylacetyl) - (4-trifluoromethyl-cyclohexyl-methyl) amino] ethyl} -8-azabicyclo [3,2,1] oct3-yl) benzamide salt TFA (m / z): [M + H] + calculated for C27H38F3N3O4S: 558.25; Found: 558.4. Example 199: 3-endo-8- {2 - [((S) -2,3-dihydroxypropionyl) - (4-trifluoromethyl-cyclohexylmethyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3 -yl) -benzamide TFA salt (m / z): [M + H] + calculated for C27H35F3N3O4: 526.28; Found: 526.4.

Example 200: Synthesis of 3-endo- (8- {2- [cyclohexylmethyl - ((R) -2,3-dihydroxy-propionyl) -aminol-ethyl} -8-azabicyclo [3,2,1] oct-3 -il) -benzamide

to. Preparation of lithium (R) -2,2-dimethyl-1,3-dioxolan-4-carboxylate

To a solution of methyl (R) -2,2-dimethyl-1,3-dioxolan-4-carboxylate (5.0 g, 31.25 mmol) in MeOH (32.0 ml) at room temperature was added a solution of lithium hydroxide monohydrate (1.31 g, 31.25 mmol) in water (10.0 ml). The resulting mixture was stirred for thirty minutes before concentrating. The resulting white solid was just dried under vacuum to give the title compound (4.59 g).

b. Preparation of (R) -2,2-dimethyl-1,3-dioxolan-4-carboxy- (2- [3-endo- (3-carbamoyl-phenyl) -8-azabicyclo [3,2,1] oct- 8-yl] ethyl} cyclohexylmethyl-amide

3-endo- {8- [2- (cyclohexylmethylamino) -ethyl] -8-azabicyclo [3.2.1] oct-3-yl} -benzamide (600 mg, 1.6 mmol) was dissolved in DMF (5 ml) and (R) -2,2-dimethyl- [1,3] dioxolan-4-solid lithium carboxylate (270 mg, 1.78 mmol) was added. The solution was stirred at room temperature until the solid dissolved; then solid HATU (687 mg, 1.78 mmol) was added. The bright yellow solution was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (100 ml). The organic solution was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic solution was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to give the title compound (781 mg) as a crude yellow oil.

C. Synthesis of 3-endo- (8- {2-cyclohexylmethyl - ((R) -2,3-dihydroxypropionyl) amino] ethyl} -8-azabicyclo [3,2,1] oct-3-yl) -benzamide

The crude product from the previous step was dissolved in acetonitrile (10 ml) and HCl (aqueous) (10 ml) was added. The yellow solution was stirred at room temperature for 2 h; The reaction was then concentrated in vacuo. The crude material was dissolved in acetonitrile / water / TFA and purified by preparative HPLC to give the TFA salt of the title compound as a white powder (386 mg, 99.4% purity). (m / z): [M + H] + calculated for C26H39N3O4: 458.30; Found: 458.4.

Example 201: Synthesis of 3-endo-8- {2 - [(2-hydroxyacetyl) - (2,2,3,3-tetramethyl-cyclopropylmetiI) amino] ethyl} -8-azabicyclo [3.2.1] oct-3 -il) -benzamide

to. Preparation of (2,2,3,3-tetramethyl-cyclopropyl) methanol

To a stirred solution of 2,2,3,3-tetramethylcyclopentancarboxylic acid (500 mg, 3.5 mmol) in THF (25 ml) was added 2.0 M borane dimethyl sulphide complex in THF (1.8 ml, 3.5 mmol) at 0 ° C. The reaction mixture was heated and stirred at 50 ° C for 3 hours. The solution was cooled to room temperature and methanol (10 ml) was added carefully. The reaction mixture was concentrated and filtered. The filtrate was concentrated to give the intermediate of the title as an oil (250 mg, 56%). 1 H NMR (CDCl3, 300 MHz) δ (ppm): 4.16 (t, J = 4.8 Hz, 1H), 3.39 (dd, J = 4.5, 7.5 Hz, 2H), 1.03 (s, 6H), 0.93 (s, 6H), 0.38 (t, J = 7.5 Hz, 1H).

b. Preparation of 2,2.3.3-tetramethyl-cyclopropancarbaldehyde

To a stirred solution of the product from the previous step and DIPEA (680 µl, 4.0 mmol) in DCM (5 mL) was added a solution of sulfur trioxide-pyridine (620 mg, 3.9 mmol) in DMSO ( 5 ml) at -20 ° C. After 2 hours, the reaction was heated to room temperature, diluted with DCM (20 ml) and washed with 1.0 N HCl (25 ml) and water (25 ml). The organic matter was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography to give the intermediate of the title (45 mg, 18%).

C. Preparation of benzyl (2-hydroxyethyl) -carbamate

Benzyl chloroformate (4.6 ml, 33 mmol) was added at 0 ° C to a stirred solution of ethanolamine (4.0 g, 66 mmol) in DCM (4 ml). After 1 h the reaction mixture was heated to room temperature and washed with 1.0 N HCl (40 ml) and water (40 ml). The organic matter was separated, dried over anhydrous sodium sulfate, filtered and concentrated. To a solution of the crude product in ethyl acetate (30 ml) hexane (30 ml) was added. The resulting crystals were filtered and dried to give the intermediate of the title as a white solid (4.5 g, 70%). 1 H NMR (CDCl3, 300 MHz) δ (ppm): 07.04-07.29 (m, 5H), 5.00 (s, 2H), 4.64 (t, J = 5.5 Hz, 1H ), 3.38 (q, J = 6.0 Hz, 2H), 3.07 (t, J = 6.0 Hz, 2H).

d. Preparation of benzyl (2-oxo-ethyl) -carbamate

To a stirred solution of benzyl (2-hydroxyethyl) carbamate (1.0 g, 5.1 mmol) and DIPEA (1.78 ml, 10.2 mmol) in DCM (15 ml) was added a trioxide solution of sulfur-pyridine (1.63 g, 10.2 mmol) in DMSO (15 ml) at -20 ° C. After 1 h the reaction was heated to room temperature, diluted with dichloromethane (50 ml) and washed with 1.0 N HCl (50 ml) and brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel chromatography to give the intermediate of the title (810 mg, 82%). 1 H NMR (CDCl3, 300 MHz) δ (ppm): 9.5 (s, 1H) 7.4-7.2 (m, 5H), 5.1 (s, 2H), 3.9 (d, J = 5.8 Hz, 2H), 2.9-3.3 (br, 1H).

