ES2347940T3 - PROLINAMIDE DERIVATIVES AS MODULATORS OF SODIUM CHANNELS. - Google Patents

Abstract

A compound of formula (I), a pharmaceutically acceptable salt or solvate thereof ** (See formula) ** R1 and R2 are independently hydrogen, C1-6 alkyl or C3-6 cycloalkyl-C1-6 alkyl; or said R1 and R2, together with the nitrogen atom to which they are attached, can form a saturated, unsubstituted, 3, 4, 5 or 6-membered ring; q is 1 or 2; R3 and R4 are hydrogen; or when q is 1, R3 and R4, together with the interconnecting atoms, can form a cyclopropane ring; or said R3 and R1, together with the interconnecting atoms can form a saturated or unsaturated 5 or 6-membered ring; X is carbon or nitrogen; n is 0, 1 or 2, where, when present, each R5 is independently selected from the list consisting of C1-3 alkyl, halogen, cyano, C1-3 haloalkyl, hydroxy, C1-3 alkoxy and C1- haloalkoxy 3; any one of R6 or R7 is -O-R8, -OCHR9R8, -NCH2R8 or - (CH2) 2R8 where the other R6 or R7 is hydrogen or R5; and wherein R8 is a phenyl ring or wherein the phenyl ring is optionally substituted with one or more groups independently selected from the list consisting of C1-3 alkyl, halogen, cyano, C1-3 haloalkyl, hydroxy, C1 alkoxy -3 and C1-3 haloalkoxy; and R9 is hydrogen or C1-3 alkyl.

Description

The present invention relates to �-aminocarboxamide derivatives, their salts and prodrugs, and the use of these derivatives, their salts and prodrugs for treating diseases and disorders mediated by modulation of sodium channels with voltage-dependent opening depending on use. In addition, the invention relates to

5 compositions containing these derivatives, their salts and prodrugs, and processes for their preparation.

The sodium channels with voltage opening are responsible for the initial phase of the action potential, which is an electric depolarization wave that usually begins in the neuron soma and propagates along the axon of the

10 nerve to the terminals. In the terminals, the action potential activates the influx of calcium and the release of neurotransmitters. Drugs such as lidocaine, which block sodium channels with voltage opening, are used as local anesthetics. Other sodium channel blockers, such as lamotrigine and carbamazepine, are used to treat epilepsy. In the latter case, the partial inhibition of the channels

15 sodium with voltage opening reduces neuronal excitability and reduces the spread of attacks. In the case of local anesthetics, the regional blockage of sodium channels in sensory neurons prevents the conduction of painful stimuli. A key feature of these drugs is their mechanism of action dependent on use. It is believed that drugs stabilize a configuration

20 channel inactivated, which is quickly adopted after the channel is opened. This inactivated state provides a refractory period before the channel returns to its idle (closed) state, ready to be reactivated. As a result, use-dependent sodium channel blockers delay the activation of neurons at high frequency, for example, in response to painful stimuli, and

25 will help prevent repetitive activation during periods of prolonged neuronal depolarization that may occur, for example, during an attack. The action potentials that are activated at low frequencies, for example, in the heart, will not be significantly affected by these drugs, although in each case the safety margin is different, since at sufficiently high concentrations, each

30 of these drugs are able to block the resting or open state of the channels.

The family of sodium channels with voltage opening consists of 10 subtypes, four of which are brain specific, NaV1.1, 1.2, 1.3 and 1.6. Of the other subtypes, NaV1.4 is found only in skeletal muscle, NaV1.5 is specific to the heart muscle, and NaV1.7, 1.8, and 1.9 are predominantly found in sensory neurons. The hypothetical binding site for use-dependent sodium channel blockers is highly conserved between

All subtypes As a result, drugs such as lidocaine, lamotrigine and carbamazepine do not distinguish between subtypes. However, selectivity can be achieved as a result of the different frequencies in which channels normally operate.

5 Drugs that block sodium channels with voltage opening in a use-dependent manner are also used in the treatment of bipolar disorder, to reduce symptoms of mania or depression, or as stabilizers of emotional state to prevent the occurrence of episodes of emotional state. Clinical and preclinical tests also suggest that sodium channel blockers

10 dependent on use can help reduce the symptoms of schizophrenia. For example, it has been shown that lamotrigine reduces the symptoms of ketamine-induced psychosis in healthy human volunteers and, in addition, there are studies with patients that suggest that the drug may increase the antipsychotic efficacy of some atypical antipsychotic drugs; such as clozapine or olanzapine. The

15 hypothesis is that the efficacy in these psychiatric disorders may be the result, in part, of a reduction in excessive glutamate release. It is believed that the reduction in glutamate release is a consequence of the inhibition of sodium channel dependent on use in key areas of the brain, such as the frontal cortex. However, interaction with calcium channels with voltage opening can also

20 contribute to the effectiveness of these drugs. The published international patent application WO05 / 000309 (Ionix Pharmaceuticals Limited) describes the use of compounds of formula (I), in which R1 is an organic substituent, X1 and X2 are direct bonds or spacer moieties, Ar is aryl or heteroaryl, and Y is a substituted aminoalkyl group or a moiety that contains

Heteroaryl, heterocyclyl or phenyl:

image 1

These compounds are specific sodium channel inhibitors of sensory neurons, and are said to be useful in the treatment of chronic and acute pain, tinnitus, intestinal disorders, bladder dysfunction and diseases

30 demyelinating Published international patent application WO04 / 083189 (Merck & Co.) describes triazole compounds substituted with biaryl of formula (I), (II) and (III) as sodium channel blockers:

image 1

These compounds are said to be useful in the treatment of disorders associated with sodium channel activity, including, for example, acute pain, chronic pain, visceral pain, epilepsy, irritable bowel syndrome, depression and others.

The published international patent application WO04 / 092140 (Merck & Co.)

describes biaryl substituted pyrazoles of formula (I), (II), (III) and (IV) as

sodium channel blockers:

image 1

The compounds are said to be useful in the treatment of disorders that include acute pain, chronic pain, visceral pain, inflammatory pain and neuropathic pain.

Published international patent application WO04 / 094395 (Merck & Co.) describes bianyl substituted thiazoles, oxazoles and imidazoles of formula (I) as sodium channel blockers:

image 1

The compounds are said to be useful in the treatment of conditions that include acute pain, chronic pain; visceral pain, inflammatory pain and neuropathic pain. International patent application WO04 / 026826 (F. Hoffman La Roche AG) describes 4-pyrrolidinophenyl benzyl ether derivatives of formula (I):

image2

The compounds are said to be inhibitors of monoamine oxidase B, and are said to be useful in the treatment of disorders, such as Alzheimer's disease

or senile dementia.

European patent application EP1524265 describes prolinamide derivatives of formula (I)

image 1

The compounds are said to be modulators of the sodium and / or calcium channels and / or selective inhibitors of MAO-B and that they are useful in the treatment of pathologies such as neurological, psychiatric or inflammatory.

The object of the present invention is to identify alternative compounds that modulate voltage dependent sodium channels.

In one embodiment, the compounds will be use dependent sodium channel inhibitors.

In another embodiment, the compounds will be sodium channel inhibitors dependent on the use of a NaV1.3 subtype.

In another embodiment, the compounds will be use dependent sodium channel inhibitors that have an adequate developmental potential profile in oral administration, for example in terms of exposure (Cmax) and / or bioavailability.

In another embodiment, the present invention provides compounds that modulate voltage-dependent sodium channels and that, in addition, exhibit inhibition of Monoamine Oxidase B.

In another embodiment, the present invention provides compounds that modulate voltage-dependent sodium channels and that do not exhibit inhibition of Monoamine Oxidase B.

Unless otherwise indicated, any alkyl group is linear or branched regardless of whether it is part of another group, for example, alkoxy, haloalkyl and haloalkoxy.

As used herein, a haloalkyl group represents an alkyl group substituted with one or more halogen atoms. A haloalkoxy group will be similarly constructed.

The phrase "5- or 6-membered aromatic heterocyclic ring" means a heterocyclic group containing one or more carbon atoms, one or more hydrogen atoms and one or more heteroatoms such as nitrogen, oxygen and sulfur; the carbon atoms and the hetero atoms being interconnected to form a ring. For example, furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and tetrazolyl.

Halo means fluorine, chlorine, bromine or iodine.

The invention provides a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof.

image 1

where

R1 and R2 are independently hydrogen, C1-6 alkyl or C3-6 cycloalkyl-C1-6 alkyl; or said R1 and R2, together with the nitrogen atom to which they are attached, can form a saturated, unsubstituted, 3, 4, 5 or 6-membered ring;

q is 1 or 2;

R3 and R4 are hydrogen; or when q is 1, R3 and R4, together with the interconnecting atoms, can form a cyclopropane ring; or said R3 and R1, together with the interconnecting atoms can form a saturated or unsaturated 5 or 6-membered ring;

X is carbon or nitrogen;

n is 0, 1 or 2, where, when present, each R5 is independently selected from the list consisting of C1-3 alkyl, halogen, cyano, C1-3 haloalkyl, hydroxy, C1-3 alkoxy and C1- haloalkoxy 3;

any one of R6 or R7 is -O-R8, -OCHR9R8, -NCH2R8 or - (CH2) 2R8 where the other R6 or R7 is hydrogen or R5; and wherein R8 is a phenyl ring or wherein the phenyl ring is optionally substituted with one or more groups independently selected from the list consisting of C1-3 alkyl, halogen, cyano, C1-3 haloalkyl, hydroxy, C1 alkoxy -3 and C1-3 haloalkoxy; Y

R9 is hydrogen or C1-3 alkyl.

In one embodiment, X is carbon.

In another embodiment, X is nitrogen.

In one embodiment, q is 1. In another embodiment, q is 2.

In one embodiment, n is 0 or 1. In another embodiment, n is 0.

In one embodiment, R1 and R2 are independently H or C1-6 alkyl. In an alternative embodiment, R1 and R2 are both H. In another embodiment R1 and R2 are independently H or C1-3 alkyl. In a further embodiment R1 and R2 are independently H or methyl.

In one embodiment, R3 and R4 are hydrogen. In another embodiment, R3 and R1, together with the interconnecting atoms can form a saturated or unsaturated 5-membered ring.

In one embodiment, n is 1 and R5 is C1-3 alkoxy or cyano. In an alternative embodiment, n is 1 and R5 is methoxy or cyano.

In one embodiment, R6 is -O-R8 or -OCH2R8, and R7 is hydrogen or R5; and wherein R8 is any one of a phenyl ring or a 5- or 6-membered aromatic heterocyclic ring (independently containing one or more nitrogen, sulfur or oxygen atoms) wherein any one of the phenyl ring or the heterocyclic ring is optionally substituted with one or more groups independently selected from the list consisting of C1-3 alkyl, halogen, cyano, C1-3 haloalkyl, hydroxy, C1-3 alkoxy and C1-3 haloalkoxy.

In one embodiment, R6 is -OCH2R8, and R7 is hydrogen or R5; and wherein R8 is any one of a phenyl ring or a 5- or 6-membered aromatic heterocyclic ring (independently containing one or more nitrogen, sulfur or oxygen atoms) wherein any one of the phenyl ring or the heterocyclic ring is optionally substituted with one or more groups independently selected from the list consisting of C1-3 alkyl, halogen, cyano, C1-3 haloalkyl, hydroxy, C1-3 alkoxy and C1-3 haloalkoxy.

In another embodiment, R6 is -OCH R9R8, -NCH2R8, -OR8, or - (CH2) 2R8 and R7 is hydrogen or R5; and wherein R8 is any one of a phenyl ring or a 5- or 6-membered aromatic heterocyclic ring (independently containing one or more nitrogen, sulfur or oxygen atoms) wherein any one of the phenyl ring or the heterocyclic ring is optionally substituted with one or more groups independently selected from the list consisting of C1-3 alkyl, halogen, cyano, C1-3 haloalkyl, hydroxy, C1-3 alkoxy and C1-3 haloalkoxy.

In one embodiment, R6 is -OCH R9R8, and R7 is hydrogen or R5; and wherein R8 is any one of a phenyl ring or a 5- or 6-membered aromatic heterocyclic ring (independently containing one or more nitrogen, sulfur or oxygen atoms) wherein any one of the phenyl ring or the heterocyclic ring is optionally substituted with one or more groups independently selected from the list consisting of C1-3 alkyl, halogen, cyano, C1-3 haloalkyl, hydroxy, C1-3 alkoxy and C1-3 haloalkoxy.

In a further embodiment, R6 is -OR8, and R7 is hydrogen or R5; and wherein R8 is any one of a phenyl ring or a 5- or 6-membered aromatic heterocyclic ring (independently containing one or more nitrogen, sulfur or oxygen atoms) wherein any one of the phenyl ring or the heterocyclic ring is optionally substituted with one or more groups independently selected from the list consisting of C1-3 alkyl, halogen, cyano, C1-3 haloalkyl, hydroxy, C1-3 alkoxy and C1-3 haloalkoxy.

In another embodiment, R6 is -NCH2R8, and R7 is hydrogen or R5; and wherein R8 is any one of a phenyl ring or a 5- or 6-membered aromatic heterocyclic ring (independently containing one or more nitrogen, sulfur or oxygen atoms) wherein any one of the phenyl ring or the heterocyclic ring is optionally substituted with one or more groups independently selected from the list consisting of C1-3 alkyl, halogen, cyano, C1-3 haloalkyl, hydroxy, C1-3 alkoxy and C1-3 haloalkoxy.

In a further embodiment, R6 is - (CH2) 2R8, and R7 is hydrogen or R5; and wherein R8 is any one of a phenyl ring or a 5- or 6-membered aromatic heterocyclic ring (independently containing one or more nitrogen, sulfur or oxygen atoms) wherein any one of the phenyl ring or the heterocyclic ring is optionally substituted with one or more groups independently selected from the list consisting of C1-3 alkyl, halogen, cyano, C1-3 haloalkyl, hydroxy, C1-3 alkoxy and C1-3 haloalkoxy.

In another embodiment, R6 is -O-R8 or -OCH R9R8, and R7 is hydrogen or R5; and wherein R8 is a phenyl ring optionally substituted with one or more groups independently selected from the list consisting of C1-3 alkyl, halogen, cyano, C1-3 haloalkyl, hydroxy, C1-3 alkoxy and C1-3 haloalkoxy.

In still another embodiment, R6 is -O-R8 or -OCH R9R8, and R7 is hydrogen or R5; and wherein R8 is any one of a phenyl ring optionally substituted with a group independently selected from the list consisting of C1-3 alkyl, halogen, cyano, C1-3 haloalkyl, hydroxy, C1-3 alkoxy and C1-3 haloalkoxy .

In another preferred embodiment, R6 is -O-R8 or -OCH R9R8, and R7 is hydrogen or R5; and wherein R8 is any one of a phenyl ring optionally substituted in ortho position with a group independently selected from the list consisting of C1-3 alkyl, halogen, cyano, C1-3 haloalkyl, hydroxy, C1-3 alkoxy and haloalkoxy C1-3.

In still another embodiment, R6 is -O-R8 or -OCH R9R8, and R7 is hydrogen or R5; and wherein R8 is any one of a phenyl ring optionally substituted in the meta position with a group independently selected from the list consisting of C1-3 alkyl, halogen, cyano, C1-3 haloalkyl, hydroxy, C1-3 alkoxy and haloalkoxy C1-3.

In yet another embodiment, R5 is -OCH2phenyl optionally substituted with one or more groups independently selected from the list consisting of C1-3 alkyl, halogen, cyano, C1-3 haloalkyl, hydroxy, C1-3 alkoxy and C1-3 haloalkoxy.

In still another embodiment, R 5 is -OCH 2 halogen substituted phenyl, trifluoromethoxy

or cyano. In a further embodiment, R5 is -OCH2phenyl substituted with a fluorine atom.

In yet another embodiment, R5 is -Ophenyl optionally substituted with one or more groups independently selected from the list consisting of C1-3 alkyl, halogen, cyano, C1-3 haloalkyl, hydroxy, C1-3 alkoxy and C1-3 haloalkoxy. In yet another embodiment, R5 is -Ophenyl substituted with halogen or cyano.

In another embodiment, R5 is phenoxy, fluorophenoxy or cyanophenoxy. In a further embodiment R5 is 2-cyanophenoxy, 4-cyanophenoxy, 3-fluorophenoxy or 4-fluorophenoxy.

In another embodiment, R5 is benzyloxy, fluorobenzyloxy, trifluoromethylbenzyloxy or cyanobenzyloxy. In a further embodiment R5 is 2-fluorobenzyloxy, 3-fluorobenzyloxy, 4-fluorobenzyloxy, 2-cyanobenzyloxy, 3-cyanobenzyloxy, 4-cyanobenzyloxy or 2trifluoromethylbenzyloxy.

In one embodiment, R9 is hydrogen or methyl. In another embodiment, R9 is hydrogen.

In one embodiment, the compounds of formula (I) are selected from the list consisting of: (2S, 6R) -6- (4 - {[(3-fluorophenyl) methyl] oxy} phenyl) -2-piperidinecarboxamide; (2R, 6S) -6- (4 - {[(3-fluorophenyl) methyl] oxy} phenyl) -2-piperidinecarboxamide; (5R) -5- {4 - [(phenylmethyl) oxy] phenyl} -L-prolinamide; (5R) -5- (4 - {[(3-fluorophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- (4 - {[(3-cyanophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- (4 - {[(4-fluorophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- (4 - {[(2-cyanophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- (4 - {[(4-cyanophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- {4 - [({2 - [(trifluoromethyl) oxy] phenyl} methyl) oxy] phenyl} -L-prolinamide; (5R) -5- (4 - {[(1R) -1-phenylethyl] oxy} phenyl) -L-prolinamide; (5R) -5- {4 - [(4-fluorophenyl) oxy] phenyl} -L-prolinamide; (5R) -5- {4 - [(4-cyanophenyl) oxy] phenyl} -L-prolinamide; (5R) -5- [4- (phenyloxy) phenyl] -L-prolinamide; (5R) -5- {4 - [(3-fluorophenyl) oxy] phenyl} -L-prolinamide; (5R) -5- {4 - [(2-cyanophenyl) oxy] phenyl} -L-prolinamide; (5S) -5- {4 - [(phenylmethyl) oxy] phenyl} -L-prolinamide; (5S) -5- {4 - [(phenylmethyl) oxy] phenyl} -D-prolinamide; (5R) -5- (2-fluoro-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -L-prolinamide; and (5R) -5- {3 - [(phenylmethyl) oxy] phenyl} -L-prolinamide;

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment the compounds of formula (I) are selected from the list consisting of: (2S, 6R) -6- (4 - {[(3-fluorophenyl) methyl] oxy} phenyl) -2-piperidinecarboxamide; (2R, 6S) -6- (4 - {[(3-fluorophenyl) methyl] oxy} phenyl) -2-piperidinecarboxamide; (5R) -5- {4 - [(phenylmethyl) oxy] phenyl} -L-prolinamide; (5R) -5- (4 - {[(3-fluorophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- (4 - {[(3-cyanophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- (4 - {[(4-fluorophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- (4 - {[(2-cyanophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- (4 - {[(4-cyanophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- {4 - [({2 - [(trifluoromethyl) oxy] phenyl} methyl) oxy] phenyl} -L-prolinamide; (5R) -5- (4 - {[(1R) -1-phenylethyl] oxy} phenyl) -L-prolinamide; (5R) -5- {4 - [(4-fluorophenyl) oxy] phenyl} -L-prolinamide; (5R) -5- {4 - [(4-cyanophenyl) oxy] phenyl} -L-prolinamide; (5R) -5- [4- (phenyloxy) phenyl] -L-prolinamide; (5R) -5- {4 - [(3-fluorophenyl) oxy] phenyl} -L-prolinamide; (5R) -5- {4 - [(2-cyanophenyl) oxy] phenyl} -L-prolinamide; (5S) -5- {4 - [(phenylmethyl) oxy] phenyl} -L-prolinamide; (5S) -5- {4 - [(phenylmethyl) oxy] phenyl} -D-prolinamide; (5R) -5- (2-fluoro-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- {3 - [(phenylmethyl) oxy] phenyl} -L-prolinamide; (5R) -5- [4 - {[(2-fluorophenyl) methyl] oxy} -3- (methyloxy) phenyl] -L-prolinamide; (5R) -5- (4 - {[(2-fluorophenyl) methyl] amino} phenyl) -L-prolinamide; (5R) -5- (3-cyano-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- [4- (2-phenylethyl) phenyl] -L-prolinamide; (5R) -5- (5 - {[(2-fluorophenyl) methyl] oxy} -2-pyridinyl) -L-prolinamide; (2S, 3aS, 6aS) -2- (4 - {[(2-fluorophenyl) methyl] oxy} phenyl) hexahydropyrrolo [3,4-b] pyrrole-6 (1H) -one; (5R) -5- (4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -N-methyl-L-prolinamide; (5R) -5- (4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -N, N-dimethyl-L-prolinamide;

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the compounds of formula (I) are selected from the group consisting of hydrochloride salts, or their solvates, of the following related compounds: (2S, 6R) -6- (4 - {[(3-fluorophenyl) methyl] oxy} phenyl) -2-piperidinecarboxamide; (2R, 6S) -6- (4 - {[(3-fluorophenyl) methyl] oxy} phenyl) -2-piperidinecarboxamide; (5R) -5- {4 - [(phenylmethyl) oxy] phenyl} -L-prolinamide; (5R) -5- (4 - {[(3-fluorophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- (4 - {[(3-cyanophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- (4 - {[(4-fluorophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- (4 - {[(2-cyanophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- (4 - {[(4-cyanophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- {4 - [({2 - [(trifluoromethyl) oxy] phenyl} methyl) oxy] phenyl} -L-prolinamide; (5R) -5- (4 - {[(1R) -1-phenylethyl] oxy} phenyl) -L-prolinamide; (5R) -5- {4 - [(4-fluorophenyl) oxy] phenyl} -L-prolinamide; (5R) -5- {4 - [(4-cyanophenyl) oxy] phenyl} -L-prolinamide; (5R) -5- [4- (phenyloxy) phenyl] -L-prolinamide; (5R) -5- {4 - [(3-fluorophenyl) oxy] phenyl} -L-prolinamide; (5R) -5- {4 - [(2-cyanophenyl) oxy] phenyl} -L-prolinamide; (5S) -5- {4 - [(phenylmethyl) oxy] phenyl} -L-prolinamide; (5S) -5- {4 - [(phenylmethyl) oxy] phenyl} -D-prolinamide; (5R) -5- (2-fluoro-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- {3 - [(phenylmethyl) oxy] phenyl} -L-prolinamide; (5R) -5- [4 - {[(2-fluorophenyl) methyl] oxy} -3- (methyloxy) phenyl] -L-prolinamide; (5R) -5- (4 - {[(2-fluorophenyl) methyl] amino} phenyl) -L-prolinamide; (5R) -5- (3-cyano-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- [4- (2-phenylethyl) phenyl] -L-prolinamide; (5R) -5- (5 - {[(2-fluorophenyl) methyl] oxy} -2-pyridinyl) -L-prolinamide; (2S, 3aS, 6aS) -2- (4 - {[(2-fluorophenyl) methyl] oxy} phenyl) hexahydropyrrolo [3,4-b] pyrrole-6 (1H) -one; (5R) -5- (4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -N-methyl-L-prolinamide; (5R) -5- (4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -N, N-dimethyl-L-prolinamide.

In another embodiment, the compounds of formula (I) are selected from the group consisting of hydrochloride salts, or their solvates, of the following related compounds: (5R) -5- [4 - {[(2-fluorophenyl) methyl] oxy} -3- (methyloxy) phenyl] -L-prolinamide; (5R) -5- (4 - {[(2-fluorophenyl) methyl] amino} phenyl) -L-prolinamide.

In another embodiment, the compound of formula (I) is selected from the list consisting of: (2S, 6R) -6- (4 - {[(3-fluorophenyl) methyl] oxy} phenyl) -2-piperidinecarboxamide; (2R, 6S) -6- (4 - {[(3-fluorophenyl) methyl] oxy} phenyl) -2-piperidinecarboxamide; (5R) -5- (4 - {[(1R) -1-phenylethyl] oxy} phenyl) -L-prolinamide; (5R) -5- {4 - [(4-fluorophenyl) oxy] phenyl} -L-prolinamide; (5R) -5- {4 - [(4-cyanophenyl) oxy] phenyl} -L-prolinamide; (5R) -5- [4- (phenyloxy) phenyl] -L-prolinamide; (5R) -5- [4 - {[(2-fluorophenyl) methyl] oxy} -3- (methyloxy) phenyl] -L-prolinamide; (5R) -5- (4 - {[(2-fluorophenyl) methyl] amino} phenyl) -L-prolinamide; (5R) -5- (4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -N-methyl-L-prolinamide; (5R) -5- (4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -N, N-dimethyl-L-prolinamide;

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the compound of formula (I) is selected from the list consisting of: (5R) -5- {4 - [(phenylmethyl) oxy] phenyl} -L-prolinamide; (5R) -5- (4 - {[(3-fluorophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- (4 - {[(3-cyanophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- (4 - {[(4-fluorophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- (4 - {[(2-cyanophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- (4 - {[(4-cyanophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- {4 - [({2 - [(trifluoromethyl) oxy] phenyl} methyl) oxy] phenyl} -L-prolinamide; (5S) -5- {4 - [(phenylmethyl) oxy] phenyl} -D-prolinamide; (5R) -5- (3-cyano-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -L-prolinamide;

or a pharmaceutically acceptable salt or solvate thereof.

