HK1196605B

HK1196605B - 2-oxo-piperidinyl derivatives

Info

Publication number: HK1196605B
Application number: HK14109987.0A
Authority: HK
Inventors: A．阿苔丝; F．蒙特尔; A．瓦拉德; O．罗蒂瓦尔
Original assignee: Ucb医药有限公司
Priority date: 2011-10-11
Filing date: 2012-10-10
Publication date: 2017-06-23

Description

2-oxo-piperidinyl derivatives

Introduction to

The present invention relates to 2-oxo-piperidinyl derivatives, their preparation and their use in the treatment of migraine.

Migraine, with an prevalence of ± 10% of the general population, is ranked by the WHO as one of the most debilitating diseases and represents a serious burden to society in terms of indirect costs due to loss of income. In european areas, 600,000 weekdays/day are missed by migraine sufferers. Migraine is significantly undiagnosed and untreated. There are two types of treatment, acute treatment, seeking to inhibit the development of ongoing migraine; and prophylactic or preventative treatment purposes to reduce the frequency and severity of headache episodes. Acute and prophylactic treatments are usually prescribed by general practitioners and specialists, respectively. The benchmarks for acute and prophylactic treatment are tryptamines (tryptamines) and topiramate (topiramate), respectively. Both approaches clearly do not meet the medical needs in terms of efficacy (overall only 50-65% of patients are relieved by these treatments) and have side effects (experienced by 40-50% of patients).

Migraine is caused by vasodilation of cranial blood vessels, associated with worsening neuronal activity of the trigeminal complex, resulting in peripheral sensitization (neurogenic infection with release of CGRP, a potent vasodilator) and subsequent central sensitization (hyperreactivity of neurons within the trigeminal nucleus cauda, leading to increased pain signaling). The mechanism of action of current acute treatments is primarily focused on counteracting vasodilation (e.g., all tryptamines are vasodilator-inducing 5-HT)₁B/D/E/F agonists, CGRP antagonists have also been approved for acute procedures, have shown comparable efficacy to tryptamines, while NO inhibitors are being evaluated in clinical trials.) common analgesics have poor efficacy on migraine.A mechanism of action for prophylactic treatment includes raising the threshold of migraine activation, increasing antinociception, inhibiting cortical spreading inhibition (a pre-headache phenomenon consisting of a wave of overactive nerves and subsequent neuroinhibition, which wave travels through the brain at a rate of about 2-3mm/min and is presumed to be the basis of the epileptic precursor experienced by 30% of migraine patients), inhibiting peripheral and central sensitization, blocking neurogenic infection and modulating the tone of sympathetic, parasympathetic or serotonergic factors.Topiramate, valproate and β -FDA adrenergic antagonists are oral drugs approved for prophylactic treatment of migraine.A these drugs have been injected intramuscularly in the next year with abontotinum toxinaAnd (4) combining. Other off-label uses of pharmaceutical drugs include 5-HT antagonists (5-HT)₂Poor selectivity), calcium antagonists and antidepressants (none are active for acute migraine treatment).

Migraine, depression and sleep disorders are characterized by5-hydroxytryptamine concentrations and conduction dysfunction. As they appear, they share a rhythmic pattern and are often associated as comorbidities, suggesting a partially common underlying mechanism. Literature evidence confirms 5-HT₇Antagonists in depression (Wesolowskaetal, Effect electrically 5-HT₇regenerative anodonist SB269970 inanimodimodsofanxietyandedpression, Neuropharmacology,2006,51578-₇receptordeletionenhancesREMsleepsuppressioninducedbyselectiveserotoninreuptakeinhibitors,butnotbydirectstimulationof5-HT₁Arecter "Neuropharmacology 2009,56, 448-.

5-HT₇The receptors belong to a large family of 5-hydroxytryptamine receptors consisting of 14 members. 5-HT₇Receptors are distributed in the central nervous system where they are highly expressed in the brainstem, hypothalamus, thalamus and hippocampus. In the periphery, high concentrations are detected in the intestines and arteries, while much lower concentrations are measured in the heart. With SB-269970 (purportedly selective 5-HT)₇Antagonists) and knock-out data (knock-outdata) show 5-HT₇Compelling evidence for receptor involvement in mood, sleep and circadian regulation (sheltonet. "5-HT₇receptordeletionenhancesREMsleepsuppressioninducedbyselectiveserotoninreuptakeinhibitors，butnotbydirectstimulationof5-HT₁Arecter "Neuropharmacology 2009, 56448-. It also clearly demonstrated that 5-HT₇Receptor-induced vasodilation of blood vessels including cerebral arteries (Terron, J.A., BrJPharmacol,1997,121:563-571 ″ -Roleof 5-HT)₇recepitorsinglastinghydrotensponesendinouducby 5-hydroxyytyptamineterhether "). Vasodilation of the cerebral vessels is an early event leading to the migraine cascade. Thus, 5-HT was used₇Antagonists inhibit 5-hydroxytryptamine-induced vasodilation and are expected to alleviate migraine. These findings turn Terron offIn 5-HT₇The original hypothesis of the possible role of receptors in migraine ((Terron, j.a., 2002, eur.j.pharmacol., 439: 1-11.

5-HT₇Antagonists are expected to have efficacy in the prophylactic (and possibly acute) treatment of migraine by:

1) preventing 5-hydroxytryptamine-induced vasodilation of cranial blood vessels (Matthys, A., et al., Roleofhe 5-HT)₇receptorinthecentralnervoussystem:fromcurrentstatustofutureperspectives.MolecularNeurobiology，2011；Leopoldo，M.，etal.，Serotonin5-HT₇receptoragents:Structure-activityrelationshipsandpotentialtherapeuticapplicationsincentralnervoussystemdisorders.Pharmacology&Therapeutics，2011，129，120-148；Hedlund，P.B.，The5-HT₇A retrieverddisorsofthenervoussystem, anoverview, psychopharmacogology, 2009, 206, 345-. In contrast to tryptamines, 5-HT₇Antagonists only reverse pre-existing vasodilation, which does not produce vasodilation itself. This will result in 5-HT₇Antagonists, in contrast to tryptamines, are suitable for chronic use and therefore for prophylactic treatment.

2) By inhibiting peripheral and central sensitization. SB-269970, 5-HT has been found in a model of Plasma Protein Extravasation (PPE) for migraine₇Receptor antagonist reference and our most advanced compounds inhibited neurogenic infection. In this rat model of migraine, epidural protein extravasation is induced by electrical stimulation of the trigeminal ganglion. In reducing protein extravasation 5-HT₇The antagonists are as effective as sumatriptan and topiramate. In addition, recent studies have shown that SB-269970 inhibits CGRP release following electrical stimulation of the trigeminal ganglion (Wangital., "Selective inhibition of 5-HT)₇recepitor Reduces CGRPReleaseeinExperimentmodelfurgiane ", Headeache, 2010, 50, 579-₇Further support for the potential efficacy of antagonists in the treatment of migraine.

Although it is used forTryptamines have been shown to reduce peripheral and central sensitization and counteract vasodilation, but their side effects on the cardiovascular system, mainly due to their activated vasoconstrictive activity, prevent their chronic use for prophylactic treatment. 5-HT₇Antagonists do not actively induce vasoconstriction but prevent vasodilation and should not be as limited as tryptamines during chronic administration (one internal study showed that SB-269970 does not induce human coronary constriction; sumatriptan was used as a comparator). Topiramate, the current standard of care, and other drugs used for prophylactic treatment suffer from side effects and limited efficacy. The side effects of topiramate were severe enough to cause a high rate of halfway withdrawal (25-30%) in clinical trials. In addition, topiramate is not effective against acute migraine. Selective5-HT from Current preclinical data₇Antagonists are not expected to have the side effects seen with most of the existing prophylactic drugs. At this stage we do not know if they can be more effective, but we expect that they can also be effective in the acute treatment of migraine. Furthermore, preclinical data show 5-HT₇Antagonists are active in depression models and sleep-modifying patterns, which indicate potential efficacy for the treatment of two common migraine comorbidities.

5-HT₇Receptor antagonists, in particular for the treatment of migraine, have been disclosed in WO2009/029439 and WO 2009/048765.

It is an object of the present invention to provide 5-HT₇Receptor antagonists, preferably selective5-HT₇A receptor antagonist. Another object is to provide novel forms for the treatment of migraine.

Disclosure of Invention

The present invention provides novel 2-oxo-piperidinyl derivatives, their preparation and their use in the treatment of migraine. Other aspects of the invention will be apparent from the detailed description.

Detailed description of the invention

The present invention relates to 2-oxo-piperidinyl derivatives according to formula I,

wherein

X is CH or N;

y is-NR⁴-or-CH = CH-, with the proviso, however, that when Y is-NR⁴When-is, X should be N; wherein R is⁴Is hydrogen or C_1-4An alkyl group.

n is an integer selected from 1,2 or 3; m is 1 or 2;

R¹selected from the group comprising or consisting of: substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C_3-8A cycloalkyl group; or R¹is-O-R²Group, wherein R²Selected from the group comprising or consisting of: substituted or unsubstituted C_1-6An alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

R³Is hydrogen, substituted or unsubstituted C_1-4Alkyl or halogen.

The invention relates in particular to 2-oxo-piperidinyl derivatives according to formula I-A,

wherein

X is CH or N;

n is an integer selected from 1,2 or 3; m is 1 or 2;

R¹selected from the group comprising or consisting of: substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero-ring, substituted or unsubstituted C_3-8A cycloalkyl group; or R¹is-O-R²Group, wherein R²Selected from the group comprising or consisting of: substituted or unsubstituted C_1-6An alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted hetero-aryl group; and

R³is hydrogen, substituted or unsubstituted C_1-4Alkyl or halogen.

In one embodiment of formula I-A, X is CH. In another embodiment, X is N.

The invention also relates to 2-oxo-piperidinyl derivatives according to formula I-B,

wherein

n is an integer selected from 1,2 or 3; m is 1 or 2;

R⁴is hydrogen or C_1-4Alkyl, preferably methyl.

In one embodiment m is 1. In another embodiment, n is 1, further n is 2, further it is 3.

In one embodiment of any of formulas I, I-A or I-B, R¹Or R²May be substituted by one, two or more halogens, or by C_1-6Alkyl radical, C_1-4Alkoxy, cyano, amido, acyl, hydroxy, or substituted with aryl, heteroaryl, heterocycloalkyl, which may also be optionally substituted with 1 to 5 substituents selected from: c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, cycloalkyl, heterocycloalkyl, amino, aryl, heteroaryl, alkoxy, halo, cyano, hydroxy, amido.

In yet another specific embodiment, R of formula I, I-A or I-B¹Is substituted or unsubstituted C_1-4An alkyl group.

In yet another specific embodiment, R¹Selected from the group comprising or consisting of: substituted or unsubstituted C_1-4An alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted pyrimidyl group, a substituted or unsubstituted thiazolyl group, a substituted or unsubstituted piperidyl group, a substituted or unsubstituted tetrahydropyranyl group, a substituted or unsubstituted tetrahydrofuranyl group, a substituted or unsubstituted cyclohexyl group; or R¹is-O-R²A group.

In another specific embodiment, R¹Is benzyl, 2-bromobenzyl, tert-butyl, 2-methylpropyl, 2-fluoro-2-methylpropyl, 2-chloro-2, 2-difluoroethyl, 2-oxo-2- (pyrrolidin-1-yl) ethyl, 2,2, 2-trifluoroethyl, propyl, phenyl, 2-carbamoylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3, 4-difluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2- (methylcarbamoyl) phenyl, 2- (3-methyl-1, 2, 4-oxadiazol-5-yl) phenyl, 2- (pyrrolidin-1-ylcarbonyl) phenyl, 2- (trifluoromethyl) phenyl, 3- (trifluoromethyl) phenyl, 4- (trifluoromethyl) phenyl, cyclohexyl, 4, 4-difluorocyclohexyl, pyridin-2-yl, 6-cyanopyridin-2-yl, 3-fluoropyridin-2-yl, 5-fluoropyridin-2-yl, 6-methoxy-pyridin-2-yl, 6-methylpyridin-2-yl-2-yl, 6- (4-fluorophenyl) pyridin-2-yl, 6- (propan-2-yloxy) pyridin-2-yl, 6- (1H-pyrazol-1-yl) pyridin-2-yl, 6-trifluoromethylpyridin-2-yl, 6- (cyclo-butyloxy) pyridin-2-yl, 6- (difluoromethoxy) pyridin-2-yl, 6- (2,2, 2-trifluoroethoxy) pyridin-2-yl, pyridin-3-yl, 2-fluoropyridin-3-yl, pyridin-4-yl, 4-methoxypyrimidin-2-yl, 4-methyl-1, 3-thiazolyl-2-yl, 4-methyl-1, 3-thiazolyl-5-yl, 1-acetylpiperidin-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydrofuran-2-yl; or R¹is-O-R²A group.

In one embodiment, R of formula I, I-A or I-B²Selected from the group comprising or consisting of: substituted or unsubstituted C_1-4-an alkyl group, or a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

In another specific embodiment of formula I, I-A or I-B, R²Selected from the group comprising or consisting of: substituted or unsubstituted benzyl, substituted or unsubstituted phenyl, or substituted or unsubstituted pyridyl; benzyl or substituted or unsubstituted phenyl is preferred.

In another particular embodiment of formula I, I-A or I-B, R²Is benzyl, phenyl, 5-bromo-2-methoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-methoxy-phenyl, 3-methoxyphenyl or 5-fluoropyridin-2-yl.

In a particular embodiment, R³Is hydrogen, fluorine or trifluoromethyl.

In a particular embodiment, R⁴Is methyl.

In yet another particular embodiment, the invention relates to 2-oxo-piperidinyl derivatives according to formula I-C,

wherein

X is CH or N;

R¹selected from the group comprising or consisting of: substituted or unsubstituted C_1-4Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted C_3-6A cycloalkyl group; or R¹is-O-R²Group, wherein R²Selected from the group comprising or consisting of: substituted or unsubstituted C_1-4-an alkylaryl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; and

R³is hydrogen, substituted or unsubstituted C_1-4Alkyl or halogen.

In another particular embodiment, R in the compounds of formula I-C¹Is benzyl, 2-methylpropyl, 2,2, 2-trifluoroethyl, propyl, phenyl, 2-carbamoylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3, 4-difluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2- (methylcarbamoyl) phenyl, 2- (3-methyl-1, 2, 4-oxadiazol-5-yl) phenyl, 2- (pyrrolidin-1-ylcarbonyl) phenyl, 2- (trifluoromethyl) -phenyl, 3- (trifluoromethyl) phenyl, 4- (trifluoromethyl) phenyl, cyclohexyl, 4, 4-difluoro-cyclohexyl, pyridin-2-yl, 6-cyanopyridin-2-yl, 3-fluoropyridin-2-yl, 6-methoxypyridin-2-yl, 6-methylpyridin-2-yl, 6- (4-fluorophenyl) pyridin-2-yl, 6- (propan-2-yloxy) pyridin-2-yl, 6- (1H-pyrazol-1-yl) pyridin-2-yl, 6-trifluoromethylpyridin-2-yl, 6- (cyclobutyloxy) pyridin-2-yl, 6- (2,2, 2-trifluoroethoxy) pyridin-2-yl, 6- (difluoromethoxy) pyridin-2-yl, pyridin-4-yl, 4-methoxypyrimidin-2-yl, 4-methyl-1, 3-thiazol-5-yl; or R¹Is of the formula-OR²Group, wherein R²Is a 4-cyanophenyl group.