and. Preparation of {2- [3-endo- (3-carbamoylphenyl) -8-azabicyclo [3.2.1] oct-8-yl] ethyl} -benzyl carbamate

A suspension of 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -benzamide and benzyl (2-oxoethyl) carbamate (0.99 g, 6.2 mmol) in DCM (20 ml) He underwent ultrasound for 5 minutes. Sodium triacetoxyborohydride (1.3 g, 6.1 mmol) was added to the stirred suspension. After stirring for 30 minutes, the reaction mixture was concentrated. The crude reaction mixture was diluted with ethyl acetate (50 ml) and washed with 1.0 N NaOH (50 ml) and water (50 ml). The organic layer was separated, dried with anhydrous sodium sulfate, filtered, concentrated and purified by silica gel chromatography to give the intermediate of the title (1.4 g, 57%). (m / z): [M + H] + calculated for C24H29N3O3: 408.22; Found: 408.5.

F. Preparation of 3-endo- [8- (2-aminoethyl) -8-azabicyclo [3.2.1] oct-3-yl] -benzamide

A solution of the product from the previous step (1.4 g, 3.4 mmol) in methanol (20 ml) was added to palladium hydroxide on carbon (50% by weight of water, 20% of Pd on a dry basis, 140 mg) The reaction mixture was stirred under a hydrogen atmosphere overnight. The solution was filtered through celite and concentrated to give an oil (1.0 g) that was used directly in the next step. (m / z): [M + H] + calculated for C16H23N3O: 274.19; Found: 274.5.

g. Preparation of 3-endo-8- {2- [2,2,3,3-tetramethyl-cyclopropylmetiI) amino] ethyl} -8-aza-bicyclo [3.2.1] oct-3-yl) -benzamide

To a solution of the product of the previous stage (100 mg, 0.37 mmol) and of the product of stage b (45 mg, 0.37 mmol) in dichloromethane (2 ml) and methanol (0.2 ml) added sodium triacetoxyborohydride (93 mg, 0.44 mmol). After stirring for 1 h, the reaction mixture was concentrated. The crude reaction mixture was diluted with ethyl acetate (20 ml) and washed with 1.0 N NaOH (2Oml). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was used directly in the next stage. (m / z): [M + H] + calculated for C24H37N3O: 384.30, found: 384.3.

h. Synthesis of 3-endo-8- {2 - [(2-hydroxyacetyl) - (2,2,3,3-tetramethyl-cyclopropylmethyl) amino] ethyl} -8-aza-bicyclo [3.2.1] oct-3- il) benzamide

To a solution of the product from the previous step (0.366 mmol) in DCM (2 ml) was added acetoxyacetyl chloride (50 µl, 0.44 mmol). After 1 h, the reaction mixture was concentrated and the resulting crude oil was stirred in methanol (2.0 ml) and 6.0 N NaOH (35 µl) overnight. The reaction mixture was concentrated and purified by preparative HPLC to give the TFA salt of the title compound (30.9 mg). (m / z): [M + H] + calculated for C26H39N3O3: 442.30; Found: 442.4.

Examples 202 to 203

The intermediates for examples 202 and 203 were prepared as follows: A solution of ethyl 4-hydroxycyclohexanecarboxylate as a mixture of cis and trans isomers (8.7 g, 50.51 mmol) in THF (300 ml) at 0 ° C added imidazole (4.8 g, 70.72 mmol), DMAP (20% mol, 1.23 g, 10.10 mmol), and tert-butyldimethylchlorosilane (9.1 g, 60.61 mmol). The reaction mixture was heated to room temperature, stirred overnight and diluted with ethyl acetate and saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulfate. The solvent was removed and the crude oil was filtered through silica gel and solvent was removed to give ethyl 4- (tert-butyldimethylsilyloxy) cyclohexanecarboxylate (11.1 g, 77%) as a mixture of diastereoisomers. To a solution of the product of the previous step (11.1 g, 38.7 mmol) in MTBE (150 ml) and methanol (2.35 ml, 58.11 mmol) was added lithium borohydride (1.27 g , 58.11 mmol). The reaction mixture was heated at 50 ° C for 2 h, cooled to room temperature and stopped with methanol. The solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. The solvent was removed in vacuo to give crude [4- (tert-butyldimethylsilyloxy) cyclohexyl] methanol as a mixture of diastereoisomers. The crude product was purified by silica gel chromatography (10-40% ethyl acetate / hexanes) to separate cis and trans diastereoisomers. Upper spot (cis isomer) NMR-H1 (300 MHz CD3OD): 3.91-3.95 (m, 1H), 3,313.32 (d, 2H), 1.61-1.63 (m, 2H), 1.36-1.46 (m, 7H), 0.85-0.86 (s, 9H), 0.00 (s, 6H). Lower spot (trans isomer) NMR-H1 data (300 MHz CD3OD): 3.49-3.53 (m, 1H), 3.27-3.28 (d, 2H), 1.81-1.84 (m, 2H), 1.71-1.74 (m, 2H), 1.28-1.36 (m, 1H), 1.18-1.26 (m, 2H), 0.93-0 , 97 (m, 2H), 0.82-0.84 (s, 9H), 0.00 (s, 6H).