For the avoidance of doubt, unless otherwise indicated, the term "substituted" means substituted with one or more defined groups. In the case where the groups can be selected from various alternative groups, the selected groups may be the same or different.

For the avoidance of doubt, the term "independently" means that when more than one substituent is selected from several possible substituents, the substituents may be the same or different.

Pharmaceutically or veterinarily acceptable salts of the compounds of formula (I) containing a basic center are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, with carboxylic acid. or with organosulfonic acids. Examples include the salts of HCl, HBr, HI, sulfate or bisulfate, nitrate, phosphate or bisphosphate, acetate, benzoate, succinate, sucrate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate. For reports on suitable pharmaceutical salts, see Berge et al., J. Pharm. Sci., 66, 1-19, 1977; P.

L. Gould, International Journal of Pharmaceutics, 33 (1986), 201-217; and Bighley et al., Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc, New York, 1996, volume 13, pp. 453-497.

Those skilled in the art of organic chemistry will appreciate that many

5 organic compounds can form complexes with solvents in which they are reacted or in which they precipitate or crystallize. These complexes are called "solvates." For example, a complex with water is called "hydrate." Pharmaceutically acceptable solvates of the compound of the invention are within the scope of the invention.

Hereinafter, the compounds and their pharmaceutically acceptable salts, solvates and prodrugs defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "compounds of the invention".

Pharmaceutically acceptable solvates of the compounds of the invention include their hydrates. Also included within the scope of the compound and various salts of the invention are its polymorphs. The compounds of the invention may have at least two or more chiral centers and, therefore, exist in various stereoisomeric forms. Within the scope 20 of the present invention all stereoisomers and mixtures thereof are included.

The person skilled in the art will appreciate that there may be at least four possible diastereoisomers for the compounds of formula (I), that is, compounds of formula (Ia), (Ib), (Ic) and (Id). These are shown below:

image3

In one embodiment, the present invention provides compounds of formula

(Ia) wherein R1, R2, R3, R4, R5, R6, R7, X, n and q are as defined above, or their pharmaceutically acceptable salts, solvates or prodrugs.

image 1

The diastereoisomers of the compounds of the invention can be obtained according to methods known in the scientific literature, for example by preparative HPLC or by chromatographic purifications. The racemic compounds can be separated using a preparative HPLC and a column with a chiral stationary phase, or they can be resolved to produce the individual enantiomers using methods known to those skilled in the art. In addition, chiral intermediates can be resolved and used to prepare chiral compounds of the invention.

The compounds of the invention may exist in one or more tautomeric forms. Within the scope of the present invention all tautomers and mixtures thereof are included.

The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom that has the same atomic number but an atomic mass different from the atomic mass normally found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F and 36Cl, respectively. Certain isotopic variations of the invention, for example, those in which a radioactive isotope such as 3H or 14C is incorporated, are useful in studies of drug distribution and / or tissue substrates. Particularly preferred are tritium isotopes, i.e. 3H, and carbon-14, i.e. 14C, for their ease of preparation and detectability. In addition, substitution with isotopes such as deuterium, that is, 2H, can produce certain therapeutic advantages that arise from greater metabolic stability, for example, a greater half-life in vivo or reduced dosage requirements and, therefore, may be preferred in Some circumstances Isotopic variations of the compounds of the invention can be prepared, in general, by conventional procedures, such as illustrative methods, or by the preparations described in the examples below, using appropriate isotopic variations of suitable reagents.

The compounds of the invention can be prepared in various ways. In the following reaction schemes and hereinafter, unless otherwise indicated, R1 to R9, X, n and q are as defined in the first aspect. These

procedures form additional aspects of the invention.

Throughout the specification, general formulas are designated by Roman numerals (I), (II), (III), (IV), etc. The subsets of these general formulas are defined as (Ia), (Ib), (Ic), etc ... (IVa), (IVb), (IVc), etc.

The hydrochloride salts of the compounds of formula (I) can be prepared according to Reaction Scheme 1 by reacting compounds of formula

(II) with an excess (eg 2.5 eq) of acetyl chloride and methanol. Typical reaction conditions comprise reacting (II) in a suitable aprotic solvent (such as EtOAc) at room temperature.

15 Reaction Scheme 1

image 1

Compounds of formula (IIa), that is, compounds of formula (II) where R6 is -OCH2R8, can be prepared according to Reaction Scheme 2 by reacting compounds of formula (III) with an excess (e.g. 1.5eq) of R8CH2Y (where Y is a suitable leaving group - for example, see J. March, Advanced Organic Chemistry: reactions, mechanisms, and structure, John Wiley & Sons (1992), 4th Ed., P. 352) . Typical reaction conditions comprise the reaction in a suitable solvent (such as acetonitrile or DMF) at a temperature in the range of room temperature to the reflux temperature of the solvent. It will be appreciated that the compounds of formula (IIa) where R7 is -OCH2R8, can be prepared by analogous methods starting from the hydroxy compound corresponding to the compounds of formula (III). Compounds of formula R8CH2Y are commercially available,

or they can be synthesized by methodologies widely known in the scientific literature.

Reaction Scheme 2

image 1

Compounds of formula (IIb), that is, compounds of formula (II) where R6

5 is -OR8, can be prepared according to Reaction Scheme 3 by reacting compounds of formula (III) with R8-B (OH) 2. Typical reaction conditions include treatment with a suitable catalyst (such as copper (II) acetate and a suitable base (such as TEA, pyridine) in a halogenated hydrocarbon as solvent (such as DCM) at a temperature in the range of

10 room temperature at the reflux temperature of the solvent. Compounds of formula R8-B (OH) 2 are commercially available, or they can be synthesized by methods known in the scientific literature. Alternatively, the compounds of formula (IIb) where R8 contains one or more electron attractant substituents, can be obtained according to the

Reaction Scheme 3 by reacting compounds of formula (III) with R8-F in the presence of a suitable base (such as K2CO3) in an appropriate solvent (such as DMF) by heating by microwave irradiation. Compounds of formula R8-F are commercially available, or they can be synthesized by methods known in the scientific literature.

It will be appreciated that the compounds of formula (II) where R7 is -OR8, can be prepared by analogous methods starting from the hydroxy compound corresponding to the compounds of formula (III).

Reaction Scheme 3

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Compounds of formula (III) can be prepared according to Reaction Scheme 4 by reacting compounds of formula (IV) with palladium on carbon under hydrogen atmosphere (such as 1 atm) in a suitable alcoholic solvent (such as methanol) at room temperature.

Reaction Scheme 4

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The compounds of formula (IV) can be obtained according to Reaction Scheme 5 by reacting compounds of formula (V) with an amine of formula (VI) in the presence of a suitable coupling agent (such as HATU or TBTU) , a suitable base (such as TEA or DIPEA) in an aprotic solvent (such as DMF) at room temperature.

15 Reaction Scheme 5

image 1

The compounds of formula (V) can be prepared according to Reaction Scheme 6. Typical reaction conditions comprise reacting compounds of formula (VII) with a suitable reagent to introduce a BOC protecting group into an amine (such as dicarbonate) of di-tert-butyl) in an aprotic solvent (such as THF) at room temperature.

Reaction Scheme 6

image 1

The compounds of formula (VII) can be prepared according to the

Reaction Scheme 7 reacting compounds of formula (VIII), wherein R is a lower alkyl group, with a suitable base (such as LiOH) in a THF / water mixture (such as 1: 1) at room temperature.

Reaction Scheme 7

image4

Compounds of formula (VIII) can be prepared according to Reaction Scheme 8 by reacting compounds of formula (IX) with PtO2 under a high pressure hydrogen atmosphere (such as 2 atm) in a suitable alcoholic solvent (such as methanol ) at room temperature.

Reaction Scheme 8

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Compounds of formula (IX) can be prepared according to Reaction Scheme 9 by reacting compounds of formula (X) with trifluoroacetic acid in a halogenated hydrocarbon solvent (such as DCM) at low temperature (such as 0 ° C) .

Reaction Scheme 9

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Compounds of formula (X) can be obtained according to Reaction Scheme 10. Typical reaction conditions comprise reacting compounds of formula (XI) with a suitable organometallic compound of formula

(XII) where M is for example MgZ (where Z is Cl, Br or I) or lithium in a suitable solvent (such as diethyl ether or THF) at low temperature (such as -78 ° C).

15 Reaction Scheme 10 Compounds of general formula (XIIa) where M is MgZ (where Z is Cl, Br

image 1

or I) can be generated according to Reaction Scheme 11 by methods known in the scientific literature by reacting the appropriate compound of general formula (XIII) with elemental magnesium in ether. Typical reaction conditions comprise reaction at low temperature (in the range of -78 ° C to 0 ° C) in a suitable solvent (such as ether or THF).

Reaction Scheme 11

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The compounds of general formula (XIII) are commercially available or can be synthesized following the procedures described in Reaction Scheme 12 by reacting compounds of formula (XIV) with benzyl bromide in the presence of a suitable base (such as carbonate of potassium) in a suitable solvent (such as acetonitrile or DMF) at a temperature in the range of

15 room temperature at reflux.

Reaction Scheme 12

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Compounds of formula (XIIb), that is, compounds of general formula

20 (XII) where M is lithium can be generated in accordance with Reaction Scheme 13 through methodologies well known in the scientific literature by reacting the appropriate compound of general formula (XIII) with n-butyllithium. Typical reaction conditions comprise reaction at low temperature (in the range of -78 ° C to 0 ° C) in a suitable solvent (such as ether or THF).

25

Reaction Scheme 13

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It will be appreciated that the reactions indicated in Reaction Schemes 2 to 13 are applicable to the preparation of compounds of formula (I) where R7 is -O-R8 or 5 OCH2R8, whichever is appropriate.

Compounds of formula (XI) can be prepared according to Reaction Scheme 14 by reacting compounds of formula (XV) with a reagent suitable for introducing a BOC group into an amine (ie di-tert-butyl dicarbonate) in the presence of a suitable base (such as 4-DMAP) in a

10 aprotic solvent (such as DCM) at room temperature.

Reaction Scheme 14

image 1

The compounds of the general formula (XV) where q is 1 and R3 and R4 are hydrogen

15 are available in the market. The compounds of formula (XV) where q is 2 and R3 and R4 are hydrogen can be prepared using procedures similar to those described in S. Huang, J. Nelson, D. Weller, Synthetic Communications, Vol 19, No. 20, 3485- 96 (1989). The compounds of formula (XV) where q is 1 and R3 and R4 together with the atoms

20 interconnecting form a cyclopropane ring, can be prepared using procedures similar to those described in I. Sagnard, N. Sasaki, A. Chiaroni, C. Riche, P. Potier, Tetrahedron Letters, 36, 3149-3152 (1995) .

Compounds of formula (le), that is, compounds of general formula (I) where q is 2 and R3 and R4 are hydrogen, can be prepared according to Reaction Scheme 15, reacting compounds of formula (XVI) with PtO2

under high pressure hydrogen atmosphere (such as 4 atmospheres) in acetic acid as a solvent at room temperature.

Reaction Scheme 15

image5

The compounds of formula (XVI) can be prepared according to Reaction Scheme 16 from compounds of formula (XVII) where R is a lower alkyl group. Typical reaction conditions are analogous to those described for Reaction Scheme 5. Alternatively, when R1 and R2 are

10 both hydrogen, the typical reaction conditions comprise reacting compounds of formula (XVII) with ammonia in methanol at a temperature in the range of room temperature to the reflux temperature of the solvent.

Reaction Scheme 16

image4

Compounds of formula (XVII) can be prepared according to Reaction Scheme 17 from compounds of formula (XVIII), where R is lower alkyl. Typical conditions are those described for Reaction Scheme 7.

20 Reaction Scheme 17 The compounds of formula (XVIII) can be prepared according to the

image 1

Reaction Scheme 18 from compounds of formula (XIX) and (XX). A

typical process comprises reacting compounds of general formula

(XIX) where Hal is Cl, Br or I with compounds of formula (XX) in the presence of a suitable palladium catalyst (such as Pd (PPh3) 4). For examples of palladium catalyzed coupling protocols see Ei-ichi Negishi, Handbook of Organopalladium Chemistry for Organic Synthesis, John Wiley & Sons, 2002.

Reaction Scheme 18

image2

The compounds of the general formula (XX) are commercially available or can be prepared by procedures known to those skilled in the art. Alternatively, the hydrochloride salts of the compounds of formula (Ih), that is, the compounds of formula (I) wherein R1 and R2 are hydrogen and R6 or R7 is

OCH2R8, can be prepared according to Reaction Scheme 19 by reacting compounds of formula (XXI) with a solution of hydrogen chloride in diethyl ether at low temperature (such as 0 ° C).

Reaction Scheme 19

image6

The compounds of formula (XXI) can be obtained in accordance with Reaction Scheme 20 by treatment of the compounds of formula (XXII), wherein R is a lower alkyl group, with a solution of NH 3 (for example a concentrated solution, such as a 7N or 11.2 M solution) in an appropriate solvent

25 (such as methanol) and at the appropriate temperature (for example room temperature).

Reaction Scheme 20

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Compounds of formula (XXII) can be prepared according to Reaction Scheme 21 by reacting compounds of formula (XXIII) with Pt / C 5 under a high pressure hydrogen atmosphere (such as 2 atm) in a solvent

suitable (such as AcOEt) at room temperature.

Reaction Scheme 21

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The compounds of formula (XXIII) can be prepared according to Reaction Scheme 22 by reacting compounds of formula (XXIV) with trifluoroacetic acid in a halogenated hydrocarbon solvent (such as DCM) at a temperature in the range of 0 ° C at room temperature. Alternatively, the compounds of formula (XXIII) with q = 1 and R3 = R4 = H are

15 can be prepared from compounds of formula (XLIV) using a metal catalyst such as silver triflate (I) in polar aprotic solvents (such as N, N-dimethylformamide, tetrahydrofuran or acetonitrile) at temperatures in the range of 0 ° to reflux. Compounds of formula (XLIV) are readily prepared by analogous procedures to those described in the scientific literature (van Esseveldt et al, Journal of

20 Organic Chemistry 2005, 70, 1791-1795 and references cited therein).

Reaction Scheme 22

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Compounds of formula (XXIV) can be obtained according to Reaction Scheme 23. Typical reaction conditions comprise reacting compounds of formula (XI) with a suitable organometallic compound of formula (XXV) where Z is Cl, Br or I in a suitable solvent (such as diethyl ether or THF) at low temperature (such as -60 ° C).

Reaction Scheme 23

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The compounds of the general formula (XXV) can be generated in accordance with Reaction Scheme 24 by reacting the appropriate compound of the general formula (XXVI) with elemental magnesium in THF. Typical reaction conditions comprise the reaction at a temperature in the range of room temperature to 65 ° C, in a suitable solvent (such as ether or THF).

fifteen

Reaction Scheme 24

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The compounds of the general formula (XXVI), are commercially available or can be synthesized following the procedures described in the Scheme of

Reaction 25 by reacting compounds of formula (XIV) as defined above with the appropriate benzyl bromide (XXVII) in the presence of a suitable base (such as potassium carbonate) in a suitable solvent (such as acetone) at a temperature in the range of room temperature to reflux.

It will be appreciated that the compounds of formula (XXVI) where R7 is -CH2OR8, can be prepared by analogous methods starting from the hydroxy compound corresponding to a compound of formula (XIV).

The compounds of the general formula (XIV) or (XXVII) are commercially available or can be prepared by procedures known to those skilled in the art.

15 Reaction Scheme 25

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Compounds of general formula (XXIIa), that is, a compound of formula

(XII) where q = 1 and R3, R4 are hydrogen, can be prepared according to the

20 Reaction Scheme 26 treating compounds of the general formula (XXVIII) with an excess (eg 2.5 eq) of acetyl chloride and methanol. Typical reaction conditions comprise reacting (XXVIII) in a suitable aprotic solvent (such as ethyl acetate) at room temperature.

25

Reaction Scheme 26

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Compounds of the general formula (XXVIIIa), that is, a compound of formula (XXVIII) wherein R6 is - (CH2) 2R8, can be prepared according to the

5 Reaction Scheme 27 by reacting compounds of the general formula (XXIX) with palladium on charcoal in a hydrogen atmosphere (1 atm) in a suitable alcoholic solvent (such as methanol). It will be appreciated that the compounds of formula (XXVIIIa) where R7 is - (CH2) 2R8 can be prepared by analogous methods from the respective compound -CH = CH-R8 corresponding to the compound (XXIX).

10 Reaction Scheme 27

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Compounds of general formula (XXIX) can be generated according to Reaction Scheme 28 by reacting compounds of general formula 15 (XXX), where Y is a halogen (such as Br), with boronic acid derivatives of general formula ( XXXI), where R 'and R "are a C1-C3 alkyl group or where BOR'OR" is a saturated five- or six-membered heterocycle (such as 4,4,5,5-tetramethyl-1,3,2-dioxaborolane) , in the presence of a metal catalyst (such as Pd (PPh3) 4) in a suitable solvent (such as dioxane) at elevated temperatures (such as 80 ° C). The compounds of general formula (XXXI) are commercially available or synthesized through methodologies well known in the scientific literature.

Reaction Scheme 28

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Compounds of general formula (XXX) can be generated in accordance with Reaction Scheme 29. Typical reaction conditions comprise reacting compounds of general formula (XXXII) with a reagent suitable for introducing a BOC protecting group into an amine (such as di-tertbutyl dicarbonate) in an aprotic solvent (such as THF or DCM) at room temperature.

Reaction Scheme 29

image2

Compounds of general formula (XXXII) can be prepared according to Reaction Scheme 30 by reacting compounds of general formula

(XXXIII) with plationo on carbon under hydrogen atmosphere (1atm) in a suitable solvent (such as ethyl acetate) at room temperature.

Reaction Scheme 30

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Compounds of general formula (XXXIII) can be generated in accordance with Reaction Scheme 31 by reacting compounds of general formula

20 (XXXIV) in the presence of a metal catalyst (such as silver triflate (I)) in a suitable solvent (such as DMF or acetonitrile) at temperatures in the range of room temperature to reflux temperature.

Reaction Scheme 31

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Compounds of general formula (XXXIV) can be generated in accordance with Reaction Scheme 32 by reacting compounds of general formula

(XXXV) under conditions well known in the scientific literature to separate the BOC protecting group (such as trifluoroacetic acid) in a suitable solvent (such as dichloromethane) at a temperature of 0 ° C at room temperature.

Reaction Scheme 32

image2

Compounds of general formula (XXXV) can be generated in accordance with Reaction Scheme 33 by reacting compounds of general formula

(XXXVI) with compounds of the general formula (XXXVII), where Z and Y represent suitable combinations of halogens (such as I and Br respectively), in the presence of a palladium catalyst (such as PdCl2 (PPh3) 2), iodide of copper (I), and a suitable amine (such as diethylamine) in a polar aprotic solvent (such as diethyl ether) at room temperature. Compounds of general formula (XXXVI) are commercially available or can be synthesized by analogous methodologies well known in the scientific literature using starting materials

20 available on the market (see B. van Esseveldt, Journal of Organic Chemistry 2005, 70, 1791-1795 and references cited therein). The compounds of the general formula (XXXVII) are commercially available or can be synthesized by analogous methodologies well known in the scientific literature.

Reaction Scheme 33

image5

Compounds of general formula (XXXVIII) can be generated in accordance with Reaction Scheme 34 by reacting compounds of general formula

(XXXIX) in a hydrogen atmosphere (1atm) in the presence of palladium on carbon in an alcoholic solvent (such as methanol) at room temperature.

Reaction Scheme 34

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Compounds of general formula (XXXIX) can be generated in accordance with Reaction Scheme 35 by reacting compounds of general formula

15 (XL) in the presence of oxygen, dimethyl sulfoxide and a suitable base (such as potassium tert-butoxide) in a suitable solvent (such as tetrahydrofuran) at room temperature.

Reaction Scheme 35

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Compounds of general formula (XL) can be generated according to Reaction Scheme 36 by reacting a compound (XLI) with compounds of general formula (XLII), wherein Z is CHO, in the presence of a suitable base

5 (such as DIPEA) in a suitable solvent (such as toluene) at elevated temperatures (such as 120 ° C). Compounds of general formula (XLII) where Z is CHO can be generated through a procedure analogous to that described above (Scheme 25) using the appropriate starting material.

10 Reaction Scheme 36

image 1

A compound (XLI) can be generated according to Reaction Scheme 37 by treating a compound (XLIII), under conditions well known in the scientific literature to separate a BOC protecting group (such as acid

15 trifluoroacetic acid in dichloromethane) at room temperature.

Reaction Scheme 37

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A compound (XLIII) can be generated in accordance with Reaction Scheme 38 by reacting a compound (XLIV), readily obtainable through procedures known in the scientific literature (eg, see D.J. Aitken, J.

Chem. Soc. Perkin Trans. 1, 1997, 1681), and N- (phenylmethyl) -2-propen-1-amine (commercially available or prepared through methods well known in the scientific literature) using an appropriate coupling agent (such as HATU or TBTU) and a suitable base (such as DIPEA) in an aprotic solvent (such as DMF) at room temperature.

Reaction Scheme 38

image 1

Alternatively, the compounds of formula (IIc), that is, compounds of

Formula (II) wherein R6 is -OCHR8R9, can be prepared according to Reaction Scheme 39 by reacting compounds of formula (III) with a compound of formula HOCHR8R9 under Mitsunobu conditions (Hughes, DL The Mitsunobu Reaction, Org React. 1992, 42, 335-656). Typical reaction conditions comprise the reaction in the presence of PPh3 and DIAD in a solvent.

15 suitable (such as THF) at low temperature. It will be appreciated that the compounds of formula (IIc) where R7 is -OCHR8R9, can be prepared by analogous methods starting from the hydroxy compound corresponding to the compounds of formula (III). Compounds of formula HOCHR8R9 are commercially available, or they can be synthesized by methodologies well known in the scientific literature.

20 Reaction Scheme 39

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As discussed hereinbefore, it is believed that the compounds of the invention may be useful in the treatment of diseases and disorders mediated by modulation of the sodium channels with voltage opening.

Therefore, according to another aspect, the invention provides a compound of the invention for use as a medicament, preferably a medicament for humans.

According to another aspect, the invention provides the use of a compound of the invention in the manufacture of a medicament for treating or preventing a disease.

or disorder mediated by modulation of the sodium channels with voltage opening.