In a preferred embodiment, R in the compounds of formula I-C¹Is phenyl, 2-carbamoylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-cyanophenyl, 4-cyanophenyl, 3, 4-difluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2- (3-methyl-1, 2, 4-oxadiazol-5-yl) phenyl, 2- (trifluoromethyl) phenyl, cyclohexyl, 6-cyanopyridin-2-yl, 3-fluoropyridin-2-yl, 6-methoxypyridin-2-yl, 6- (propan-2-yloxy) pyridin-2-yl, 6- (cyclobutyl-oxy) pyridin-2-yl, 6- (2,2, 2-trifluoroethoxy) pyridin-2-yl, 6- (difluoromethoxy) pyridin-2-yl, 4-methyl-1, 3-thiazolyl-2-yl.

In another preferred embodiment, R in the compounds of formula I-C¹Is phenyl, 4-cyanophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-hydroxyphenyl, cyclohexyl, 6-methoxypyridin-2-yl, 6- (propan-2-yloxy) pyridin-2-yl or 6- (cyclobutyloxy) pyridin-2-yl.

In a preferred embodiment, R in the compound of formula I-C³Is hydrogen, fluorine or trifluoromethyl. More preferably R in the compounds of formula I-C³Is hydrogen or trifluoromethyl, most preferably hydrogen.

In yet another specific embodiment, the present invention relates to 2-oxo-piperidinyl derivatives according to formula I-D,

wherein

X is CH or N;

R¹selected from the group comprising or consisting of: substituted or unsubstituted C_1-4Alkyl, substituted or unsubstituted aryl, substituted or unsubstitutedSubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted C_3-6A cycloalkyl group; or R¹is-O-R²Group, wherein R²Selected from the group comprising or consisting of: substituted or unsubstituted C_1-4-an alkylaryl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

In another particular embodiment, R in the compounds of formula I-D¹Is benzyl, 2-bromobenzyl, 3-cyanophenyl, 2-fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl; or R¹Is of the formula-OR²Group, wherein R²Is phenyl, 5-bromo-2-methoxyphenyl, 2-cyanophenyl, 2-fluorophenyl or 4-fluorophenyl.

In a preferred embodiment, R in the compounds of formula I-D¹Is 2-bromobenzyl, 2-methoxyphenyl; or R¹Is of the formula-OR²Group, wherein R²Is 5-bromo-2-methoxy-phenyl or 4-fluorophenyl.

In another preferred embodiment, R in the compounds of formula I-D¹Is 2-bromobenzyl OR of formula-OR²Group, wherein R²Is 5-bromo-2-methoxyphenyl.

In yet another particular embodiment, the invention relates to 2-oxo-piperidinyl derivatives according to formula I-E,

wherein

X is CH or N;

R¹selected from the group comprising or consisting of: substituted or unsubstituted C_1-4Alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted thiazolyl, substituted or unsubstitutedSubstituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted cyclohexyl; or R¹is-O-R²Group, wherein R²Is a substituted or unsubstituted benzyl, substituted or unsubstituted phenyl, or substituted or unsubstituted pyridyl; benzyl or substituted or unsubstituted phenyl is preferred.

In another particular embodiment, R in the compounds of formula I-E¹Is phenyl, 2-carbamoylphenyl, 4-cyanophenyl or 2-methoxyphenyl, preferably 2-methoxyphenyl.

Also included are tautomers, geometric isomers, enantiomers, diastereomers and mixtures, or pharmaceutically acceptable salts, of the compounds of formulas I, I-A, I-B, I-C, I-D and I-E, as well as any deuterated variant at any position. Any group "H" in formulas I, I-A, I-B, I-C, I-D, and I-E may be isotopically hydrogen, deuterium, or tritium.

Particular compounds of the invention are those selected from the group consisting of:

(+) -2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) benzamide oxalate;

n-methyl-2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) benzamide oxalate;

2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) benzonitrile oxalate;

2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } piperidin-3-yl) benzamide oxalate;

1- [2- (2- {3- [2- (trifluoromethyl) phenyl ] pyrrolidin-1-yl } ethyl) phenyl ] piperidin-2-one oxalate;

1- (2- {2- [3- (2-methoxyphenyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- (2- {2- [3- (3-methoxyphenyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- (2- {2- [3- (4-methoxyphenyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- (2- {2- [3- (2-fluorophenyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- (2- {2- [3- (2-chlorophenyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- [2- (2- {3- [2- (3-methyl-1, 2, 4-oxadiazol-5-yl) phenyl ] pyrrolidin-1-yl } ethyl) phenyl ] piperidin-2-one;

(+) -2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) benzonitrile oxalate;

(-) -2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) benzonitrile oxalate;

1- {2- [2- (3-phenylpyrrolidin-1-yl) ethyl ] phenyl } piperidin-2-one;

3- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) benzonitrile oxalate;

4- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) benzonitrile oxalate;

(-) -1- [2- (2- {3- [2- (pyrrolidin-1-ylcarbonyl) phenyl ] pyrrolidin-1-yl } ethyl) phenyl ] piperidin-2-one;

1- (2- {2- [3- (2-methoxyphenyl) piperidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

(+) -1- (2- {2- [3- (2-methoxyphenyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

(-) -1- (2- {2- [3- (2-methoxyphenyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- [2- (2- {3- [3- (trifluoromethyl) phenyl ] pyrrolidin-1-yl } ethyl) phenyl ] piperidin-2-one oxalate;

1- (2- {2- [3- (3-fluorophenyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- {2- [2- (3-phenylazetidin-1-yl) ethyl ] phenyl } piperidin-2-one oxalate;

1- (2- {2- [3- (3-fluorophenyl) piperidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- (2- {2- [3- (3-methoxyphenyl) piperidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- {2- [2- (3-phenylpiperidin-1-yl) ethyl ] phenyl } piperidin-2-one oxalate;

1- (2- {2- [3- (4-chlorophenyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- (2- {2- [3- (3-chlorophenyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- (2- {2- [3- (benzyloxy) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- (2- {2- [3- (4-fluorophenyl) azetidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

3- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } azetidin-3-yl) benzonitrile oxalate;

1- (2- {2- [3- (2-fluorophenyl) azetidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- {2- [2- (3-cyclohexylpyrrolidin-1-yl) ethyl ] phenyl } piperidin-2-one oxalate;

1- (2- {2- [3- (2-hydroxyphenyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- (2- {2- [3- (pyridin-2-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one hydrogen oxalate;

1- (2- {2- [3- (pyridin-2-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one;

1- (2- {2- [3- (4-fluorophenyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- (2- {2- [ (3R) -3- (2,2, 2-trifluoroethyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- (2- {2- [ (3S) -3- (2,2, 2-trifluoroethyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one trifluoroacetate salt;

1- (2- {2- [ (3S) -3- (2,2, 2-trifluoroethyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

4- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } piperidin-3-yl) benzonitrile oxalate;

(-) -4- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) benzonitrile oxalate;

(+) -4- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) benzonitrile oxalate;

1- (2- {2- [3- (2-methoxyphenyl) azetidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- (2- {2- [3- (3-fluorophenyl) azetidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- (2- {2- [3- (3, 4-difluorophenyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- (2- {2- [3- (3-methoxyphenyl) azetidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- {2- [2- (3-benzylpyrrolidin-1-yl) ethyl ] phenyl } piperidin-2-one oxalate;

1- (2- {2- [3- (2-methoxyphenoxy) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

4- [ (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) oxy ] benzonitrile;

1- (2- {2- [3- (tetrahydro-2H-pyran-4-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- {2- [2- (3-benzylazetidin-1-yl) ethyl ] phenyl } piperidin-2-one;

1- (2- {2- [3- (pyridin-3-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one;

1- (2- {2- [3- (4, 4-difluorocyclohexyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one trifluoroacetate salt;

4- [ (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } azetidin-3-yl) oxy ] benzonitrile oxalate;

1- (2- {2- [3- (2-methylpropyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one trifluoroacetate salt;

1- {2- [2- (3-propylpyrrolidin-1-yl) ethyl ] phenyl } piperidin-2-one trifluoroacetate salt;

3- [ (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } azetidin-3-yl) oxy ] benzonitrile;

2- [ (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } azetidin-3-yl) oxy ] benzonitrile;

1- (2- {2- [3- (4-fluorophenoxy) azetidin-1-yl ] ethyl } phenyl) piperidin-2-one;

1- (2- {2- [3- (3-methoxyphenoxy) azetidin-1-yl ] ethyl } phenyl) piperidin-2-one;

1- (2- {2- [3- (2-bromobenzyl) azetidin-1-yl ] ethyl } phenyl) piperidin-2-one;

4- (1- {2- [2- (2-oxopiperidin-1-yl) pyridin-3-yl ] ethyl } pyrrolidin-3-yl) benzonitrile;

1- (2- {2- [3- (4-methyl-1, 3-thiazolyl-5-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one;

1- (2- {2- [3- (5-bromo-2-methoxyphenoxy) azetidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- {2- [2- (3-phenoxyazetidin-1-yl) ethyl ] phenyl } piperidin-2-one oxalate;

1- {2- [2- (3-tert-butylpyrrolidin-1-yl) ethyl ] phenyl } piperidin-2-one;

1- (2- {2- [3- (2-methoxyphenoxy) azetidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- (2- {2- [3- (2-chloro-2, 2-difluoroethyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one;

1- (3- {2- [3- (pyridin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one;

1- (3- {2- [3- (pyridin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one oxalate;

1- (2- {2- [3- (1-acetylpiperidin-2-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one;

1- (2- {2- [3- (pyridin-4-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one;

1- (2- {2- [3- (2-fluoropyridin-3-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one;

1- (2- {2- [3- (tetrahydrofuran-2-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one;

1- (2- {2- [3- (tetrahydrofuran-2-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

(+) -1- (2- {2- [3- (tetrahydro-2H-pyran-4-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one trifluoroacetate salt;

(+) -1- (2- {2- [3- (tetrahydro-2H-pyran-4-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- (3- {2- [ (3S) -3- (2,2, 2-trifluoroethyl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one oxalate;

1- (3- {2- [ (3S) -3- (2,2, 2-trifluoroethyl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one;

1- (2- {2- [3- (tetrahydro-2H-pyran-3-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one trifluoroacetate salt;

1- (2- {2- [3- (6-methoxypyridin-2-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one;

1- (2- {2- [3- (5-fluoropyridin-2-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one;

1- (2- {2- [3- (3-fluoropyridin-2-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one;

1- (2- {2- [3- (2-fluoro-2-methylpropyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one;

1- [2- (2- {3- [ 2-oxo-2- (pyrrolidin-1-yl) ethyl ] pyrrolidin-1-yl } ethyl) phenyl ] piperidin-2-one;

1- (2- {2- [3- (4-methyl-1, 3-thiazolyl-2-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate;

1- (3- {2- [3- (5-fluoropyridin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one;

1- (3- {2- [3- (pyridin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one oxalate, isomer a;

(+) -1- (3- {2- [3- (4, 4-difluorocyclohexyl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one oxalate;

(-) -1- (3- {2- [3- (4, 4-difluorocyclohexyl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one oxalate;

1- (3- {2- [3- (6-methoxypyridin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one;

1- (3- {2- [3- (6-methoxypyridin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one oxalate;

1- [3- (2- {3- [6- (propan-2-yloxy) pyridin-2-yl ] pyrrolidin-1-yl } ethyl) pyridin-2-yl ] piperidin-2-one oxalate;

1- (3- {2- [ (3R) -3- (2,2, 2-trifluoroethyl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one oxalate;

6- (1- {2- [2- (2-oxopiperidin-1-yl) pyridin-3-yl ] ethyl } pyrrolidin-3-yl) pyridine-2-carbonitrile oxalate;

1- (3- {2- [3- (3-fluoropyridin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one oxalate;

1- [3- (2- {3- [6- (trifluoromethyl) pyridin-2-yl ] pyrrolidin-1-yl } ethyl) pyridin-2-yl ] piperidin-2-one;

1- [3- (2- {3- [ (5-fluoropyridin-2-yl) oxy ] azetidin-1-yl } ethyl) pyridin-2-yl ] piperidin-2-one;

1- (3- {2- [3- (4-fluorophenoxy) azetidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one oxalate;

1- (3- {2- [3- (2-fluorophenoxy) azetidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one oxalate;

(-) -1- (3- {2- [3- (pyridin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one oxalate;

1- (3- {2- [3- (6-methylpyridin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one;

1- [3- (2- {3- [6- (1H-pyrazol-1-yl) pyridin-2-yl ] pyrrolidin-1-yl } ethyl) pyridin-2-yl ] piperidin-2-one oxalate;

1- (3- {2- [3- (4-methoxy-pyrimidin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one;

1- [3- (2- {3- [6- (4-fluorophenyl) pyridin-2-yl ] pyrrolidin-1-yl } ethyl) pyridin-2-yl ] piperidin-2-one;

1- [3- (2- {3- [6- (cyclobutyloxy) pyridin-2-yl ] pyrrolidin-1-yl } ethyl) pyridin-2-yl ] piperidin-2-one oxalate;

1- [3- (2- {3- [6- (2,2, 2-trifluoroethoxy) pyridin-2-yl ] pyrrolidin-1-yl } ethyl) pyridin-2-yl ] piperidin-2-one;

1- [3- (2- {3- [6- (difluoromethoxy) pyridin-2-yl ] pyrrolidin-1-yl } ethyl) pyridin-2-yl ] piperidin-2-one; 1- [3- {2- [3- (pyridin-2-yl) pyrrolidin-1-yl ] ethyl } -5- (trifluoromethyl) pyridin-2-yl ] piperidin-2-one:

1- [3- {2- [3- (pyridin-2-yl) pyrrolidin-1-yl ] ethyl } -5- (trifluoromethyl) pyridin-2-yl ] piperidin-2-one oxalate;

1- (5-fluoro-3- {2- [3- (pyridin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one as a mixture of (+) -1- (5-fluoro-3- {2- [3- (pyridin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one and (-) -1- (5-fluoro-3- {2- [3- (pyridin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one.

The following paragraphs provide definitions of the various chemical groups that assemble the compounds according to the invention and are intended to apply uniformly throughout the specification and claims, unless an otherwise expressly recited definition provides a broader definition.

“C_1-6Alkyl "or" C_1-4Alkyl "refers to a group that represents a saturated monovalent hydrocarbon radical having straight (unbranched) or branched moieties or combinations thereof and containing 1 to 6 carbon atoms or 1 to 4 carbon atoms. C_1-4Examples of alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl. "C_1-4Alkyl "or" C_1-6An "alkyl" group may be substituted with one or more substituents selected from halo, amido, aryl or alkoxy. Specific alkyl groups according to the invention are methyl, difluoromethyl, trifluoromethyl, 2-chloro-2, 2-difluoroethyl, 2,2, 2-trifluoroethyl, propyl, 2-methylpropyl, 2-fluoro-2-methylpropyl, tert-butyl, 2-oxo-2- (pyrrolidin-1-yl) ethyl, benzyl and 2-bromobenzyl.

"alkoxy" refers to a group of the formula-O-R, wherein R includes "C_1-4Alkyl groups ". Examples of alkoxy according to the invention are methoxy, difluoromethoxy, 2,2, 2-trifluoroethoxy, propan-2-yloxy, and cyclobutoxy.

“C_3-8Cycloalkyl "refers to a saturated cyclic hydrocarbon of 3 to 8 carbon atoms having a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl). Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Examples of aryl groups according to the invention are cyclobutyl, cyclohexyl and 4, 4-difluorocyclohexyl.

"aryl" refers to an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl). The "aryl" group may be unsubstituted or substituted with 1 to 3 groups independently selected from C_1-4Alkyl radical, C_1-4Alkoxy, halogen, cyano, amido, hydroxy or heterocyclic. Aryl groups include phenyl and the like. Examples of aryl groups according to the invention are phenyl, 2-bromophenyl, 5-bromo-2-methoxyphenyl, 2-carbamoylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3, 4-difluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2- (methylcarbamoyl) phenyl, 2- (3-methyl-1, 2, 4-oxadiazol-5-yl) phenyl, 2- (pyrrolidin-1-ylcarbonyl) phenyl, 2- (trifluoromethyl) phenyl, and 3- (trifluoromethyl) phenyl.