Example 202: Synthesis of 3-endo- (8- {2 - [(trans-4-hydroxycyclohexylmethyl) - ((S) -2,3-dihydroxypropionyl) amino] ethyl} 8-azabicyclo [3.2.1] oct-3 -il) -benzamide

to. Preparation of trans-4- (tert-butyldimethylsilyloxy) -cyclohexylmethyl 4-toluenesulfonate

To a solution of trans- [4-tert-butyldimethylsilyloxy) cyclohexyl] methanol (555 mg, 2.24 mmol) in DCM (20 ml) at 0 ° C was added DIPEA (0.59 ml, 3.37 mmol), DMAP (20% mol, 54 mg), and p-toluenesulfonyl chloride (570 mg, 2.68 mmol). The reaction mixture was stirred at room temperature for 2 h and DABCO (250 mg) was added. The reaction mixture was stirred overnight. The solution was diluted with DCM, washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. The solvent was removed in vacuo to give the intermediate of the title. 1 H NMR (300 MHz CD3OD): 7.75-7.77 (d, 2H), 7.40-7.42 (d, 2H), 3.80-3.81 (d, 1H), 3, 45-3.51 (m, 1H), 2.40 (s, 3H) 1.78-1.82 (m, 2H), 1.62-1.71 (m, 2H), 1.48-1 , 58 (m, 1H), 1.30-1.33 (m, 1H), 1.15-1.21 (m, 2H), 0.85-1.00 (m, 2H), 0.85 -0.90 (s, 9H), 0.00 (s, 6H).

b. Preparation of 2 - {[trans-4- (tert-butyldimethylsilyloxy) cyclohexylmethyl] amino} -ethanol

To a solution of trans-4- (tert-butyldimethylsilyloxy) -cyclohexylmethyl 4-toluenesulfonate (600 mg, 1.50 mmol) in acetonitrile (15 ml) ethanolamine (2.0 ml, 25 eq) was added. The solution was heated at 50 overnight. The reaction was diluted with DCM (200 ml), washed with saturated aqueous sodium bicarbonate and brine and dried over potassium carbonate. The solvent was removed to give the crude intermediate of the title (0.44 g) as a yellow oil. (m / z): [M + H] + calculated for C15H33NSi2: 288.3, found: 288.2.

C. Preparation of tert-butyl [trans-4- (tert-butyldimethylsilyloxy) cyclohexylmethyl] - (2-hydroxyethyl) -carbamate

To a solution of the product from the previous step (0.44 g, 1.50 mmol) in DCM (30 ml) was added di-tert-butyl dicarbonate (324 mg, 1.48 mmol). The reaction mixture was stirred at room temperature for 2 h, diluted with DCM (100 ml), washed with saturated aqueous sodium bicarbonate and brine and dried over potassium carbonate. The solvent was removed to give the intermediate of the title (0.496 g) as a yellow oil.

d. Preparation of tert-butyl [trans-4- (tert-butyldimethylsilyloxy) cyclohexylmethyl] - (2-oxoethyl) carbamate

To a solution of the product from the previous step (496 mg, 1.27 mmol) in DCM (20 ml) at -15 ° C was added DMSO (12.7 mmol, 0.905 ml) and DIPEA (1.103 ml, 6.35 mmol ). The reaction was stirred for 10 minutes and pyridine-sulfur trioxide complex (1.01 g, 6.35 mmol) was added. The reaction mixture was stirred for 1 h, heated to room temperature, diluted with DCM (50 ml), washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. The solvent was removed in vacuo to give the title intermediate (480 mg) as a yellow oil.

and. Preparation of [trans-4- (tert-butyldimethylsilyloxy) cyclohexylmethyl] - {2- [3-endo- (3-carbamoylfenyl) -8azabicyclo [3.2.1] oct-8-yl] -ethyl} tert-butyl carbamate

To a solution of the product from the previous step (480 mg, 1.24 mmol) in DCM (20 ml) was added 3-endo- (8azabicyclo [3.2.1] oct-3-yl) -benzamide (343 mg, 1.48 mmol). The reaction mixture was stirred for 30 minutes and then sodium triacetoxyborohydride (525 mg, 2.48 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature, diluted with DCM (100 ml), washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. The solvent was removed in vacuo to give the crude intermediate of the title (700 mg, 94%) as a crisp yellow solid. (m / z): [M + H] + calculated for C34H58N3SiO4: 600.4; Found: 600.6.

F. Preparation of 3-endo- (8- {2 - [(trans-4-hydroxycyclohexylmethyl) amino] -ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide

The product from the previous step (700 mg, 1.16 mmol) was dissolved in DCM (15 ml) and trifluoroacetic acid (7 ml) was added. The reaction mixture was stirred for 2 hours at room temperature and then diluted with DCM (100 ml) and 1 N NaOH (100 ml). The aqueous layer was extracted with dichloromethane (2 x 25 ml) and the combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed in vacuo to give the crude intermediate of the title (425 mg, 94% yield). (m / z): [M + H] + calculated for C23H30N3O2: 386.3; Found: 386.5.

g. Preparation of (S) -2,2-dimethyl- [1,3] dioxolan-4-carboxy- {2- [3-endo- (3-carbamoylphenyl) -8-azabicyclo [3.2.1] oct-8-yl ] ethyl} (trans-4-hydroxy-cyclohexylmethyl) amide

To a solution of the product from the previous step (425 mg, 1.10 mmol) in DMF (15 ml) was added (S) -2,2-dimethyl [1,3] dioxolan-4-carboxylate lithium (0 , 19 g, 1.21 mmol) and HATU (0.46 g, 1.21 mmol). The reaction mixture was stirred at room temperature overnight, diluted with DCM (100 ml), washed with water, with a 1: 1 mixture of water and saturated aqueous sodium bicarbonate and with brine; then dried over potassium carbonate. The solvent was removed in vacuo to give the crude intermediate of the title as a yellow oil. (m / z): [M + H] + calculated for C29H43N3O5: 514.3; Found: 514.5.

h. Synthesis of 3-endo- (8- {2 - [(trans-4-hydroxycyclohexylmethyl) - ((S) -2,3-dihydroxypropionyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl )-benzamide

The product from the previous step was dissolved in acetonitrile (15 ml) and HCl (15 ml) and the solution was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM (200 ml) and NaOH (150 ml). The aqueous layer was extracted with dichloromethane (2 x 50 ml) and the combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed in vacuo and the crude product was purified by preparative HPLC to give the TFA salt of the title compound (45 mg) as a white powder. (m / z): [M + H] + calculated for C26H39N2O5: 474.29; Found: 474.4. 1 H NMR (300 MHz CD3OD): 8.00-8.02 (s, 1H), 7.65-7.80 (m, 2H), 7.40-7.45 (t, 1H), 4, 59-4.62 (m, 1H), 3.95-4.20 (m, 3H), 3.65-3.79 (m, 2H), 3.40-3.60 (m, 2H), 3.10-3.20 (m, 2H), 2.05-2.19 (m, 2H), 1.95-2.00 (m, 2H), 1.40-1.85 (m, 4H ), 1.20-1.35 (m, 2H), 1.01-1.20 (m, 2H).