Without wishing to be limited by theory, diseases or disorders that can be mediated by modulation of the sodium channels with voltage opening are selected from the list consisting of [the numbers in parentheses after the diseases listed below refer to the code of classification in Diagnostic and Statistical Manual of Mental Disorders, 4th edition, published by the American Psychiatric Association (DSM-IV) and / or International Classification of Diseases, 10th edition (ICD-10)]:

i) Depression and emotional state disorders, which include major depressive episode, manic episode, mixed episode and hypomanic episode; depressive disorders that include the main depressive disorder, dysthymic disorder (300.4), depressive disorder not otherwise specified (311); bipolar disorders that include bipolar I disorder, bipolar II disorder (major recurrent depressive episodes with hypomanic episodes) (296.89), cyclothymic disorder (301.13) and bipolar disorder not otherwise specified (296.80); other disorders of emotional state, including disorders of emotional state due to a generalized medical disorder (293.83) comprising subtypes with depressive manifestations, with episodes of the main depressive type, with manic manifestations and with mixed manifestations), induced emotional state disorder by substances (including subtypes with depressive manifestations, with manic manifestations and with mixed manifestations) and emotional state disorder not otherwise specified (296.90):

ii) Schizophrenia, which includes the subtypes of the paranoid type (295.30), of the disorganized type (295.10), of the catatonic type (295.20), of the undifferentiated type (295.90) and of the residual type (295.60); schizophreniform disorder (295.40); schizoaffective disorder (295.70), which includes bipolar and depressive type subtypes; delusional disorder (297.1) which includes the subtypes of the erotomanic type, delusional type of grandeur, celotypy, persecutory type, somatic type, mixed type and unspecified type; brief psychotic disorder (298.8); shared psychotic disorder (297.3); psychotic disorder due to a generalized disorder that includes subtypes with delusions and hallucinations; drug-induced psychotic disorder that includes subtypes with delusions (293.81) and hallucinations (293.82); and psychotic disorder not otherwise specified (298.9).

iii) Anxiety disorders, which include panic attack; panic disorder, which includes panic disorder without agoraphobia (300.01) and panic disorder with agoraphobia (300.21); agoraphobia; agoraphobia without a history of panic disorder (300.22), specific phobia (300.29, formerly simple phobia), which include subtypes of animal type, environmental type, blood-injection-damage type, situational type and other types), social phobia (social anxiety disorder, 300.23), obsessive-compulsive disorder (300.3), post-traumatic stress disorder (309.81), acute stress disorder (308.3), generalized anxiety disorder (300.02), anxiety disorder due to a disorder general practitioner (293.84), substance-induced anxiety disorder, separation anxiety disorder (309.21), anxiety adjustment disorders (309.24) and anxiety disorder not otherwise specified (300.00):

iv) Substance-related disorders, which include substance use disorders, such as substance dependence, desire for substances and substance abuse; substance-induced disorders, such as substance intoxication, substance withdrawal, substance-induced delirium, substance-induced persistent dementia, substance-induced persistent amnestic disorder, substance-induced psychotic disorder, substance-induced emotional state disorder, substance-induced anxiety, substance-induced sexual dysfunction, substance-induced sleep disorder and persistent hallucinogenic perception disorder (flashbacks); alcohol-related disorders, such as alcohol dependence (303.90), alcoholism (305.00), alcohol intoxication (303.00), alcohol withdrawal (291.81), alcohol intoxication delirium, alcohol withdrawal delirium, induced persistent dementia by alcohol, alcohol-induced persistent amnesic disorder, alcohol-induced psychotic disorder, alcohol-induced emotional state disorder, alcohol-induced anxiety disorder, alcohol-induced sexual dysfunction, alcohol-induced sleep disorder and otherwise not specified related to alcohol (291.9); disorders related to amphetamines (or similar to amphetamines), such as amphetamine dependence (304.40), amphetamine abuse (305.70), amphetamine poisoning (292.89), amphetamine withdrawal (292.0), amphetamine poisoning delirium, psychotic disorder amphetamine-induced disorder, amphetamine-induced emotional state disorder, amphetamine-induced anxiety disorder, amphetamine-induced sexual dysfunction, amphetamine-induced sleep disorder, and an otherwise unspecified disorder related to amphetamines (292.9); caffeine-related disorders, such as caffeine intoxication (305.90), caffeine-induced anxiety disorder, caffeine-induced sleep disorder and otherwise specified caffeine-related disorder (292.9); cannabis-related disorders, such as cannabis dependence (304.30), cannabis abuse (305.20), cannabis poisoning (292.89), delirium from cannabis poisoning, cannabis-induced psychotic disorder, cannabis-induced anxiety disorder and disorder related to cannabis not otherwise specified (292.9); Cocaine-related disorders, such as cocaine dependence (304.20), cocaine abuse (305.60), cocaine intoxication (292.89), cocaine withdrawal (292.0), cocaine intoxication delirium, cocaine-induced psychotic disorder, Cocaine-induced emotional state disorder, cocaine-induced anxiety disorder, cocaine-induced sexual dysfunction, cocaine-induced sleep disorder and cocaine-related disorder not otherwise specified (292.9); hallucinogen-related disorders, such as hallucinogen dependence (304.50), hallucinogen abuse (305.30), hallucinogen poisoning (292.89), hallucinogenic disorder with persistent perception (retrospective scenes) (292.89), hallucinogen poisoning, psychotic disorder hallucinogen-induced, hallucinogen-induced emotional state disorder, hallucinogen-induced anxiety disorder and hallucinogen-related disorder not otherwise specified (292.9); inhaler-related disorders, such as inhaler dependence (304.60), inhaler abuse (305.90), inhaler poisoning (292.89), delirium from inhaler poisoning, persistent inhaler-induced dementia, inhaler-induced psychotic disorder, state disorder Inhaler-induced emotional, inhaler-induced anxiety disorder and inhaler-related disorder not otherwise specified (292.9); nicotine-related disorders, such as nicotine dependence (305.1), nicotine withdrawal (292.0) and nicotine-related disorder not otherwise specified (292.9); Opioid related disorders, such as opioid dependence (304.00), opioid abuse (305.50), opioid poisoning (292.89), opioid withdrawal (292.0),

delusions of opioid poisoning, opioid-induced psychotic disorder, opioid-induced emotional state disorder, opioid-induced sexual dysfunction, opioid-induced sleep disorder and opioid-related disorder not otherwise specified (292.9); disorders related to phencyclidine (or similar to phencyclidine), such as dependence on phencyclidine (or similar to phencyclidine) (304.60), abuse of phencyclidine (305.90), poisoning with phencyclidine (292.89), delirium from poisoning with phencyclidine , psychotic disorder induced by phencyclidine, emotional state disorder induced by phencyclidine, anxiety disorder induced by phencyclidine and disorder related to phencyclidine not otherwise specified (292.9); sedative-related disorders, hypnotics

or anxiolytics, such as sedative, hypnotic or anxiolytic dependence (304.10), sedative, hypnotic or anxiolytic abuse (305.40), sedative, hypnotic or anxiolytic poisoning (292.89), sedative, hypnotic or anxiolytic withdrawal (292.0), delirium from sedative, hypnotic or anxiolytic poisoning, delirium from sedative, hypnotic or anxiolytic withdrawal, persistent sedative, hypnotic or anxiolytic dementia, persistent sedative, hypnotic or anxiolytic amnestic disorder, sedative-induced psychotic disorder, hypnotic or anxiolytic disorder of emotional state induced by sedatives, hypnotics or anxiolytics, anxiety disorder induced by sedatives, hypnotics or anxiolytics, sexual dysfunction induced by sedatives, hypnotics or anxiolytics, sleep disorder induced by sedatives, hypnotics or anxiolytics, and sedative-related disorder, hypnotics or anxiolytics I don't expect otherwise cited (292.9); polysubstance-related disorder, such as polysubstance dependence (304.80); and other disorders related to substances (or unknown), such as anabolic steroids, nitrate and nitrous oxide inhalers:

v) Enhancement of cognition, including the treatment of impaired cognition in other diseases, such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic disorders associated with a deterioration of cognition, for example, Alzheimer's disease:

vi) Sleep-related disorders, including primary sleep disorders, such as dysomnias, such as primary insomnia (307.42), primary hypersomnia (307.44), narcolepsy (347), sleep-related sleep disorders (780.59), sleep disorders circadian rhythm sleep (307.45) and dysomnia not otherwise specified (307.47); primary sleep disorders, such as parasomnias such as nightmare disorder (307.47), night terrors disorder (307.46), sleepwalking disorder (307.46) and parasomnias not otherwise specified (307.47); sleep disorders related to another mental disorder, such as insomnia related to another mental disorder

(307.42) and hypersomnia related to another mental disorder (307.44); sleep disorder due to a generalized medical disorder, in particular sleep disorders associated with such diseases such as neurological disorders, neuropathic pain, restless legs syndrome, heart and lung diseases; and substance-induced sleep disorder, which includes subtypes of the insomnia type, hypersomnia type, parasomnia type and mixed type; Sleep apnea and time lag syndrome:

vi) Eating disorders, such as anorexia nervosa (307.1), which includes the restrictive and compulsive / purgative subtypes; bulimia nervosa (307.51), which includes the purgative and non-purgative subtypes; obesity; compulsive eating behavior disorder; excessive eating behavior disorder; and eating behavior disorder not otherwise specified (307.50).

vii) Autism spectrum related disorders, including autistic disorder (299.00), Asperger disorder (299.80), Rett disorder (299.80), childhood disintegrating disorder (299.10) and generalized disorder not otherwise specified (299.80 , which includes atypical autism).

viii) Disorder related to attention deficit / hyperactivity, which includes the subtypes of attention deficit / hyperactivity of the combined type (314.01), attention deficit / hyperactivity disorder predominantly of type of lack of attention (314.00), disorder of attention deficit hyperactivity / hyperactive-impulsive type (314.01) and attention deficit / hyperactivity disorder not otherwise specified (314.9); hyperkinetic disorder; disorders related to destructive behavior, such as behavior disorder that includes the subtypes of type of appearance in childhood (321.81), type of appearance in adolescence (312.82) and of unspecified appearance (312.89), provocative disorder with resistance (313.81) and disorder related to destructive behavior not otherwise specified; and disorders related to tics, such as Tourette's disorder (307.23):

ix) Personality disorders, including subtypes of paranoid personality disorder (301.0), schizoid personality disorder (301.20), schizotypal personality disorder (301.22), antisocial personality disorder (301.7), borderline personality disorder (301.83), histrionic personality disorder (301.50), narcissistic personality disorder (301.81), avoidance personality disorder (301.82), dependent personality disorder (301.6), obsessive-compulsive personality disorder (301.4) and personality disorder not otherwise specified (301.9): and

x) Sexual dysfunctions, which include disorders related to sexual desire, such as hypoactive sexual desire disorder (302.71), and sexual aversion disorder (302.79); sexual arousal disorder, such as female sexual arousal disorder (302.72) and male erectile disorder (302.72); disorders related to orgasm, such as female orgasm disorder (302.73), male orgasm disorder (302.74) and premature ejaculation (302.75); sexual pain disorder, such as dyspareunia (302.76) and vaginismus (306.51); sexual dysfunction not otherwise specified (302.70); paraphilias, such as exhibitionism (302.4), fetishism (302.81), rubbing (302.89), pedophilia (302.2), sexual masochism (302.83), sexual sadism (302.84), tragic fetishism (302.3), voyeurism (302.82) and non-paraphilias otherwise specified (302.9); sexual identity disorders, such as sexual identity disorder in children (302.6) and sexual identity disorder in adolescents or adults (302.85); and sexual disorder not otherwise specified (302.9).

xi) disorders related to impulse control, including: intermittent explosive disorder (312.34), kleptomania (312.32), ludopathy (312.31), pyromania (312.33), trichotillomania (312.39), impulse control disorders not otherwise specified way (312.3), overeating, compulsive shopping, compulsive sexual behavior and compulsively accumulating objects.

In another embodiment, the diseases or disorders that can be mediated by modulating the sodium channels with voltage opening are depression or emotional state disorders.

In another embodiment, the diseases or disorders that can be mediated by modulating the sodium channels with voltage opening are substance-related disorders.

In another embodiment, the diseases or disorders that may be mediated by modulation of the sodium channels with voltage opening are bipolar disorders (which includes bipolar I disorder, bipolar II disorder (i.e. recurrent major depressive episodes with hypomanic episodes) (296.89), cyclothymic disorder (301.13) or bipolar disorder not otherwise specified (296.80)).

In another embodiment, the diseases or disorders that can be mediated by modulating the sodium channels with voltage opening are nicotine-related disorders, such as nicotine dependence (305.1),

Nicotine withdrawal (292.0) or nicotine-related disorder not otherwise specified (292.9).

In one embodiment, the compounds of the invention may be useful as analgesics. For example, they may be useful in the treatment of chronic inflammatory pain (for example, pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis); musculoskeletal pain; lumbar and cervical pain; sprains and sprains; neuropathic pain; pain maintained by the sympathetic; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with the flu or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders, such as dyspepsia without ulcer, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial schema; postoperative pain; headache; toothache; and dysmenorrhea.

The compounds of the invention may be useful in the treatment of neuropathic pain. Neuropathic pain syndromes may develop after a neuronal injury, and the resulting pain may persist for months or years, even after the original lesion has healed. A neuronal lesion may occur in peripheral nerves, dorsal roots, bone marrow or certain regions of the brain. Neuropathic pain syndromes are traditionally classified according to the disease or event that caused them. Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific low back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; postherpetic neuralgia; trigeminal neuralgia; and pain due to physical trauma, amputation, cancer, toxins or chronic inflammatory disorders. These disorders are difficult to treat and although several drugs are known to have limited efficacy, complete pain control is rarely achieved. The symptoms of neuropathic pain are incredibly heterogeneous and are often described as stabbing and spontaneous penetrating pain or ongoing burning. In addition, there is pain associated with normally non-painful sensations such as "pins and needles" (paraesthesia and dysesthesia), greater sensitivity to touch (hyperesthesia), painful sensation after an innocuous stimulus (dynamic, static or thermal allodynia), greater sensitivity to harmful stimuli (thermal, cold or mechanical hyperalgesia), continued pain sensation after stimulus removal (hyperpathy), or an absence or deficit in the selective sensory pathways (hypoalgesia).

The compounds of the invention may also be useful in the improvement of inflammatory disorders, for example, in the treatment of skin disorders (for example, sunburn, eczema, dermatitis, psoriasis); ophthalmic diseases; pulmonary disorders (eg, asthma, bronchitis, emphysema, allergic rhinitis, nonallergic rhinitis, cough, respiratory failure syndrome, pigeon lover's disease, farmer's lung, chronic obstructive pulmonary disease (COPD); gastrointestinal tract disorders ( for example, Crohn's disease, ulcerative colitis, celiac disease, regional ileitis, irritable bowel syndrome, inflammatory bowel disease, gastroesophageal reflux disease); other disorders with an inflammatory component, such as migraine, multiple sclerosis, myocardial ischemia.

The compounds of the invention may also be useful in the treatment and / or prevention of treatable and / or preventable disorders with anticonvulsant agents, such as epilepsy, which includes post-traumatic epilepsy, obsessive-compulsive disorders (OCD), sleep disorders (which include circadian rhythm disorders, insomnia and narcolepsy), tics (for example, Giles de la Tourette syndrome), ataxias, muscle stiffness (spasticity) and temporomandibular joint dysfunction.

The compounds of the invention may also be useful in the treatment of bladder hyperrelexia after a bladder inflammation.

The compounds of the invention may also be useful in the treatment of neurodegenerative diseases and neurodegeneration, such as dementia, in particular degenerative dementia (which includes senile dementia, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease and Creutzfeldt-Jakob, motor neuron disease). The compounds may also be useful for the treatment of amyotrophic lateral sclerosis (ALS) and neuroinflammation.

The compounds of the invention may also be useful in neuroprotection and in the treatment of neurodegeneration after strokes, cardiac arrest, pulmonary bypass, traumatic brain damage, bone marrow damage or the like.

The compounds of the invention can also be useful in the treatment of tinnitus, and as local anesthetics.

The compounds of the invention can also be used in combination with other therapeutic agents. Therefore, the invention provides, in another aspect, a combination comprising a compound of the invention, or its pharmaceutically acceptable derivative, together with another therapeutic agent.

When a compound of the invention, or its pharmaceutically acceptable derivative, is used in combination with a second therapeutic agent against the same disease state, the dose of each compound may be different from that used when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention necessary for use in a treatment will vary depending on the nature of the disorder being treated, and the age and disorder of the patient and, ultimately, will be left to the discretion of the doctor or veterinarian. Treatment manager The compounds of the present invention can be used in combination with other antithrombotic drugs, such as thrombin inhibitors, thromboxane antagonists, prostacyclin mimetics, phosphodiesterase inhibitors, fibrinogen antagonists, thrombolytic drugs, such as tissue plasminogen activator and streptokinase, non-steroidal anti-inflammatory drugs, such as aspirin, and the like.

The aforementioned combinations may conveniently be presented for use in the form of a pharmaceutical formulation and, therefore, pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient represent another aspect of the invention. The individual components of such formulations can be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.

When administration is sequential, the compound of the invention or the second therapeutic agent can be administered first. When administration is simultaneous, the combination can be administered in the same pharmaceutical composition or in different compositions.

When combined in the same formulation, it will be appreciated that the two compounds must be stable and compatible with each other and with the other components of the formulation. When formulated separately, they can be provided in any convenient formulation, conveniently in a manner that is known in the art for such compounds.

The compounds of the invention can be used in combination with the following agents to treat or prevent psychotic disorders: i) antipsychotics; ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperidene, procyclidine and trihexyphenyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognitive enhancers, for example, cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine).

The compounds of the invention can be used in combination with antidepressants to treat or prevent depression and emotional state disorders. The compounds of the invention can be used in combination with the following agents to treat or prevent bipolar disease: i) stabilizers of emotional state; ii) antipsychotics; and iii) antidepressants.

The compounds of the invention can be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants.

The compounds of the invention can be used in combination with the following agents to improve nicotine withdrawal and reduce nicotine cravings: i) nicotine replacement therapy, for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches ; and ii) bupropione.

The compounds of the invention can be used in combination with the following agents to improve alcohol withdrawal and reduce alcohol cravings: i) NMDA receptor antagonists, for example acamprosate; ii) GABA receptor agonists, for example tetrabamate; and iii) opioid receptor antagonists, for example naltrexone.

The compounds of the invention can be used in combination with the following agents to improve opioid withdrawal and reduce opioid cravings: i) opioid mu receptor agonist / opioid kappa receptor antagonist, for example buprenorphine; ii) opioid receptor antagonists, for example naltrexone. and iii) vasodilator antihypertensives, for example lofexidine.

The compounds of the invention can be used in combination with the following agents to treat or prevent sleep disorders: i) benzodiazepines, for example temazepam, lormetazepam, estazolam and triazolam; ii) non-benzodiazepine hypnotics, for example zolpidem, zopiclone, zaleplona and indiplone; iii) barbiturates, for example approbital, butabarbital, pentobarbital, secobarbita and phenobarbital; iv) antidepressants; v) other sedative-hypnotics, for example chloral hydrate and chlormethiazole.

The compounds of the invention can be used in combination with the following agents to treat anorexia: i) appetite stimulants, for example, cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; and v) premenstrual agents, for example, pyridoxine and progesterones.

The compounds of the invention can be used in combination with the following agents to treat or prevent bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics, for example ondansetrone; iv) testosterone receptor antagonists, for example, flutamide; v) stabilizers of emotional state; vi) zinc; and vii) premenstrual agents.

The compounds of the invention can be used in combination with the following agents to treat or prevent autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; and iv) stimulants, for example, methylphenidate, amphetamine and pemoline formulations.

The compounds of the invention can be used in combination with the following agents to treat or prevent ADHD: i) stimulants, for example, methylphenidate, amphetamine and pemoline formulations; and ii) non-stimulants, for example, norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, and cholinesterase inhibitors (such as galantamine and donezepil).

The compounds of the invention can be used in combination with the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) stabilizers of emotional state; and iv) anxiolytics.

The compounds of the invention can be used in combination with the following agents to treat or prevent male sexual dysfunction: i) phosphodiesterase V inhibitors, for example, vardenafil and sildenafil; ii) dopamine agonists / dopamine transport inhibitors, for example, apomorphine and buproprione; iii) alpha adrenoceptor antagonists, for example, phentolamine; iv) prostaglandin agonists, for example, alprostadil; v) testosterone agonists, such as testosterone; vi) serotonin transport inhibitors, for example, serotonin reuptake inhibitors; v) noradrenaline transport inhibitors, for example, reboxetine; and vii) 5-HT1A agonists, for example, flibanserin.

The compounds of the invention can be used in combination with the same agents specified for male sexual dysfunction to treat or prevent female sexual dysfunction, and also an estrogen agonist, such as estradiol.

Antipsychotic drugs comprise typical antipsychotics (for example, chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixin, haloperidol, molindone and loxapine); and atypical antipsychotics (eg clozapine, olanzapine, risperidone, quetiapine, aripyrazole, ziprasidone and amisulpride).

Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine and sertraline); dual serotonin / noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); norepinephrine reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); and others (such as bupropiona, mianserin, mirtazapine, nefazodone and trazodone).

The emotional state stabilizing drugs include lithium, sodium valproate / valproic acid / divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and thiagabine.

Anxiolytics comprise benzodiazepines such as alprazolam and lorazepam.

It will be appreciated that references herein to "treatment" include prophylaxis, prevention of recurrence and suppression or improvement of symptoms (whether mild, moderate or severe), as well as the treatment of established disorders.

The compound of the invention can be administered as the crude chemical, but the active ingredient is preferably presented as a pharmaceutical formulation.

According to another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, in association with one or more pharmaceutically acceptable carriers, diluents and / or excipients. The vehicle, diluent and / or excipient must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not be harmful to the patient receiving it.

The compounds of the invention can be administered in conventional dosage forms prepared by combining a compound of the invention with conventional pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as is most appropriate for the desired preparation.

The pharmaceutical compositions of the invention can be formulated for administration by any route, and comprise those that are in a form adapted for oral, topical or parenteral administration to mammals, including humans.

The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as sterile or oral parenteral solutions or suspensions.

Topical formulations of the present invention may be presented as, for example, ointments, creams or lotions, eye ointments and eye drops or ear drops, impregnated bandages and aerosols and may contain appropriate conventional additives such as preservatives, solvents to help in the penetration of the drug and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such vehicles may be present from about 1% to about 98% of the formulation. More commonly they will constitute up to approximately 80% of the formulation.

Tablets and capsules for oral administration may be in unit dosage form, and may contain conventional excipients, such as binding agents, for example syrup, gum arabic, gelatin, sorbitol, tragacanth

or polyvinylpyrrolidone; fillers, for example, lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricants for the formation of tablets, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulfate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form, for example, of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or they may be presented as a dry product to be reconstituted with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate or gum arabic; non-aqueous vehicles (which may include edible oils), for example, almond oil, oily esters, such as glycerin, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.

Suppositories will contain conventional suppository bases, for example cocoa butter or other glyceride.

For parenteral administration, fluid unit dosage forms are prepared using the compound and a sterilized vehicle, water being preferred. The compound, depending on the vehicle and the concentration used, can be suspended or dissolved in the vehicle. In the preparation of solutions, the compound can be dissolved in water for injections and can be sterilized by filtration before loading it into a suitable vial or vial and sealing it.

Advantageously, agents such as a local anesthetic, preservatives and buffering agents can be dissolved in the vehicle. To enhance stability, the composition can be frozen after loading it in the vial and the water can be removed under vacuum. The dried lyophilized powder is then sealed in the vial and a vial of injectable water can be provided attached to reconstitute the liquid before use. Parenteral suspensions are prepared in essentially the same manner, except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be carried out by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending it in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The compositions may contain 0.1% by weight, for example 10-60% by weight of the active material, depending on the method of administration. When the compositions comprise dosage units, each unit will contain, for example, 5-1000 mg of the active ingredient. The dosage used for the treatment of a human adult can vary from 10 to 3000 mg daily, depending on the route and frequency of administration. For oral administration, a typical dose may be in the range of 50 to 1500 mg daily, for example 120 to 800 mg daily.

One skilled in the art will recognize that the optimum amount and spacing of individual dosages of a compound of the invention will be determined by the nature and spread of the disorder being treated, the form, route and point of administration, and the particular mammal. that is being treated, and these optimal amounts can be determined by conventional techniques. One skilled in the art will also recognize that the optimal course of treatment, that is, the number of doses of a compound of the invention administered per day for a defined number of days, can be determined by those skilled in the art using determination assays. of the conventional course of treatment.

All publications, including, but not limited to, patents and patent applications cited in this specification, are incorporated herein by reference as if each individual publication was specifically and individually indicated to be incorporated herein by reference as if exposed in its entirety.

It will be appreciated that the invention includes the following additional aspects. The embodiments described for the first aspect apply, similarly, to these other aspects. The diseases and disorders described above extend, when appropriate, to these other aspects:

i) A compound of the invention for use in the treatment or prevention of a disease or disorder mediated by modulation of the sodium channels with voltage opening.

ii) A method of treatment or prevention of a disease or disorder mediated by modulating sodium channels with voltage opening in a mammal, comprising administering an effective amount of a compound of the invention.

iii) The use of a compound of the invention in the manufacture of a medicament for treating or preventing a disease or disorder mediated by modulating the sodium channels with voltage opening.

iv) The use of a compound of the invention to treat or prevent a disease or disorder mediated by modulation of the sodium channels with voltage opening.

Examples

The invention is illustrated by the examples described below.

In the procedures that follow, after each starting material, the reference to a description or example is typically provided by a number. This is provided merely as an aid to the skilled chemist. The starting material may not necessarily have been prepared from the indicated batch.

The compounds described in the examples described below have all been prepared as a first step from methyl 5-oxo-L-prolinate or stereochemically pure ethyl 5-oxo-D-prolinate, for example 99% ee. The stereochemistry of the compounds of the descriptions and examples has been assigned assuming that the pure configuration of 5-oxoprolinate is maintained throughout any subsequent reaction condition.

When reference is made to the use of a "similar" procedure, as those skilled in the art will appreciate, this procedure may involve minimal variation, for example the reaction temperature, the amount of reagent / solvent, the reaction time, the treatment conditions, or chromatographic purification conditions.

The absolute configuration of the stereocenter in position 2, as shown below, has been assigned based on 1H NMR NMR experiments, determining the relative stereochemistry of this stereocenter with respect to that in position 5.

image 1

Compounds are named using the chemical naming software ACD / Name PRO 6.02 (Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada).

Proton magnetic resonance (NMR) spectra were recorded on Varian instruments at 300, 400 or 500 MHz, or on a Bruker instrument at 300 MHz or 400 MHz. Chemical shifts are presented in ppm (�) using the line of

15 residual solvent as internal standard. Disintegration patterns are called s, singlet; d, double up; t, triplet; c, quadruplet; m, multiplet; to width. NMR spectra were recorded at temperatures ranging from 25 to 90 ° C. When more than one conformer was detected, chemical shifts are indicated for the most abundant.