C_1-4By alkylaryl is meant C having an aryl substituent as defined above_1-4An alkyl group. C according to the invention_1-4Examples of-alkylaryl are benzyl and 2-bromobenzyl.

"heterocycle" means a saturated or unsaturated ring system containing at least one heteroatom other than carbon, such as nitrogen, oxygen, and/or sulfur. "heterocycle" includes "heteroaryl" and "heterocycloalkyl".

"heteroaryl" refers to a monocyclic heteroaromatic or a bicyclic or tricyclic fused ring heteroaryl. Specific examples of heteroaryl groups include optionally substituted pyridyl, pyrimidinyl, pyrrolyl, furanyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-triazinyl, 1,2, 3-triazinyl, benzofuranyl, [2, 3-dihydro ] benzofuranyl, isobenzofuranyl, benzothiazolyl, benzotriazolyl, isobenzothiazolyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo [1,2-a ] pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl, dinitronaphthyl, pyrido [3,4-b ] pyridyl, pyrido [3,2-b ] pyridyl, pyrido [4,3-b ] pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7, 8-tetrahydroquinolyl, 5,6,7, 8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthyl or benzoquinolyl, imidazopyrimidine, imidazopyridazine, imidazothiazole, imidazothiadiazole, preferably pyridyl, pyrimidinyl, oxazolyl, thiazolyl, pyrazolyl and 1,2, 4-oxadiazolyl. Examples of heteroaryl groups according to the invention are pyridin-2-yl, 1-acetylpiperidin-2-yl, 3-fluoropyridin-2-yl, 5-fluoropyridin-2-yl, 6-cyanopyridin-2-yl, 6- (trifluoromethyl) pyridin-2-yl, 6-methylpyridin-2-yl, 6-methoxypyridin-2-yl, 6- (propan-2-yloxy) pyridin-2-yl, 6- (4-fluorophenyl) pyridin-2-yl, 6- (cyclobutoxy) pyridin-2-yl, 6- (difluoromethoxy) pyridin-2-yl, 6- (2,2, 2-trifluoroethoxy) pyridin-2-yl, 6- (1H-pyrazol-1-yl) pyridin-2-yl, pyridin-3-yl, 2-fluoropyridin-3-yl, pyridin-4-yl, 3-methyl-1, 2, 4-oxadiazol-5-yl, 4-methyl-1, 3-thiazolyl-2-yl, 4-methyl-1, 3-thiazolyl-5-yl, 1H-pyrazol-1-yl, and 4-methoxypyrimidin-2-yl.

"Heterocycloalkyl" means C as defined above_3-8Cycloalkyl in which 1 to 3 carbon atoms are selected from O, S, NR (R being defined as hydrogen, acyl or C)_1-6Alkyl) groups. Preferred heterocycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, 1-acetylpiperazinyl, 1-methylpiperazinyl, morpholinyl, tetrahydropyranyl, tetrahydropalmitanyl, and the likeFuryl, and the like. Examples of heterocycloalkyl according to the invention are pyrrolidin-1-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl and tetrahydrofuran-2-yl.

“C_2-6Alkenyl "means a group preferably having 2 to 6 carbon atoms and having at least 1 or 2 sites of ethylenic unsaturation. Preferred alkenyl groups include vinyl (vinyl, -CH = CH)₂) N-2-propenyl (allyl, -CH)₂CH=CH₂) And so on.

“C_2-6Alkynyl "means an alkynyl group preferably having 2 to 6 carbon atoms and having at least 1 to 2 sites of alkynyl unsaturation. Preferred alkynyl groups include ethynyl (-C.ident.CH), propynyl (-CH)₂C ≡ CH), and the like.

"amido" refers to the group-C (= O) NRR 'where each R, R' is independently hydrogen and "C_1-6Alkyl group and C_2-6Alkenyl "," C_2-6Alkynyl and C_3-8Cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl ", and wherein R and R', together with the nitrogen atom to which they are attached, may optionally form a 3-8-membered heterocycloalkyl ring. Examples of acylamino groups according to the invention are carbamoyl, methylcarbamoyl and pyrrolidin-1-ylcarbonyl.

"amino" refers to the group-NRR 'where each R, R' is independently hydrogen, "C_1-6Alkyl group and C_2-6Alkenyl "," C_2-6Alkynyl and C_3-8Cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl ", and wherein R and R', together with the nitrogen atom to which they are attached, may optionally form a 3-8-membered heterocycloalkyl ring.

"halogen" means fluorine, chlorine, bromine and iodine atoms.

"cyano" means-CN.

"acyl" refers to the group-C (= O) R where R is "C_1-6Alkyl group and C_2-6Alkenyl "," C_2-6Alkynyl and C_3-8Cycloalkyl "," heteroCycloalkyl "," aryl "or" heteroaryl ". An example of an acyl group according to the invention is acetyl.

"substituted or unsubstituted" unless otherwise constrained by the definition of a single substituent, groups represented above, such as "alkyl", "alkenyl", "alkynyl", "aryl", and "heteroaryl", may be optionally substituted with 1 to 5 substituents selected from the group consisting of "C_1-6Alkyl "or" C_1-4Alkyl group and C_2-6Alkenyl "," C_2-6Alkynyl, cycloalkyl, heterocycloalkyl, amino, aryl, heteroaryl, alkoxy, halo, cyano, hydroxy, mercapto, nitro, amido, acyl, and the like.

"pharmaceutically acceptable salts" according to the invention include therapeutically active non-toxic acid or base salt forms that the compounds of formula I are capable of forming.

Acid addition salts of compounds of formula I which are present in free form as bases may be obtained by treating the free base with a suitable acid, for example, an inorganic acid, for example, a hydrohalic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or an organic acid such as, for example, acetic acid, trifluoroacetic acid, oxalic acid, glycolic acid, propionic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid (pamoic) and the like.

The compounds of formula I containing an acidic proton may be converted into their therapeutically active, non-toxic base addition salt forms, such as metal or amine salts, by treatment with a suitable organic or inorganic base. Suitable basic salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts, e.g., lithium, sodium, potassium, magnesium, calcium salts, and the like, salts with organic bases, e.g., N-methyl-D-glucosamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine, and the like.

Conversely, the salt form may be converted to the free form by treatment with a suitable base or acid.

The compounds of formula I and salts thereof may be in the form of solvates which are included within the scope of the present invention. Such solvates include, for example, hydrates, alcoholates and the like.

Some compounds of formula I and some of their intermediates have at least one stereogenic center of origin (stereogenic center) in their structure. The stereogenic center may exist in the R or S configuration, said R and S markers being used correspondingly according to the rules described in PureAppl. chem.1976, 45, 11-30.

The invention also relates to all stereoisomeric forms such as enantiomeric and diastereomeric forms of the compounds of formula I or mixtures thereof (including all possible stereoisomeric mixtures).

In connection with the present invention, reference to a compound or compounds is intended to include the compound in each and every possible isomeric form, as well as mixtures thereof, unless the particular isomeric form is specifically mentioned.

The expression "enantiomerically pure" as used herein refers to a compound having an enantiomeric excess (ee) of greater than 95%.

The compounds according to the invention may exist in different polymorphic forms. Although not explicitly indicated in the above formula, such forms are intended to be included within the scope of the present invention.

In one embodiment, the compounds of formula (I) exhibit good p-5-HT₇The affinity of the receptor. This property can be determined by methods known to those skilled in the art, including the method set forth in example 20.

In one embodiment of the invention, the compound of formula (I) is 5-HT₇(i.e., they inhibit 5-HT)₇Agonist activity). This property can be determined by methods known to those skilled in the art, including the method set forth in example 21.

In another embodiment of the invention, some compounds of formula (I) are directed to 5-HT as compared to other 5-hydroxytryptamine receptor subtypes₇Receptors have higher selectivity factors ranging from 10-1000 or higher.

The compounds of formula I according to the invention can be prepared analogously by customary methods understood by those skilled in the art of synthetic organic chemistry.

According to one embodiment, some compounds of general formula I may be prepared according to the reaction scheme by reaction of an amine (or corresponding salt) of formula II with an aldehyde of formula III:

wherein X, Y, m, n, R¹And R³Have the same definitions as defined above for the compounds of formula I.

The reductive amination can be carried out in an alcohol such as methanol in the presence of an acid such as acetic acid and a mild reducing agent such as sodium cyanoborohydride at a temperature of 0 ℃ to room temperature, or according to any other method known to those skilled in the art.

According to another embodiment, some of the compounds of formula I-A (wherein X is C, R³Is hydrogen, m =1 and n =2 or 3) can be prepared according to the reaction scheme from the reaction of an amine (or corresponding salt) of formula II with an alkylating agent of formula IV, such as tosylate:

wherein X is C, m =1, n =2 or 3, R³Is hydrogen and R¹Have the same definitions as above for the compounds of formula I.

The reaction may be carried out in an inert solvent such as acetonitrileIn bases such as K₂CO₃At reflux temperature or according to any method known to those skilled in the art.

Alternatively, some compounds of formula I-a (wherein X is C, m =1, n =2, R³Is hydrogen and R¹Is heteroaryl) can be prepared according to the reaction scheme by reaction of a vinyl aromatic compound of formula V with a compound of formula VI:

wherein X is C, m =1, n =2, R³Is hydrogen and R¹Is a heteroaryl group.

The reaction can be carried out at room temperature in a polar solvent such as dichloromethane, in the presence of a Bronstedt acid such as trifluoroacetic acid, or according to any method known to those skilled in the art.

Alternatively, some compounds of formula I-a wherein X is N, m =1, N =2, R³Is substituted or unsubstituted C_1-4Alkyl or halogen and R¹Having the same definition as above for the compounds of formula I-a, can be prepared according to the reaction scheme by hydroxylamination of a vinyl heteroaromatic of the formula VII with an amine of the formula II:

wherein X is N, m =1, N =2, R³Is substituted or unsubstituted C_1-4Alkyl or halogen and R¹Have the same definitions as those described above for the compounds of formula I-A.

The reaction can be carried out under reflux in a polar solvent such as ethanol, in the presence of a Bronstedt base such as triethylamine, or according to any method known to those skilled in the art.

Alternatively, some compounds of formula I may be prepared by functional group transformation on already assembled analogues of compounds of formula I using methods described in the literature or known to those skilled in the art.

An amine of formula II (wherein m =1, n =2 and R¹Is heteroaryl) can be prepared according to the reaction scheme by reacting a heteroaromatic vinyl group of the formula V with a compound of the formula VIII and then deprotecting the resulting compound of the formula IX:

wherein m =1, n =2, R¹Is heteroaryl and PG represents a protecting group such as benzyl or allyl. The reaction can be carried out at room temperature in a polar solvent such as dichloromethane, in the presence of a Bronstedt acid such as trifluoroacetic acid, or according to any method known to those skilled in the art.

Subsequent deprotection of the compound of formula IX can be carried out using methods described in the literature such as palladium based deprotection (when PG is allyl), hydrogenolysis using ammonium acetate as hydrogen source (when PG is benzyl), or according to any other method known to those skilled in the art.

Alternatively, an amine of formula II (wherein m =1, n =2 and R)¹Is a substituted or unsubstituted alkyl group or a substituted or unsubstituted cycloalkyl group) can be prepared according to the reaction scheme by reduction of the corresponding pyrrolidone of formula X:

the reaction can be carried out in LiAlH in THF at reflux temperature₄In the presence of (a) or according to any method known to the person skilled in the art.

Alternatively, some amines of formula II (where m is 1 and n is 1,2 or 3) can be prepared by functional group conversion of commercially available pyrrolidine or pyrrolidin-3-one (when n =2) or azetidine (when n =1) or piperidine (when n =3) using methods described in the literature or methods known to those skilled in the art.

Alternatively, some amines of formula II (where m =1 and n =3) can be prepared by hydrogenation of the corresponding substituted pyridines using methods described in the literature or known to those skilled in the art.

The synthesis of the aldehydes of the formula III can be carried out by oxidation of the corresponding alcohols of the formula XI (Dess, D.B., Martin, J.C., J.Org.Chem.1983,48,4155-4156) by processes described in the literature, such as by Dess-Martin oxidizer (DessMartinylperiodinane), or by hydrolysis of the enol ethers of the formula XII, or according to any other method known to the person skilled in the art.

The tosylate of formula IV can be prepared from the corresponding alcohol of formula XI (where X is C) according to any method known to those skilled in the art.

The synthesis of compounds of formula V may be carried out using literature-described methods such as heteroaralkylation or cross-coupling of heteroaromatic halides, or according to any other method known to those skilled in the art.

The compound of formula VI can be prepared by refluxing at temperature in an inert solvent such as acetonitrile in a base such as K₂CO₃Reacting the tosylate of formula IV with 1- (trimethylsilyl) methylamine (methanamine) in the presence of (A) and then reacting with a catalyst at 0 ℃ in the presence of (B) and (C) in the presence of (B)₂CO₃Is treated with a mixture of aqueous formaldehyde and methanol in the presence of (a) or is prepared according to any method known to those skilled in the art.

The vinyl heteroaromatic compounds of formula VII may be prepared by a cross-coupling reaction between vinyl boronic acid pinacol ester and the corresponding heteroaromatic halide of formula XIII, wherein Hal is bromide, chloride or iodide, or according to any method known to those skilled in the art.

The compound of formula VIII (wherein PG is allyl) may be prepared according to the methods described in PCT patent application WO2009/087058 or according to any other method known to those skilled in the art.

The synthesis of compounds of formula X can be carried out using methods described in the literature or using methods known to those skilled in the art.

The alcohol of formula XI can be carried out according to any conventional method known to those skilled in the art.

Some of the enol ethers of formula XII can be carried out by a Wittig type reaction on an aldehyde of formula XIV or according to any other method known to those skilled in the art.

Some of the enol ethers of formula XII may be performed by lactamization of the corresponding aromatic amines of formula XV, or according to any other method known to those skilled in the art.