Example 203: Synthesis of 3-endo- (8- {2 - [(cis-4-hydroxycyclohexylmethyl) - ((S) -2,3-dihydroxypropionyl) amino] ethyl} -8azabicyclo [3.2.1] oct-3- il) -benzamide

Following the procedure of Example 202 and using the corresponding cis, cis- [4-tert-butyldimethylsilyloxy) cyclohexyl] methanol isomer in step a, the title compound was prepared. (m / z): [M + H] + calculated for C26H39N2O5: 474.29; Found: 474.4. 1 H NMR (300 MHz CD3OD): 8.00-8.02 (s, 1H), 7.65-7.80 (m, 2H), 7.407.50 (t, 1H), 4.60-4, 62 (m, 1H), 3.95-4.20 (m, 3H) 3.65-3.79 (m, 2H), 3.40-3.60 (m, 2H), 3.10-3 , 20 (m, 2H), 2.05-2.19 (m, 2H), 1.40-1.85 (m, 6H), 1.20-1.30 (m, 4H).

Example 204: Synthesis of 3-endo- (8- {2- [cyclohexylmethyl - ((S) -2,3-dihydroxypropionyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) - benzoic

to. Preparation of methyl 3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -benzoate

3-endo- (8-azabicyclo [3.2.1] oct-3-yl) -benzamide (2.5 g, 9.36 mmol) was weighed in a 200 ml flask and purged with nitrogen. Methanol (100 ml) was added followed by hydrochloric acid in dioxane (7 ml of 4.0 N solution, 28 mmol). The solution was heated to reflux and stirred overnight. The methanol was removed by evaporation and the reaction mixture was diluted with DCM (200 ml) and NaOH (150 ml). The aqueous layer was extracted with DCM (2 x 50 ml) and the combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed and the crude residue was purified by preparative HPLC. The pure fractions were pooled to obtain the intermediate of the title (1.66 g) as a white powder. (m / z): [M + H] + calculated for C15H20N2: 246; Found: 246.3.

b. Preparation 3-endo- {8- [2- (benzyloxycarbonyl-cyclohexylmethylamino) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} methyl benzoate To a solution of the product from the previous step (1.66 g , 4.61 mmol) in DCM (20 ml) and methanol (20 ml), benzyl cyclohexylmethyl- (2-oxoethyl) -carbamate (1.27 g, 4.61 mmol) was added. The reaction mixture was stirred for 20 minutes, then sodium triacetoxyborohydride (1.95 g, 9.22 mmol) was added. The reaction mixture was stirred for 2 h and then diluted with DCM (100 ml), washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. The solvent was removed in vacuo to give the title intermediate (2.65 g,> 100% yield) as a yellow crisp solid that was used directly in the next step.

C. Preparation of methyl 3-endo- {8- [2- (cyclohexylmethylamino) ethyl] -8-aza-bicyclo [3.2.1] oct-3-yl} benzoiao

To a solution of the product from the previous step (2.65 g) in ethanol (20 ml) and in aqueous HCl (10 ml) was added palladium on carbon (10% e.p., 270 mg). The reaction was purged with hydrogen gas and stirred under hydrogen atmosphere overnight. The catalyst was filtered off and the reaction was diluted with DCM (200 ml) and 1 N NaOH (150 ml). The aqueous layer was extracted with DCM (2 x 50 ml) and the combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed to give the intermediate of the title (2.0 g) as a waxy yellow oil. (m / z): [M + H] + calculated for C24H36N2O2: 385.3; Found: 385.5.

d. Preparation of 3-endo- (8- {2- [cyclohexylmethyl - ((S) -2,2-dimethyl- [1,3] dioxolan-4-carbonyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) methyl benzoate

To a solution of the product of the previous step (2.0 g, 5.2 mmol) in DMF (35 ml) was added (S) -2,2-dimethyl [1,3] dioxolan-4-carboxylate lithium (0.72 g, 5.7 mmol) and HATU (2.18 g, 5.7 mmol). The reaction mixture was stirred at room temperature overnight and then diluted with DCM (100 ml), washed with water, 1: 1 mixture of water / saturated aqueous sodium bicarbonate and brine; then dried over potassium carbonate. The solvent was removed in vacuo to give the crude intermediate of the title as a brown oil that was used directly in the next step.

and. Preparation of methyl 3-endo- (8- {2- [cyclohexylmethyl - ((S) -2,3-dihydroxypropionyl) amino] -ethyl} 8-azabicyclo [3.2.1] oct-3yl) benzoate

The product from the previous step was dissolved in acetonitrile (15 ml) and HCl (15 ml) and the solution was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM (200 ml) and NaOH (150 ml). The aqueous layer was extracted with DCM (2 x 50 ml) and the combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed in vacuo to give the intermediate of the title (2.2 g) as a yellow oil. (m / z): [M + H] + calculated for C27H40N2O5: 473.3; Found: 473.3.

F. Synthesis of 3-endo- (8- {2- [cyclohexylmethyl - ((S) -2,3-dihydroxypropionyl) amino] ethyl} -8-aza-bicyclo [3.2.1] oct-3-yl) benzoic acid

To a solution of the product from the previous step (2.2 g, 5.2 mmol) in THF (5 ml) was added a solution of lithium hydroxide (1.31 g, 31.2 mmol) in water (5 ml) . The solution was vigorously stirred at room temperature. After the ester hydrolysis was complete, THF was removed in vacuo and the residue was purified by preparative HPLC. The pure fractions were combined to give the title compound (0.32 g) as a white powder. (m / z): [M + H] + calculated for C26H38N2O5: 459.28; Found: 459.5.