20 HPLC analysis indicated by Rt (HPLC): x min, was performed on an Agilent 1100 series instrument using a Luna 3u C18 column (2) 100A (50 x 2.0 mm) (mobile phase: 100% [water + 0.05% TFA] to 95% [acetonitrile + 0.05% TFA] in 8 min, flow = 1 ml / min, detection wavelength 220 nm). Mass spectra (MS) are typically recorded in a

25 quadrupole 4 II mass spectrometer (Micromass UK) or on an Agilent MSD 1100 mass spectrometer, operating in the ES (+) and ES (-) ionization mode, or on an Agilent LC / MSD mass spectrometer 1100, operating in the ES (+) and ES (-) ionization mode coupled with an Agilent 1100 series HPLC instrument [LC / MS -ES (+): analysis performed on a Supelcosil ABZ + Plus (33 x 4, 6

30 mm, 3 µm) (mobile phase: 100% of [water + 0.1% HCO2H] for 1 min, after 100% of [water + 0.1% HCO2H] at 5% of [water + HCO2H at 0.1%] and 95% of [CH3CN] in 5 min, finally under these conditions for 2 min; T = 40 ° C; flow = 1 ml / min; LC / MS-ES (-): analysis performed in a Supelcosil ABZ + Plus (33 x 4.6 mm, 3 µm) (mobile phase: 100% [water + 0.05% NH3] for 1 min, after 100% [water + 0.05% NH3 ] at 5% [water + 0.05% NH3] and 95% [CH3CN] in 5 min, and finally under these conditions for 2 min; T = 40 ° C; flow = 1 ml / min]. Mass spectra only show a peak in the group of molecular ions.

The total ion current (TIC) and DAD UV chromatographic paths along with the MS and UV spectra associated with the peaks are also normally taken in a UPLC / MS AcquityTM system equipped with a 2996 PDA detector and coupled to a Waters Micromass ZQTM mass spectrometer that operates in positive or negative electrospray ionization mode. [LC / MS - ES (+/-): analyzes performed using an AcquityTM UPLC BEH C18 column (50 x 21 mm, particle size 1.7 µm), column temperature 40 ° C (mobile phase: A-water + 0.1% HCOOH / B -MeCN + 0.075% HCOOH, Flow rate: 1.0 mL / min Gradient: t = 0 min 3% B, t = 0.05 min 6% B, t = 0.57 min 70% of B, t = 1.4 min 99% of B, t = 1.45 min 3% of B)]. The use of this methodology is indicated by "UPLC" in the analytical characterization of the compounds described.

The optical rotation was measured on a JASCO DIP-360 digital polarimeter (� = 589 nm, T = 20 ° C, c = 1 in MeOH).

For reactions involving microwave irradiation, an optimized Personal Chemistry EmrysTM was used.

Flash chromatography on silica gel was performed on 230-400 mesh silica gel (supplied by Merck AG Darmstadt, Germany) or on Varian Mega Be-Si pre-filled cartridges or on pre-filled Biotage silica cartridges.

SPE-SCX cartridges are solid-phase ion exchange columns supplied by Varian. The eluent used with the SPE-SCX cartridges is methanol followed by a 2 N solution of ammonia in methanol.

In a series of preparations, purification was performed using Biotage manual rapid resolution chromatography (Flash +) or automatic rapid resolution chromatography (Horizon) systems. All these instruments work with a Biotage Silica cartridge.

SPE-SI cartridges are silica solid phase extraction columns supplied by Varian.

It will be appreciated that the spectra and diffraction data will vary slightly depending on factors, such as temperature, concentration and instrumentation used. The person skilled in the art will appreciate that the differences in the weight of the samples affect the positions of the XRPD peaks. The positions of the peaks indicated herein are subject to a variation of +/- 0.15 degrees 2-tit.

5 X-ray powder diffraction

X-ray powder diffraction analysis (XRPD) was performed on a Bruker D5005, using a Sol-X detector. The acquisition conditions were: radiation: Cu K�, generator voltage: 40 kV, generator current: 50 mA, initial angle: 2.0 ° 2�, final angle: 45.0 ° 2�, step size: 0.02 ° 2�, time per step: 1 second.

10 The sample was prepared on a sample holder with a zero background value. Differential scanning calorimetry (DSC): It should be noted that the measured endothermic peak depends on several factors that include the machine used, the heating rate, the calibration pattern, the humidity and the purity of the sample used.

15 The melting points indicated in the experimental part are estimated based on the appearance of the endothermic peaks recorded during the DSC analysis. The following table lists the abbreviations used:

BOC2O

- bis (1,1-dimethylethyl) dicarbonate

DCM

- dichloromethane

DAY D

- diisopropyl diazodicarboxylate

DIPEA

- diisopropylethylamine

DMAP

- dimethylaminopyridine

DMF

- dimethylformamide

HEY YOU

- O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate

TBTU

- O- (benzotriazol-1-yl) -N, N, N'N'-tetramethyluronium tetrafluoroborate

TFA

- trifluoroacetic acid

TORCH

- triethylamine

THF

- tetrahydrofuran

TMEDA

- N, N, N ', N'-tetramethylethylenediamine

MTBE

image 1 methyl t-butyl ether

Et2O

image 1 diethyl ether

AcOEt

image 1 ethyl acetate

Description 1: ethyl 6-Bromo-2-pyridinecarboxylate (D1)

image 1

5 6-Bromo-2-pyridinecarboxylic acid (925mg, 4.95mmol) (Aldrich) was dissolved in hydrochloric acid / ethanol (1.25M, 20ml) and stirred at reflux for 3h. Then, the solvent was evaporated under reduced pressure. The remaining residue was taken up with DCM and washed with a saturated aqueous solution of NaHCO3. Evaporation of the solvent gave the title compound (1.045g, 92%). The material was used in the following

10 stage without further purification; 1H-NMR (300 MHz, CDCl3) � (ppm): 8.1-8.0 (m, 1H), 7.8-7.5 (m, 2H), 4.4 (q, 2H), 1 , 4 (t, 3H). Description 2: 6- (4-Hydroxyphenyl) -2-ethyl pyridinecarboxylate (D2)

image 1

To a solution of ethyl 6-bromo-2-pyridinecarboxylate (D1, 460mg, 2.0mmol) in dioxane (4ml), 4-hydroxy-phenyl boronic acid (414mg, 3.0mmol), Pd (PPh3) 4 (450mg, 0.4mmol) and potassium carbonate (420mg, 4.0mmol) dissolved in water (2ml). The reaction mixture was heated in a microwave synthesizer for 15min at 150 ° C. The reaction mixture was diluted with ethyl acetate (150ml) and

20 was washed with saturated aqueous ammonium chloride (40ml). The resulting crude material was purified by chromatography on silica gel using ethyl acetate / cyclohexane (1: 1) to provide the title compound (340mg, 72%); 1H-NMR (300 MHz, CDCl3)

� (ppm): 8.05 (d, 2H), 8.0 (m, 1H), 7.80 (d, 2H), 7.05 (d, 2H), 6.80 (ta, 1H), 4.50 (q, 2H), 1.45 (t, 3H).

Description 3: 6- (4 - {[(3-Fluorophenyl) methyl] oxy} phenyl) -2-pyridinecarboxylate (D3)

image 1

A solution of ethyl 6- (4-hydroxyphenyl) -2-pyridinecarboxylate (D2, 100mg, 0.41mmol), 1- (bromomethyl) -3-fluorobenzene (117mg, 0.62mmol) and potassium carbonate (138mg, 1 , 0mmol) was stirred at 60 ° C for 4h. Then the solvent is

5 evaporated under reduced pressure and the resulting crude material was purified by chromatography on silica gel using ethyl acetate / cyclohexane (1: 1) to provide the title compound (110mg, 76%); MS: (ES / +) m / z: 352 [MH +], C21H18FN03 requires 351; 1H-NMR (300 MHz, CDCl3) � (ppm): 8.05 (d, 2H), 8.0 (m, 1H), 7.80 (d, 2H), 7.35 (m, 1H), 7.20 (m, 2H), 7.05 (d, 2H), 7.00 (m, 1H), 5.15 (s, 2H), 4.50 (q, 2H), 1.45 (t , 3H).

Description 4: 6- (4 - {[(3-Fluorophenyl) methyl] oxy} phenyl) -2-pyridinecarboxamide (D4)

image 1

A solution of ethyl 6- (4 - {[(3-fluorophenyl) methyl] oxy} phenyl) -2-pyridinecarboxylate (D3, 110mg, 0.30mmol) in MeOH / NH3 (7M, 5ml) was stirred at 60 ° C in a closed tube

15 tightly for 6h. Then, the solvent was evaporated under reduced pressure to provide the title compound (95mg); MS: (ES / +) m / z: 323 [MH +], C19H15FN03 requires 322; 1H-NMR (300 MHz, DMSO) � (ppm): 8.25 (sa, 2H), 8.20 (d, 1H), 8.05 (d, 1H), 7.95 (t, 1H), 7.85 (d, 1H), 7.65 (sa, 1H), 7.40 (t, 1H), 7.30 (d, 2H), 7.15 (t, 1H), 7.10 (d , 2H), 5.20 (s, 2H).

Description 5: (2S) -5-Oxo-1,2-pyrrolidinedicarboxylate of 1- (1,1-dimethylethyl) and 2-methyl (D5):

image 1

To a commercially available solution of methyl 5-oxo-L-prolinate (Aldrich)

25 (20g, 140mmol) in DCM (200ml) triethylamine (19.6ml, 140mmol), 4 (dimethylamino) pyridine (17.2g, 140mmol) were added and finally, dropwise, a solution of BOC2O (61g, 280mmol ) in DCM (100ml). The resulting red mixture was stirred at

room temperature for 2 hours. The solvent was then removed in vacuo, and the crude material was purified by chromatography on silica gel, eluting with cyclohexane / ethyl acetate (from 7: 3 to 4: 6) to produce (after trituration in hexane / ether 1: 1 diethyl) the title compound as a white solid (32.4 g, 96%); Rf (cyclohexane: ethyl acetate = 65:35): 0.21; 1H-NMR (300 MHz, CDCl3)

� (ppm): 4.62 (dd, 1H), 3.78 (s, 3H), 2.68-2.58 (m, 1H), 2.52-2.45 (m, 1H), 2 , 37-2.27 (m, 1H), 2.08-1.97 (m, 1H), 1.48 (s, 9H).

Description 6: (2S) -2 - ({[(1,1-Dimethylethyl) oxy] carbonyl} amino) -5-oxo-5- {4 [(phenylmethyl) oxy] -phenyl} methyl pentanoate (D6):

10

image 1

To a commercially available solution of 1-bromo-4 - [(phenylmethyl) oxy] benzene (Aldrich) (390mg, 1.48mmol) in dry THF (2ml) at -78 ° C under nitrogen atmosphere was added dropwise to drop a 1.6M solution of n-butyllithium in hexane (0.88ml, 1.4mmol). The

The resulting suspension was stirred at -78 ° C for 40 minutes, and then added dropwise to a solution of (2S) -5-oxo-1,2-pyrrolidinedicarboxylate of 1- (1,1-dimethylethyl) -2-methyl (D5, 300 mg, 1.23 mmol) in dry THF (2.4 ml) previously cooled to 78 ° C. The mixture was stirred at -78 ° C for 40 minutes and at -40 ° C for 1 h, and then quenched at -40 ° C with a saturated aqueous solution of ammonium chloride. Mix

20 was diluted with water and extracted with ethyl acetate. Then, the organic phase was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to yield the crude material, which was purified by chromatography on silica gel, eluting with cyclohexane / ethyl acetate (95: 5). , thereby producing the title compound as a white solid (170 mg, 32%); Rf (cyclohexane: ethyl acetate = 8: 2): 0.30;

1HNMR (300 MHz, CDCl3) � (ppm): 7.95 (d, 2H), 7.50-7.33 (m, 5H), 7.03 (d, 2H), 5.20 (sa, 1H), 5.15 (s, 2H), 4.45-4.35 (m, 1H), 3.78 (s, 3H), 3.15-2.95 (m, 2H), 2.36 -2.26 (m, 1H), 2.16-2.02 (m, 1H), 1.45 (s, 9H). Description 7: (2S) -5- {4 - [(Phenylmethyl) oxy] phenyl} -3,4-dihydro-2H-pyrrol-2-carboxylic acid methyl ester (D7):

image 1

To a solution of (2S) -2 - ({[(1,1-dimethylethyl) oxy] carbonyl} amino) -5-oxo-5- {4 [(phenylmethyl) oxy] phenyl} methyl pentanoate (D6, 323 mg, 0.75 mmol) in dry DCM (4 ml) at 0 ° C, under a nitrogen atmosphere, trifluoroacetic acid (1 ml) was added drop

5 drop. The resulting pale pink solution was allowed to warm to room temperature for 1 hour, then evaporated in vacuo to provide the title compound (291mg, 0.94mmol, 91%) as a greenish oil that was used in the next step. without further purification; Rt (HPLC): 3.69 min; MS: (ES / +) m / z: 310 [MH +], C19H19N03 requires 309.

Description 8: (5R) -5- {4 - [(phenylmethyl) oxy] phenyl} -prolinate methyl (D8):

Description 9: (5S) -5- {4 - [(phenylmethyl) oxy] phenyl} -prolinate methyl (D9):

image 1

To a solution of (2S) -5- {4 - [(phenylmethyl) oxy] phenyl} -3,4-dihydro-2H-pyrrole-2

Methyl carboxylate (D7, 13.7 g, 32.4 mmol) in MeOH (200 ml) was added PtO2 (240 mg), and the mixture was stirred under a hydrogen atmosphere (202.6 kPa) for 6 hours. The catalyst was then removed by filtration and the solvent was removed under reduced pressure to yield a red oil that was dissolved in ethyl acetate and washed with a NaHCO3 solution. The resulting crude material was purified by

20 a silica gel chromatography, eluting with cyclohexane / ethyl acetate (from 9: 1 to 8: 2) to produce the title compounds: D8: (4.15g, 13.3mmol, 41%); Rt (HPLC): 3.80 min; Rf (cyclohexane: ethyl acetate = 7: 3): 0.18; MS: (ES / +) m / z: 312 [MH +], C19H21NO3 requires 311; 1H-NMR (300 MHz, CDCl3) � (ppm): 7.40 (d, 2H); 7.35 (t, 2H); 7.33 (d, 2H); 7.29 (t, 1 H); 6.93 (d, 2H);

5.03 (s, 2H); 4.23 (dd, 1 H); 4.00 (dd, 1 H); 3.71-3.79 (m, 3H); 2.18-2.30 (m, 1 H); 2,092.18 (m, 2H); 1.67-1.78 (m, 1 H); NOE was observed between the proton in C2 and the proton in C5.

D9: (0.6g, 1.9mmol. 6%): Rt (HPLC): 3.73 min; Rf (cyclohexane: ethyl acetate = 7: 3): 0.32; MS: (ES / +) m / z: 312 [MH +]. C19H21NO3 requires 311; 1HNMR (300 MHz, CDCl3) � (ppm): 7.40 (d, 2H); 7.35 (t, 2H); 7.29 (d, 2H); 7.28 (t, 1 H); 6.91 (d, 2H); 4,975.07 (m, 2H); 4.29 (dd, 1 H); 4.09 (dd, 1 H); 3.71-3.75 (m, 3H); 2.29-2.42 (m, 1 H); 2,092.20 (m, 1 H); 1.90-2.02 (m, 1 H); 1.69-1.82 (m, 1 H); No NOE was observed between the proton in C2 and the proton in C5.

Description 10: (5R) -5- {4 - [(Phenylmethyl) oxy] phenyl} -L-proline (D10):

image 1

To a solution of (5R) -5- {4 - [(phenylmethyl) oxy] phenyl} -L-methyl prolinate (D8, 120

10 mg, 0.38 mmol) in THF (2.3 ml) was added LiOH monohydrate (26 mg, 0.61 mmol) dissolved in water (1.1 ml), followed by methanol (1.1 ml). The resulting solution was stirred at room temperature for 3 hours (hydrolysis being monitored by HPLC). When the hydrolysis was complete, the organic solvent was evaporated under reduced pressure (keeping the temperature at 38 ° C) to give a crude aqueous residue that

15 contained the title compound; Rt (HPLC) = 3.63min; MS: (ES / +) m / z: 298 [MH +], C18H19NO3 requires 297). Description 11: (5R) -1 - {[(1,1-dimethylethyl) oxy] carbonyl} -5- {4 - [(phenylmethyl) oxy] phenyl} -Lproline (D11):

image 1

The crude reaction mixture of Description 10 was treated with BOC2O (168mg, 0.77mmol) dissolved in THF (1.1ml). The reaction mixture was stirred at room temperature for 3.5 hours. Then, the organic solvent was evaporated and the basic aqueous solution was treated at 0 ° C with a 1 N aqueous solution of HCl until pH = 3, and this acidic aqueous solution was extracted with ethyl acetate (2 x 10 ml). The organic phase is

25 dried over Na2SO4 and evaporated under reduced pressure to give a solid, which was triturated in n-hexane (36ml) to give the title compound as a white powder (137mg); Rt (HPLC): 5.81 min; Rf (cyclohexane: ethyl acetate = 1: 1): 0.34; MS: (ES / +) m / z: 420 [M + Na +] C23H27NO5; requires 397; MS: (ES / -) m / z: 396 [M-H] C23H27NO5 requires 397; 1HNMR (300 MHz, CDCl3) � (ppm): 7.5-7.3 (m, 5H), 7.10 (ma, 2H), 6.90 (d, 2H), 5.08 (s,, 2H), 4.65 (ma, 1H), 4.50 (ma, 1H), 2.58 (ma, 1H), 2.31 (ma, 1H), 2.11-1.90 (m, 2H ), 1.16 (s, 9H).

Description 12: 1,1-dimethylethyl (D12) (2S, 5R) -2- (aminocarbonyl) -5- {4 - [(phenylmethyl) oxy] phenyl} -1-pyrrolidinecarboxylate (D12):

image 1

To a solution of (5R) -1 - {[(1,1-dimethylethyl) oxy] carbonyl} -5- {4 - [(phenylmethyl) oxy] phenyl} -L-proline (D11, 1.44 g, 3 , 62 mmol) in dry DMF (20 ml) DIPEA (1.26 ml, 7.24 mmol) was added, then TBTU (1.23 g, 3.98 mmol) and, after 20 minutes,

1,1,1,3,3,3-hexamethyldisilazane (1.15 ml, 5.43 mmol). The reaction mixture was stirred at room temperature for 2 h, and then treated with a 5% aqueous NaHCO3 solution (30 ml) and stirred for a further 30 minutes. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic phase was then washed twice with brine / ice, dried over Na2SO4 and evaporated to yield a

15 colorless oil. This crude material was purified by chromatography on silica gel, eluting with cyclohexane / ethyl acetate (from 7: 3 to 5: 5) to yield the title compound (1.25 g, 87%); Rt (HPLC): 5.51 min; Rf (cyclohexane: ethyl acetate = 1: 1): 0.29. MS: (ES / +) m / z: 419 [M + Na +]; C23H28N2O4 requires 396.

Description 13: (2S, 5R) -2- (Aminocarbonyl) -5- (4-hydroxyphenyl) -1-pyrrolidinecarboxy20 1,1-dimethylethyl (D13) can:

image 1

To a solution of (2S, 5R) -2- (aminocarbonyl) -5- {4 - [(phenylmethyl) oxy] phenyl} -1-pyrrolidinecarboxylate of 1,1-dimethylethyl (D12, 1.2 g, 3.02 mmol) in methanol (25 ml), 10% Pd / C by weight (210 mg) was added, and the mixture was stirred under an atmosphere of

25 hydrogen (101.3 kPa) for 6 hours. The catalyst was removed by filtration and the solvent was removed under reduced pressure to yield the title compound as a white solid (870 mg, 94%); Rt (HPLC): 3.61 min; Rf (cyclohexane: ethyl acetate = 1: 1): 0.18; MS: (ES / +) m / z: 329 [M + Na +]; C16H22N2O4 requires 306; 1H NMR (300 MHz, d6-DMSO) � ppm: 9.15 (sa, 1H); 7.40 (ma, 2 H); 7.30 (s, 1 H); 6.90 (s, 1 H); 6.65 (d, 2H); 4,50-4.80 (m, 1 H); 4.05-4.28 (m, 1 H); 2.07-2.24 (m, 1 H); 1.95-2.07 (m, 1 H); 1.60-1.89 (m, 2H); 1.00-1.45 (m, 9H).

Description 14: (2S, 5R) -2- (Aminocarbonyl) -5- (4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -1-1,1-dimethylethyl pyrrolidinecarboxylate (D14):

image 1

1- (Bromomethyl) -2-fluorobenzene (30 µl, 0.220 mmol) was added to a solution of (2S, 5R) -2- (aminocarbonyl) -5- (4-hydroxyphenyl) -1-pyrrolidinecarboxylate of 1,1- dimethyl ethyl (D13, 45 mg, 0.146 mmol) and potassium carbonate (30 mg, 0.217 mmol) in acetonitrile

10 (2 ml). The mixture was stirred at room temperature overnight. Then ethyl acetate and water were added. The organic phase was then washed with brine, dried (Na2SO4), filtered and evaporated. The crude material was purified by chromatography on silica gel, using cyclohexane / ethyl acetate (from 7: 3 to 6: 4) to yield the title compound (51 mg, 85%); Rt (HPLC): 5.56 min; Rf

15 (cyclohexane: ethyl acetate = 1: 1): 0.28; 1H-NMR (300 MHz, CDCl3) � (ppm): 7,567.48 (m, 1H); 7.37-7.28 (m, 1 H); 7.24-7.06 (m, 5H); 6.93 (d, 2H); 5.45-5.37 (sa, 1 H); 5.15 (s, 2H); 4.73-4.60 (m, 1 H); 4.53-4.45 (m, 1 H); 2.58-2.48 (m, 1 H); 2.34-2.25 (m, 1 H); 2.09-1.93 (m, 2H); 1.28-1.13 (sa, 9H). The following compounds of formula (IIc) were prepared using a

A procedure similar to that described in Description 14 starting from (2S, 5R) -2 (aminocarbonyl) -5- (4-hydroxyphenyl) -1-pyrrolidinecarboxylate 1,1-dimethylethyl (D13) and using the appropriate benzyl bromide.

image 1

No.

R8 Characterization

D15

3-fluorophenyl Rf (cyclohexane: ethyl acetate = 1: 1): 0.28. Rt (HPLC): 5.62 min. MS: (ES / +) 437 m / z: [M + Na +]. C23H27FN2O4 requires 414; 1H-NMR (300 MHz, CDCl3) � (ppm): 7.42-7.28 (m, 2H); 7.25-7.12 (m, 4H); 7.02 (dt, 1 H); 6.90 (d, 2H); 5,455.37 (sa, 1 H); 5.08 (s, 2 H); 4.75-4.60 (m, 1 H); 4.53-4.45 (m, 1 H); 2.58-2.48 (m, 1 H); 2.34-2.25 (m, 1 H); 2.09-1.90 (m, 2H); 1.30-1.12 (sa, 9H).

D16

3-cyanophenyl Rf (cyclohexane: ethyl acetate = 1: 1): 0.25, MS: (ES / +) 444 m / z: [M + Na +]. C24H27N3O4 requires 421; 1H-NMR (300 MHz, CDCl3) � (ppm): 7.9 (s, 1H), 7.8 (d, 2H), 7.7-7.4 (m, 3H), 7.3 (s , 1H), 6.9 (m, 3H), 5.2 (s, 2H), 4.8-4.5 (m, 1H), 2.2 (m, 1H), 2.0 (m, 2H), 1.9-1.5 (m, 3H), 1.4-1.0 (m, 8H).

D17

4-fluorophenyl Rf (cyclohexane: ethyl acetate = 1: 1): 0.29, MS: (ES / +) 437 m / z: [M + Na +]. C23H27FN2O4 requires 414.

D18

2-cyanophenyl Rf (cyclohexane: ethyl acetate = 1: 1): 0.25, MS: (ES / +) 444 m / z: [M + Na +]. C24H27N3O4 requires 421.

D19

4-cyanophenyl Rf (cyclohexane: ethyl acetate = 1: 1): 0.25, MS: (ES / +) 444 m / z: [M + Na +]. C24H27N3O4 requires 421.

D20

2- (trifluoromethoxy) phenyl Rf (cyclohexane: ethyl acetate = 1: 1): 0.29, MS: (ES / +) 503 m / z: [M + Na +]. C24H27F3N2O5 requires 480.

Description 21: (2S, 5R) -2- (Aminocarbonyl) -5- (4 - {[(1R) -1-phenylethyl] oxy} phenyl) -1 1,1-dimethylethyl pyrrolidinecarboxylate (D21):

image 1

5 PPh3 supported on polystyrene (100mg, 1.5mmol) and DIAD (30mg, 1.5mmol) were added to a solution of (2S, 5R) -2- (aminocarbonyl) -5- (4-hydroxyphenyl) -1-pyrrolidinecarboxylate of 1 , 1-dimethyl ethyl (D13, 30mg, 0.10mmol) in dry THF (1ml) at 0 ° C. After 15min, (1R) -1-phenylethanol (24.4mg, 0.2mmol) was added and the reaction mixture was stirred at 0 ° C for 2h. The resin was filtered off and the solvent

10 evaporated. The crude material was purified by chromatography on silica gel using cyclohexane / ethyl acetate / (8: 2) to provide the title compound (20mg, 48%); Rt (HPLC): 5.70min, 1H-NMR (400 MHz, DMSO-d6) � (ppm): 1.31 (s, 9H); 1.53 (d, 3 H); 1.65-1.78 (m, 1 H); 1.79 -1.92 (m, 1 H); 1.93-2.03 (m, 1 H); 2.07-2.21 (m, 1 H); 4.50 (sa, 1 H); 4.70 (sa, 1 H); 5.41-5.50 (m, 1 H); 6.78 (d, 2H); 6.91 (s, 1 H); 7.23 (sa, 1 H); 7.31 (sa, 2H); 7.39 (sa, 4H); 7.44 (sa, 1 H).