In further embodiments, the invention includes the synthesis of the following intermediates:

tert-butyl 3- [2- (methoxycarbonyl) phenyl ] pyrrolidine-1-carboxylate;

tert-butyl 3- (2-carbamoylphenyl) pyrrolidine-1-carboxylate;

tert-butyl 3- (2-carbamoylphenyl) pyrrolidine-1-carboxylate, enantiomer 1;

tert-butyl 3- (2-carbamoylphenyl) pyrrolidine-1-carboxylate, enantiomer 2;

2- (pyrrolidin-3-yl) benzamide, enantiomer 1;

2- (pyrrolidin-3-yl) benzamide, enantiomer 2;

(3R) -3- (2,2, 2-trifluoroethyl) pyrrolidine;

(3S) -3- (2,2, 2-trifluoroethyl) pyrrolidine;

3- (2-chloro-2, 2-difluoroethyl) pyrrolidine;

methyl 3- (4, 4-difluorocyclohexyl) prop-2-enoate;

methyl 3- (tetrahydro-2H-pyran-4-yl) prop-2-enoate;

methyl 3- (tetrahydrofuran-2-yl) prop-2-enoate;

methyl 3- (tetrahydro-2H-pyran-3-yl) prop-2-enoate;

methyl 3- (4, 4-difluorocyclohexyl) -4-nitrobutanoate;

methyl 3- (4, 4-difluorocyclohexyl) -4-nitrobutanoate enantiomer 1;

methyl 3- (4, 4-difluorocyclohexyl) -4-nitrobutanoate enantiomer 2;

methyl 4-nitro-3- (tetrahydro-2H-pyran-4-yl) butanoate;

methyl 4-nitro-3- (tetrahydrofuran-2-yl) butyrate;

methyl 4-nitro-3- (tetrahydro-2H-pyran-3-yl) butanoate;

4- (4, 4-difluorocyclohexyl) pyrrolidin-2-one;

4- (4, 4-difluorocyclohexyl) pyrrolidin-2-one enantiomer 1;

4- (4, 4-difluorocyclohexyl) pyrrolidin-2-one enantiomer 2;

4- (tetrahydro-2H-pyran-4-yl) pyrrolidin-2-one;

4- (tetrahydro-2H-pyran-4-yl) pyrrolidin-2-one enantiomer 1;

4- (tetrahydro-2H-pyran-4-yl) pyrrolidin-2-one enantiomer 2;

4- (tetrahydrofuran-2-yl) pyrrolidin-2-one;

4- (tetrahydro-2H-pyran-3-yl) pyrrolidin-2-one;

3- (4, 4-difluorocyclohexyl) pyrrolidine;

3- (4, 4-difluorocyclohexyl) pyrrolidine enantiomer 1;

3- (4, 4-difluorocyclohexyl) pyrrolidine enantiomer 2;

3- (tetrahydro-2H-pyran-4-yl) pyrrolidine enantiomer 1;

3- (tetrahydro-2H-pyran-4-yl) pyrrolidine enantiomer 2;

3- (tetrahydrofuran-2-yl) pyrrolidine;

3- (tetrahydro-2H-pyran-3-yl) pyrrolidine;

tert-butyl 3- (3-cyanophenoxy) azetidine-1-carboxylate;

tert-butyl 3- (5-bromo-2-methoxyphenoxy) azetidine-1-carboxylic acid ester;

3- (5-bromo-2-methoxyphenoxy) azetidine;

tert-butyl 3- [ (5-fluoropyridin-2-yl) oxy ] azetidine-1-carboxylate;

2- (azetidin-3-yloxy) -5-fluoropyridine;

2-vinyl-6- (propan-2-yloxy) pyridine;

2-vinyl-6- (1H-pyrazol-1-yl) pyridine;

2-methoxy-6- [1- (prop-2-en-1-yl) pyrrolidin-3-yl ] pyridine;

4-methoxy-2- [1- (prop-2-en-1-yl) pyrrolidin-3-yl ] pyrimidine;

2- (propan-2-yloxy) -6- [1- (prop-2-en-1-yl) pyrrolidin-3-yl ] pyridine;

2- [1- (prop-2-en-1-yl) pyrrolidin-3-yl ] -6- (1H-pyrazol-1-yl) pyridine;

4-methoxy-2- (pyrrolidin-3-yl) pyrimidine;

2- (propan-2-yloxy) -6- (pyrrolidin-3-yl) pyridine;

2- (1H-pyrazol-1-yl) -6- (pyrrolidin-3-yl) pyridine;

2- (1-benzylpyrrolidin-3-yl) pyridine enantiomer 1;

2- (1-benzylpyrrolidin-3-yl) pyridine enantiomer 2;

2- (pyrrolidin-3-yl) pyridine enantiomer 1 dihydrochloride;

2- (pyrrolidin-3-yl) pyridine enantiomer 2 dihydrochloride;

4- (pyrrolidin-3-yl) benzonitrile enantiomer 2;

4- (pyrrolidin-3-yl) benzonitrile enantiomer 1;

2- (cyclobutyloxy) -6- (pyrrolidin-3-yl) pyridine; 5-bromo-N- [2- (2-hydroxyethyl) phenyl ] pentanamide;

1- [2- (2-hydroxyethyl) phenyl ] piperidin-2-one;

2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl 4-methylbenzenesulfonate;

[2- (2-oxopiperidin-1-yl) phenyl ] acetaldehyde;

2- (2-oxopiperidinyl-1-yl) pyridine-3-carbaldehyde (carbaldehyde);

1- [3- (2-methoxyvinyl) pyridin-2-yl ] piperidin-2-one;

[2- (2-oxopiperidin-1-yl) pyridin-3-yl ] acetaldehyde;

1- [2- (2- { [ (trimethylsilyl) methyl ] amino } ethyl) phenyl ] piperidin-2-one;

1- [2- (2- { (methoxymethyl) [ (trimethylsilyl) methyl ] amino } ethyl) phenyl ] piperidin-2-one;

3-vinyl-2-fluoropyridine;

2-vinyl-3-fluoropyridine;

methyl 2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } piperidin-3-yl) benzoate;

methyl 2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) benzoate;

methyl 2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) benzoate enantiomer 1;

methyl 2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) benzoate enantiomer 2;

2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } piperidin-3-yl) benzoic acid;

2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) benzoic acid;

2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) benzoic acid enantiomer 1;

2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) benzoic acid enantiomer 2;

1- {2- [2- (3-hydroxypyrrolidin-1-yl) ethyl ] phenyl } piperidin-2-one;

1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl methanesulfonate;

1- {2- [2- (3-hydroxyazetidin-1-yl) ethyl ] phenyl } piperidin-2-one;

1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } azetidin-3-yl methanesulfonate;

1- (2- {2- [3- (piperidin-2-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one;

methyl (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) acetate;

1- (2- {2- [3- (2-hydroxy-2-methylpropyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one;

(1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) acetic acid;

1- (3- {2- [3- (6-fluoropyridin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one;

1- (3- {2- [3- (6-hydroxypyridin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one;

4- (2-methoxyvinyl) -1-methyl-1H-pyrazol-3-amine;

1- [4- (2-methoxyvinyl) -1-methyl-1H-pyrazol-3-yl ] piperidin-2-one;

[ 1-methyl-3- (2-oxopiperidin-1-yl) -1H-pyrazol-4-yl ] acetaldehyde;

1- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] piperidin-2-one;

1- [5- (trifluoromethyl) -3-vinylpyridin-2-yl ] piperidin-2-one;

5-fluoro-2- (2-oxopiperidin-1-yl) nicotinaldehyde;

1- [ 5-fluoro-3- (2-methoxyvinyl) pyridin-2-yl ] piperidin-2-one; and

[ 5-fluoro-2- (2-oxopiperidin-1-yl) pyridin-3-yl ] acetaldehyde.

The compounds of the invention are useful as medicaments in the acute or prophylactic treatment of migraine.

The methods of the present invention comprise administering to a mammal (preferably a human) suffering from migraine, a compound according to the present invention in an amount sufficient to alleviate or prevent the disorder or condition.

The compounds are conveniently administered in any suitable unit dosage form, including, but not limited to, a unit dosage form containing from 0.1 to 2000mg, preferably from 0.1 to 1000mg, more preferably from 0.1 to 500mg of active ingredient per unit dosage form.

The term "treatment" as used herein includes both curative and prophylactic treatment.

By "preventing" is meant preventing the occurrence or recurrence of the disorder or condition.

Another aspect of the invention relates to pharmaceutical compositions comprising an effective amount of a compound of formula I in combination with a pharmaceutically acceptable diluent or carrier.

For the treatment of diseases, the compounds of formula I or pharmaceutically acceptable salts thereof may be used in effective daily doses and administered in the form of pharmaceutical compositions.

Accordingly, another embodiment of the present invention is directed to pharmaceutical compositions comprising an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.

To prepare the pharmaceutical compositions of this invention, one or more compounds of formula I, or a pharmaceutically acceptable salt thereof, are combined directly with a pharmaceutically acceptable diluent or carrier according to conventional pharmaceutical compounding techniques well known to those skilled in the art.

Suitable diluents and carriers can take a variety of forms depending on the desired route of administration, e.g., oral, rectal, parenteral or intranasal.

For example, a pharmaceutical composition comprising a compound of the invention may be administered orally, parenterally, i.e. intravenously, intramuscularly or subcutaneously, intrathecally, transdermally (patch), by inhalation or intranasally.

Pharmaceutical compositions suitable for oral administration may be solid or liquid and may be in the form of, for example, tablets, pills, lozenges, gelatin capsules, solutions, syrups, chewing gums and the like.

For this purpose, the active ingredient may be mixed with an inert diluent or a non-toxic pharmaceutically acceptable carrier, such as starch or lactose. These pharmaceutical compositions may also optionally comprise binders, such as microcrystalline cellulose, gum tragacanth or gelatin, disintegrants, such as alginic acid, lubricants, such as magnesium stearate, glidants, such as colloidal silicon dioxide, sweetening agents, such as sucrose or saccharin, or coloring or flavoring agents, such as peppermint or methyl salicylate.

The invention also concerns compositions that can release an active substance in a controlled manner.

Pharmaceutical compositions which may be used for parenteral administration are in the usual form, for example, as aqueous or oily solutions or suspensions, typically contained in ampoules, disposable syringes, glass or plastic vials or infusion containers.

In addition to the active ingredient, these solutions or suspensions may optionally contain sterile diluents such as water for injection, physiological saline solution, oils, polyethylene glycols, glycerol, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediamine-tetra-acetic acid, buffers such as acetates, citrates or phosphates and agents for adjusting the osmolarity such as sodium chloride or glucose.

These pharmaceutical forms are prepared using methods commonly used by pharmacists.

The amount of active ingredient in the pharmaceutical composition may fall within a wide concentration range and depends on various factors such as sex, age, weight and medical condition of the patient and the method of administration. Thus, the amount of the compound of formula I in the composition for oral administration is at least 0.5% by weight and may be at most 80% by weight of the total weight of the composition.

For oral compositions, the daily dose is from 0.1mg to 2000mg of the compound of formula I. For oral compositions, the dosage unit is from 0.1mg to 2000mg of the compound of formula I, preferably from 0.1mg to 500 mg.

In compositions for parenteral administration, the compound of formula I is present in an amount of at least 0.5% by weight and up to 33% by weight, based on the total weight of the composition. For preferred parenteral compositions, the dosage unit is from 0.1mg to 2000mg of the compound of formula I.

The daily dose may fall within a wide range of dosage units of the compound of formula I and is generally in the range from 0.1 to 2000mg, preferably from 0.1 to 1000 mg. However, it is to be understood that specific dosages may be adapted to specific cases under the judgment of the clinician, according to individual requirements.

Examples

The following examples illustrate how the compounds covered by formula (I) can be synthesized. They are provided for illustrative purposes only and are not intended to be, nor should they be construed as, limiting the invention in any way. Those skilled in the art will appreciate that conventional variations and modifications may be made to the following examples without departing from the spirit or scope of the invention.

NMR spectra were recorded on a BRUKERAVANCE400NMR spectrometer equipped with a Linux workstation running XWINNMR3.5 software and 5mm inverted¹H/BB probe head, alternatively recorded on BRUKERDRX400NMR, fitted with SGFuel running XWINNMR2.6 software and 5mm inverted geometry¹H/¹³C/¹⁹F triple probe head. The compounds are described in₆Dimethyl sulfoxide (or d)₃Chloroform) at a probe temperature of 300K and a concentration of 10 mg/ml. Instrument lock at d₆Dimethyl sulfoxide (or d)₃-chloroform) on the deuterium signal. Chemical shifts are given in ppm downfield from TMS (tetramethylsilane) as internal standard.

HPLC analysis was performed using an Agilent1100 series HPLC system fitted with a Waters XBridgeMSC18, 5 μm, 150X4.6mm column. The gradient was run for 6 minutes from 100% solvent A (water/acetonitrile/ammonium formate solution 85/5/10(v/v/v)) to 100% solvent B (water/acetonitrile/ammonium formate solution 5/85/10(v/v/v), maintained at 100% B5 minutes.the flow rate was set at 1.8ml/min during 6 minutes, then increased to 2.3ml/min during 2 minutes, held at 2.3ml/min3 minutes. 1/25 splits were used just before the API source.chromatography was performed at 45 deg.C.the ammonium formate solution (pH 8.5) was prepared by dissolving ammonium formate (630mg) in water (1l) and adding ammonium hydroxide 30% (500. mu.l).

Mass spectrometry in LC/MS mode was performed as follows:

HPLC conditions

For alkaline elution, the analysis is carried out using:

WATERSAllianceHPLC system with diode array detector fitted with a WATERSXBridgeMSC18, 5 μm, 150X4.6mm column. The gradient was run for 6 minutes from 100% solvent a (water/acetonitrile/ammonium formate solution 85/5/10(v/v/v)) to 100% solvent B (water/acetonitrile/ammonium formate solution 5/85/10(v/v/v)) for 100% B5 minutes. The flow rate was set at 1.8ml/min for a period of 6 minutes and then increased to 2.3ml/min for 2.3ml/min3 minutes during 2 minutes. The 1/25 crack was used just before the API source. Chromatography was performed at 45 ℃. The ammonium formate solution (pH 8.5) was prepared by dissolving ammonium formate (63mg) in water (1l) and adding 30% (500. mu.l) ammonium hydroxide.

WATERSAcQUTYLLC system with diode array detector mounted with AcquisyUPLCBEHC 18, 1.7 μm, 100x2.1mm column. The gradient was run for 2 minutes from a mixture of solvent A/solvent B99/1(v/v) to solvent A/solvent B5/95(v/v) over 4.5 minutes. The flow rate was set at 0.4ml/min for 4.5 minutes and then increased to 0.5ml/min, held at 0.5ml/min2 minutes with no cracks before the API source. Chromatography was performed at 55 ℃. Solvent A (pH 8.5) was prepared by dissolving ammonium formate (63mg) in water (1l) and adding ammonium hydroxide 30% (500. mu.l) and solvent B was acetonitrile.

For the acid elution analysis a watersalliance hplc system with a diode array detector fitted with a waters sunfire msc18, 5 μm, 150x4.6mm column was used. The gradient was run for 6 minutes from 100% solvent A (water/acetonitrile/trifluoroacetic acid solution 85/5/10(v/v/v)) to 100% solvent B (water/acetonitrile/trifluoroacetic acid solution 5/85/10(v/v/v) held at 100% B5 minutes. the flow setting was 1.8ml/min during 6 minutes then increased to 2.3ml/min during 2 minutes, held at 2.3ml/min3 minutes. employing 1/25 slits just before the API source.

MS Condition

The sample was dissolved in acetonitrile/water 70/30, v/v, at a concentration of about 250. mu.g/ml. Using an API spectroscopy (+ or-) assay:

FINNIGANLCQ ion trap mass spectrometer. The APCI source was operated at 450 ℃ and the capillary heater at 160 ℃. The ESI source was operated at 3.5kV and the capillary heater was operated at 210 ℃.

SQDWaters single quadrupole mass spectrometer with ESI source. The source parameters were ESI capillary voltage 3.0kV, cone and extraction voltage (ConeandExtractorVoltage) 25 and 2V, respectively, source module temperature (Source Block temperature) 130 ℃, desolvation temperature 370 ℃, cone gas flow 120L/Hr (nitrogen), desolvation gas flow 800L/Hr.

Quattro MicroWaters triple quadrupole mass spectrometer with ESI source. The source parameters are that ESI capillary voltage is 2.8kV, taper hole and extraction voltage are 30V and 2V respectively, source module temperature is 120 ℃, desolvation temperature is 320 ℃, taper hole gas flow is 120L/Hr (nitrogen), and desolvation gas flow is 550L/H.

Mass spectrometric determination of DIP/EI modes was carried out as follows: the sample was vaporized by heating the probe from 50 ℃ to 250 ℃ within 5 min. EI (electron impact) spectra were recorded using an FINNIGANTSQ700 quadrupole mass spectrometer. The source temperature was set at 150 ℃.

Use of a compound from J&Mass spectrometry was performed on a TSQ700 quadrupole mass spectrometer (finnigan mat) by WScientific on a model 3400 gas chromatograph (Varian) equipped with split/no-split injectors and a DB-5MS fused silica column (15mx0.25mmi.d., 1 μm) in GC/MS mode. Helium (99.999% pure) was used as the carrier gas. The syringe (CTCA200S autosampler) and transfer line were run at 290 and 250 ℃, respectively. The sample (1 μ Ι) was injected in splitless mode and the oven temperature was run according to the following procedure: 50 deg.C, 5min, increased to 280 deg.C (23 deg.C/min) and held for 10 min. TSQ700 spectrometers using Electron Impact (EI) or chemical ionization (CI/CH)₄) The mode (mass range 33-800, scan time 1.00 seconds) was run. The source temperature was set at 150 ℃.