Test 1: radioligand binding assay to Mu opioid receptors of humans, Delta of humans and Kappa of guinea pigs

to. Membrane Preparation

CHO-K1 (Chinese hamster ovary) cells stably transfected with human mu opioid receptor cDNA or guinea pig kappa were cultured in a Ham's-F12 medium supplemented with 10% SFB, 100 units / ml of penicillin -100 µg / ml of streptomycin and 800 µg / ml of geneticin in a humidified incubator, with 5% CO2, at 37 ° C. Receptor expression levels (Bmax ~ 2.0 and ~ 0.414 pmol / mg protein, respectively) were determined using [3H] -diprenorphine (specific activity ~ 50-55 Ci / mmol) in a radioligand binding assay on membranes

Cells were grown up to 80-95% confluence (<25 subculture passages). For the passage of the cell line, the cell monolayer was incubated for 5 minutes at room temperature and collected by mechanical agitation in 10 ml of PBS supplemented with 5 mM EDTA. After resuspending them, the cells were transferred to 40 ml of fresh culture medium for centrifugation for 5 minutes at 1000 rpm and suspended again in fresh culture medium, using an appropriate number of subcultures.

To prepare the membrane, the cells were collected by gentle mechanical agitation with 5 mM EDTA in PBS and then by centrifugation (5 minutes at 2500 g). The sediments were resuspended in assay buffer (4- (2-hydroxyethyl) piperazin-1-ethanesulfonic acid (N- (2-hydroxyethyl) piperazin-N '- (2 m-ethanesulfonic acid, HEPES) 50 mM), pH 7.4 and they were homogenized with a Polytron disruptor on ice.The resulting homogenates were centrifuged (5 minutes at 1200 g), the sediments were discarded and the supernatant was centrifuged (20 minutes at 40,000 g). The sediments were washed once by resuspension in buffer. Assay and centrifuged again (20 minutes at 40,000 g) The final sediments were resuspended in assay buffer (1 vial of T-225/1 ml assay buffer) The protein concentration was determined by an assay kit of Bradford Bio-Rad proteins and membranes were preserved until used in frozen aliquots at -80 ° C.

Human delta opioid receptor membranes (hDOP) were purchased from Perkin Elmer. The Kd and Bmax values indicated for these membranes -determined by saturation analysis in radioligand binding assays [3H] -natrindole -were 0.14 nM (pKd = 9.85) and 2.2 pmol / mg protein respectively. Protein concentration was determined by a Bradford protein assay kit from Bio-Rad. The membranes were preserved until used in frozen aliquots at -80 ° C.

b. Radioligand binding assays

The radioligand binding assays were carried out on a 96-well Axygen 96-well polypropylene plate with a depth of 200 ml and a total assay volume, containing the appropriate amount of membrane protein (~ 3, ~ 2 and ~ 20 µg of mu, delta and kappa, respectively) in assay buffer supplemented with 0.025% bovine serum albumin (BSA). Binding saturation studies were performed to determine the Kd values of the radioligand, using [3H] -diprenorphine at 8-12 different concentrations, from 0.001 nM to 5 nM. Displacement assays to determine the pKi values of the compounds were carried out with [3 H] diprenorphine at 0.5, 1.2 and 0.7 nM for mu, delta and kappa, respectively, and eleven concentrations of compound, from 10 pM up to 100 µM.

The fixation data were analyzed by non-linear regression with the GraphPad Prism software (GraphPad Software, Inc., San Diego, CA), using the 3-parameter model for competition on a site. The curve minimum was set at the non-specific binding value, determined in the presence of 10 µM naloxone. The Ki values for the test compounds were calculated, in Prism, from the best adjusted IC50 values and the radioligand Kd value, using the Cheng-Prusoff equation (Ki = IC50 / (1 + ([L]) / Kd)), where [L] = the concentration of [3 H] diprenorphine The results are expressed as the negative decimal logarithm of the Ki, pKi values.

The compounds analyzed that have a higher pKi value in these assays have a greater affinity for binding to the opioid receptor mu, delta or kappa. The compounds of examples 1-204 were tested in these tests. With the exception of the compound of example 204, which showed binding to the mu receptor at the micromolar level, all compounds had pKi values between about 8.0 and 10.5 for the human mu opioid receptor. For example, the compounds of examples 1, 46B, 58, 59 and 136 respectively gave pKi values of 10.1, 10.0, 9.9, 9.2 and 9.8. The compounds of Examples 1-203 also gave pKi values between about 7.0 and 10.5 for the human delta opioid and guinea pig kappa receptors.

Test 2: activation of the opioid receptor mu mediated by agonists in membranes prepared from CHO-K1 cells expressing the human mu opioid receptor

In this test the potency and intrinsic activity values of the tested compounds were determined, measuring the amount of GTP-Eu fixed after activation of the receptors in membranes prepared from CHO-K1 cells expressing the human mu opioid receptor.

to. Preparation of mu opioid receptor membranes:

Human mu opioid receptor membranes (hMOP) were prepared as described above or purchased from Perkin Elmer. The Kd and Bmax values indicated for purchased membranes - determined by saturation analysis in radioligand binding assays [3H] -natrindole - were respectively 10.06 and 2.4 pmol / mg protein. Protein concentration was determined by a Bradford protein assay kit from Bio-Rad. The membranes were preserved until used in frozen aliquots at -80 ° C. The lyophilized GTP-Eu and GDP were diluted respectively to 10 µM and 2 mM in doubly distilled H2O and then mixed and allowed to stand at room temperature 30 minutes before transferring to individual aliquots for storage at -20 ° C.

b. GTP-Eu nucleotide exchange assay with human mu

GTP-Eu nucleotide exchange assays were performed with the DELPHIA GTP binding kit (Perkin / Elmer) on AcroWell 96 filter plates, according to the manufacturer's specifications. The membranes were prepared in the manner described above and, before starting the assay, the aliquots were diluted to a concentration of 200 µg / ml in assay buffer (50 mM HEPES, pH 7.4 at 25 ° C); They were then homogenized for 10 seconds using a Polytron homogenizer. The test compounds were received as standard 10 mM solutions in DMSO, diluted to 400 µM in assay buffer containing 0.1% BSA and then serial dilutions (1: 5) were made to obtain ten concentrations of compound, from 40 pM to 80 µM - GDP and GTP-Eu-were diluted respectively to 4 µM and 40 nM in assay buffer. The assay was performed in a total volume of 100 µl containing 5 µg of membrane protein, test compound from 10 pm to 20 µM, 1 µM GDP and 10 nM GTP-Eu diluted in 10 mM MgCl2, 50 mM NaCl and 0 , 0125% BSA (final test concentrations). A concentration curve of DAMGO (Tyr-D-Ala-Gly- (methyl) Phe-Gly-ol) -response (from 12.8 pM to 1 µM was included for each plate)