Description 22: (2S, 5R) -2- (Aminocarbonyl) -5- {4 - [(4-fluorophenyl) oxy] phenyl} -1-1,1-dimethylethyl pyrrolidinecarboxylate (D22)

image 1

This compound was prepared in two batches under different conditions

10 (Conditions A and B). In a closed vial, (2S, 5R) -2- (aminocarbonyl) -5- (4-hydroxyphenyl) -1,1-dimethylethyl pyrrolidinecarboxylate (D13, 19mg, 0.062mmol), copper (II) acetate (11mg, 0.062mmol), boronic (4-fluorophenyl) acid (17mg, 0.124mmol) and molecular sieve were suspended in DCM. Then, either pyridine (Condition A, 24.5mg, 0.31mmol) or triethylamine (Condition B, 31.3mg, 0.31mmol) was added and the reaction was shaken to

15 room temperature for 24h. The crude reaction products of Conditions A and B were combined, filtered and evaporated. The crude residue was purified by chromatography on silica gel using cyclohexane / ethyl acetate / (7: 3) to provide the title compound (28mg, 56%); Rt (HPLC): 5.61 min; MS: (ES / +) m / z: 423 [M + Na +], C22H25N2O4 requires 400; 1H NMR (400 MHz, DMSO-d6) � ppm:

20 1.08 (s, 9H); 1.73-1.84 (m, 1 H); 1.86 - 1.96 (m, 1 H); 2.00 -2.11 (m, 1 H); 2.17-2.27 (m, 1 H); 4.56-4.73 (m, 1 H); 4.74-4.86 (m, 1 H); 6.92 (sa, 2 H); 6.95 (sa, 1 H); 7.02 (sa, 2H); 7.21 (t, 2H); 7.38 (s, 1 H); 7.64 (sa, 2H).

The following compounds of formula (IId) were prepared using a procedure similar to that described in Description 22 starting from (2S, 5R) -225 (aminocarbonyl) -5- (4-hydroxyphenyl) -1-pyrrolidinecarboxylate of 1,1-dimethylethyl (D13) and

using the appropriate boronic acid in Condition A.

image 1

No.

R8 Characterization

D23

4-cyanophenyl Rt (HPLC): 5.29 min; 1H-NMR (400 MHz, DMSO-d6) � ppm: 1.10 (s, 9H); 1.79 (sa, 1 H); 1.93 (sa, 1 H); 2.03 -2.13 (m, 1H); 2.19 -2.30 (m, 1 H); 4.62 -4.77 (m, 1 H); 4.81 -4.92 (m, 1 H); 6.97 (sa, 1 H); 7.06 (sa, 4H); 7.41 (s, 1 H); 7.74 (sa, 2H); 7.83 (d, 2H).

D24

phenyl Rt (HPLC): 5.51 min; MS: (ES / +) 405 m / z: [M + Na +]. C22H26N2O4 requires 382. 1H-NMR (400 MHz, CHCl3-d) � (ppm): 1.24 (s, 9H); 1.59-1.81 (m, 2H); 1.97 (sa, 1 H); 2.25-2.39 (m, 1 H); 4.59-4.76 (m, 1 H); 5.34-5.45 (m, 1 H); 6.93-7.03 (m, 3H); 7.17-7.38 (m, 8H).

D25

3-fluorophenyl MS: (ES / +) 423 m / z: [M + Na +]. C22H25FN2O4 requires 400.

Description 26: (2S, 5R) -2- (Aminocarbonyl) -5- {4 - [(2-cyanophenyl) oxy] phenyl} -1-1,1-dimethylethyl pyrrolidinecarboxylate (D26):

image 1

5 A solution of (2S, 5R) -2- (aminocarbonyl) -5- (4-hydroxyphenyl) -1-pyrrolidinecarboxylate 1,1-dimethylethyl (D13, 50mg, 0.163mmol), 2-fluorobenzonitrile (40mg, 0.326mmol ) and K2CO3 (34mg, 0.245mmol) in DMF (1ml) was heated under microwave irradiation for 30min at 120 ° C. Water and ethyl acetate were then added to the mixture. The organic layer was washed with ice cold brine. The solution dried

10 on Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified by chromatography on silica gel using cyclohexane / ethyl acetate /

(75:25) to provide the title compound (50mg, 75%); Rf (cyclohexane: ethyl acetate = 1: 1): 0.10; Rt (HPLC) 5.17min .; MS: (ES / +) m / z: 430 [M + Na +], C23H25N3O4 requires 407.

Description 27: (5S) -5- {4 - [(Phenylmethyl) oxy] phenyl} -L-proline (D27):

image 1

The title compound was synthesized following a procedure similar to that indicated above in Description 10, starting from methyl (5S) -5- {4 [(phenylmethyl) oxy] phenyl} -L-prolinate (D9, 600 mg, 1, 92 mmol); Rt (HPLC): 3.66 min; MS: (ES / -) m / z: 296 [M-H]; MS: (ES / +) m / z: 298 [M + H]; C18H19NO3 requires

5 297. Description 28: (5S) -1 - {[(1,1-Dimethylethyl) oxy] carbonyl} -5- {4 - [(phenylmethyl) oxy] phenyl} -prproline (D28)

image 1

The title compound was synthesized (695 mg, 90% in two stages) following a

A procedure similar to that indicated above in description 11, starting from (5S) -5- {4 - [(phenylmethyl) oxy] phenyl} -L-proline (D27). The crude material can be used without further purification in the next stage; Rt (HPLC): 5.72 min; MS: (ES / -) m / z: 396 [M-H]; MS: (ES / +) m / z: 420 [M + Na +], C23H27NO5 requires 397, 1H NMR (400 MHz, DMSO-d6) � (ppm): 12.70-12.42 (sa, 1H); 7.47-7.42 (m, 2H); 7.42-7.35 (m,

15 2H); 7.35-7.29 (m, 1 H); 7.13-7.07 (m, 2H); 6.98-6.92 (m, 2H); 5.08 and 5.06 (s, s, 2H); 4.96-4.91 and 4.86-4.81 (m, m, 1H); 4.44-4.40 and 4.39-4.34 (m, m, 1H); 2.36-2.13 (m, 2H); 1.90-1.80 (m, 1 H); 1.69-1.57 (m, 1 H); 1.33 and 1.09 (s, s, 9H). Description 29: (2S, 5S) -2- (Aminocarbonyl) -5- {4 - [(phenylmethyl) oxy] phenyl} -1-pyrrolidinecarboxylate of 1,1-dimethylethyl (D29):

image6

The title compound was synthesized (600 mg, 87%) following a procedure similar to that indicated above in Description 12, starting from (5S) -1 {[(1,1-dimethylethyl) oxy] carbonyl} 5- { 4 - [(phenylmethyl) oxy] phenyl} -L-proline (D28, 690 mg, crude material); Rt (HPLC): 5.23 min; MS: (ES / +) m / z: 419 [M + Na +]; C23H28N2O4 requires 396.

Description 32: 1- (1,1-dimethylethyl) -2-ethyl (D32) -5-Oxo-1,2-pyrrolidinedicarboxylate (D32):

image 1

The title compound was synthesized (14 g, 71%) following a procedure similar to that indicated above in Description 5, starting from ethyl 5-oxo-D-prolinate (12 g, 75.6 mmol) commercially available; Rf (cyclohexane: ethyl acetate = 7: 3): 0.25; Rt (HPLC): 3.94 min; 1H NMR (400 MHz, DMSO-d6) � (ppm): 4.61 (dd, 1H); 4.25 (q, 2H); 2.58-2.69 (m, 1 H); 2.44-2.55 (m, 1 H); 2.26-2.38 (m, 1 H); 2.00-2.08 (m, 1 H); 1.50 (s, 9H); 1.31 (t, 3H).

Description 33: (2R) -2 - ({[(1,1-Dimethylethyl) oxy] carbonyl} amino) -5-oxo-5- {4 [(phenylmethyl) oxy] -phenyl} ethyl pentanoate (D33):

image2

The title compound was synthesized (2.9 g, 16%) following a procedure similar to that indicated above in description 6, starting from (2R) -5oxo-1,2-pyrrolidinedicarboxylate of 1- (1,1- dimethylethyl) -2-ethyl (D32, 10.5 g, 40.8 mmol) and 4-iodophenyl phenylmethyl ether (13.34 g, 43 mmol); Rt (HPLC): 6.37 min; MS: (ES / +) 464 m / z:

15 [M + Na +], C25H31NO6 requires 441; 1H NMR (400 MHz, DMSO-d6) � (ppm): 7.92 (d, 2H); 7.29-7.45 (m, 5H); 6.99 (d, 2H); 5.18 (sa, 1 H); 5.12 (s, 2H); 4.29-4.4 (ma, 1 H); 4.20 (q, 2H); 2.94-3.16 (m, 2H); 2.22-2.33 (m, 1 H); 2.00-2.15 (m, 1 H); 1.39 (s, 9H); 1.28 (t, 3H).

Description 34: ethyl (2R) -5- {4 - [(Phenylmethyl) oxy] phenyl} -3,4-dihydro-2H-pyrrol-2-carboxylate (D34):

image 1

The title compound was synthesized following a procedure similar to that indicated above in Description 7, starting from (2R) -2 - ({[(1,1-dimethylethyl) oxy] carbonyl} amino) -5-oxo-5- { Ethyl 4 - [(phenylmethyl) oxy] phenyl} pentanoate (D33,

25 2.9 g, 6.57 mmol). The crude material can be used without further purification in the next stage; Rt (HPLC): 3.80 min; MS: (ES / +) 324 m / z: [MH +], C20H21NO3 requires 323.

Description 35: (5S) -5- {4 - [(Phenylmethyl) oxy] phenyl} -D-ethyl prolinate (D35):

image 1

The title compound was synthesized (1.84 g, 86% over two stages) following a procedure similar to that indicated above in description 8, using the raw material obtained in description 34; Rt (HPLC): 4.03 min; MS: (ES / +) 326 m / z: [MH +]; C20H23NO3 requires 325; 1H-NMR (500 MHz, CHCl3-d) � (ppm): 7.30 - 7.47 (m, 7H), 6.96 (d, 2H), 5.06 (s, 2H), 4.23 (q, 2H), 4.15 (dd, 1H), 3.90 (dd, 1H), 2.17-2.28 (m, 1H), 2.07-2.17 (m, 2H), 1.61 - 1.76 (m, 1H), 1.31 (t, 3H).

Description 36: (5S) -5- {4 - [(phenylmethyl) oxy] phenyl} -D-proline (D36):

image2

The title compound was synthesized following a procedure similar to that indicated above in Description 10, starting from (5S) -5- {4 [(phenylmethyl) oxy] phenyl} -D-ethyl prolinate (D35, 340 mg, 1,045 mmol); Rt (HPLC): 3.62 min; MS: (ES / +) 298 m / z: [MH +], C18H19N03 requires 297.

Description 37: (5S) -1 - {[(1,1-Dimethylethyl) oxy] carbonyl} -5- {4 - [(phenylmethyl) oxy] phenyl} -Dproline (D37):

image 1

The title compound was synthesized (440 mg, quant. Over two stages) following a procedure similar to that indicated above in Description 11,

20 starting from (5S) -5- {4 - [(phenylmethyl) oxy] phenyl} -D-proline (D36); Rt (HPLC): 5.77 min; MS: (ES / +) 420 m / z: [M + Na +]; C23H27NO5 requires 397; 1H NMR (500 MHz, DMSO-d6) � (ppm): 12.55 (sa, 1H); 6.65-6.78 (m, 7H); 6.95 (d, 2H); 5.10 (s, 2H); 4,604.84 (m, 1 H); 4.23 (m, 1 H); 2.10-2.30 (m, 2H); 1.63-1.95 (m, 2H); 1.05-1.39 (m, 9H).

Description 38: (2R, 5S) -2- (Aminocarbonyl) -5- {4 - [(phenylmethyl) oxy] phenyl} -1-pyrrolidine25 1,1-dimethylethyl carboxylate (D38):

image 1

The title compound was synthesized (250 mg, 56%) following a procedure similar to that indicated above in Description 12, starting from (5S) -1 - {[(1,1-dimethylethyl) oxy] carbonyl} -5- {4- [(phenylmethyl) oxy] phenyl} -D-proline (D37, 440 mg, 1.11 mmol); Rt (HPLC): 5.52 min; MS: (ES / +) 419 m / z: [M + Na +]; C23H28N204 requires 396.

Description 41: 4-Bromo-3-fluorophenyl (2-fluorophenyl) methyl ether (D41)

image 1

A solution of 4-bromo-3-fluorophenol (5g, 25mmol), 2fluorobenzyl bromide (4.94g, 26mmol) and potassium carbonate (5.39g, 39mmol) was stirred at

10 room temperature for 6h. The solvent was evaporated, the residue was taken up in water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure to provide the title compound (8.11g) as a white solid; Rt (HPLC) 6.31 min.

Description 42: (2S) -2 - ({[(1,1-Dimethylethyl) oxy] carbonyl} amino) -5- (2-fluoro-4 - {[(215 fluorophenyl) methyl] oxy} phenyl) -5- methyl oxopentanoate (D42):

image 1

To a solution of 4-bromo-3-fluorophenyl (2-fluorophenyl) methyl ether (D41, 500mg, 1.67mmol) and TMEDA (178mg, 1.53mmol) in dry THF (7ml) at -78 ° C in an atmosphere of nitrogen was added a 1.6 M solution of n-butyllithium in hexane (1ml, 1.6mmol) drop by

20 drop The resulting suspension was stirred at -78 ° C for 15 minutes and then added dropwise to a solution of (2S) -5-oxo-1,2-pyrrolidinedicarboxylate of 1- (1,1-dimethylethyl) and 2-methyl ( D5, 338mg, 1.39mmol) in dry THF (2ml). The mixture was stirred at -78 ° C for 1h, then quenched with a saturated aqueous solution of ammonium chloride. The phases were separated and the organic layer was washed with brine, dried

25 over Na2SO4, filtered, and evaporated under reduced pressure. The resulting residue was purified by chromatography on silica gel eluting with cyclohexane / ethyl acetate (9: 1 to 85:15) to give the title compound as a white solid (254mg, 39%); 1H NMR (300 MHz, CDCl3-d) � (ppm): 8.00-7.80 (m, 1H); 7.53-7.42 (m, 1 H); 7.42-7.25 (m, 1 H); 7.23-7.05 (m, 2H); 6.90-6.80 (m, 1 H); 6.75-6.65 (m, 1 H); 5.18 (s, 2H); 4,50-4,30 (m, 1 H); 3.71 (s, 3 H); 3.18-2.85 (m, 2H); 2.40-2.20 (m, 1 H); 2,151.90 (m, 1 H); 1.40 (s, 9H).

Description 43: (2S) -5- (2-Fluoro-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -3,4-dihydro-2H-pyrrol-2-carboxylate methyl (D43):

image 1

The title compound was synthesized by the procedure of Description 7 from (2S) -2 - ({[(1,1-dimethylethyl) oxy] carbonyl} amino) -5- (2-fluoro-4- { Methyl [(2-fluorophenyl) methyl] oxy} phenyl) -5-oxopentanoate (D42, 250mg, 0.54mmol). The crude material was used in the next step without further purification; Rt (HPLC): 3.84 min; MS: (ES / +) 346 m / z: [MH +]. C19H17F2N03 requires 345.

Description 44: (5R) -5- (2-Fluoro-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -L-methyl prolinate (D44):

image 1

The title compound was synthesized (150mg, 80% in 2 steps) by the procedure of Description 8 from (2S) -5- (2-fluoro-4 - {[(220 fluorophenyl) methyl] oxy} phenyl) -3,4-methyl dihydro-2H-pyrrole-2-carboxylate (D43, as the crude product obtained in Description 43). In addition, in the Description 8 procedure, an additional purification was performed on the SCX cartridge; Rt (HPLC): 3.91 min; 1H NMR (500 MHz, CDCl3-d) � (ppm): 7.45-7.58 (m, 2H); 7.27-7.38 (m, 1 H); 7.15 (t, 1 H); 7.08 (t, 1 H); 6.79 (d, 1 H); 6.70 (d, 1 H); 5.10 (s, 2H); 4.47 (dd, 1 H); 3.96 (dd,

1H); 3.78 (s, 3 H); 2.17-2.28 (m, 2H); 2.05-2.16 (m, 1 H); 1.70-1.80 (m, 1 H).

Description 45: (5R) -5- (2-Fluoro-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -L-proline (D45):

image 1

The title compound was synthesized by the procedure of Description 10 from (5R) -5- (2-fluoro-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -L-methyl prolinate (D44 , 150mg, 0.43mmol); Rt (HPLC): 3.76 min; MS: (ES / -) m / z: 332 [M-H], C18H17F2NO3 requires 333.

Description 46: (5R) -1 - {[(1,1-Dimethyl ethyl) oxy] carbonyl} -5- (2-fluoro-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -L-proline ( D46):

image5

The title compound was synthesized (260mg, quant.) By the procedure of Description 11 from (5R) -5- (2-fluoro-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -L -proline (D45). The crude material can be used without further purification in the next stage; Rt (HPLC): 6.04 min; MS: (ES / -) m / z: 432 [M-H]; MS: (ES / +) m / z: 456 [M + Na +],

C23H25F2NO5 requires 433. Description 47: (2S, 5R) -2- (aminocarbonyl) -5- (2-fluoro-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -1-pyrrolidinecarboxylate of 1,1 -dimethyl ethyl (D47):

image 1

The title compound was synthesized (130mg, 70% in three stages) by

Method of Description 12 from (5R) -1 - {[(1,1-dimethylethyl) oxy] carbonyl} -5- (2fluoro-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -L -proline (D46, 260mg of raw material, max. 0.43mmol); Rt (HPLC): 5.73 min; MS: (ES / +) m / z: 455 [M + Na +], C23H26F2N2O4 requires 432. Description 48: 3-Bromophenyl phenylmethyl ether (D48):

image6

The title compound was synthesized (4.8g, quant.) By the procedure of Description 41 from 3-bromophenol (3g, 17.3mmol) and benzyl bromide (2.1ml); Rt (HPLC): 6.42 min;

Description 49: (2S) -2 - ({[(1,1-Dimethylethyl) oxy] carbonyl} amino) -5-oxo-5- {3 - [(phenyl25 methyl) oxy] -phenyl} methyl pentanoate (D49 ):

image 1

The title compound was synthesized (420mg, 6%) by the procedure of the

Description 6 from 1- (1,1-dimethylethyl) (5S-5-oxo-1,2-pyrrolidinedicarboxylate) and

2-methyl (D5, 3.69g, 15.2mmol) and 3-bromophenyl phenylmethyl ether (D48); Rt (HPLC): 6.2 min;

Description 50: (2S) -5- {3 - [(Phenylmethyl) oxy] phenyl} -3,4-dihydro-2H-pyrrol-2-carboxylic acid methyl ester (D50):

image 1

The title compound was synthesized (666mg) by the procedure of Description 7 from (2S) -2 - ({[(1,1-dimethylethyl) oxy] carbonyl} amino) -5-oxo-5- {310 [(phenylmethyl) oxy] -phenyl} methyl pentanoate (D49, 420mg, 1mmol). Raw material

it can be used without further purification in the next stage; Rt (HPLC): 3.99 min;

Description 51: (5R) -5- {3 - [(Phenylmethyl) oxy] phenyl} -L-methyl prolinate (D51):

image 1

The title compound was synthesized (270mg, 87%) by the procedure of the

Description 8 from (2S) -5- {3 - [(phenylmethyl) oxy] phenyl} -3,4-dihydro-2H-pyrrole-2-carboxylate methyl (D50, crude material of Description 50, 666mg); Rt (HPLC): 3.70 min; MS: (ES / +) m / z: 312 [MH +], C19H21NO3 requires 311; 1H NMR (400 MHz, CHCl3-d) � (ppm): 7.41 (d, 2H); 7.35 (t, 2H); 7.26-7.32 (m, 1 H); 7.19-7.25 (m, 1H); 7.09 (t, 1 H); 7.00 (d, 1 H); 6.84 (dd, 1 H); 5.04 (s, 2H); 4.17 (dd, 1 H); 3.94 (dd, 1 H); 3.74

20 (s, 3H); 2.01-2.24 (m, 3H); 1.63-1.75 (m, 1 H). Description 52: 1- (1,1-dimethylethyl) and 2-methyl (D52) (2S, 5R) -5- {3 - [(Phenylmethyl) oxy] phenyl} -1,2-pyrrolidinedicarboxylate;

image 1

The title compound was synthesized (2.6g, quant.) By the procedure of Description 11 from (5R) -5- {3 - [(phenylmethyl) oxy] phenyl} -L-methyl prolinate (D51, 1.66g, 5.33mmol). The crude material was used in the next step without further purification; Rt (HPLC): 6.54min.

Description 53: (5R) -1 - {[(1,1-Dimethylethyl) oxy] carbonyl} -5- {3 - [(phenylmethyl) oxy] phenyl} -Lproline (D53):

image 1

The title compound was synthesized (400mg, 99%) by the procedure of Description 11 from (2S, 5R) -5- {3 - [(phenylmethyl) oxy] phenyl} -1,2-pyrrolidinedicarboxylate of 1 - (1,1-dimethylethyl) and 2-methyl (D52, 600mg, crude material); Rt (HPLC): 5.81 min.

Description 54: 1,1-dimethylethyl (D54) (2S, 5R) -2- (Aminocarbonyl) -5- {3 - [(phenylmethyl) oxy] phenyl} -1-pyrrolidinecarboxylate (D54):

image 1

The title compound was synthesized (430mg, quant.) By the procedure of Description 12 from (5R) -1 - {[(1,1-dimethylethyl) oxy] carbonyl} -5- {3 [(phenylmethyl) oxy] phenyl} -L-proline (D53, 430mg, 1.08mmol); Rt (HPLC): 5.54 min; MS: (ES / +) m / z: 419 [M + Na +]; C23H28N2O4 requires 396.

Description 59: 4-Bromo-1 - {[(2-fluorophenyl) methyl] oxy} -2- (methyloxy) benzene (D59)

image 1

A suspension of 4-bromo-2- (methyloxy) phenol (3.0g, 14.78mmol), potassium carbonate (2.99g, 22.17mmol) and 2-fluorobenzyl bromide (1.78ml, 14.78mmol) in acetonitrile (20ml) it was stirred at room temperature overnight. Ether was added

5 diethyl. Then, the organic phase was washed with water and 1 M NaOH, dried (Na2SO4), filtered and evaporated to give the title compound (4.388g, quant.). Rt (HPLC): 6.25 min; 1H-NMR (400 MHz, DMSO-d6) � (ppm): 7.5 (m, 1H), 7.4 (m, 1H), 7.2 (m, 2H), 7.1 (s, 1H ), 7.0 (m, 2H), 5.1 (s, 2H), 3.7 (s, 3H).

Description 60: (2S) -2 - ({[(1,1-Dimethylethyl) oxy] carbonyl} amino) -5- [4 - {[(2-fluorophenyl) 10 methyl] oxy} -3- (methyloxy) phenyl ] -5-methyl oxopentanoate (D60)

image 1

1,2-Dibromethane (106uL, 232mg, 1,233mmol) was added to a magnesium suspension (300mg, 12.33mmol) in dry THF (3mL). Then a solution of 4-bromo-1 - {[(2-fluorophenyl) methyl] oxy} -2- (methyloxy) benzene (D59, 2.40g, was added dropwise.

15,22mmol), prepared by a procedure analogous to that described above, in dry THF (17ml). The mixture was heated at reflux for 1.5h. Grignard compound formation was followed by HPLC (Rt (HPLC, 1-fluoro-2 - ({[2 (methyloxy) phenyl] oxy} methyl) benzene): 5.59min, Rt (HPLC, D59): 6, 24min) When the reaction stopped, an additional amount of 1,2-dibromethane (0.1eq) was added. When

The formation of the Grignard compound was complete, the mixture was added dropwise to a solution of (2S) -5-oxo-1,2-pyrrolidinedicarboxylate of 1- (1,1-dimethylethyl) and 2methyl (D5, 1g , 4.11mmol) in dry THF (20ml) at -65 ° C. Stirring at -65 ° C was continued for 3.5h. After isopropanol and diethyl ether were added, the organic layer was washed with aqueous ammonium chloride solution, dried (Na2SO4) and evaporated. He

The residue was purified by flash chromatography using a gradient of cyclohexane / ethyl acetate (40% to 100%) to provide the title compound (900mg, 46%). MS: (ES / +) m / z: 376 [M-BOC +], C25H30FNO7 requires 475; UPLC: 0.84min, m / z: 476 [MH +], 1H NMR (400 MHz, DMSO-d6) � (ppm): 7.6 (m, 2H), 7.4 (m, 2H), 7, 37.2 (m, 4H), 5.2 (s, 2H), 4.1 (m, 1H), 3.8 (s, 3H), 3.6 (s, 3H), 3.2-3 , 0 (m, 2H), 2.1-2.0 (m, 1H), 1.9 (m, 1H), 1.4 (s, 9H).