High resolution mass spectrometry using a waters lcttime flight mass spectrometer fitted with an ESI source. The source parameters are as follows: ESI capillary voltage 2.5kV, taper hole voltage 135V, source module temperature 135 ℃, desolvation temperature 350 ℃, taper hole gas flow 20L/Hr (nitrogen), desolvation gas flow 800L/Hr. The detector was set at 7.2KV for the flight tube and at 2,500V for the MCP detector.

Specific optical rotations were recorded using a Perkin-Elmer341 polarimeter. The angle of rotation was recorded at 589nm or 365nm in a solution in methanol at 25 ℃.

The melting points were determined either in Buchi 535 or 545 Tottoli-type fusiometres and were not calibrated or determined according to the onset temperature on a Perkin Elmer DSC 7.

In Kromasil spherical silica gel, particle size is 10-13 μmPreparative chromatography was performed using a Novasep kinetic shaft pressure (80mmID) at a flow rate of 140 ml/min. The solvent mixture was as described in each operation. Reverse phase separation was carried out on an 80mmID column using 500g of Kromasil C1810 μ M (acidic or neutral conditions) or Phenomenex GeminiC1810 μ M (basic conditions) at a flow rate of 150 ml/min. Unless otherwise specified, the product was detected at 215 nm.

Preparative chiral chromatographic separations were performed using a liquid chromatograph with various mixtures of lower alcohols and C5-C8 linear, branched or cyclic alkanes at ± 350 ml/min. The solvent mixture and column were as described in each run.

Experiments requiring microwave irradiation were performed with a biotage initiatorsix microwave oven with modified version 2.0 operating software. The experiment was run as fast as possible to reach the desired temperature (maximum irradiation power: 400W, no external cooling).

Example 1 Synthesis of an amine of formula II.

1.1 Synthesis of 2- (pyrrolidin-3-yl) benzamide, enantiomer 1a 8.

1.1.1 Synthesis of tert-butyl 3- [2- (methoxycarbonyl) phenyl ] pyrrolidine-1-carboxylate a 1-2.

To a stirred solution of methyl 2- (pyrrolidin-3-yl) benzoate hydrochloride a1-1(4.83g, 20mmol, 1eq) in dichloromethane (100ml) was added 4-dimethylaminopyridine (244mg, 2mmol, 0.1eq) and triethylamine (8.43ml, 60mmol, 3eq) at room temperature. The solution was stirred at room temperature for 5 minutes and added (Boc)₂O (4.58g, 21mmol, 1.05eq) in dichloromethane. The reaction mixture was stirred at room temperature overnight and quenched with 1M HCl (100 ml). The organic layer was MgSO₄Drying, filtration and evaporation in vacuo gave 6.1g of pure tert-butyl 3- [2- (methoxycarbonyl) phenyl]Pyrrolidine-1-carboxylic acid ester a 1-2.

The yield is 100%.

1.1.2 Synthesis of 2- [1- (tert-butoxycarbonyl) pyrrolidin-3-yl ] benzoic acid a 1-3.

NaOH5M (7.7ml, 38.6mmol, 2eq) was added to a stirred 3- [2- (methoxycarbonyl) phenyl at 65 deg.C]Azole compoundsAlkane-1-carboxylic acid ester a1-2(5.9g, 19.3mmol, 1eq) in MeOH (50 ml). The reaction mixture was stirred at 65 ℃ overnight, then evaporated in vacuo and water (40ml) added. The resulting mixture was extracted with ethyl acetate/ethanol (100ml/10ml) and again with ethyl acetate (100 ml). The combined organic layers were over MgSO₄Drying, filtration and evaporation under vacuum afforded 5.5g of pure 2- [1- (tert-butoxycarbonyl) pyrrolidin-3-yl]Benzoic acid a 1-3.

The yield was 98%.

1.1.3 Synthesis of tert-butyl 3- (2-carbamoylphenyl) pyrrolidine-1-carboxylic acid ester a1-4 and enantiomers a1-5 and a 1-6.

With gaseous ammonia NH at 0 DEG C₃Saturated 2- [1- (tert-butoxycarbonyl) pyrrolidin-3-yl]A stirred solution of benzoic acid a1-3(5.5g, 19mmol, 1eq) in dichloromethane (150ml) was left for 1 h. BOP reagent (8.82g, 19.9mmol, 1.05eq) was added in portions to the solution. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was filtered and the solid washed with dichloromethane (100 ml). The organic layer was evaporated under vacuum and the resulting residue was purified by chromatography on silica gel (eluent: CH)₂Cl₂MeOH98.5/1.5) gave 5.4g of tert-butyl 3- (2-carbamoylphenyl) pyrrolidine-1-carboxylic acid ester a 1-4.

The yield is 100%.

LC-MS(MH⁺):291。

The two enantiomers were separated by chiral chromatography (phase: LUX-CELL-2; 76X370mm column; 200 ml/min; eluent: iPrOH/heptane 30/70) to yield 2.5g of enantiomer 1a1-5 (first elution) and 2.35g of enantiomer 2a1-6 (second elution).

The yield of a1-5 is 45%.

The yield of a1-6 is 42%.

LC-MS(MH⁺):291。

1.1.4 Synthesis of 2- (pyrrolidin-3-yl) benzamide, enantiomer 1a 1-8.

Tert-butyl 3- (2-carbamoylphenyl) pyrrolidine-1-carboxylate, enantiomer 1a1-5(2.5g, 8.61mmol, 1eq) was dissolved in ethanol (100 ml). A saturated solution of HCl in EtOH (10ml) was added. The reaction mixture was stirred for 20h and evaporated to dryness to afford 1.64g of 2- (pyrrolidin-3-yl) benzamide, enantiomer 1a1-8, which was used in the next step without further purification.

Yield-assumed quantitative.

LC-MS(MH⁺) 191.2- (pyrrolidin-3-yl) benzamide a1-7 and 2- (pyrrolidin-3-yl) benzamide, enantiomer 2a1-9 can be prepared according to the same method.

1.2 Synthesis of 3- (2,2, 2-trifluoroethyl) pyrrolidine a 1-11.

To a solution of 4- (2,2, 2-trifluoroethyl) pyrrolidin-2-one a1-10(4.0g, 23.9mmol, 1eq) in freshly distilled THF at 0 deg.C LiAlH was carefully added₄(2.27g, 60mmol, 2.5 eq). After the addition was complete, the mixture was heated under reflux for 1.5h in a flask equipped with a condenser cooled to-10 ℃. The reaction mixture was then carefully quenched with water at 0 ℃ and over celite/MgSO₄Filtering on the pad. The filtrate was concentrated under reduced pressure at room temperature to give 2.82g of 3- (2,2, 2-trifluoroethyl) pyrrolidine a 1-11.

The yield was 77%.

LC-MS(MH⁺):154。

The following intermediates can be synthesized according to the same method.

a1-12	(3R) -3- (2,2, 2-trifluoroethyl) pyrrolidine	LC-MS(MH⁺):154
			a1-13	(3S) -3- (2,2, 2-trifluoroethyl) pyrrolidine	LC-MS(MH⁺):154
a1-14	3- (2-chloro-2, 2-difluoroethyl) pyrrolidine	LC-MS(MH⁺):170/172

1.3 Synthesis of 3- (4, 4-difluorocyclohexyl) pyrrolidine a 1-34.

1.3.1 Synthesis of methyl 3- (4, 4-difluorocyclohexyl) prop-2-enoate a 1-16.

Methyl (triphenylphosphine) acetate (8.827g, 26mmol, 1.1eq) was added to a solution of 4, 4-difluorocyclohexanecarboxaldehyde (3.55g, 24mmol, 1eq) in anhydrous THF (60ml) at room temperature. The mixture was stirred for 6h and the solvent was evaporated. Hexane (50ml) was added to the crude product, the mixture was left in an ultrasonic bath for a few minutes, stirred for 1h and filtered. Concentration of the filtrate under reduced pressure afforded 4.05g of methyl 3- (4, 4-difluorocyclohexyl) prop-2-enoate a 1-16.

The yield was 83%.

¹HNMR(400MHz，CDCl₃)6.91(m，1H)，5.85(m，1H)，3.75(m，3H)，2.29(m，1H)，2.12(m，3H)，1.80(m，5H)，1.56(t，2H，J=12.5Hz)。

The following intermediates can be synthesized according to the same method.

1.3.2 Synthesis of methyl 3- (4, 4-difluorocyclohexyl) -4-nitrobutanoate a 1-20.

Methyl 3- (4, 4-Difluorocyclohexyl) prop-2-enoate (4.054g, 0.198mol, 1eq) was dissolved in nitromethane (23L, 0.423mol, 21.3eq) and 1, 8-diazabicyclo [5,4,0 ] was added at room temperature]Undec-7-ene (3.025g, 0.198mol, 1 eq). The solution was stirred at room temperature overnight and then evaporated. The residue was dissolved in ethyl acetate and the solution was washed with 1M HCl and water. The organic phase is over MgSO₄Dried and evaporated under vacuum. The residue is purified by chromatography on silica gel (eluent: CH)₂Cl₂100%) to provide methyl 3- (4, 4-difluorocyclohexyl) -4-nitrobutanoate a 1-20.

The yield was 68%.

LC-MS(MH⁺):266。

The following intermediates can be synthesized according to the same method.

a1-23	Methyl 4-nitro-3- (tetrahydro-2H-pyran-4-yl) butanoate	LC-MS(MH⁺):232
			a1-24	Methyl 4-nitro-3- (tetrahydrofuran-2-yl) butanoic acid ester	LC-MS(MH⁺):218
a1-25	Methyl 4-nitro-3- (tetrahydro-2H-pyran-3-yl) butanoate	LC-MS(MH⁺):232

Methyl 3- (4, 4-difluorocyclohexyl) -4-nitrobutyrate enantiomer 1a1-21 (first elution) and enantiomer 2a1-22 (second elution) can be obtained by chiral chromatography of a1-20 (phase: ChiralpakASV; 50x490mm column; 80 ml/min; eluent: i-PrOH/heptane 50/50). The yield of a1-21 is 70%.

The yield of a1-22 is 70%.

LC-MS(MH⁺):266。

1.3.3 Synthesis of 4- (4, 4-difluorocyclohexyl) pyrrolidin-2-one a 1-26.

Methyl 3- (4, 4-difluorocyclohexyl) -4-nitrobutyrate a1-20(1.390g, 5.24mmol, 1eq) was dissolved in methanol (35ml) and raney nickel (50% in water, 200mg, 1.7mmol, 0.3eq) was added to the solution rinsing 3 times with methanol. The mixture was at 50 ℃ in H₂The atmosphere (20 bar) was heated overnight. The mixture was then filtered and the filtrate was evaporated under reduced pressure to give 4- (4, 4-difluorocyclohexyl) pyrrolidin-2-one a 1-26.

Yield-assumed quantitative.

LC-MS(MH⁺):204。

The following intermediates can be synthesized according to the same method.

a1-27	4- (4, 4-Difluorocyclohexyl) pyrrolidin-2-one enantiomer 1	LC-MS(MH⁺):204
			a1-28	4- (4, 4-Difluorocyclohexyl) pyrrolidin-2-one enantiomer 2	LC-MS(MH⁺):204
a1-29	4- (tetrahydro-2H-pyran-4-yl) pyrrolidin-2-one	LC-MS(MH⁺):169
			a1-32	4- (tetrahydrofuran-2-yl) pyrrolidin-2-one	LC-MS(MH⁺):156
a1-33	4- (tetrahydro-2H-pyran-3-yl) pyrrolidin-2-one	LC-MS(MH⁺):170

The 4- (tetrahydro-2H-pyran-4-yl) pyrrolidin-2-one enantiomer 1a1-30 (first elution) and enantiomer 2a1-31 (second elution) can be obtained by chiral chromatography of a1-29 (ChiracelOJ phase; solvent: iPrOH/heptane 30/70).

The overall yield before chiral separation (over 4 steps, starting from the corresponding aldehyde) for a1-30 and a1-31 was 55%.

LC-MS(MH⁺):169。

1.3.4 Synthesis of 3- (4, 4-difluorocyclohexyl) pyrrolidine a 1-34.

Lithium aluminium hydride (397.6mg, 10.49mmol, 2eq) was added portionwise to a solution of 4- (4, 4-difluorocyclohexyl) pyrrolidin-2-one a1-26 (assumed quantitative, from previous step, 5.24mmol, 1eq) in anhydrous THF (10ml) at 0 ℃. The reaction mixture was allowed to warm to room temperature and stirred overnight, then quenched with water at 0 ℃ and filtered over celite. Evaporation of the solvent under reduced pressure afforded 3- (4, 4-difluorocyclohexyl) pyrrolidine a 1-34.

Yield-assumed quantitative.

LC-MS(MH⁺):190。

The following intermediates can be synthesized according to the same method.

a1-35	3- (4, 4-Difluorocyclohexyl) pyrrolidine enantiomer 1	LC-MS(MH⁺):190
			a1-36	3- (4, 4-Difluorocyclohexyl) pyrrolidine enantiomer 2	LC-MS(MH⁺):190
a1-37	3- (tetrahydro-2H-pyran-4-yl) pyrrolidine	LC-MS(MH⁺):156
			a1-38	3- (tetrahydro-2H-pyran-4-yl) pyrrolidine enantiomer 1	LC-MS(MH⁺):156
a1-39	3- (tetrahydro-2H-pyran-4-yl) pyrrolidine enantiomer 2	LC-MS(MH⁺):156
			a1-40	3- (tetrahydrofuran-2-yl) pyrrolidine	LC-MS(MH⁺):142
a1-41	3- (tetrahydro-2H-pyran-3-yl) pyrrolidine	LC-MS(MH⁺):142

1.4 Synthesis of 3- (azetidin-3-yloxy) benzonitrile a 1-45.

1.4.1 Synthesis of tert-butyl 3- (3-cyanophenoxy) azetidine-1-carboxylate a 1-43.

3-cyanophenol (284mg, 2.38mmol, 1.2eq) was added to tert-butyl 3- [ (methylsulfonyl) oxy group]Azetidine-1-carboxylic acid ester (500mg, 1.99mmol, 1eq) and Cs₂CO₃(2.27g, 6.96mmol, 3.5eq) in a mixture of DMF (20 ml). The reaction was heated at 80 ℃ overnight and then cooled to room temperature. The mixture was extracted twice with diethyl ether by addition of brine (100 ml). The combined organic phases were washed with brine, over MgSO₄Dried and evaporated under reduced pressure. The residue was purified by basic reverse phase chromatography (gradient: acetonitrile/H)₂O/NH₄OH from 50/50/0.1 to 80/20/0.1) provided 262.4mg of tert-butyl 3- (3-cyanophenoxy) azetidine-1-carboxylic acid ester a 1-43.

The yield was 48%.

LC-MS(MH⁺):275。

Tert-butyl 3- (5-bromo-2-methoxyphenoxy) azetidine-1-carboxylic acid ester a1-44 can be synthesized according to the same method.

1.4.2 Synthesis of 3- (azetidin-3-yloxy) benzonitrile a 1-45.

Trifluoroacetic acid (10ml) was added to a solution of tert-butyl 3- (3-cyanophenoxy) azetidine-1-carboxylic acid ester a1-43(260mg, 0.95mmol, 1eq) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 2 hours, then concentrated to dryness to provide 262.3mg of crude 3- (azetidin-3-yloxy) benzonitrile a1-45 as an oil. The oil was used in the next step without further purification.

The yield is 100%.

LC-MS(MH⁺):175。

3- (5-bromo-2-methoxyphenoxy) azetidine a1-46 can be synthesized according to the same method.