The plates were prepared immediately before the test, after adding 25 µl of assay buffer, 25 µl of the test compound and 25 µl of GDP and GTP-UE. The assay was started by adding 25 µl of membrane protein and allowed to incubate for 30 minutes. The test plates were then filtered with a Waters vacuum manifold connected to the domestic vacuum, regulated to 10-12 inches of mercury, and washed at room temperature with GTP wash solution (2 x 300 ml). The bottoms of the plates were transferred to remove excess liquid. The plates were read immediately to determine the amount of GTP-Eu fixed, measuring the time-resolved fluorescence (TRF), in a Packard Fusion Plate ReaderVehicle plate reader: the final concentration of DMSO should not exceed 1% in the assay .

The amount of GTP-Eu fixed is proportional to the degree of activation of the opioid receptors mu by the compound tested. Intrinsic activity (AI), expressed as a percentage, was determined as the ratio between the amount of fixed GTP-UE, observed for activation by the test compound, with respect to the amount observed for activation by DAMGO, which is supposedly a complete agonist (AI = 100). The compounds of examples 1 to 204 showed in this test intrinsic activities below 40, generally below 25. For example, the compounds of examples 1, 46B, 58, 59, and 136 gave AI values of 6, - 3, -3, -2, and 14 respectively. Therefore it has been shown that the compounds of the present invention act as antagonists of the human mu opioid receptor.

Trial 3: mouse model for in vivo efficacy

In these tests the efficacy of the test compounds was evaluated in a gastrointestinal transit model that assesses peripheral activity, as well as in a model of analgesia detection, using a hot plate with rodents, which evaluates the activity of the central nervous system. Obtaining the results of these two models allows calculating the peripheral selectivities of the test compounds. These studies were approved by the Institutional Committee for Animal Care and Use, of Theravance, Inc., and conforms to the Guide for the Care and Use of Laboratory Animals published by the National Academy of Sciences (© 1996).

to. Intestinal transit test in mice

The test compounds were evaluated in an intestinal transit test with mice to determine their ability to reverse morphine-induced gastrointestinal transit delay. Mice were fasted for up to 24 hours before administering test compounds or vehicle intravenously, subcutaneously, intramuscularly or orally at doses of 0.001 to about 10 milligrams / kilogram (mg / kg). After administration of the test compound, morphine was administered subcutaneously, at a dose of 3 mg / kg, or vehicle. Five minutes after the administration of morphine or vehicle, a meal of non-nutritive or absorbable charcoal was administered through a bucogastric tube and the animals were allowed free access to water during the sixty minutes of the experiment. The animals were then sacrificed by asphyxiation with carbon dioxide and thoracotomy was performed, carefully removing the stomach to the blind. The stomach was ligated by the lower esophageal sphincter and the pyloric sphincter to prevent further emptying of the small intestine during the period of the measurements. Intestinal transit was defined as the distance traveled by the front front of the food with respect to the total length of the intestine (at the ileocecal junction).

b. Hot plate assay with mice

The activities of the compounds were investigated in mice, using the hot plate model (from Letica Scientific Instruments Model # 7406; Panlab, S.L., Barcelona, Spain), to determine their ability to reverse the action of centrally mediated morphine. The ability of the compounds to reverse morphine-induced analgesia was evaluated, based on the decrease in latency time until the mice begin to lick their legs, relative to morphine controls. The test compounds were administered intravenously, subcutaneously, intramuscularly or orally at doses of 0.1 to 30 mg / kg, followed by subcutaneous administration of morphine at a dose of 10 mg / kg or vehicle. The animals were returned to their cage for the remaining thirty minutes of the test. They were then placed on the hot plate apparatus (53 ° C) and the time it took the mouse to lick its leg was recorded covertly with respect to the treatment group. Animals that did not show the behavior of licking their paws before a limit of 35 seconds were automatically assigned a latency time of 35 seconds.

C. Analysis of the data and results The percentage reversal curves were constructed by non-linear regression analysis, using the sigmoidal dose-response model (of variable slope) and the best adjusted DI50 values were calculated. The minimum and maximum curves were set for morphine control values (indicating 0% reversal) and vehicle controls (indicating 100% reversal), respectively. The results are expressed as DI50, the dose needed to reverse 50% the effects of morphine, in milligrams per kilogram. In this model, selected compounds of the present invention were tested. The compounds of the present invention administered subcutaneously or orally showed DI50 values in the intestinal transit model between 0.1 and 3 mg / kg.

Peripheral selectivity was calculated for each compound based on the DI50 value of the hot plate (central measure) divided by DI50 value of the intestinal transit (peripheral measure). The compounds of the present invention tested in these tests had peripheral selectivities of the order of about 2 to 500 times. In particular, the compounds of examples 46B, 48B, 58, 59 and 63 showed peripheral selectivities of 15, 30, 300, 43 and 22, respectively, after subcutaneous administration, and of 19, 42, 35, 6, and 22, respectively, after oral administration.

Although the present invention has been described with reference to the specific embodiments thereof, those skilled in the art should understand that several equivalent changes and substitutions can be made without departing from the true spirit and scope of the present invention. In addition, many modifications can be made to adapt a situation, a substance, a material composition, a process, a stage or stages of the process particular to the purpose, spirit and scope of the present invention. It is intended that all of these modifications be within the scope of the appended claims. Likewise, all publications, patents and patent documents cited above are incorporated into this document, in whole or individually, as a reference.