Description 61: (2R) -5- {4 - [(phenylmethyl) oxy] phenyl} -3,4-dihydro-2H-pyrrole-2-carboxylate ethyl (D61):

image5

The title compound was synthesized by the procedure of Description 7 from (2S) -2 - ({[(1,1-dimethylethyl) oxy] carbonyl} amino) -5- [4 - {[(2-fluorophenyl) ) methyl] oxy} -3 (methyloxy) phenyl] -5-methyl oxopentanoate (D60, 900mg, 1,892mmol). The crude material (1.6g) was used without further purification in the next step. UPLC: Rt = 0.60min, MS:

10 (ES / +) 358 m / z: [MH +], C20H20FNO4 requires 357. Description 62: (5R) -5- [4 - {[(2-Fluorophenyl) methyl] oxy} -3- (methyloxy) phenyl] -L-methyl prolinate (D62):

image 1

The title compound was synthesized by the procedure of Description 58 a

Starting from (2R) -5- {4 - [(phenylmethyl) oxy] phenyl} -3,4-dihydro-2H-pyrrol-2-carboxylate ethyl (D61, 1.6g). The crude material was purified through an SCX cartridge to provide the title compound (D62, 605mg). UPLC: Rt = 0.56min, MS: (ES / +) m / z: 360 [MH +], C20H22FNO4 requires 359; 1H NMR (400 MHz, DMSO-d6) � (ppm): 7.5 (m, 1H), 7.4 (m, 1H), 7.2 (m, 2H), 7.1 (s, 1H) , 7.0 (m, 1H), 6.9 (m, 1H), 5.1 (s, 2H), 4.1 (m, 1H), 3.8

20 (m, 1H), 3.7 (s, 3H), 3.6 (s, 3H), 3.0 (sa, 1H), 2.1 (m, 2H), 1.9 (m, 1H ), 1.5 (m, 1 H).

Description 63: N - [(2-Fluorophenyl) methyl] -4-iodoaniline (D63)

image 1

A solution of 4-iodoaniline (1g, 4.5mmol), 2-fluorobenzaldehyde (0.48ml, 0.566g, 4.5mmol) and triacetoxyborohydride (1.9g, 9.0mmol) in 1,2-dichloroethane (20ml) is 25 stirred for 4 days at room temperature. After adding water, the mixture was extracted with DCM. The combined organic layers were dried (Na2SO4), filtered and evaporated to give the title compound (1.612g, quant.). The raw material was used

Without further purification. MS: (ES / +) m / z: 328 [MH +], C13H11FIN requires 327; 1H NMR (400 MHz, DMSO-d6) � (ppm): 7.4-7.1 (m, 6H), 6.4 (d, 2H), 4.3 (m, 1H), 2.5 ( m, 2H).

Description 64: (2S) -2 - ({[(1,1-Dimethylethyl) oxy] carbonyl} amino) -4-methyl pentinoate (D64)

image5

Thionyl chloride (16ml, 26g, 221mmol) was added dropwise to a cooled solution (0 ° C) of (2S) -2-amino-4-pentinoic acid (5.0g, 44.18mmol, commercial) in methanol (dry , 100ml). After stirring the mixture at room temperature for 5.5 h, the solvent was evaporated and the residue was taken up in 1,4-dioxane (100ml) and a

10 saturated aqueous solution of NaHCO3 (50ml). Then BOC2O (10.1g, 46.4mmol) was added and the mixture was stirred overnight at room temperature. Ethyl acetate and an aqueous solution of NaHCO3 were added. The separated organic layer was washed with bicarbonate solution, dried (Na2SO4), filtered and evaporated. The resulting crude material was purified by chromatography on silica gel.

15 using ethyl acetate / cyclohexane (1: 100 to 3: 7) to provide the title compound (7.35g, 73%); MS: (ES / +) m / z: 250 [MNa] +, C11H17NO4 requires 227. 1H-NMR (400 MHz, DMSO-d6) � (ppm): 7.3 (d, 1H), 4.1 ( m, 1H), 2.9 (s, 1H), 2.6-2.5 (m, 2H), 1.4 (s, 9H).

Description 65: (2S) -2 - ({[(1,1-dimethylethyl) oxy] carbonyl} amino) -5- (4 - {[(2-fluorophenyl) 20 methyl] -amino} phenyl) -4-pentinoate methyl (D65)

image 1

To a stirred solution of (2S) -2 - ({[(1,1-dimethylethyl) oxy] carbonyl} amino) -4pentinoate (D64, 365mg, 1.60mmol), prepared by a procedure analogous to that described here more above, N - [(2-fluorophenyl) methyl] -4-iodoaniline (D63, 630mg,

1.92mmol) and diethylamine (0.82ml, 585mg, 8mmol) Cul (30mg, 0.08mmol) and PdCl2 (PPh3) 2 (56mg, 0.08mmol) were added. After stirring at room temperature for 5h, ethyl acetate was added and the solution was extracted with a saturated solution of ammonium chloride. The organic layer was dried (Na2SO4), filtered and evaporated. The resulting crude material was purified by flash chromatography using a gradient of cyclohexane, ethyl acetate (5% -40%) on silica gel to provide the title compound - (192mg, 28%); UPLC: 0.88min, MS: (ES / +) m / z: 427 [MH] +, C24H27FN2O4 requires 426.

Description 66: (2S) -2-Amino-5- (4 - {[(2-fluorophenyl) methyl] amino} phenyl) -4-methyl pentinoate (D66)

image 1

A solution of (2S) -2 - ({[(1,1-dimethylethyl) oxy] carbonyl} amino) -5- (4 - {[(2-fluorophenyl) methyl] amino} phenyl) -4-methyl pentinoate (D65, 192mg, 0.450mmol) in DCM that

10 contains 5% TFA (10.5ml) stirred at room temperature for 4.5h. Then 28% NH3 in water was added and the mixture was extracted with DCM. The combined organic layers were dried (Na2SO4), filtered and evaporated to provide the title compound (132mg). The crude product was used without purification in the next step. UPLC: 0.56min, MS: (ES / +) m / z: 327 [MH] +, C19H19FN202 requires 326.

Description 67: (2S) -5- (4 - {[(2-Fluorophenyl) methyl] amino} phenyl) -3,4-dihydro-2H-pyrrol2-methyl carboxylate (D67)

image 1

A solution of (2S) -2-amino-5- (4 - {[(2-fluorophenyl) methyl] amino} phenyl) -4-methyl pentinoate D66, 132mg) and silver triflate (11mg, 0.045mmol) is stirred up

20 room temperature 6.5h. Then silica gel was added and the solvent was evaporated. The residue was purified by flash chromatography eluting a gradient of cyclohexane / ethyl acetate (12% to 100%) to provide the title compound (39mg, 26%). MS: (ES / +) m / z: 327 [MH] +, C19H19FN2O2 requires 326.

Description 68: (5R) -5- (4 - {[(2-Fluorophenyl) methyl] amino} phenyl) -L-methyl prolinate 25 (D68)

image 1

A solution of (2S) -5- (4 - {[(2-fluorophenyl) methyl] amino} phenyl) -3,4-dihydro-2H-pyrrol-2-carboxylate (D67, 39mg, 0.119mmol) and Pt al 5% on carbon in ethyl acetate (10ml) was stirred under 1 atm of hydrogen for 4.5h, filtered over celite and evaporated to provide the title compound (36mg, 92%). MS: (ES / +) m / z: 329 [MH] +, C19H21FN2O2 requires 328.

Description 69: 5-Bromo-2 - {[(2-fluorophenyl) methyl] oxy} benzonitrile (D69):

image5

A solution of 5-bromo-2-hydroxybenzonitrile (3.31g, 16.71mmol), synthesized as described in J. Org. Chem. 1997, 13, 4504-4506, 2-fluorobenzyl bromide (commercially available, 2.02ml, 3.16g, 16.71mmol) and potassium carbonate (3.46g, 25.06mmol) was stirred for one night at room temperature. Then it was added

10 diethyl ether and the solution was washed with water, 1M NaOH and brine. The organic layer was dried (Na2SO4), filtered and evaporated to give the title compound (4.74g, 92%). 1H-NMR (400 MHz, DMSO-d6) � (ppm): 8.0 (M, 1H), 7.9 (m, 1H), 7.6 (m, 1H), 7.5-7.3 (m, 2H), 7.2 (m, 2H), 5.3 (s, 2H).

Description 70: (2S) -5- (3-Cyano-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -2 - ({[(1,1-dimethyl15 ethyl) oxy] carbonyl} amino) - Methyl 4-pentinoate (D70)

image 1

The title compound (65mg, 32%) was synthesized in a manner analogous to that described in Description 65 from 5-bromo-2 - {[(2-fluorophenyl) methyl] oxy} benzonitrile (D69, 161 mg, 0 , 53mmol). UPLC: Rt = 0.86min, MS: (ES / +) m / z: 453 [MH +],

C25H25FN2O5 requires 452. Description 71: (2S) -2-Amino-5- (3-cyano-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -4pentinoate methyl (D71):

image 1

Acetyl chloride (225ul, 248mg, 3.16mmol) was added dropwise to a solution of (2S) -5- (3-cyano-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -2- ({[(1,1-dimethylethyl) oxy] carbonyl} amino) -4-pentinoate (D70, 286mg, 0.631 mmol), prepared by a procedure analogous to that described above, in dry ethyl acetate (10ml) Y

5 dry methanol (2ml). After stirring at room temperature overnight, the solvent was evaporated, water (10ml) and dioxin (10ml) were added and the pH was adjusted to 10 using 28% NH3 in water. The mixture was extracted with DCM. The combined organic layers were dried (Na2SO4), filtered and evaporated. The crude product was used in the next stage. MS: (ES / +) m / z: 353 [MH +], C20H17FN2O3 requires 352.

Description 72: (2S) -5- (3-cyano-4 - {[(2-fluorophenyl) -methyl] oxy} phenyl) -3,4-dihydro-2H-pyrrol-2-carboxylate methyl (D72):

image 1

Methyl (2S) -5- (3-cyano-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -3,4-dihydro-2H-pyrrole-2-carboxylate (D72, 70mg) was prepared following the procedure described in the

Description 67 using: (2S) -2-Amino-5- (3-cyano-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -4pentinoate methyl (D71). UPLC: Rt = 0.72min, MS: (ES / +) m / z: 353 [MH +], C20H17FN2O3 requires 352. Description 73: (5R) -5- (3-Cyano-4 - {[(2-fluorophenyl) ) methyl] oxy} phenyl) -L-prolinate

image7

A suspension of (2S) -5- (3-cyano-4 {[(2-fluorophenyl) methyl] oxy} phenyl) -3,4-dihydro2H-pyrrole-2-carboxylate methyl (D72, 70mg, 0.198mmol) and Pt (5% on carbon) in ethyl acetate (10ml) was stirred at room temperature for 24 h. Filtration on celite and subsequent evaporation gave the title compound (64mg, 91%).

The material obtained was used without purification in the next step. UPLC: Rt = 0.55min, MS: (ES / +) m / z: 355 [MH +], C20H19FN203 requires 354. Description D74: (2S) -5- (4-Bromophenyl) -2 - ({[(1 , Methyl 1-dimethylethyl) oxy] carbonyl} amino) -4pentinoate (D74)

image 1

A solution of (2S) -2 - ({[(1,1-dimethylethyl) oxy] carbonyl} amino) -4-pentinoate (D64, 1.020g, 4.49 mmol), prepared by a procedure analogous to that described herein above, 4-iodo-bromobenzene (1.524g, 5.38mmol), diethylamine (2.28ml,

1.62g, 22.12mmol), CuI (84mg, 0.441mmol) and Pd (PPh3) 2Cl2 (156mg, 0.22mmol) in diethyl ether (10ml) was stirred at room temperature for 24h. Ethyl acetate was added and the organic layer was washed with aqueous ammonium chloride solution, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by flash chromatography using a gradient of cyclohexane and ethyl acetate (98: 2 to 80:20) to

10 provide the title compound (1,199g, 69%). MS: (ES / +) m / z: 404, 406 [MH +], C17H20BrNO4 requires 404. 1H-NMR (400MHz, DMSO-d6) � (ppm): 7.56 (d, 1H), 7.45 ( d, 1H), 7.32 (d, 1H), 4.30 (m, 1H), 3.67 (s, 3H), 2.82 (m, 2H), 1.40 and 1.38 (2xs , 9H). Description D75: (2S) -2-Amino-5- (4-bromophenyl) -4-methyl pentinoate (D75)

image 1

To a solution of (2S) -5- (4-bromophenyl) -2 - ({[(1,1-dimethylethyl) oxy] carbonyl} amino) 4-pentinoate (D74, 1,199g, 3,136mmol) in Dry EtOAc (18ml) and dry methanol (2ml) AcCl (1.14ml, 1.25g, 15.98mmol) was added. Once the solvent was removed, the residue was purified using an SCX cartridge to provide the title compound (849mg, 95%). UPLC: Rt 0.51 min, MS: (ES / +) m / z: 282, 284

[MH +], C12H12BrNO2 requires 282. Description D76: (2S) -5- (4-Bromophenyl) -3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester (D76)

image 1

A solution of methyl (2S) -2-amino-5- (4-bromophenyl) -4-pentinoate (D75,

849mg, 3.009mmol) and silver triflate (I) in acetonitrile (30ml) was stirred overnight at room temperature. Then brine was added and the product was extracted with dichloromethane. The combined organic layers were dried (Na2SO4), filtered and evaporated to provide the title compound (874mg, 96%). UPLC: Rt 0.70min; MS: (ES / +) m / z: 282, 284 [MH +], C12H12BrN02 requires 282.

Description D77: (5R) -5- (4-Bromophenyl) -L-methyl prolinate (D77)

image 1

A solution of (2S) -5- (4-bromophenyl) -3,4-dihydro-2H-pyrrole-2-carboxylate (D76, 799mg, 2.83mmol) and Pt / C (50mg) was stirred under hydrogen (1atm) overnight. Then TFA (0.25ml) was added and hydrogenation was continued another 2h. Then more Pt / C (100mg) was added and the mixture was stirred for 9 h under hydrogen (1atm). After that, more catalyst (100mg) and TFA (0.25ml) was added

10 and stirring was continued another 5h under hydrogen atmosphere. Then more catalyst (100mg) was added. After 4 h more the reaction was terminated and the solution was filtered over celite, evaporated and purified using an SCX cartridge to provide the title compound (641mg, 79%). UPLC: Rt 0.47min; MS: (ES / +) m / z: 284, 286 [MH +]. C12H14BrN02 requires 284.

Description D78: (2S, 5R) -5- (4-Bromophenyl) -1,2-pyrrolidinedicarboxylate of 1- (1,1-dimethylethyl) and 2-methyl (D78)

image 1

A solution of (5R) -5- (4-bromophenyl) -L-methyl prolinate (D77, 641mg, 2.25mmol) and di-tert-butyl dicarbonate (517mg, 2.37mmol) in dry DCM (10ml) be

20 stirred for 6.5h at room temperature. The reaction was evaporated and purified by flash chromatography using a gradient of ethyl acetate / cyclohexane (5:95 to 40:60) to provide the title compound (636mg, 73%). UPLC: Rt 0.92min; MS: (ES / +) m / z: 384, 386 [MH +], C17H228rNO4 requires 384.

Description 79: (2S, 5R) -5- {4 - [(E) -2-Phenyletenyl] phenyl} -1,2-pyrrolidinedicarboxylate of 1- (1,1-dimethylethyl) and 2-methyl (D79)

image 1

To a vial containing (2S, 5R) -5- (4-bromophenyl) -1,2-pyrrolidinedicarboxylate 1- (1,1-dimethylethyl) and 2-methyl (D78, 100mg, 0.26mmol), carbonate sodium (138mg, 1.30mmol), 4,4,5,5-tetramethyl-2 - [(E) -2-phenyletenyl] -1,3,2-dioxaborolane (90mg, 0.39mmol) and Pd (PPh3) 4 (30mg, 0.026mmol), dioxane (2ml) and water (1ml) were added. The mixture was stirred for 2h at 80 ° C. After cooling, the mixture was extracted with ethyl acetate. The organic layer was filtered through a phase separator tube and

5 evaporated. The residue was purified by chromatography on silica gel using cyclohexane / ethyl acetate (1: 0 to 9: 1) to give the title compound as a light yellow solid (90mg, 85%). Rt (HPLC): 7.02 min; MS: (ES / +) m / z: 308 (MH-Boc) C25H29NO4 requires 407.

Description 80: (2S, 5R) -5- [4- (2-Phenylethyl) phenyl] -1,2-pyrrolidinedicarboxylate of 110 (1,1-dimethylethyl) and 2-methyl (D80)

image 1

To a solution of 1- (1,1-dimethylethyl) and 2-methyl (D79, 50mg) (2-methyl-5-phenylenyl) -phenyl} -1,2-pyrrolidinedicarboxylate , 0.12mmol) in methanol palladium (10mg, 10% by weight as dry matter on active carbon) was added and the

The mixture was stirred under a hydrogen atmosphere (1 atm) for 4h. One more catalyst charge (20mg) was needed for the reaction to be complete (as demonstrated by HPLC). The catalyst was filtered off, the solvent was removed under reduced pressure to provide the title compound as a colorless oil (45mg, 92%). Rt (HPLC): 7.04 min; MS: (ES / +) m / z: 432 [M + Na] C25H31NO4 requires 409.

Description 81: (5R) -5- [4- (2-Phenylethyl) phenyl] -L-prolinamide (D81)

image 1

To a solution of (2S, 5R) -5- [4- (2-phenylethyl) phenyl] -1,2-pyrrolidinedicarboxylate of 1 (1,1-dimethylethyl) and 2-methyl (D80, 43mg, 0.1mmol) in ethyl acetate (0.9ml) and methanol (0.1ml) at 0 ° C AcCl (86µl, 1.20mmol) was added and the mixture was stirred for six hours

25 from 0 ° C to t.a. The solvent was removed in vacuo and the residue was filtered through an SCX cartridge and then dissolved in a 7N solution of ammonia in methanol. This solution was stirred for 18h at t.a. The solvent was evaporated to provide the title compound as a white solid (30mg, quantitative). Rt (HPLC): 3.84 min; MS: (ES / +) m / z: 295 [MH] + C19H22N20 requires 294; 1H-NMR (400 MHz, CDCl3)

30 � (ppm): 7.45-7.69 (sa, 1H); 7.28-7.35 (m, 4H); 7.16-7.25 (m, 5H); 5.31-5.63 (sa, 1 H); 4.30-4.36 (m, 1 H); 3.87-3.93 (m, 1 H); 2.94 (s, 4H); 2.26-2.39 (m, 1 H); 2.11-2.26 (m, 2H); 1.63-1.77 (m, 1 H).

Description 82: 2-Bromo-5 - {[(2-fluorophenyl) methyl] oxy} pyridine (D82)

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5 To a solution of 6-bromo-3-pyridinol (commercial source, 0.870g, 5.0mmol) in acetone (20ml) were added potassium carbonate (1.04g, 7.5mmol) and 1- (bromomethyl) 2- fluorobenzene (Aldrich, 1.2ml, 10.0mmol) and the mixture was stirred for three hours at

t.a. The solvent was evaporated and the residue was diluted with water and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by

Chromatography on silica gel using cyclohexane / ethyl acetate (1: 0 to 98: 2) to provide the title compound as a white solid (1.28g, 90%). MS: (ES / +) m / z: 282,284 [MH] + C12H9BrFNO requires 281,283; 1H-NMR (400 MHz, CDCl3)

� (ppm): 8.12-8.20 (m, 1H); 7.43-7.53 (m, 1 H); 7.32-7.43 (m, 2H); 7.16-7.24 (m, 2H); 7,077.16 (m, 1 H); 5.17 (s, 2H).

Description 83: (2S) -2 - ({[(1,1-Dimethylethyl) oxy] carbonyl} amino) -5- (5 - {[(2-fluorophenyl) methyl] oxy} -2-pyridinyl) -4 -methylpentinoate (D83)

image 1

To a solution of 2-bromo-5 - {[(2-fluorophenyl) methyl] oxy} pyridine (D82, 0.60g, 2.13mmol), (2S) -2 - ({[(1,1-dimethylethyl) Oxy] carbonyl} amino) -4-methyl pentinoate (D64, 1.20g, 5.30mmol), synthesized by a procedure analogous to that described above, and diethylamine (1.10ml, 10.65mmol) in diethyl ether (20ml) copper iodide (0.042g, 0.22mmol) and PdCl2 (PPh3) 2 (0.077g, 0.11mmol) were added and the mixture was stirred for three hours at room temperature. The reaction was quenched with a saturated solution of ammonium chloride, diluted with water and extracted with diethyl ether. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel using cyclohexane / ethyl acetate (9: 1 to 8: 2) to give the title compound as a yellow solid (0.36g, 40%). Rt (HPLC): 5.64 min; MS: (ES / +) m / z: 429 [MH] + C23H25FN2O5 requires 428; 1H-NMR (400 MHz, CDCl3) � (ppm): 8.28-8.39 (m, 1H); 7.44-7.53 (m, 1 H); 7.32-7.41 (m, 2H); 7.16

7.25 (m, 2H); 7.08-7.16 (m, 1 H); 5.37-5.55 (m, 1 H); 5.19 (s, 2 H); 4.46-4.66 (m, 1 H); 3.81 (s, 3 H); 2.91-3.07 (m, 2H); 1.47 (s, 9H).

Description 84: (2S) -2-amino-5- (5 - {[(2-fluorophenyl) methyl] oxy} -2-pyridinyl) -4-methyl pentinoate (D84)

image5

To a solution of (2S) -2 - ({[(1,1-dimethylethyl) oxy] carbonyl} amino) -5- (5 - {[(2fluorophenyl) methyl] oxy} -2-pyridinyl) -4-pentinoate of methyl (D83, 0.43g, 1.0mmol), prepared by a procedure analogous to that described above, in ethyl acetate (4.5ml) and methanol (0.5ml) at 0 ° C was added dropwise AcCl (0.5ml, 7.0mmol) and the

10 mixture was stirred at 0 ° C at t.a. for four hours The solvent was removed in vacuo. The residue was diluted with a saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried, filtered and evaporated to give the title compound as a yellow oil (0.30g, 91%). Rt (HPLC): 3.60 min; MS: (ES / +) m / z: 329 [MH] + C18H17FN203 requires 328; 1H-NMR (400 MHz, CDCl3)

15 � (ppm): 8.30-8.36 (m1H); 7.45-7.51 (m, 1 H); 7.31-7.40 (m, 2H); 7.16-7.24 (m, 2H); 7,077.16 (m, 1 H); 5.19 (s, 2 H); 3.75-3.81 (m, 1 H); 3.79 (s, 3 H); 2.80-2.99 (m, 2H). Description 85: (2S) -5- (5 - {[(2-fluorophenyl) methyl] oxy} -2-pyridinyl) -3,4-dihydro-2Hpyrrol-2-carboxylic acid methyl ester (D85)

image 1

A solution of methyl (2S) -2-amino-5- (5 - {[(2-fluorophenyl) methyl] oxy} -2-pyridinyl) -4pentinoate (D84, 300mg, 0.91mmol) in acetonitrile is Silver triflate (24mg, 0.091mmol) was added and the mixture was stirred for 60 hours at room temperature. The solvent was evaporated and the residue was diluted with water and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated to provide the compound of

25 title as a yellow solid (300mg, quantitative). Rt (HPLC): 3.58 min; MS: (ES / +) m / z: 329 [MH] + C18H17FN203 requires 328. Description 86: (5R) -5- (5 - {[(2-Fluorophenyl) methyl] oxy} -2-pyridinyl) -L -methylprolinate (D86) To a solution of (2S) -5- (5 - {[(2-fluorophenyl) methyl] oxy} -2-pyridinyl) -3,4-dihydro-2Hpyrrol-2-carboxylate (D85, 300mg, 0.91mmol) in ethyl acetate was added platinum on active carbon (70mg, 5% by weight as dry matter Degussa type F101 RAW) and the mixture was stirred under hydrogen atmosphere (P = 1atm) for 4 hours. After adding another load of acetic acid (0.4ml) and stirring for 12 hours the reaction remained incomplete. It was necessary to add more catalyst (70mg) and trifluoroacetic acid for the reaction to end. The catalyst was filtered off, the solvent was removed under reduced pressure and the residue was filtered on an SCX cartridge. The residue was purified by chromatography on silica gel using cyclohexane / ethyl acetate (7: 3 to 6: 4) to provide the title compound as a colorless oil (180mg, 60%). Rt (HPLC): 3.69 min; MS: (ES / +) m / z: 331 [MH] + C18H19FN203 requires 330; 1H-NMR (400 MHz, CDCl3) � (ppm): 8.27-8.43 (m, 1H); 7.45-7.56 (m, 1 H); 7.38-7.44 (m, 1 H); 7.31-7.38 (m, 1 H); 7.24-7.31 (m, 1 H); 7,157.23 (m, 1 H); 7.08-7.15 (m, 1 H); 5.18 (s, 2H); 4.32-4.41 (m, 1 H); 3.98-4.05 (m, 1 H); 3.79 (s, 3 H); 2.19-2.31 (m, 2H); 2.04-2.13 (m, 1 H); 1.77-1.90 (m, 1 H). Description 87: N- (Phenylmethyl) -2-propen-1-amine (D87)

image 1

image 1

To a solution of benzylamine (5.7ml, 52.2mmol) and sodium iodide (38mg, 0.25mmol) in DMSO (30ml) allyl bromide (2.2ml, 25.4mmol) was added dropwise at 0 ° C in argon. After stirring for 3h at room temperature the reaction was complete as indicated by TLC (cyclohexane: ethyl acetate 1: 1). Then a saturated aqueous solution of sodium bicarbonate was added, the product was extracted with diethyl ether (100ml) and the organic layer was washed with brine. The crude product was purified by flash chromatography to give the title compound (2.1g, 57%) as a clear oil. 1H NMR (400 MHz, CDCl3) � (ppm): 7.4-7.2 (m, 5H), 6.0-5.9 (m, 1H), 5.35.1 (m, 2H), 3.8 (s, 2H), 3.3 (d, 2H), 1.5 (sa, 1H). Description 88: N - {[(1,1-Dimethylethyl) oxyl] carbonyl} -N- (phenylmethyl) glycine (D88)

image 1

A solution of N- (phenylmethyl) glycine (990mg, 6.0mmol), triethylamine (1.58ml, 12mmol) and Boc2O (1.44g, 6.6mmol) in water / THF (1: 1, 30ml) was stirred at room temperature for 1h. The THF was evaporated 5% HCl was added until pH = 4. The product was extracted with ethyl acetate and evaporated. The residue was purified by flash chromatography to give the title compound (1.47g, 92%).