1.5 Synthesis of 2- (azetidin-3-yloxy) -5-fluoropyridine a 1-49.

1.5.1 Synthesis of tert-butyl 3- [ (5-fluoropyridin-2-yl) oxy ] azetidine-1-carboxylate a 1-48.

Sodium tert-butoxide (1M in THF, 14.4ml, 14.4mmol, 5eq) and 2, 5-difluoropyridine (498.3mg, 4.33mmol, 1.5eq) were added to a mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate a1-47(500mg, 2.89mmol, 1eq) in DMSO (50 ml). The reaction was stirred at room temperature for 4 h. Brine (70ml) and water (10ml) were added. The resulting mixture was extracted with ethyl acetate (3 × 50 ml). The combined organic phases were over MgSO₄Dried, filtered and concentrated in vacuo.The evaporated residue was purified by flash chromatography on silica gel (eluent: EtOAc/heptane 10/90) to give 240mg of tert-butyl 3- [ (5-fluoropyridin-2-yl) oxy]Azetidine-1-carboxylic acid ester a 1-48.

The yield was 31%.

LC-MS(MH⁺):269。

1.5.2 Synthesis of 2- (azetidin-3-yloxy) -5-fluoropyridine a 1-49.

2- (azetidin-3-yloxy) -5-fluoropyridine a1-49 can be prepared by deprotection of tert-butyl 3- [ (5-fluoropyridin-2-yl) oxy ] azetidine-1-carboxylate a1-48 as described in example 1.4.2.

LC-MS(MH⁺):169。

1.6 Synthesis of 2-methoxy-6- (pyrrolidin-3-yl) pyridine a 1-59.

1.6.1 Synthesis of 2-vinyl-6-methoxypyridine a 1-51.

To a suspension of methyl (triphenyl) phosphonium bromide (7.07g, 19.8mmol, 1.1eq) in anhydrous THF (50ml) was added n-butyllithium (1.6M in cyclohexane, 12.5ml, 19.8mmol, 1.1eq) at 0 deg.C. After stirring at 0 ℃ for 20 minutes, a solution of 6-methoxypyridine-2-carbaldehyde a1-50(2.5g, 18mmol, 1eq) in dry THF (10ml) was added dropwise to the mixture. The reaction mixture was warmed to room temperature for 30 minutes. The reaction mixture was quenched with 3 drops of water and Rochelle's salt (10g) was added. The mixture is mixed with diatomite and MgSO₄And (5) filtering. Distillation of the crude residue afforded 400mg of pure 2-vinyl-6-methoxypyridine a 1-51.

The yield was 16%.

¹HNMR7.51(t，J=7.6Hz，1H)，6.82(d，J=7.2Hz，1H)，6.72(dd，J=17.0，10.6Hz，1H)，6.62(d，J=8.2Hz，1H)，6.29(dd，J=17.2，1.4Hz，1H)，5.41(dd，J=10.6，1.4Hz，1H)，3.96(s，3H)。

Alternatively, 2-vinyl-4-methoxypyrimidine a1-52 and 2-vinyl-6- (1H-pyrazol-1-yl) pyridine a1-54 can be prepared from the reaction of 2-bromo-4-methoxypyrimidine with potassium vinyl (trifluoro) borate.

a1-52，LC-MS(MH⁺):137。

a1-54，LC-MS(MH⁺):172。

Alternatively, 2-vinyl-6- (propan-2-yloxy) pyridine a1-53 can be prepared from the reaction of 2-bromo-6- (propan-2-yloxy) pyridine with tributyl (vinyl) tin hydride.

LC-MS(MH⁺):400。

1.6.2 Synthesis of 2-methoxy-6- [1- (prop-2-en-1-yl) pyrrolidin-3-yl ] pyridine a 1-55.

To a solution of 2-vinyl-6-methoxypyridine a1-51(400mg, 3mmol, 1eq) in trifluoroacetic acid/dichloromethane (200. mu.l/2 ml) was added N- (methoxymethyl) -N- [ (trimethylsilyl) methyl]Prop-2-en-1-amine until all styrene a1-51 is consumed. The solvent was removed in vacuo and the crude residue was purified by basic reverse phase chromatography on silica gel (gradient: CH)₃CN/H₂O/NH₄OH from 50/50/0.1 to 80/20/0.1) provides 210mg of pure 2-methoxy-6- [1- (prop-2-en-1-yl) pyrrolidin-3-yl]Pyridine a 1-55.

The yield is 30%.

LC-MS(MH⁺):219。

The following intermediates can be synthesized according to the same method.

a1-56	4-methoxy-2- [1- (prop-2-en-1-yl) pyrrolidin-3-yl]Pyrimidines	LC-MS(MH⁺):220
			a1-57	2- (propan-2-yloxy) -6- [1- (prop-2-en-1-yl) pyrrolidin-3-yl]Pyridine compound	LC-MS(MH⁺):247
a1-58	2- [1- (prop-2-en-1-yl) pyrrolidin-3-yl]-6- (1H-pyrazol-1-yl) pyridine	LC-MS(MH⁺):255

1.6.3 Synthesis of 2-methoxy-6- (pyrrolidin-3-yl) pyridine a 1-59.

To 2-methoxy-6- [1- (prop-2-en-1-yl) pyrrolidin-3-yl]Pyridine a1-55(218mg, 1mmol, 1eq) in dichloromethane (3ml) was added 1, 3-dimethyl barbituric acid (470mg, 3mmol, 3eq) and Pd (PPh)₃)₄(20mg) and the mixture was warmed at 40 ℃ overnight. The reaction mixture was loaded into an ion-exchange acidic resin cartridge, washed with methanol (2 × 50ml) and then released with a solution of 1M ammonia in methanol (20ml) to afford 150mg of crude 2-methoxy-6- (pyrrolidin-3-yl) pyridine a1-59, which was used in the next step without further purification.

The yield was 84%.

The following intermediates can be synthesized according to the same method.

a1-60	4-methoxy-2- (pyrrolidin-3-yl) pyrimidines	-
			a1-61	2- (propan-2-yloxy) -6- (pyrrolidin-3-yl) pyridine	LC-MS(MH⁺):207
a1-62	2- (1H-pyrazol-1-yl) -6- (pyrrolidin-3-yl) pyridine	LC-MS(MH⁺):215

1.7 Synthesis of 2- (pyrrolidin-3-yl) pyridine enantiomers a1-66 and a 1-67.

1.7.1 Synthesis of 2- (1-benzylpyrrolidin-3-yl) pyridine enantiomers a1-64 and a 1-65.

2- (1-Benzylpyrrolidin-3-yl) pyridine enantiomers a1-64 and a1-65 were obtained by chiral chromatography of racemic mixture a1-63 (phase: ChiralpakAD; 80X 475mm column; 200 ml/min; eluent: CH)₃CN)。

2- (1-benzylpyrrolidin-3-yl) pyridine enantiomer 1a1-64:

¹HNMR(400MHz，CDCl₃)8.53(d，1H，J=4.3Hz)，7.58(td，1H，J=7.7，1.4Hz)，7.33(m，4H)，7.23(m，2H)，7.09(m，1H)，3.69(m，2H)，3.55(m，1H)，3.08(t，1H，J=8.6Hz)，2.87(m，1H)，2.69(m，2H)，2.34(m，1H)，2.10(m，1H)。

2- (1-benzylpyrrolidin-3-yl) pyridine enantiomer 2a1-65:

¹HNMR(400MHz，CDCl₃)8.53(d，1H，J=4.1Hz)，7.58(td，1H，J=7.7，1.7Hz)，7.33(m，4H)，7.23(m，2H)，7.09(m，1H)，3.69(m，2H)，3.55(m，1H)，3.08(t，1H，J=8.6Hz)，2.87(m，1H)，2.69(m，2H)，2.34(m，1H)，2.11(m，1H)。

1.7.2 Synthesis of 2- (pyrrolidin-3-yl) pyridine enantiomer 1 dihydrochloride salt a 1-66.

To 2- (1-benzylpyrrolidin-3-yl) pyridine enantiomer 1a1-64(10.01g, 41.96mmol, 1eq) in methanol (340ml) was added Pd/C (5%, 1.98 g). A solution of ammonium formate (10.69g, 167.83mmol, 4eq) in water (55ml) was then added dropwise over a period of 10 minutes. The reaction mixture was heated at 68 ℃ for 45 minutes and then cooled to room temperature. The catalyst was filtered using celite, washed with methanol (60ml) and the collected filtrate evaporated to dryness. The residue was redissolved in methanol (50ml) and evaporated again. Dichloromethane (100ml) was added to the residue, the resulting solid was filtered, washed with dichloromethane (30ml) and the collected filtrate was evaporated to dryness to give a yellow oil. The oil was dissolved in isopropanol (60ml) and a mixture of isopropanol (21 ml)/aqueous HCl6N (21ml, 3eq) was slowly added to the solution over 15 minutes. The mixture was stirred at room temperature overnight and the resulting precipitate was filtered, washed with isopropanol (10ml) and then dried under vacuum at 40 ℃ for 4 hours to provide 7.90g of 2- (pyrrolidin-3-yl) pyridine enantiomer 1 dihydrochloride a 1-66. The yield was 85%.

LC-MS(MH⁺):149。

2- (pyrrolidin-3-yl) pyridine enantiomer 2 dihydrochloride a1-67 can be prepared according to the same method. The yield was 85%.

LC-MS(MH⁺):149。

Chiral separation of 84- (pyrrolidin-3-yl) benzonitrile a 1-68.

The 4- (pyrrolidin-3-yl) benzonitrile enantiomer 1a1-70 and the 4- (pyrrolidin-3-yl) benzonitrile enantiomer 2a1-69 may be prepared from chiral chromatography of 4- (pyrrolidin-3-yl) benzonitrile a 1-68.

1.9 Synthesis of 2- (cyclobutyloxy) -6- (pyrrolidin-3-yl) pyridine a 1-72.

Sodium tert-butoxide (337mg, 3mmol, 3eq) was added dropwise to a solution of cyclobutanol (144mg, 2mmol, 2eq) in DMSO (2ml) at room temperature and the mixture was stirred for 2 days. 2-fluoro-6- (pyrrolidin-3-yl) pyridine hydrochloride (202mg, 1mmol, 1eq) in DMSO (2ml) was added and the mixture was stirred for 48 h. Dichloromethane and water were then added to the reaction mixture and the two phases were separated after vigorous shaking. The aqueous layer was re-extracted with dichloromethane. The combined organic layers were over MgSO₄Drying, filtration and concentration of the filtrate under reduced pressure afforded crude 2- (cyclobutyloxy) -6- (pyrrolidin-3-yl) pyridine a1-72, which was used in the next step without further purification.

Yield-assumed quantitative.

LC-MS(MH⁺):219。

EXAMPLE 2 Synthesis of 1- (2- {2- [3- (3-fluorophenyl) piperidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate 24.

2.1 Synthesis of 5-bromo-N- [2- (2-hydroxyethyl) phenyl ] pentanamide a 2-1.

A solution of 2- (2-aminophenyl) ethanol a2-0(450g, 3.28mol, 1eq) and triethylamine (332g, 3.28mol, 1eq) in dichloromethane (2l) was cooled to-5 ℃ and bromovaleryl chloride (654g, 3.28mol, 1eq) in dichloromethane (2l) was added dropwise at no more than 0 ℃. The organic phase was washed with HCl1N (4x2l) and brine (1x2 l). The aqueous layer was extracted with dichloromethane (1 × 2 l).The combined organic layers were over MgSO₄Drying, filtration and evaporation under vacuum afforded 1008g of 5-bromo-N- [2- (2-hydroxyethyl) phenyl]Valeramide a 2-1.

The yield is 100%.

LC-MS(MH⁺):301。

2.2 Synthesis of 1- [2- (2-hydroxyethyl) phenyl ] piperidin-2-one a 2-2.

5-bromo-N- [2- (2-hydroxyethyl) phenyl]A solution of pentanamide a2-1(938g, 3.28mol, 1eq) in THF (6l) was cooled to-5 ℃. Sodium tert-butoxide (552g, 4.92mol, 1.5eq) was added dropwise at no more than 0 ℃ and the mixture was warmed to room temperature. The reaction mixture was washed with a saturated aqueous solution of NaCl (3 × 2 l). The aqueous layer was extracted with dichloromethane (2 × 2l) and the combined organic layers were over MgSO₄Dried, filtered and concentrated under reduced pressure. Recrystallization of the residue from tert-butyl methyl ether afforded 510g of 1- [2- (2-hydroxyethyl) phenyl]Piperidin-2-one a 2-2.

The yield was 71%.

LC-MS(MH⁺):220。

2.3 Synthesis of 2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl 4-methylbenzenesulfonate a 2-3.

Dimethylaminopyridine (1.83g, 15mmol, 0.05eq) and triethylamine (63.5ml, 450mmol, 1.5eq) were added to 1- [2- (2-hydroxyethyl) phenyl at 0 deg.C]Solution of piperidin-2-one a2-2(65.7g, 300mmol, 1eq) in dichloromethane (250 ml). The mixture was stirred at 0 ℃ for 15 minutes, then a solution of 4-toluenesulfonyl chloride (63g, 330mmol, 1.1eq) in dichloromethane (250ml) was added dropwise. The reaction mixture was then warmed to room temperature and stirred overnight. The reaction mixture was washed with water, 1N HCl, then MgSO₄Dried, filtered and evaporated under vacuum. The residue was purified by chromatography on silica gel (gradient: CH)₂Cl₂MeOH from 100/0 to 98/2) provided 99g of 2- [2- (2-oxopiperidin-1-yl) phenyl]Ethyl 4-methylbenzenesulfonate a 2-3.

The yield was 88%.

LC-MS(MH⁺):374。

2.4 Synthesis of 1- (2- {2- [3- (3-fluorophenyl) piperidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate 24.

3- (3-fluorophenyl) piperidine hydrochloride salt a2-4(432mg, 2mmol, 1eq) and K₂CO₃(829mg, 6mmol, 3eq) 2- [2- (2-oxopiperidin-1-yl) phenyl]Ethyl 4-methylbenzenesulfonate a2-3(747mg, 2mmol, 1eq) in acetonitrile (10 ml). The reaction mixture was stirred at 85 ℃ overnight, then filtered and the filtrate concentrated under reduced pressure. The residue was purified by basic reverse phase chromatography on silica gel (gradient CH)₃CN/H₂O/NH₄OH from 50/50/0.1 to 80/20/0.1) provides 472mg (1.24mmol) of 1- (2- {2- [3- (3-fluorophenyl) piperidin-1-yl]Ethyl } phenyl) piperidin-2-one as the free base. Oxalic acid (111mg, 1.24mmol, 1eq) was added to the residue dissolved in diethyl ether. The resulting precipitate was filtered and dried under vacuum to provide 517mg of 1- (2- {2- [3- (3-fluorophenyl) piperidin-1-yl group]Ethyl } phenyl) piperidin-2-one oxalate 24.

The yield was 55%.

LC-MS(MH⁺):381。

Compounds 1,3, 5,6,7,8, 9, 10, 14, 15, 16, 18, 21, 22, 24, 25, 26, 27, 28, 29, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 46, 48, 49, 51, 53, 54, 56, 57, 67, 69, 73, 75, 76, 77, 78 and 81 can be synthesized according to the same method.

Compounds 12 and 13 can be obtained by chiral chromatography of 3.

Compounds 19 and 20 can be obtained by chiral chromatography on 6.

EXAMPLE 3 Synthesis of 3- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } azetidin-3-yl) benzonitrile oxalate 31.

3.1 Synthesis of [2- (2-oxopiperidin-1-yl) phenyl ] acetaldehyde a 3-1.

Dess-Martin oxidant (DessMartinperiodinane) (3.36g, 7.91mmol, 1.3eq) was added dropwise to 1- [2- (2-hydroxyethyl) phenyl ] piperidin-2-one a2-2(1.33g, 6.09mmol, 1eq) in dichloromethane (40ml) with stirring. After a few hours, additional dess-martin oxidant (desssmatinperodianane) (1.29g, 3.04mmol, 0.5eq) was added and the reaction mixture was stirred overnight at room temperature, then filtered and evaporated to dryness to provide crude [2- (2-oxopiperidin-1-yl) phenyl ] acetaldehyde a3-1, which was used in the next step without further purification.