Claims (20)

1. A compound of formula (I): image 1 Where: R1 is chosen from-ORa, -C (O) NRaRb, -NHS (O) 2Rc, -NRaRb, -C (O) ORa and -CH2OH; A is C1-4 alkylenyl; R2 is C3-12 cycloalkyl or C6-10 aryl, so that C3-12 cycloalkyl and C6-10 aryl are each optionally substituted with a -ORa, with one or two halogens, with one or two C1-3 alkyls substituted with two or three 10 halogens, or with one, two, three or four C1-3 alkyls; G is C1-4 alkylenyl; R3 is selected from hydrogen, -C (O) R4, -C (O) NHR5, -S (O) 2Rc and -S (O) 2NRaRb; R4 is C3-6 cycloalkyl or C1-6 alkyl, where The C3-6 cycloalkyl is optionally substituted with a -ORa and the C1-6 alkyl is optionally substituted with one or two substituents chosen from -ORa, -C (O) ORa, -S (O) 2R6, -C (O ) NRaRb, -NRaRb, -NHC (O) NRaRb, -CN, C3-6 cycloalkyl and phenyl, or with a D- (CH2) JR7, where D is image2 20 where j is 1.2, or 3, n is 1 or 2 and p is 1, 2, R6 is C1-6 alkyl optionally substituted with R7, R7 is -C (O) ORa, -C (O) NRaRb, -NRaRb or -NHC (O) NRaRb, R5 is C1-6 alkyl, benzo [1.3] dioxol or - (CH2) q-phenyl, where the phenyl is optionally substituted with one or two substituents chosen from halogen, -ORa, C1-3 alkyl and C1-3 alkoxy, where C1-3 alkyl and C1-3 alkoxy are optionally substituted with 2 or 3 halogens, and q is 0, 1, 2, Ra and Rb are, independently, hydrogen or C1-4 alkyl, and Rc is C1-3 alkyl, with the proviso that, when R2 is phenyl substituted in the 4-position R3 is not -C (O) R4, where R4 it is C1-4 alkyl substituted with -C (O) ORa; or a pharmaceutically acceptable salt or solvate thereof. 2. The compound of claim 1 wherein: R2 is C3-12 cycloalkyl or C6-10 aryl, where C3-12 cycloalkyl and C6-10 aryl are optionally substituted with a -ORa, with one or two halogens or with one or two C1-3 alkyls optionally substituted with 2 or 3 halogens; R3 is chosen from hydrogen, -C (O) R4 and -C (O) NHR5; and R4 is C3-6 cycloalkyl or C1-6 alkyl, where C1-6 alkyl is optionally substituted with one or two -ORa or with a substituent selected from -C (O) ORa, -S (O) 2R6, -C (O) NRaRb, -NRaRb, -NHC (O) NRaRb , C3-6 cycloalkyl, D- (CH2) JR7 and phenyl, and Ra and Rb are independently hydrogen or C1-4 alkyl. 3. The compound of claim 1 wherein R1 is -ORa or -C (O) NR3Rb. Four. Five 4. The compound of claim 1 wherein R2 is selected from cyclobutyl, cyclopentyl, cyclohexyl, adamantyl and phenyl, wherein cyclohexyl and phenyl are each optionally substituted with one or two halogens or with C1-3 alkyl substituted with two or three halogens . The compound of claim 1 wherein A is - (CH2) 2-or -CH2- and G is - (CH2) 2-o-CH2-. 6. The compound of claim 1 wherein R3 is chosen from -C (O) R4, -S (O) 2Rc and -S (O) 2NRaRb; R4 is C3-6 cycloalkyl or C1-6 alkyl, where C3-6 cycloalkyl is optionally substituted with a -ORa, and C1-6 alkyl is optionally substituted with one or two substituents chosen from -ORa, -C (O) OR3, -S (O) 2R6, -C (O) NRaRb, -NRaRb, -CN, C3-6 cycloalkyl and phenyl, where R6 is C1-3 alkyl optionally substituted with R7, where 5 R7 is –C (O) ORa. 7. The compound of claim 1 wherein R3 is -C (O) NHR5, and R5 is C1-4 alkyl, benzo [1.3] dioxol or - (CH2) q-phenyl, where q is 0 or 1 and phenyl is optionally substituted with 10 one or two substituents chosen from chlorine, fluorine, -OH and -OCF2. 8. The compound of claim 1, which is a compound of formula (I ’): image 1 Where: R2 is cyclohexyl or phenyl, where cyclohexyl and phenyl are each optionally substituted with one or two halogens, and R4 is C3-6 cycloalkyl or C1-4 alkyl, where The C3-6 cycloalkyl is optionally substituted with a -ORa, and the C1-4 alkyl is optionally substituted with one or two substituents chosen from -ORa, -S (O) 2R6, -NRaRb, -CN and C3-6 cycloalkyl , Ra and Rb are, independently, hydrogen or C1-3 alkyl, and R6 is C1-3 alkyl, 25 or a pharmaceutically acceptable salt or solvate thereof. 9. The compound of claim 8, wherein R4 is C1-4 alkyl optionally substituted with one or two substituents chosen from -OH, -OCH3, -S (O) 2CH3, -NH2, -NHCH3, and -NH (CH3) 2. 10. The compound of claim 8, wherein R2 is cyclohexyl or 4.4 difluorocyclohexyl and R4 is C1-4 alkyl substituted with one or two-OH. 11. The compound of claim 1, chosen from: 3-endo- (8- {2- [cyclohexylmethyl- (2-hydroxyacetyl) -amino] -ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2- [benzyl- (2-hydroxyacetyl) -amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2- [cyclohexylmethyl - ((S) -2,3-dihydroxy-propionyl) amino] ethyl} -8-aza-bicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2- [cyclohexylmethyl- (2-methanesulfonyl-acetyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2 - [(2-hydroxyacetyl) phenethylamino] -ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2 - [(4,4-difluorocyclohexylmethyl) - (2-hydroxyacetyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- {8- [2- (3-benzo [1,3] dioxol-5-yl-1-cyclohexylmethylureido) ethyl] -8-azabicyclo [3.2.1] oct-3-yl} -benzamide; 3-endo- {8- [2- (1-cyclohexylmethyl-3-isopropylureido) ethyl] -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {3- [cyclohexylmethyl- (2-hydroxy-acetyl) amino] propyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2- [cyclohexylmethyl- (4-dimethylamino-butyryl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2- [benzyl- (2-methanesulfonylacetyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2 - [(2,6-difluorobenzyl) - (2-hydroxy-acetyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2 - [(2-methanesulfonylacetyl) - (4-trifluoromethyl-benzyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2 - [(2,6-difluorobenzyl) - (2-methanesulfonylacetyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {3- [benzyl- (2-hydroxyacetyl) amino] -propyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2 - [(4,4-difluorocyclohexylmethyl) - (2-methanesulfonylacetyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2 - [[2- (4-fluorophenyl) ethyl] - (2-hydroxyacetyl) amino] -ethyl-8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2 - [(3-fluorobenzyl) - (2-methanesulfonyl-acetyl) -amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2 - [[2- (4-fluorophenyl) ethyl] - (2-methanesulfonyl-acetyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide ; 3-endo- (8- {2 - [(4-fluorocyclohexylmethyl) - (2-hydroxyacetyl) amino] -ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2 - [(2-hydroxyacetyl) - (5-hydroxy-tricycle [3.3.1.1] (3,7)] decan-2-ylmethyl) -amino] -ethyl} -8-azabicyclo [3.2.1] oct-3-il) 55 benzamide; 3-endo- (8- {2- [cyclohexylmethyl - ((S) -3-hydroxy-2-methylaminopropionyl) amino] ethyl} -8-aza-bicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2 - [(2,6-difluorobenzyl) - (2-hydroxy-2-methylpropionyl) -amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide ; 3-endo- (8- {2 - [(2,6-difluorobenzyl) - (2-methoxyacetyl) -amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2 - [(2,6-difluorobenzyl) - ((S) -2-hydroxypropionyl) amino] -ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide ; 65 3-endo- (8- {2 - [(2-cyanoacetyl) - (2,6-difluorobenzyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2 - [(2,6-difluorobenzyl) - (trans-4-hydroxycyclohexancarbonyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2- [cyclopentylmethyl- (2-methanesulfonylacetyl) -amino] ethyl-8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2- [cyclopentylmethyl- (2-hydroxyacetyl) amino] -ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 5 3-endo- (8- {2- [benzyl - ((R) -3-hydroxy-2- (S) -hydroxybutyryl) amino] -ethyl} -8-azabicyclo [3.2.1] oct-3-yl )-benzamide; 3-endo- (8- {2- [benzyl- (2,2-dimethylpropionyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2- [benzyl- (2-hydroxy-2-methylpropionyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2- [benzyl - ((S) -2-hydroxy-1-oxopropyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {3- [benzyl - ((S) -2-hydroxypropionyl) -amino] propyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 10 3-endo- (8- {2-cyclohexylmethyl - ((S) -4-dimethylamino-2-hydroxybutyryl) -amino] -ethyl} -8-azabicido [3.2.1] oct-3-yl) -benzamide; 3-endo- (8- {2- [cyclohexylmethyl- (3-dimethylamino-2-hydroxypropionyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8-2 - [(4,4-difluorocyclohexylmethyl) - ((S) -2-hydroxypropionyl) -amino] ethyl-8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 3-endo- (8-2- [cyclohexylmethyl - ((S) -2,4-dihydroxybutyryl) amino] ethyl-8-azabicyclo [3.2.1] oct-3-yl) -benzamide; and 3-endo- (8- {2- [cyclohexylmethyl- (4-hydroxybutyryl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) -benzamide; 15 or a pharmaceutically acceptable salt or solvate thereof. 12. The compound of claim 11, selected from: 3-endo- (8- {2- [cyclohexylmethyl - ((S) -2,3-dihydroxy-propionyl) amino] ethyl} -8-azabicyclo [3.2.1 ] oct-3-yl) benzamide; 3-endo- (8- {2 - [(4,4-difluorocyclohexylmethyl) - (2-hydroxyacetyl) amino] ethyl} -8-azabicyclo [3.2.1] oct-3-yl) benzamide; Y 3-endo- (8-2 - [(4,4-difluorocyclohexylmethyl) - ((S) -2-hydroxypropionyl) -amino] ethyl-8-azabicyclo [3.2.1] oct-3-yl) -benzamide; or a pharmaceutically acceptable salt or solvate thereof. 13. The compound of claim 13, which is 3-endo- (8- {2- [cyclohexylmethyl - ((S) -2,3-dihydroxy-propionyl) amino]] ethyl} -8-azabicyclo [3,2.1] oct-3-yl) benzamide glycolate. 25 14. The compound of claim 13, which is 3-endo- (8- {2- [cyclohexylmethyl - ((S) -2,3-dihydroxy-propionyl) amino] ethyl} -8-azabicyclo [3,2.1] oct-3-yl) benzamide oxalate. 15. A pharmaceutical composition comprising the compound of any one of claims 1 to 14 and 30 a pharmaceutically acceptable carrier. 16. A process for preparing a compound of formula (I), image 1 wherein R1, R2, R3, A and G have the meanings of any one of claims 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, consisting of: (a) reacting a compound formula (II): image 1 40 with a compound of formula R4aC (O) -L or a compound of formula R5-N = C = O, where R4a is R4 or a protected form of R4 and L is a leaving group or R4aC (O) -L is an acid carboxylic or a carboxylate salt; or (b) reacting a compound formula (III): image 1 with a compound of formula (XVII): and image3 (c) optionally removing the R4 protecting group or groups to obtain a compound of formula (I) or a protected salt or solvate or derivative thereof. 17. A compound of formula (II): image 1 wherein R1, R2, A and G have the meanings of any one of claims 1 to 14, or a salt thereof. 10 18. The compound of claim 17, wherein R1 is -C (O) NH2; R2 is cyclohexyl or phenyl optionally substituted with one or two halogens; G is -CH2-; Y 15 A is -CH2-. 19. A compound of formula (III): where R1 is –ORa or –C (O) NRaRb. twenty image 1 20. The compound of claim 19, wherein R1 is –OH or –C (O) NH2. 21. A compound as claimed in any one of claims 1 to 14, for therapeutic use. 25 22. Use of a compound according to any of claims 1 to 14, to make a medicament for the treatment of a disease or medical condition related to the activity of mu opioid receptors in a mammal. 23. The use of claim 22, wherein the disease or condition is opioid-induced intestinal dysfunction. or postoperative ileus.