Description 89: 1,1-dimethylethyl {2-Oxo-2 - [(phenylmethyl) (2-propen-1-yl) -amino] ethyl} (phenylmethyl) carbamate (D89):

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A solution of N - {[(1,1-dimethylethyl) oxy] carbonyl} -N- (phenylmethyl) glycine (D88, 1.06g, 4.0mmol), DIPEA (1.38ml, 8.0mmol) and TBTU (1.61g, 5.0mmol) in dry DMF (8ml) was stirred at room temperature for 30min. Then N (phenylmethyl) -2-propen-1-amine (D87, 647mg, 4.4mmol) was added and stirring was continued another 2h. After completion of the reaction, ethyl acetate was added and the organic layer was

15 washed with water and brine. The residue was purified by flash chromatography to give the title compound (1.50g, 95%). 1H NMR (400 MHz, CDCl3) � (ppm): 7.4-7.2 (m, 10H), 5.8-5.5 (m, 1H), 5.2-5.0 (m, 2H ), 4.7-4.3 (m, 4H), 4.1-3.7 (m, 4H), 1.5 (s, 9H); MS: (ES / +) m / z: 295 [M-BOC +], C24H30N2O3 requires 394. Description 90: N1, N2-bis (phenylmethyl) -N1-2-propen-1-ylglycinamide (D90):

image6

TFA (3ml) was added dropwise to a solution of {2-oxo-2 - [(phenylmethyl) (2propen-1-yl) -amino] ethyl} (phenylmethyl) carbamate 1,1-dimethylethyl (D89, 1 , 18g, 3mmol) in dry dichloromethane (12ml) at 0 ° C. After stirring at room temperature for 3h the solvent was evaporated and the residue was purified on an SCX cartridge to give the

25 title compound (880mg, quant.) As a clear oil. 1H NMR (400 MHz, CDCl3)

� (ppm): 7.4-7.2 (m, 10H), 5.9-5.6 (m, 1H), 5.2-5.0 (m, 2H), 4.6, 4, 4 (s, 2H), 4.1-3.7 (m, 4H), 3.5 (s, 2H), 2.4 (sa, 1H).

image8

To a solution of (2-fluorophenyl) methanol (Aldrich, 10.0g, 79.3mmol) and triphenylphosphine (29.1g, 111mmol) in DCM was added CBr4 (31.6g, 95.2mmol) in

5 small portions at 0 ° C. The mixture was stirred for 2h at room temperature. The solvent was evaporated and the residue was purified by flash chromatography (cyclohexane: ethyl acetate 95: 5) to give the title compound (14g, 93%). 1H NMR (400 MHz, CDCl3) � (ppm): 7.42 (t, 1H), 7.36-7.28 (m, 1H), 7.17-7.07 (m, 2H), 4, 55 (s, 2H).

Description 92: 4 - {[(2-Fluorophenyl) methyl] oxy} benzaldehyde (D92)

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A suspension of 1- (bromomethyl) -2-fluorobenzene (D91, 11.5g, 60.8mmol), 4-hydroxybenzaldehyde (5.3g, 43.3mmol) and K2CO3 (12.0g, 86.8mmol) in acetone was divided into three equal parts and heated in a microwave at 80 ° C for

15 40min. The mixtures were diluted with water and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (cyclohexane: ethyl acetate 95: 5) to give the title compound (7.9g, 79%). Rf (cyclohexane: ethyl acetate 8: 2): 0.38.

Description 93: rac- (2R, 3aR, 6aR) -2- (4 - {[(2-Fluorophenyl) methyl] oxy} phenyl) -1,5-bis (fe20 nylmethyl) hexahydropyrrolo [3,4-b] pyrrole -6 (1H) -one (D93)

image 1

A solution of 4 - {[(2-fluorophenyl) methyl] oxy} benzaldehyde (D92, 920mg, 4.0mmol), prepared by a procedure analogous to that described above, N1, N2bis (phenylmethyl) -N1-2-propen -1-ilglicinamide (D90, 588mg, 2.0mmol) and DIPEA (0.68ml,

4.0mmol) in dry toluene (8ml) was stirred at 120 ° C for 72h. Once the reaction was over, it was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The residue was purified by flash chromatography to provide the title compound (503mg, 50%) as a racemate. Rf (cyclohexane: ethyl acetate 1: 1): 0.57.

Description 94: rac- (2R, 3aR, 6aR) -2- (4 - {[(2-Fluorophenyl) methyl] oxy} phenyl) -1- (phenylmethyl) hexahydropyrrolo [3,4-b] pyrrole-6 (1H ) -one (D94)

image5

Rac- (2R, 3aR, 6aR) -2- (4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -1,5-bis (phenylmethyl) -hexahydropyrrolo [3,4-b] pyrrole was dissolved 6 (1H) -one (D93, 503mg, 1.0mmol) in DMSO (647mg, 10.0mmol) and the solution was stirred at room temperature. Then tBuOK (7.0ml, 1M solution in THF) was added. Then an oxygen stream was passed to

10 through the solution, using a gas dispersion tube for 30min. Saturated ammonium chloride was added. The crude product was purified by flash chromatography to provide the title compound (60mg, 20%). 1H NMR (400 MHz, CHCl3-d) � ppm 7.48 (t, 1 H), 7.41 (d, 2 H), 7.30 (d, 2 H), 7.24 (t, 3 H ), 7.16 (dd, 1 H), 7.13 (t, 1 H), 7.05 (t, 1 H), 6.95 (d, 2 H), 5.48-5.59 ( m, 1 H), 5.09 (s, 2 H), 4.21

15 (d, 1 H), 3.76-3.85 (m, 1 H), 3.71 (d, 1 H), 3.45-3.54 (m, 2 H), 3.09 ( d, 1 H), 2.88-2.97 (m, 1 H), 2.08-2.21 (m, 1 H), 1.96-2.07 (m, 1 H). Description 95, Description 96: (2S, 5R) -2 - [(dimethylamino) carbonyl] -5- (4 - {[(2fluorophenyl) methyl] oxy} phenyl) -1-pyrrolidinecarboxylate of 1,1-dimethylethyl (D95) and (2R, 5S) -2- (4 - {[(2-fluorophenyl) methyl] oxy} phenyl-5 - [(methylamino) carbonyl] -1-pyrrolidinecarb

20-1,1-dimethylethyl xylate (D96)

image 1

To a solution of (2S, 5R) -2- (aminocarbonyl) -5- (4 - {[(2-fluorophenyl) methyl] oxy} phenyl) 1-pyrrolidinecarboxylate of 1,1-dimethylethyl (D14, 80mg, 0, 19mmol), prepared using a procedure analogous to that described above, in N, N-dimethylformamide at 0 ° C

25 added sodium hydride (8.0mg, 0.22mmol, 60% dispersion in mineral oil) and the mixture was stirred for 10 min at the same temperature. Methyl iodide (18 µL, 0.29mmol) was added and the mixture was stirred for one hour at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with ice-cold brine, dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica gel. D96 (40mg, 49%). Rt (HPLC): 5.73 min; MS: (ES / +) m / z: 451 [M + Na] C24H29FN2O4 requires 428; 1H NMR (400 MHz, DMSO-d6)

� (ppm): 7.78-8.02 (sa, 1H); 7.47-7.68 (m, 3H); 7.34-7.47 (m, 1 H); 7.17-7.33 (m, 2H); 6.87

5 6.89 (m, 2H); 5.12 (s, 2H); 4.70-4.90 and 4.50-4.70 (m, m, 1H); 4.01-4.28 (m, 1 H); 2.64 and 2.65 (s, s, 3H); 2.11-2.30 (m, 1 H); 1.92-2.11 (m, 1 H); 1.65-1.92 (m, 2H); 1.31 and 1.06 (s, s, 9H). D95 (20mg) as a mixture (1: 1) of the dimethyl compound [(R1 = R2 = CH3) Rt (HPLC): 5.96 min; MS: (ES / +) m / z: 343 [MH-Boc] C25H31FN2O4 requires 442] and the starting material (R1 = R2 = H) [Rt (HPLC): 5.54min; MS: (ES / +) m / z: 315 [MH-Boc] C23H27FN2O4

10 requires 414].

Examples

Example 1, Example 2: (2,6) -6- (4 - {[(3-Fluorophenyl) methyl] oxy} phenyl) -2-piperidinecarboxamide (enantiomer 1, E1), (2,6) -6- ( 4 - {[(3-Fluorophenyl) methyl] oxy} phenyl) -2

15 piperidinecarboxamide (enantiomer 2, E2)

image 1

A solution of 6- (4 - {[(3-fluorophenyl) methyl] oxy} phenyl) -2-pyridinecarboxamide (D4, 80mg, 0.26mmol) and PtO2 (27mg, 0.12mmol) in acetic acid (20ml) was stirred under hydrogen atmosphere (4 atmospheres) for 16h. The acetic acid evaporated and the

The residue was taken up in DCM and washed with a solution of NaHCO3. The resulting crude material was purified by chromatography on silica gel to provide the title compound (40mg, 46%) as a mixture of enantiomers and starting material (D4, 16mg); MS: (ES / +) m / z: 329 [MH +], C19H21FN2O2 requires 328; 1H NMR (500 MHz, DMSO-d6) � (ppm): 7.39-7.46 (m, 1H), 7.31 (d, 2H), 7.26 (t, 2H), 7.14 ( t

1H), 7.05-7.11 (m, 1H), 6.88-6.98 (m, 3 H), 5.02-5.17 (m, 2H), 3.53 (d, 1H), 3.11 (d, 1H), 2.28-2.38 (m, 1H), 1.82 (d, 2H), 1.64 (d, 1H), 1.39-1.53 (m, 1H), 1.16-1.30 (m, 2H).

The enantiomers were separated by chiral preparative HPLC using a Chiralcel OD 10 um column (250 x 4.6 mm, mobile phase: A: n-hexane; B: ethanol, 30 gradient: isocratic 30% B, flow rate: 0.8 ml / min, UV wavelength range: 200

400 nm). E1: Rt = 11.99min, 49.9% y / y; E2: Rt = 14.95min, 50.1% a / a).

Example 3: (5R) -5- {4 - [(phenylmethyl) oxy] phenyl} -L-prolinamide hydrochloride (E3):

image 1

To a solution of (2S, 5R) -2- (aminocarbonyl) -5- {4 - [(phenylmethyl) oxy] phenyl} -1-1,1-dimethyl ethyl pyrrolidinecarboxylate (D12, 45mg, 0.113mmol) in an acetate mixture of ethyl and methanol (9/1, 1ml) acetyl chloride (20 µl, 0.282mmol) was added to

5 0 ° C. The mixture was stirred for 1.5 h and slowly allowed to warm to room temperature. After 4h under these conditions, more acetyl chloride (20 µl, 0.654mmol) was added. After evaporating the solvent, the residue was triturated with diethyl ether to yield the title compound as a white solid (25 mg, 66%); Rt (HPLC): 3.55 min; 1H NMR (300 MHz, DMSO-d6) � (ppm): 10.50 (sa, 1H); 8.15 (sa,

10 1H); 8.05 (s, 1 H); 7.73 (s, 1 H); 7.42-7.49 (m, 4H); 7.40 (t, 2H); 7.30-7.36 (m, 1 H); 7.08 (d, 2H); 5.15 (s, 2H); 4.60 (dd, 1 H); 4.30 (dd, 1 H); 2.23-2.40 (m, 2H); 2.10-2.20 (m, 1 H); 1.95-2.08 (m, 1 H). Example 5: (5R) -5- (4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -L-prolinamide hydrochloride

image9

Procedure 1: To a solution of (2S, 5R) -2- (aminocarbonyl) -5- (4 - {[(2fluorophenyl) methyl] oxy} phenyl) -1-pyrrolidinecarboxylate of 1,1-dimethylethyl (D14, 51 g , 0.123 mmol) in a mixture of ethyl acetate (0.9 ml) and methanol (1 ml), acetyl chloride (28 µl, 2.5 eq.) Was added at 0 ° C. The mixture was stirred for 1.5 h and slowly left

20 to warm to room temperature. After evaporating the solvent, the residue was triturated with diethyl ether to yield the title compound as a white solid (42 mg, quant.); Chiral HPLC: Column: Chiralcel OD 10 um, 250 x 4.6 mm; Mobile phase: A: n-hexane; B: ethanol; Gradient: isocratic, 30% B; Flow rate: 0.8 ml / min; UV wavelength range: 200-400 nm; Analysis time: 22 min;

25 Ret time: 12.0 min; [�] D = -30.5 °. MS: (ES / +) m / z: 315 [MH +]; C18H19FN2O2 requires 314; 1H NMR (400 MHz, DMSO-d6) � ppm 10.19 (sa, 1H), 8.13 (sa, 1H), 7.94 (s, 1H), 7.60-7.77 (m, 1H ), 7.51 (dt, 1H), 7.43 (d, 2H), 7.34-7.41 (m, 1H), 7.23 (d, 1H), 7.18 (dd, 1H) , 7.05 (d, 2H), 5.13 (s, 2H), 4.49-4.60 (m, 1H), 4.19 -4.28 (m, 1H), 2.17-2 , 38 (m, 2H), 2.05-2.16 (m, 1H), 1.92-2.03 (m, 1H).

The hydrochloride salts of the following compounds of formula (If) were prepared by a procedure similar to that used for Example 5, Procedure 1. For each compound, a reference to a starting material is provided. This is provided merely as an aid to the skilled chemist. The starting material may not necessarily have been prepared from the indicated batch.

image 1

No.

YE R6 Characterization

E6

D15 3-fluorobenzoxy MS: (ES / +) m / z: 315 [MH +]. C18H19FN2O2 requires 314; 1H NMR (400 MHz, DMSO-d6) � ppm 10.00 (sa, 1H), 8.23 (sa, 1H), 7.95 (s, 1H), 7.68 (s, 1H), 7, 42 (d, 2H), 7.36-7.41 (m, 1H), 7.20 -7.27 (m, 2H), 7.11 (dt, 1H), 7.03 (d, 2H) , 5.13 (s, 2H), 4.47-4.60 (m, 1H), 4.15-4.30 (m, 1H), 2.18 -2.36 (m, 2H), 2 , 04 -2.17 (m, 1H), 1.88-2.04 (m, 1H).

E7

D16 3-cyanobenzoxy Rt (HPLC) 3.40min; MS: (ES / +) 322 m / z: [MH +]. C19H19N3O2 requires 321; 1H-NMR (400 MHz, DMSO-d6) � (ppm): 1.99 -2.07 (m, 1H); 2.10 -2.21 (m, 1 H); 2.23-2.40 (m, 2H); 4.26 -4.33 (m, 1 H); 4.54 -4.65 (m, 1 H); 5.22 (s, 2H); 7.10 (d, 2H); 7.48 (d, 2H); 7.62 (t, 1 H); 7.74 (s, 1 H) 7.79 (s, 1 H); 7.82 (d, 1 H); 7.93 (s, 1 H); 8.12 (sa, 1 H); 8.05 (s, 1 H); 10.48 (sa, 1 H).

E8

D17 4-fluorobenzoxy Rt (HPLC) 3.65min; MS: (ES / +) 315 m / z: [MH +]. C18H19FN2O2 requires 314.

E9

D18 2-cyanobenzoxy Rt (HPLC) 3.37min; MS: (ES / +) 322 m / z: [MH +]. C19H19N3O2 requires 321; 1H NMR (500 MHz, DMSO-d6) � (ppm): 10.47 (sa, 1H), 8.18 (sa, 1H), 8.03 (s, 1H), 7.91 (d, 1H) , 7.69-7.80 (m, 3H), 7.58 (dt, 1H), 7.49 (d, 2H), 7.11 (d, 2H), 5.28 (s, 2H), 4.61 (dd, 1H), 4.28 (dd, 1H), 2.22 2.41 (m, 2H), 2.10 - 2.19 (m, 1H), 1.95 -2.09 (m, 1H).

No.

YE R6 Characterization

E10

D19 4-cyanobenzoxy Rt (HPLC) 3.39min; MS: (ES / +) 322 m / z: [MH +]. C19H19N3O2 requires 321.,

E11

D20 2- (trifluoromethoxy) benzoxy Rt (HPLC) 4.14min; MS: (ES / +) 381 m / z: [MH +]. C19H19F3N2O3 requires 380. 1H NMR (500 MHz, DMSO-d6) � (ppm): 10.44 (sa, 1H), 8.21 (sa, 1H), 8.02 (s, 1H), 7.72 ( s, 1H), 7.65 (dd, 1H), 7.50-7.55 (m, 1H), 7.48 (d, 2H), 7.43 (t, 2H), 7.08 (d , 2H), 5.16 (s, 2H), 4.59 (dd, 1H), 4.29 (dd, 1H), 2.23 -2.39 (m, 2H), 2.11 -2, 19 (m, 1H), 1.96-2.08 (m, 1H).

E12

D21 (1R) -1-phenylethyloxy Rt (HPLC) 3.75min; MS: (ES / +) m / z: 311 [MH +]. C19H22N2O2 requires 310; 1H NMR (500 MHz, DMSO-d6) � ppm 10.27 (sa, 1H), 8.17 (sa, 1H), 7.98 (s, 1H), 7.69 (s, 1H), 7, 40 (d, 2H), 7.29-7.36 (m, 4H), 7.24 (t, 1H), 6.95 (d, 2H), 5.54 (q, 1H), 4.47 -4.56 (m, 1H), 4.21 -4.29 (m, 1H), 2.17 -2.39 (m, 2H), 2.06 -2.16 (m, 1H), 1 , 91 -2.06 (m, 1H), 1.54 (d, 3H).

E13

D22 4-fluorophenoxy Rt (HPLC) 3.47 min; MS: (ES / +) m / z: 301 [MH +]. C17H17FN2O2 requires 300; 1H-NMR (500 MHz, DMSO-d6) � ppm 10.51 (sa, 1H), 8.28 (sa, 1H), 8.03 (s, 1H), 7.74 (s, 1H), 7 , 55 (d, 2H), 7.26 (t, 2H), 7.07-7.12 (m, 2H), 7.04 (d, 2H), 4.63 (dd, 1H), 4, 31 (dd, 1H), 2.26 -2.43 (m, 2H), 2.11-2.21 (m, 1H), 1.96-2.11 (m, 1H).

E14

D23 4-cyanophenoxy Rt (HPLC) 3.31min. MS: (ES / +) 308 m / z: [MH +]. C18H17N3O2 requires 307.

E15

D24 phenoxy Rt (HPLC) 3.45min. MS: (ES / +) 283 m / z: [MH +]. C17H18N3O2 requires 282. 1H NMR (500 MHz, DMSO-d6) � (ppm): 10.23 (sa, 1H), 8.22 (sa, 1H), 7.95-8.07 (m, 1H), 7.74 (s, 1H), 7.56 (d, 2H), 7.41 (t, 2H), 7.18 (t, 1H), 7.08 (d, 2H), 7.02

No.

YE R6 Characterization

 image 1

 image 1

 image 1

(d, 2H), 4.63 (dd, 1H), 4.30 (dd, 1H), 2.27 -2.44 (m, 2H), 2.11-2.22 (m, 1H), 1.96 - 2.12 (m, 1 H).

E16

D25 3-fluorophenoxy Rt (HPLC) 3.61min. MS: (ES / +) 301 m / z: [MH +]. C17H17FN2O2 requires 336. 1H-NMR (400 MHz, DMSO-d6) 8 (ppm): 1.98 -2.11 (m, 1H); 2.11 -2.22 (m, 1 H); 2.28 -2.42 (m, 2H); 4.27 -4.35 (m, 1 H); 4.61 -4.70 (m, 1 H); 6.85 (d, 1 H); 6.88 (dd, 1 H); 7.00 (t, 1 H); 7.14 (d, 2H); 7.44 (dd, 1 H); 7.58 (d, 2H); 7.73 (s, 1 H); 8.02 (s, 1 H); 8.25 (sa, 1 H); 10.40 (sa, 1 H).

E17

D26 2-cyanophenoxy Rt (HPLC) 3.21min. MS: (ES / +) m / z: 308 [MH +]. C17H17FN2O2 requires 336. 1H NMR (500 MHz, DMSO-d6) � (ppm): 10.63 (sa, 1H), 8.36 (sa, 1H), 8.03-8.11 (m, 1H), 7.93 (dd, 1H), 7.76 (s, 1H), 7.71 (dt, 1H), 7.64 (d, 2H), 7.34 (t, 1H), 7.23 (d , 2H), 7.01 (d, 1H), 4.63 -4.75 (m, 1H), 4.29 -4.37 (m, 1H), 2.31 -2.43 (m, 2H ), 2.11 -2.22 (m, 1H), 1.99 - 2.12 (m, 1H).

The hydrochloride salts of the following compounds of formula (Ig) were prepared by a procedure similar to that used for Example 5, Procedure 1. For each compound, a reference to a starting material is provided. This is provided merely as an aid to the skilled chemist. The starting material may not necessarily have been prepared from the indicated batch.

image 1

No.

YE R6 Characterization

E18

D29 benzoxy Rt (HPLC): 3.49 min. MS: (ES / +) m / z: 297 [MH +]. C18H20N2O2 requires 296. 1H NMR (500 MHz, DMSO-d6) � (ppm): 9.39-9.14 (sa, 2H), 8.01 (s, 1H), 7.67 (s, 1H), 7.48 (d, 2H), 7.46-7.42 (m, 2H), 7.38 (t, 2H), 7.34-7.29 (m, 1H), 7.06 (d, 2H), 5.13 (s, 2H), 4.61 (dd, 1H), 4.31 (t, 1H), 2.57-2.46 (m, 1H), 2.37-2.26 (m, 1H), 2.16-2.03 (m, 1H), 1.99-1.88 (m, 1H).