Yield-assumed quantitative.

3.2 Synthesis of 3- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } azetidin-3-yl) benzonitrile oxalate 31.

To methanol (4ml) of [2- (2-oxopiperidin-1-yl) phenyl]To acetaldehyde a3-1(108.6mg, 0.5mmol, 1eq) and 3- (azetidin-3-yl) benzonitrile a3-2(97.33mg, 0.5mmole, 1eq) was added acetic acid (42.9. mu.l, 0.75mmol, 1.5eq) followed by NaBH₃CN (94.3mg, 1.5mmol, 3 eq). The reaction mixture was stirred at room temperature overnight. The crude reaction mixture was then loaded onto an ion-exchange acidic resin cartridge (2g) pre-washed with methanol. The cartridge was washed twice with about 3 column volumes of methanol, then 3 column volumes of 1MNH₃The methanol solution was eluted. The eluate was evaporated to dryness to give 141mg of crude material which was subjected to reverse phase chromatography (basic mode; gradient: H)₂O/acetonitrile/NH₄OH from 60/40/0.1 to 30/70/0.1, in 10 minutes). The resulting residue was redissolved in acetone (ca. 3ml) and after addition of oxalic acid (22.7mg, 0.25mmol, 1eq), a precipitate slowly appeared. The precipitate was filtered, washed with diethyl ether and dried at 40 ℃ overnight under vacuum to provide 69.6mg of 3- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl]Ethyl } azetidin-3-yl) benzonitrile oxalate 31.

The yield was 31%.

LC-MS(MH⁺):360。

Compounds 23, 30, 32, 44, 45, 47, 52, 58, 59, 60, 61, 62, 65, 66 and 68 can be synthesized according to the same method.

EXAMPLE 4 Synthesis of 1- [3- (2- {3- [6- (propan-2-yloxy) pyridin-2-yl ] pyrrolidin-1-yl } ethyl) pyridin-2-yl ] piperidin-2-one oxalate 94.

4.1 Synthesis of 2- (2-oxopiperidin-1-yl) pyridine-3-carbaldehyde a 4-1.

2-bromopyridine-3-carbaldehyde a4-0(0.5g, 2.7mmol, 1eq) was dissolved in anhydrous and degassed 1, 4-dioxane (15 ml). Piperidin-2-one (0.4g, 4.03mmol, 1.5eq), 9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene (0.31g, 0.538mmol, 0.2eq), tris (dibenzylideneacetone) dipalladium (0) (0.123g, 0.134mmol, 0.05eq) and cesium carbonate (1.752g, 5.376mmol, 2eq) were added. The mixture was heated in a sealed tube in a microwave oven at 120 ℃ for 45 min. The resulting suspension was filtered over celite and the celite was washed with 1, 4-dioxane. The filtrate was evaporated under reduced pressure. The residue was then dispersed in ethyl acetate, sonicated, filtered and the filtrate evaporated under reduced pressure to afford 1.1g of crude 2- (2-oxopiperidinyl-1-yl) pyridine-3-carbaldehyde a4-1, which was used in the next step without further purification.

The yield is 50%.

LC-MS(MH⁺):204。

4.2 Synthesis of 1- [3- (2-methoxyvinyl) pyridin-2-yl ] piperidin-2-one a 4-2.

Methoxymethyl-triphenylphosphonium chloride (3.59g, 10.4) under nitrogen8mmol, 1.3eq) was dissolved in anhydrous tetrahydrofuran (150 ml). The solution was cooled at 0 ℃ and sodium tert-butoxide (1.085g, 9.67mmol, 1.2eq) was added. The reaction mixture was stirred at 0 ℃ for 30 min. A solution of crude 2- (2-oxopiperidin-1-yl) pyridine-3-carbaldehyde a4-1(4.2g, 8.06mmol, 1eq) in anhydrous THF (50ml) was added and the reaction mixture was warmed to room temperature and stirred for 1 hour. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate, stirred, filtered and the solid cake was washed with ethyl acetate (2 times). The filtrate was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (gradient: CH)₂Cl₂/MeOH/NH₄OH100/0/0 to 97/3/0.3). The resulting product was redissolved in methanol, captured on an acidic column, washed with methanol and then released with a 1M solution of ammonia in methanol. Evaporation of the solvent under reduced pressure gave 540mg of 1- [3- (2-methoxyvinyl) pyridin-2-yl]Piperidin-2-one a 4-2.

The yield was 11%.

LC-MS(MH⁺):233。

4.3 Synthesis of [2- (2-oxopiperidin-1-yl) pyridin-3-yl ] acetaldehyde a 4-3.

1- [3- (2-Methoxyvinyl) pyridin-2-yl ] piperidin-2-one a4-2(0.340g, 1.464mmol, 1eq) was dissolved in a mixture of formic acid and water (10ml/0.5 ml). The reaction mixture was heated at 50 ℃ overnight. Removal of the solvent under reduced pressure afforded the crude [2- (2-oxopiperidin-1-yl) pyridin-3-yl ] acetaldehyde a4-3, which was used in the next step without further purification.

LC-MS(MH⁺):219。

4.4 Synthesis of 1- [3- (2- {3- [6- (propan-2-yloxy) pyridin-2-yl ] pyrrolidin-1-yl } ethyl) pyridin-2-yl ] piperidin-2-one oxalate 94.

2- (propan-2-yloxy) -6- (pyrrolidin-3-yl) pyridine a1-61(0.302g, 1.464mmol, 1eq) was dissolved in methanol (15ml) and the solution was cooled at 0 ℃. Acetic acid (0.527g, 8.784mmol, 6eq), N, N, -diisopropylethylamine (0.378g, 2.928mmol, 2eq) and sodium cyanoborohydride (0.552g, 8.784mmol, 6eq) were added. Reaction mixingThe mixture was stirred for 5min and then poured onto the cooled crude [2- (2-oxopiperidin-1-yl) pyridin-3-yl]Acetaldehyde a4-3(1.46mmol, 1 eq). After 10min at 0 ℃ the reaction mixture was warmed to room temperature. Hydrochloric acid 1N was added until acidic pH. The solution was captured on an acid column, washed with methanol and then liberated with a 1M solution of ammonia in methanol. The residue was reversed phase by LC-MS basic (gradient CH)₃CN/H₂O/NaHCO₃From 5/95/0.5 to 95/5/0.5). The evaporated residue was dissolved in a minimum amount of acetone and oxalic acid (1eq) was added to form a salt. The solvent was removed under reduced pressure. The residue was dissolved in diethyl ether, the mixture was stirred, sonicated and filtered. The precipitate was washed with diethyl ether (2 times) to give 75mg of 1- [3- (2- {3- [6- (propan-2-yloxy) pyridin-2-yl)]Pyrrolidin-1-yl } ethyl) pyridin-2-yl]Piperidin-2-one oxalate salt 94.

The yield was 12.5%.

LC-MS(MH⁺):409。

Compounds 63, 70, 71, 79, 80, 88, 89, 90, 91, 92, 93, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105 and 106 can be synthesized according to the same method.

EXAMPLE 5 Synthesis of 1- (2- {2- [3- (4-methyl-1, 3-thiazolyl-2-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate 87.

5.1 Synthesis of 1- [2- (2- { [ (trimethylsilyl) methyl ] amino } ethyl) phenyl ] piperidin-2-one a 5-1.

To 2- [2- (2-oxopiperidin-1-yl) phenyl in acetonitrile (100ml)]Ethyl 4-methylbenzenesulfonate a2-3(22.4g, 0.060mol, 1eq) 1- (trimethylsilyl) methanolamine (6.8g, 0.066mol, 1.1eq) and K were added₂CO₃(16.6g, 0.120mol, 2 eq). The reaction mixture was heated at 85 ℃ for 2 hours under nitrogen. After filtrationThe solvent was removed under reduced pressure and the residue obtained was purified by basic reverse phase chromatography (gradient CH)₃CN/H₂O/NaHCO₃From 50/50/0.1 to 80/20/0.1) provides 7.66g of 1- [2- (2- { [ (trimethylsilyl) methyl ] methyl]Amino } ethyl) phenyl]Piperidin-2-one a 5-1.

The yield was 42%.

LC-MS(MH⁺):305。

5.2 Synthesis of 1- [2- (2- { (methoxymethyl) [ (trimethylsilyl) methyl ] amino } ethyl) phenyl ] piperidin-2-one a 5-2.

1- [2- (2- { [ (trimethylsilyl) methyl ] at-10 deg.C]Amino } ethyl) phenyl]Piperidin-2-one a5-1(912mg, 3mmol, 1eq) was added slowly to a solution of methanol (220. mu.l, 5.4mmol, 1.8eq) and aqueous formaldehyde (37%, 600. mu.l). The reaction mixture was stirred at 0 ℃ for 1 h. Potassium carbonate (2g) was added and the mixture was stirred at 0 ℃ for 1 h. Dichloromethane (15ml) was added and the resulting mixture was MgSO₄Drying, filtration, and concentration of the filtrate in vacuo afforded 2.34g of 1- [2- (2- { (methoxymethyl) [ (trimethylsilyl) methyl ] methyl]Amino } ethyl) phenyl]Piperidin-2-one a 5-2.

The yield is 99%.

¹HNMR(CDCl₃，400MHz):7.23(m，1H)，7.18(m，2H)，7.04(dd，J1=5.0Hz，J2=3.6Hz，1H)，5.23(s，1H)，4.02(m，1H)，3.52(m，1H)，3.35(m)，3.18(s，2H)，2.80(m，2H)，2.62(m，2H)，2.47(m，2H)，2.17(m，2H)，1.90(m，4H)，1.67(m，1H)，0.03(m，9H)

5.3 Synthesis of 2-vinyl-4-methyl-1, 3-thiazole a 5-3.

BuLi (1.6M in hexane, 3.43ml, 5.5mmol, 1.1eq) was added slowly to methyl (triphenyl) phosphorus bromide (1.79g, 5mmol, 1eq) in THF (15ml) at no more than 5 ℃ in a three-neck round-bottom flask under argon. After stirring at 0 ℃ for 1h, 4-methyl-1, 3-thiazole-2-carbaldehyde (635mg, 5mmol, 1eq) was added. The reaction mixture was returned to ambient temperature and stirred overnight. Reaction ofQuench with Rochelle salt (Rochelle salt) (sodium potassium tartrate) (2g) and 3 drops of water. The mixture was diluted with diethyl ether and dried over magnesium sulfate. The solvent was removed in vacuo and the crude product was distilled (+/-60 ℃ C.; 10)^-2Bar) provided 335mg of 2-vinyl-4-methyl-1, 3-thiazole a5-3 as a clear oil.

The yield was 54%.

¹HNMR(CDCl₃，400MHz):6.87(dd，J₁=17.5Hz，J₂=10.9Hz，1H)，6.78(s，1H)，6.01(d，J=17.5Hz，1H)，5.50(d，J=10.9Hz，1H)，2.44(s，3H)。

The following intermediates can be synthesized according to the same method.

5.4 Synthesis of 1- (2- {2- [3- (4-methyl-1, 3-thiazolyl-2-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one oxalate 87.

1- [2- (2- { (methoxymethyl) [ (trimethylsilyl) methyl ] is reacted at 0 deg.C]Amino } ethyl) phenyl]Piperidin-2-one a5-2(696mg, 2mmol, 2eq) was added slowly to 2-vinyl-4-methyl-1, 3-thiazole a5-3(125mg,1mmol, 1eq) diluted with dichloromethane/TFA (90. mu.l/10. mu.l). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by basic reverse phase chromatography on silica gel (gradient: acetonitrile/H)₂O/NH₄OH from 30/70/0.1 to 60/40/0.1 in 10 minutes). The product was dissolved in a minimum amount of acetone, oxalic acid (1eq) was added to form a salt which was filtered, washed with diethyl ether and dried under vacuum to give 215mg of 1- (2- {2- [3- (4-methyl-1, 3-thiazolyl-2-yl) pyrrolidin-1-yl]Ethyl } phenyl) piperidin-2-one oxalate salt 87.

The yield was 47%.

LC-MS(MH⁺):370。

Compounds 64, 74, 82, 83 and 84 can be synthesized according to the same method.

EXAMPLE 6 Synthesis of 2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } piperidin-3-yl) benzamide oxalate 4.

6.1 Synthesis of methyl 2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } piperidin-3-yl) benzoate a 6-1.

Methyl 2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } piperidin-3-yl) benzoate a6-1 may be prepared according to the method described in example 2.4.

LC-MS(MH⁺):421。

This also applies to the case of the following compounds:

6.2 Synthesis of 2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } piperidin-3-yl) benzoic acid a 6-5.

Methyl 2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } piperidin-3-yl) benzoate a6-1(0.35g, 0.84mmol, 1eq) was dissolved in methanol (5 ml). NaOH5N (0.84ml, 4.20mmol, 5eq) was added and the mixture was heated at 80 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in MeOH, filtered and evaporated to give 0.34g of crude 2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } piperidin-3-yl) benzoic acid a6-5, which was used in the next step without further purification.

Yield-assumed quantitative.

LC-MS(MH⁺):407。

The following intermediates can be synthesized according to the same method.

6.3 Synthesis of 2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } piperidin-3-yl) benzamide oxalate 4.

2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl]Ethyl } piperidin-3-yl) benzoic acid a6-5(0.34g, 0.84mmol, 1eq) was dissolved in anhydrous dichloromethane. Gaseous ammonia was bubbled through the solution for 15min at 0 ℃. BOP (0.56g, 1.27mmol, 1.5eq) was added and the mixture was warmed to room temperature overnight while maintaining the ammonia stream. The mixture was evaporated to dryness and redissolved in dichloromethane. The organic layer was washed with 10% NaHCO₃Washing with an aqueous solution over MgSO₄Dried and concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient: acetonitrile/H)₂O/TFA from 20/80/0.1 to 50/50/0.1). The solution was captured on an acidic column, washed with methanol and then with a 1M solution of ammonia in methanol. The solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate as the oxalate salt to give 62mg of 2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl]Ethyl } piperidin-3-yl) benzamide oxalate 4.

The yield was 15%.

LC-MS(MH⁺):406。

EXAMPLE 7 Synthesis of N-methyl-2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) benzamide oxalate 2.

2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl]Ethyl } pyrrolidin-3-yl) benzoic acid a6-6(0.67g, 1.71mmol, 1eq) was dissolved in dichloromethane (13 ml). At 0 ℃ gaseous MeNH₂The solution was bubbled through for 5 min. BOP (1.13g, 2.56mmol, 1.5eq) was added and the MeNH maintained₂And (5) flowing for 5 min. The mixture was allowed to warm to room temperature, stirred overnight, and then concentrated in vacuo. The residue was redissolved in dichloromethane and the organic layer was washed with 10% NaHCO₃Washing with an aqueous solution over MgSO₄Dried and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel (eluent: CH)₂Cl₂/MeOH/NH₄OH94/6/0.6), followed by reverse phase HPLC (gradient: acetonitrile/H)₂O/NH₄OH (aqueous, 0.1%) from 30/60/10 to 60/30/10 in 15 minutes). The residue was recrystallized from ethyl acetate as the oxalate salt to give 250mg of N-methyl-2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl]Ethyl } pyrrolidin-3-yl) benzamide oxalate 2.

The yield is 36%.

LC-MS(MH⁺):406。

EXAMPLE 8 Synthesis of 1- [2- (2- {3- [2- (3-methyl-1, 2, 4-oxadiazol-5-yl) phenyl ] pyrrolidin-1-yl } ethyl) phenyl ] piperidin-2-one 11.