Example 20: (5S) -5- {4 - [(phenylmethyl) oxy] phenyl} -D-prolinamide hydrochloride (E20):

image 1

5 To a solution of (2R, 5S) -2- (aminocarbonyl) -5- {4 - [(phenylmethyl) oxy] phenyl} -1-pyrrolidinecarboxylate of 1,1-dimethyl ethyl (D38, 50mg, 0.126mmol) in a mixture of ethyl acetate (0.9 ml) and methanol (0.1 ml) acetyl chloride (50 µl, 0.63mmol) was added at 0 ° C. The mixture was stirred for 2 h and slowly allowed to warm to room temperature. After evaporating the solvent, the

The residue was triturated with diethyl ether to yield the title compound as a white solid (35 mg, 85%); Rt (HPLC): 3.55 min; MS: (ES / +) m / z: 297 [MH +], C18H20N2O2 requires 296; 1H NMR (400 MHz, DMSO-d6) � (ppm): 10.50 (sa, 1H); 8.15 (sa, 1 H); 8.05 (s, 1 H); 7.73 (s, 1 H); 7.42-7.49 (m, 4H); 7.40 (t, 2H); 7.30-7.36 (m, 1 H); 7.08 (d, 2H); 5.15 (s, 2H); 4.60 (dd, 1 H); 4.30 (dd, 1 H); 2.23-2.40 (m, 2H); 2.10-2.20 (m, 1 H);

15 1.95-2.08 (m, 1 H). Example 23: (5R) -5- (2-Fluoro-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -Lprolinamide hydrochloride (E23):

image 1

To a solution of (2S, 5R) -2- (aminocarbonyl) -5- (2-fluoro-4 - {[(2

1,1-Dimethyl ethyl -1-pyrrolidinecarboxylate (D47, 130mg, 0.300mmol) in a mixture of ethyl acetate (2.3ml) and methanol (0.230ml) was added acetyl chloride (64µl, 2.5eq) at 0 ° C. The mixture was stirred for 2 h and slowly allowed to warm to room temperature. After evaporating the solvent, the residue was triturated with diethyl ether to yield the title compound as a white solid (101 mg, 92%); Rt (HPLC): 3.66 min; MS: (ES / +) m / z: 333 [MH +], C18H18F2N202 requires 332; 1H NMR (400 MHz, DMSO-d6) � (ppm): 10.36 (sa, 1H), 8.35 (sa, 1H), 8.04 (s, 1H), 7.72 (s, 1H) , 7.51-7.64 (m, 2H), 7.40-7.49 (m, 1H), 7.20-7.32 (m, 2H), 7.05 (dd, 1H), 6 , 98 (dd, 1H), 5.19 (s, 2H), 4.81 (dd, 1H), 4.31 (dd, 1H), 2.22 - 2.42 (m, 2H), 2, 01-22 (m, 2H).

Example 24: (5R) -5- {3 - [(phenylmethyl) oxy] phenyl} -L-prolinamide hydrochloride (E24):

image 1

To a solution of (2S, 5R) -2- (aminocarbonyl) -5- {3 - [(phenylmethyl) oxy] phenyl} -1

1,1-dimethylethyl pyrrolidinecarboxylate (D54, 142mg, 0.358mmol) in a mixture of ethyl acetate (2.3 ml) and methanol (0.23 ml) was added acetyl chloride (64 µl, 2.5eq) at 0 ° C. The mixture was stirred for 1.5 h and slowly allowed to warm to room temperature. After evaporating the solvent, the residue was triturated with diethyl ether to yield the title compound as a white solid (71 mg, 60%);

15 Rt (HPLC): 3.51 min. MS: (ES / +) m / z: 297 [MH +], C18H20N2O2 requires 296; 1H NMR (400 MHz, DMSO-d6) � (ppm): 10.52 (sa, 1H), 8.41 (sa, 1H), 8.03 (s, 1H), 7.73 (s, 1H) , 7.31-7.50 (m, 6 H), 7.26 (t, 1H), 7.10 (d, 1H), 7.06 (dd, 1H), 5.13 (s, 2H) , 4.62 (dd, 1H), 4.32 (dd, 1H), 2.24-2.44 (m, 2H), 2.09-2.23 (m, 1H), 1.93-2 , 09 (m, 1H).

Example 25: (5R) -5- [4 - {[(2-fluorophenyl) methyl] oxy} -3- (methyloxy) phenyl] 20 L-prolinamide (E25) hydrochloride

image 1

The title compound was synthesized by a procedure analogous to that described as procedure 2 for Example 4 using (5R) -5- [4 - {[(2-fluorophenyl) methyl] oxy} -3 (methyloxy) phenyl] -L- methyl prolinate (D62, 95mg, 0.264mmol). The free base was purified

25 by flash chromatography using dichloromethane with MeOH (2% to 20%) and converted as described in Example 4 by procedure 2 in the hydrochloride salt. MS: (ES / +) m / z: 344 [MH +], C19H21FN2O3 requires 344. 1H NMR (300 MHz, DMSO-d6) 8 ppm: 9.79 (sa, 2 H), 7.96 (s, 1 H), 7.71 (s, 1 H), 7.55 (t, 1 H), 7.42 (q, 1 H), 7.19-7.33 (m, 3 H), 7.12 (d, 1 H), 7.01 (d, 1 H), 5.13 (s, 2 H), 4.49-4.62 (m,

30 1 H), 4.20-4.30 (m, 1 H), 3.78 (s, 3 H), 1.91 - 2.45 (m, 4 H).

Example 26: (5R) -5- (4 - {[(2-fluorophenyl) methyl] amino} phenyl) -Lprolinamide hydrochloride (E26):

image 1

The title compound was synthesized by a procedure analogous to that described.

5 as procedure 2 for Example 5 using (5R) -5- (4 - {[(2-fluorophenyl) methyl] amino} phenyl) -L-methyl prolinate (D68, 36mg, 0.109mmol). The free base was purified by flash chromatography using dichloromethane with MeOH (2% to 20%) and converted as described in Example 4 by procedure 2 in the hydrochloride salt. MS: (ES / +) m / z: 314 [MH +], C18H20FN3O requires 313; 1H NMR (300

10 MHz, DMSO-d6) � ppm 10.17 - 10.32 (m, 1 H), 8.02 (s, 1 H), 7.77 - 7.91 (m, 1 H), 7.72 (s, 1 H), 7.35-7.45 (m, 1 H), 7.27-7.33 (m, 1 H), 7.24 (d, 2 H), 7.12-7 , 23 (m, 2 H), 6.65 (d, 2 H), 4.40 - 4.55 (m, 1 H), 4.35 (s, 2 H), 4.20 - 4.31 (m, 1 H), 2.26 - 2.42 (m, 1 H), 2.09 - 2.25 (m, 2 H), 1.91 - 2.08 (m, 1 H)

Example 27: (5R) -5- (3-cyano-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -L15 prolinamide hydrochloride (E27):

image 1

A solution of (5R) -5- (3-cyano-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -L-methyl prolinate (D73, 64mg, 0.188mmol) in 7M NH3 / MeOH (2ml ) stirred 10.5h at 40 ° C. The solvent was evaporated and the residue was purified by flash chromatography using a

20 DCM / MeOH (98: 2 to 8: 2) to give (5R) -5- (3-cyano-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -Lprolinamide (44mg, 72%) in free base shape. The title compound (32mg) was prepared as described for example 4 in procedure 2. MS: (ES / +) m / z: 340 [MH +], C19H18FN302 requires 339. 1H NMR (300 MHz, DMSO- d6) � ppm 10.37 (sa, 1 H), 8.54 (sa, 1 H), 8.04 (sa, 1 H), 7.97 (d, 1 H), 7.85 (dd, 1 H), 7.74 (sa, 1 H),

25 7.63 (td, 1 H), 7.50 (d, 1 H), 7.43 - 7.55 (m, 1 H), 7.25 - 7.36 (m, 2 H), 5 , 32-5.44 (m, 2 H), 4.56-4.82 (m, 1 H), 4.21-4.42 (m, 1 H), 2.22-2.43 (m , 2 H), 1.94-2.26 (m, 2 H). Example 28: (5R) -5- [4- (2-phenylethyl) phenyl] -L-prolinamide hydrochloride (E28)

image 1

To a suspension of (5R) -5- [4- (2-phenylethyl) phenyl] -L-prolinamide (D81, 30mg, 0.1 mmol) in diethyl ether (2ml) was added hydrochloric acid (1N in Et2O, 150µl ) and the mixture was crushed. The solvent was removed in vacuo to provide the compound of

5 title as a white solid (30mg, 91%). Rt (HPLC): 3.81 min; MS: (ES / +) m / z: 295 [M] + C19H22N2O requires 294; 1H NMR (500 MHz, DMSO-d6) � (ppm): 8.15-8.98 (sa, 2H); 8.01 (s, 1 H); 7.71 (s, 1 H); 7.43 (d, 2H); 7.30 (d, 2H); 7.26 (d, 2H); 7.24 (t, 2H); 7.17 (t, 1 H); 4.51-4.65 (m, 1 H); 4.23-4.33 (m, 1 H); 2.81-2.95 (m, 4H); 2.25-2.39 (m, 2H); 2,082.20 (m, 1 H); 1.92-2.06 (m, 1 H).

Example 29: (5R) -5- (5 - {[(2-fluorophenyl) methyl] oxy} -2-pyridinyl) -Lprolinamide hydrochloride (E29)

image 1

Methyl (5R) -5- (5 - {[(2-fluorophenyl) methyl] oxy} -2-pyridinyl) -L-prolinate (D86, 50mg) was dissolved in 7M ammonia in methanol (2ml) and the mixture was stirred overnight at room temperature. The solvent was removed in vacuo; The residue was dissolved in diethyl ether (1ml) and hydrochloric acid (0.35ml, 1M solution in Et2O) was added. The suspension was triturated and the solvent removed to give the title compound as a white solid (38mg, 72%). Rt (HPLC): 3.34 min; MS: (ES / +) m / z: 316 [MH] + C17H18FN302 requires 315; 1H NMR (500 MHz, DMSO-d6) � (ppm): 10.43

20 10.64 (m, 1 H); 8.37 (d, 1 H); 8.29-8.41 (m, 1 H); 8.00-8.06 (m, 1 H); 7.72-7.77 (m, 1 H); 7.59 (dd, 1 H); 7.54 (t, 1 H); 7.46 (t, 1 H); 7.36-7.44 (m, 1 H); 7.18-7.26 (m, 2H); 5.21 (s, 2H); 7.71-4.89 (m, 1 H); 4.20-4.37 (m, 1 H); 2.25-2.45 (m, 2H); 1.91-2.09 (m, 1 H); 1,671.89 (m, 1 H).

Example 30: Rac- (2R, 3aR, 6aR) -2- (4 - {[(2-fluorophenyl) methyl] 25 oxy} phenyl) hexahydropyrrolo [3,4-b] pyrrole-6 (1H) -one hydrochloride (E30)

image 1

Rac- (2R, 3aR, 6aR) -2- (4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -1 (phenylmethyl) hexahydropyrrolo [3,4-b] pyrrole-6 (1H) - one (D94, 42mg, 0.1mmol) in dry MeOH (12ml), some drops of AcOH and 42mg of Pd / C (10%) were added and the solution

5 was stirred at room temperature under 1 atm of hydrogen overnight. The solvent was evaporated and the residue was purified by mass directed preparative HPLC to give the free base of the title compound (15mg). The free base was converted into the hydrochloride salt through a procedure analogous to that described above to give the title compound.

Example 31: (5R) -5- (4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -N-methyl-Lprolinamide hydrochloride (E31)

image 1

To a solution of (2R, 5S) -2- (4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -5 - [(methylamino) carbonyl] -1-pyrrolidinecarboxylate of 1,1-dimethylethyl (D96, 40mg, 0.09mmol) in ethyl acetate (0.9ml) and methanol (0.1ml) at 0 ° C AcCl (40µl, 0.56mmol) was added and the mixture was stirred for two hours at room temperature. The solvent was removed under a stream of nitrogen and the residue was triturated with Et2O. The solvent was removed to provide the title compound as a white solid (28mg, 85%). Rt (HPLC): 3.74 min; MS: (ES / +) m / z: 329 [MH +] C19H21FN2O2 requires 328; 1H NMR (500

20 MHz, DMSO-d6) � (ppm): 10.03-10.78 (sa, 1H); 8.56 (q, 1 H); 7.95-8.46 (sa, 1 H); 7.55 (dt, 1 H); 7.49 (d, 2H); 7.39-7.46 (m, 1 H); 7.20-7.29 (m, 2H); 7.09 (d, 2H); 5.16 (s, 2H); 4.58 (dd, 1 H); 4.28 (dd, 1 H); 2.70 (d, 3H); 2.21-2.37 (m, 2H); 1.98-2.17 (m, 2H). Example 32: (5R) -5- (4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -N, N-dimethylL-prolinamide hydrochloride (E32)

image 1

To a solution of the mixture D95 (20mg) in N, N-dimethylformamide at 0 ° C was added sodium hydride (10.0mg, 0.25mmol, 60% dispersion in mineral oil) and the mixture was stirred for 10 min at the same temperature Methyl iodide (20 µl, 0.3mmol) was added and the mixture was stirred for one hour at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with ice-cold brine, dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica gel to give the title compound as a white solid (16mg). This residue was dissolved in ethyl acetate (0.45ml) and methanol (0.05ml) at 0 ° C, AcCl (16µl) was added and the mixture was stirred for two hours at room temperature. The solvent was removed under a stream of nitrogen and the residue was triturated with Et2O. The solvent was removed to provide the title compound as a white solid (10mg, 85%). Rt (HPLC): 3.84 min; MS: (ES / +) m / z: 343 [MH] + C20H23FN2O2 requires 342; 1H NMR (500 MHz, DMSO-d6) � (ppm): the wide signals of the acid protons in the range between 7.50 and 11.50; 7.55 (dt, 1 H); 7.49 (d, 2H); 7.39-7.46 (m, 1 H); 7.21-7.29 (m, 2H); 7.10 (d, 2H); 5.18 (s, 2H); 4,684.79 (m, 1 H); 4.52-4.65 (m, 1 H); 3.04 (s, 3 H); 2.92 (s, 3 H); 1.90-2.48 (m, 4H).

Biological test Na channel test protocol

The ability of the compounds of the invention to modulate the sodium channel with opening by subtype voltage NaV 1.3 can be determined by the following test. Cell biology

Stable cell lines expressing hNaV1.3 channels were created by transfecting CHO cells with the pCIN5-hNav1,3 vector using the lipofectamine transfection method (Invitrogen). PCIN5 is a bicistronic vector for the creation of mammalian cell lines that predispose all neomycin resistant cells to express a recombinant protein (see Rees S., Coote J., Stable J., Goodson S., Harris S and Lee MG (1996), Biotechniques, 20, 102112) because a recombinant cDNA is linked to the cDNA of the selectable neomycin marker downstream of the CMV promoter (for full details see Chen YH, Dale TJ, Romans MA, Whitaker WR, Xie XM, Clare JJ, Cloning, distribution and functional analysis of the type III sodium channel from human brain, Eur. J. Neurosci., December 2000, 12, 4281-4289). Cells were grown in Iscove modified Dulbecco medium (Invitrogen) containing 10% fetal bovine serum, 1% L-glutamine, 1% penicillin-streptomycin (Invitrogen), 1% non-essential amino acids, HT supplement at 2%, and 1% G418 (Invitrogen), and were maintained at 37 ° C in a humidified medium containing 5% CO2 in air. Cells were released from the T175 culture flask for transfer and collection using Versene (Invitrogen).

Cell preparation

The cells were grown to a confluence of 60-95% in a T75 flask. The cells were raised by removing the growth medium and incubating with 1.5 ml of Versene (Invitrogen, 15040-066) heated (37 ° C) for 6 min. The raised cells were suspended in 10 ml of PBS (Invitrogen, 14040-133). The cell suspension was then placed in a 10 ml centrifuge tube and centrifuged for 2 min at 700 rpm. After centrifugation, the supernatant was removed and the cell pellet was resuspended in 3 ml of PBS. Electrophysiology

The currents were recorded at room temperature (21–23 ° C) using IonWorksHT (Molecular Devices Corp.) planar disposition electrophysiology technology. Stimulation protocols and data acquisition were performed using a microcomputer (Dell Pentium 4). To determine the planar electrode (Rp) gap resistors, at 10 mV, a potential difference of 160 ms was applied along each hole. These measurements were performed before the addition of the cells. After the addition of the cells, a sealing test was carried out before the circulation of the antibiotic (amphotericin) to achieve intracellular access. Losses were subtracted in all experiments by applying a hyperpolarizing pre-pulse of 160 ms (10 mV) 200 ms before the test pulses to measure the conductance of the losses. Test pulses advancing from the priming potential of -90 mV to 0 mV were applied for 20 ms and repeated 10 times with a frequency of 10 Hz. In all experiments, the test pulse protocol was performed in the absence (pre-reading) and in the presence (post-reading) of a compound. The pre- and post-readings were separated by the addition of a compound, followed by an incubation of 3-3.5 min. Solutions and drugs

The intracellular solution contained the following (in mM): K-gluconate 100, 40 mM KCl, 3.2 MgCl2, EGTA 3, HEPES 5, adjusted to pH 7.25. The amphotericin was prepared as a 30 mg / ml stock solution and diluted to a final working concentration of 0.1 mg / ml in internal buffer solution. The external solution was Dulbecco PBS (Invitrogen) and contained the following (in mM): CaCl2 0.90, KCl 2.67, K3PO4 1.47, MgCl2 0.50, NaCl 138, Na3PO4 8.10, with a pH of 7.4. The compounds were prepared in DMSO as 10 mM stock solutions and subsequent 1: 3 serial dilutions were made. Finally, the compounds were diluted 1: 100 in external solution, producing a final DMSO concentration of 1%. Data analysis

The records were analyzed and filtered using the sealing resistance (> 40 M�) and the peak current amplitude (> 200 pA) in the absence of the compound, to eliminate the unsuitable cells from the subsequent analysis. Paired comparisons between the pre-drug and post-drug additions were used to determine the inhibitory effect of each compound. The concentrations of compounds required to inhibit by 50% the current produced by the first depolarizing pulse (tonic pIC50) were determined by adjusting the Hill equation to the concentration-response data. In addition, the inhibitory properties dependent on the use of the compounds were determined by evaluating the effect of the compounds on the tenth depolarizing pulse against the first. The ratio between the tenth pulse to the first was calculated in the absence and presence of the drug, and the percentage of use-dependent inhibition was calculated. The data were adjusted using the same equation as the tonic pIC50, and the concentration that produces 15% inhibition (use-dependent pUD15) was calculated.

The compounds of Examples 1 to 3 and 5 to 32 were tested in the previous test and gave pUD15 values of 4.5 or greater. Monoamine Oxidase-B Test Protocol

The protocol describes the assay to test MAO-B inhibition. This is a fluorescence based endpoint assay using benzylamine as a substrate. Oxidation of the substrate by MAO-B leads to the release of hydrogen peroxide, and this product is then used by peroxidase to convert non-fluorescent Amplex Red (TM) into fluorescent resorufin. The overall reaction is:

image10

Thus the inhibition of the enzyme by a test compound leads to reduced fluorescence. The assay uses recombinant human monoamine oxidase B that is present

5 in microsomes of insect cells infected with baculovirus (supplied by Sigma). The compounds are tested over a wide range of concentrations to determine the concentration that causes semi-maximal inhibition of enzyme activity in the assay (IC50). Pargiline (Sigma) is used as a positive control in the assay, giving an IC50 in the range of 0.4-2 µM.

10 0.1 µl of test compound is dispensed in net DMSO in a 384-well black Greiner small volume plate. 5µl of substrate solution (400µM benzylamine (Sigma), Amplex Red 50µM (Molecular Probes), 50mM potassium phosphate, pH 7.4) are added. 5 µl of the assay buffer (50mM potassium phosphate, pH 7.4) is added to wells used as blank. 5µl of the solution is added

15 enzyme (0.23 IU / ml of human recombinant monoamine oxidase B, 1 IU / ml of horseradish peroxidase type XII (Sigma), 50mM potassium phosphate, pH 7.4) to the other wells. It is shaken to ensure proper mixing. It was included for 60 minutes at room temperature in the dark. Fluorescence is read using Analyst / Gemini (Molecular Devices; Resorufin: Ex530 / Em580 / Dichr561

20 (Analyst) - Ex555 / Em590 / Cutoff570 (Gemini)). The effect of a given compound is calculated as:% Inh = 100 x [(data - control1) / (control2 - control1)], where control1 corresponds to the enzyme that shows its maximum activity (i.e., not inhibited) and control2 corresponds at the minimum fluorescence of the enzyme in the absence of HRP.

25 5 where

Claims (12)

Claims

1. A

compound from formula (I), a Salt or solvate of the same

pharmaceutically acceptable

image 1 R1 and R2 are independently hydrogen, C1-6 alkyl or C3-6 cycloalkyl-C1-6 alkyl; or said R1 and R2, together with the nitrogen atom to which they are attached, can form a saturated, unsubstituted, 3, 4, 5 or 6-membered ring; q is 1 or 2; R3 and R4 are hydrogen; or when q is 1, R3 and R4, together with the interconnecting atoms, can form a cyclopropane ring; or said R3 and R1, together with the interconnecting atoms can form a saturated or unsaturated 5 or 6-membered ring; X is carbon or nitrogen; 15 n is 0, 1 or 2, where, when present, each R5 is independently selected from the list consisting of C1-3 alkyl, halogen, cyano, C1-3 haloalkyl, hydroxy, C1-3 alkoxy and C1 haloalkoxy -3; any one of R6 or R7 is -O-R8, -OCHR9R8, -NCH2R8 or - (CH2) 2R8 where the other R6 or R7 is hydrogen or R5; and where R8 is a phenyl ring or where the The phenyl ring is optionally substituted with one or more groups independently selected from the list consisting of C1-3 alkyl, halogen, cyano, C1-3 haloalkyl, hydroxy, C1-3 alkoxy and C1-3 haloalkoxy; and R9 is hydrogen or C1-3 alkyl. 2. A compound according to claim 1, wherein X is C. A compound according to claim 1 or claim 2, wherein q is one.

Four.

A compound according to any of the preceding claims, wherein R6 is -O-R8 or -OCH R9R8, and R7 is hydrogen or R5; and wherein R8 is a phenyl ring optionally substituted with one or more selected groups

regardless of the list consisting of C1-3 alkyl, halogen, cyano, C1-3 haloalkyl, hydroxy, C1-3 alkoxy and C1-3 haloalkoxy.

5.

A compound according to any of the preceding claims, wherein R3 and R4 are hydrogen.

6.

A compound according to any one of claims 1 to 4 wherein R3 and R1, together with the interconnecting atoms can form a saturated or unsaturated 5-membered ring.

7.

A compound of formula (I) selected from: (2S, 6R) -6- (4 - {[(3-fluorophenyl) methyl] oxy} phenyl) -2-piperidinecarboxamide; (2R, 6S) -6- (4 - {[(3-fluorophenyl) methyl] oxy} phenyl) -2-piperidinecarboxamide; (5R) -5- {4 - [(phenylmethyl) oxy] phenyl} -L-prolinamide; (5R) -5- (4 - {[(3-fluorophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- (4 - {[(3-cyanophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- (4 - {[(4-fluorophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- (4 - {[(2-cyanophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- (4 - {[(4-cyanophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- {4 - [({2 - [(trifluoromethyl) oxy] phenyl} methyl) oxy] phenyl} -L-prolinamide; (5R) -5- (4 - {[(1R) -1-phenylethyl] oxy} phenyl) -L-prolinamide; (5R) -5- {4 - [(4-fluorophenyl) oxy] phenyl} -L-prolinamide; (5R) -5- {4 - [(4-cyanophenyl) oxy] phenyl} -L-prolinamide; (5R) -5- [4- (phenyloxy) phenyl] -L-prolinamide; (5R) -5- {4 - [(3-fluorophenyl) oxy] phenyl} -L-prolinamide; (5R) -5- {4 - [(2-cyanophenyl) oxy] phenyl} -L-prolinamide; (5S) -5- {4 - [(phenylmethyl) oxy] phenyl} -L-prolinamide; (5S) -5- {4 - [(phenylmethyl) oxy] phenyl} -D-prolinamide; (5R) -5- (2-fluoro-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- {3 - [(phenylmethyl) oxy] phenyl} -L-prolinamide; (5R) -5- [4 - {[(2-fluorophenyl) methyl] oxy} -3- (methyloxy) phenyl] -L-prolinamide; (5R) -5- (4 - {[(2-fluorophenyl) methyl] amino} phenyl) -L-prolinamide; (5R) -5- (3-cyano-4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -L-prolinamide; (5R) -5- [4- (2-phenylethyl) phenyl] -L-prolinamide; (5R) -5- (5 - {[(2-fluorophenyl) methyl] oxy} -2-pyridinyl) -L-prolinamide; (2S, 3aS, 6aS) -2- (4 - {[(2-fluorophenyl) methyl] oxy} phenyl) hexahydropyrrolo [3,4-b] pyrrole-6 (1H) -one; (5R) -5- (4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -N-methyl-L-prolinamide; and (5R) -5- (4 - {[(2-fluorophenyl) methyl] oxy} phenyl) -N, N-dimethyl-L-prolinamide;

or a pharmaceutically acceptable salt or solvate thereof. 8. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, or solvate thereof, and a pharmaceutically acceptable carrier. 9. A compound of formula (I) according to any one of claims 1 to 7 or 5 a pharmaceutically acceptable salt or solvate thereof, for use in therapy. 10. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 7, in the manufacture of a medicament for treating or preventing a ddepressant or emotional disorder, or a related disorder with substances 10. Use according to claim 10, wherein the depressive or emotional disorder is a bipolar disorder. 12. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof according to any of claims 1 to 7, in the manufacture of a medicament for treating or preventing epilepsy. 13. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof according to any of claims 1 to 7, in the manufacture of a medicament for treating or preventing compulsive eating behavior disorder or excessive eating behavior disorder 14. Use of a compound of formula (I), or a salt or solvate thereof Pharmaceutically acceptable according to any one of claims 1 to 7, in the manufacture of a medicament for treating or preventing inflammatory pain or neuropathic pain. 15. Use according to claim 14 to treat or prevent neuropathic pain. 25