2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl]Ethyl } pyrrolidin-3-yl) benzoic acid a6-6(0.31g, 0.79mmol, 1eq) was dissolved in DMF and N, N' -carbonyldiimidazole (140mg, 0.87mmol, 1.1eq) was added. The mixture was stirred at room temperature for 30min, N-hydroxyacetamidine hydrochloride (95mg, 0.87mmol, 1.1eq) was added and stirring was carried out for 4 h. Additional 1.1eq of N, N' -carbonyldiimidazole and 1.1eq of N-hydroxyacetamidine hydrochloride were added and the reaction mixture was stirred overnight at reflux. Adding dichloromethane and water andthe latter organic layer was washed with water, HCl1N, NaHCO₃Saturated aqueous solution and brine. The organic layer was over MgSO₄Dried, evaporated and purified by preparative alkaline LC/MS (gradient: H)₂O/acetonitrile/NH₄HCO₃From 85/5/10 to 5/95/0 at 0.5% w/v in 6.5 minutes) provides 19mg of 1- [2- (2- {3- [2- (3-methyl-1, 2, 4-oxadiazol-5-yl) phenyl ]]Pyrrolidin-1-yl } ethyl) phenyl]Piperidin-2-one 11.

The yield was 6%.

LC-MS(MH⁺):431。

EXAMPLE 9 Synthesis of (-) -1- [2- (2- {3- [2- (pyrrolidin-1-ylcarbonyl) phenyl ] pyrrolidin-1-yl } ethyl) phenyl ] piperidin-2-one 17.

2- (1- {2- [2- (2-oxopiperidin-1-yl) phenyl]Ethyl } pyrrolidin-3-yl) benzoic acid enantiomer 2a6-8(2.72g, 6.97mmol, 1eq) was dissolved in dichloromethane (100 ml). Pyrrolidine (0.69ml, 8.36mmol, 1.2eq) and then OP reagent (benzotriazol-1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate; 4.62g, 10.45mmol, 1.5eq) were added and the reaction mixture was stirred at room temperature for 4 h. The mixture was evaporated to dryness, redissolved in dichloromethane and the organic layer washed with HCl1N and water, over MgSO₄Dried and evaporated. By reverse phase HPLC (gradient: acetonitrile/H)₂O/ammonium formate from 5% to 95% acetonitrile in 8 minutes) to afford 385mg of (-) -1- [2- (2- {3- [2- (pyrrolidin-1-ylcarbonyl) phenyl group]Pyrrolidin-1-yl } ethyl) phenyl]Piperidin-2-one 17.

The yield is 12%.

LC-MS(MH⁺):446。

EXAMPLE 10 Synthesis of 4- [ (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) oxy ] benzonitrile 50.

10.1 Synthesis of 1- {2- [2- (3-hydroxypyrrolidin-1-yl) ethyl ] phenyl } piperidin-2-one a 10-1.

To 2- [2- (2-oxopiperidin-1-yl) phenyl]Ethyl 4-methylbenzenesulfonate a2-3(11.95g, 32mmol, 1eq) in acetonitrile (70ml) was added K₂CO₃(9.95g, 48mmol, 1.5eq) then pyrrolidin-3-ol a10-0(2.78g, 32mmol, 1eq) was added. The reaction mixture was stirred at 85 ℃ overnight. After filtration over celite, the solvent is removed and the residue is purified by chromatography on silica gel (eluent: CH)₂Cl₂MeOH93/7) to give 6.68g of 1- {2- [2- (3-hydroxypyrrolidin-1-yl) ethyl]Phenyl } piperidin-2-one a 10-1.

The yield is 72%.

LC-MS(MH⁺):289。

10.2 Synthesis of 1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl methanesulfonate a 10-2.

To a stirred 1- {2- [2- (3-hydroxypyrrolidin-1-yl) ethyl group at room temperature]Phenyl } piperidin-2-one a10-1(5.6g, 19.5mmol, 1eq) in acetonitrile (50ml) was added dimethylaminopyridine (0.238g, 1mmol, 0.1eq) and triethylamine (10.9ml, 78mmol, 4 eq). The solution was stirred at room temperature for 30 minutes. Methanesulfonyl chloride (4.5ml, 59.5mmol, 3eq) was added to the solution. The reaction mixture was stirred at room temperature overnight. After removal of the solvent, the residue was redissolved in dichloromethane (250ml) and the organic layer was washed with water (100ml), 1M HCl (120ml) and water (250 ml). The combined aqueous phases were neutralized by addition of aqueous NaOH and extracted with dichloromethane (3 × 200 ml). The combined organic layers were over MgSO₄Dried and evaporated under vacuum. The residue obtained is purified over silica gel (eluent: CH)₂Cl₂/MeOH/NH₃97/2.7/0.3) gave 5.07g of pure1- {2- [2- (2-oxopiperidin-1-yl) phenyl]Ethyl } pyrrolidin-3-yl methanesulfonate a 10-2.

The yield was 71%.

LC-MS(MH⁺):367。

10.3 Synthesis of 4- [ (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) oxy ] benzonitrile 50.

To 1- {2- [2- (2-oxopiperidin-1-yl) phenyl]Ethyl } pyrrolidin-3-yl methanesulfonate a10-2(0.183g, 0.5mmol, 1eq) in acetonitrile (4ml) was added K₂CO₃(0.138g, 1mmol, 2 eq.) and 4-hydroxybenzonitrile (0.060g, 0.5mmol, 1 eq.). The solution was stirred at 85 ℃ overnight. After filtration the solvent is removed and the residue is purified by basic reverse phase chromatography on silica gel (gradient: CH)₃CN/H₂O/NH₄OH from 40/60/0.1 to 70/30/0.1) to obtain 85mg of pure 4- [ (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] 4]Ethyl } pyrrolidin-3-yl) oxy]Benzonitrile 50.

The yield was 43%.

LC-MS(MH⁺):390。

EXAMPLE 11 Synthesis of 4- [ (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } azetidin-3-yl) oxy ] benzonitrile oxalate 55.

11.1 Synthesis of 1- {2- [2- (3-hydroxyazetidin-1-yl) ethyl ] phenyl } piperidin-2-one a 11-1.

[2- (2-Oxopiperidin-1-yl) phenyl group in methanol (50ml)]Acetaldehyde a3-1(1.32g, 6.09mmol, 1eq) was added azetidine-3-ol hydrochloride a11-0(0.76g, 6.96mmol, 1.14 eq). After stirring at room temperature for about 30 minutes, acetic acid (522. mu.l, 9.13mmol, 1.5eq) was added followed by NaBH₃CN (1.15g, 18.26mmol, 3 eq). The reaction mixture was stirred at room temperature overnight, then filtered and loaded onto an ion-exchange acidic resin cartridge pre-washed with methanol. The cartridge was then washed with about 3 column volumes of methanol, then 3 column volumes of 1M aqueous ammonia methanol. The eluate was evaporated to dryness. To the resulting residue were added water (50ml) and dichloromethane (50 ml). After vigorous stirring and addition of brine, phase 2 was separated. The organic phase was washed with water (50 ml). The aqueous phases were combined and washed with iPrOH/CH₂Cl₂(25ml/50ml) 3 washes. The combined organic phases were evaporated to dryness to give 212.6mg of 1- {2- [2- (3-hydroxyazetidin-1-yl) ethyl]Phenyl } piperidin-2-one a11-1(212.6mg, 0.775mmole, if pure, 12.7% yield), which was used in the next step without further purification.

The yield was 13%.

LC-MS(MH⁺):275。

11.2 Synthesis of 1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } azetidin-3-yl methanesulfonate a 11-2.

1- {2- [2- (3-Hydroxyazetidin-1-yl) ethyl ] in dichloromethane (15ml) under nitrogen]Phenyl } piperidin-2-one a11-1(212mg, 0.77mmol, 1eq) was added triethylamine (216.04. mu.l, 1.55mmol, 2 eq). Methanesulfonyl chloride (106.53mg, 0.93mmol, 1.2eq) was added at 0 ℃ and the reaction mixture was allowed to reach room temperature with stirring under nitrogen atmosphere for 2 hours. Additional triethylamine (216 μ l, 1.55mmol, 2eq) and methanesulfonyl chloride (106.53mg, 0.93mmol, 1.2eq) were added and the reaction mixture was stirred at room temperature under nitrogen for an additional 1 hour. Water (50ml) was then added, the two phases stirred vigorously and separated. The organic phase was passed over MgSO₄Drying, filtration and evaporation to dryness to give 1- {2- [2- (2-oxopiperidin-1-yl) phenyl]Ethyl } azetidin-3-yl methanesulfonate a11-2, which was used in the next step without further purification.

Yield-assumed quantitative.

LC-MS(MH⁺):353。

11.3 Synthesis of 4- [ (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } azetidin-3-yl) oxy ] benzonitrile oxalate 55.

To acetonitrile (5ml) was added 1- {2- [2- (2-oxopiperidin-1-yl) phenyl group with stirring]Ethyl } azetidin-3-yl methanesulfonate a11-2(273mg, 0.775mmol, 1eq) and 4-hydroxybenzonitrile (110.8mg, 0.93mmol, 1.2eq) were added K₂CO₃(374.9mg, 2.71mmol, 3.5 eq). The reaction mixture was heated at 100 ℃ for 10 minutes under microwave conditions. Cooling the reaction mixture with acetonitrile/CH₂Cl₂A mixture of/MeOH/DMF (1/1/1/1) (approximately 10ml) was diluted to ensure dissolution of the desired product. The resulting suspension was loaded onto an ion-exchange acidic resin cartridge (2g) pre-washed with methanol. The cartridge was washed with about 3 column volumes of methanol and then eluted with 3 column volumes of 1M aqueous ammonia in methanol. The eluate was evaporated to dryness and the crude material was chromatographed on reverse phase (gradient: acetonitrile// H)₂O/NH₄OH from 40/60/0.1 to 70/30/0.1 in 10 minutes). The resulting residue was dissolved in acetone (ca. 2ml) and a solution of oxalic acid (4.4mg, 0.05mmole, 1eq) in acetone (2ml) was added. The solution was slowly evaporated and some crystals appeared. Addition of acetone (ca.2 ml) followed by diethyl ether (ca.10 ml) gave a white precipitate which was filtered, washed with copious amounts of diethyl ether and dried overnight at 40 ℃ under vacuum to give 15.5mg of 4- [ (1- {2- [2- (2-oxopiperidin-1-yl) phenyl]Ethyl } azetidin-3-yl) oxy]Benzonitrile oxalate 55.

The yield was 4.3%, via 2 steps.

LC-MS(MH⁺):376。

EXAMPLE 12 Synthesis of 1- (2- {2- [3- (1-acetylpiperidin-2-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one 72.

12.1 Synthesis of 1- (2- {2- [3- (piperidin-2-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one a 12-1.

At 40 ℃ and 40Psi in a H-cube reactor at PtO₂Hydrogenation of 1- (2- {2- [3- (pyridin-2-yl) pyrrolidin-1-yl) in glacial acetic acid]Ethyl } phenyl) piperidin-2-one 36(30mg, 0.085mmol, 1eq) for 0.5 h. Removal of the solvent under vacuum provided 28mg of crude 1- (2- {2- [3- (piperidin-2-yl) pyrrolidin-1-yl)]Ethyl } phenyl) piperidin-2-one a12-1 as a yellow oil, which was used in the next step without further purification.

The yield was 93%.

LC-MS(MH⁺):356。

12.2 Synthesis of 1- (2- {2- [3- (1-acetylpiperidin-2-yl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one 72.

To 1- (2- {2- [3- (piperidin-2-yl) pyrrolidin-1-yl group at 0 deg.C]Ethyl } phenyl) piperidin-2-one a12-1(25mg, 0.070mmol, 1eq) in diethyl ether (2ml) was added triethylamine and acetic anhydride (7. mu.l, 0.077mmol, 1.1 eq). The mixture was stirred at room temperature for 1 hour. The solvent was removed under vacuum. The residue obtained is purified by basic reverse phase chromatography (gradient: acetonitrile/H)₂O/ammonium formate from 5% to 95% acetonitrile in 8 min) to provide 14.5mg of 1- (2- {2- [3- (1-acetylpiperidin-2-yl) pyrrolidin-1-yl]Ethyl } phenyl) piperidin-2-one 72 as a yellow oil.

The yield is 50%.

LC-MS(MH⁺):398。

EXAMPLE 13 Synthesis of 1- (2- {2- [3- (2-fluoro-2-methylpropyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one 85.

13.1 Synthesis of methyl (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) acetate a 13-1.

To 2- [2- (2-oxopiperidin-1-yl) phenyl at room temperature]To a solution of ethyl 4-methylbenzenesulfonate a2-3(2.85g, 7.65mmol, 1eq) in DMF (10ml) was added diisopropylethylamine (2.65ml, 15.30mmol, 2eq) and methyl pyrrolidin-3-ylacetate a13-0(1.08g, 7.65mmol, 1 eq). The mixture was stirred at 80 ℃ overnight. The solvent was removed under vacuum. The residue obtained is purified by chromatography on silica gel (eluent: CH)₂Cl₂EtOH95/5) afforded 1.05g of methyl (1- {2- [2- (2-oxopiperidin-1-yl) phenyl]Ethyl } pyrrolidin-3-yl) acetate a13-1 as a yellow oil.

The yield was 42%.

LC-MS(MH⁺):345。

13.2 Synthesis of 1- (2- {2- [3- (2-hydroxy-2-methylpropyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one a 13-2.

Methyl (1- {2- [2- (2-oxopiperidin-1-yl) phenyl]Ethyl } pyrrolidin-3-yl) acetate a13-1(0.15g, 0.435mmol, 1eq) was dissolved in THF (5 ml). MeMgBr (3M in diethyl ether, 435ml, 1.3mmol, 3eq) was added dropwise at 0 ℃. The reaction mixture was stirred at room temperature for 1 hour and then with NH₄And (4) quenching by a saturated Cl aqueous solution. The phases were separated and the aqueous layer was further extracted with AcOEt (3X20ml) and the collected organic phases were washed with brine (20ml) over Na₂SO₄Drying and concentration under reduced pressure afforded 54mg of 1- (2- {2- [3- (2-hydroxy-2-methylpropyl) pyrrolidin-1-yl]Ethyl } phenyl) piperidin-2-one a13-2 as a yellow oil, which was used in the next step without further purification.

The yield is 36%.

LC-MS(MH⁺):345。

13.3 Synthesis of 1- (2- {2- [3- (2-fluoro-2-methylpropyl) pyrrolidin-1-yl ] ethyl } phenyl) piperidin-2-one 85.

Diethylamino trifluorideSulfur (31. mu.l, 0.235mmol, 1.5eq) was added dropwise to 1- (2- {2- [3- (2-hydroxy-2-methylpropyl) pyrrolidin-1-yl) dichloromethane (5ml)]Ethyl } phenyl) piperidin-2-one a13-2(54mg, 0.157mmol, 1eq) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water and stirred for 1 hour. After phase separation, the aqueous phase was further extracted with dichloromethane (3 times). The combined organic phases were washed with brine (1 time) and over Na₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by basic reverse phase chromatography (gradient: acetonitrile/H)₂O/ammonium formate from 5% to 40% acetonitrile in 8 minutes) to provide 6mg of 1- (2- {2- [3- (2-fluoro-2-methylpropyl) pyrrolidin-1-yl]Ethyl } phenyl) piperidin-2-one 85 as a yellow oil.

The yield is 65%.

LC-MS(MH⁺):347。

EXAMPLE 14 Synthesis of 1- [2- (2- {3- [ 2-oxo-2- (pyrrolidin-1-yl) ethyl ] pyrrolidin-1-yl } ethyl) phenyl ] piperidin-2-one 86.

14.1 Synthesis of (1- {2- [2- (2-oxopiperidin-1-yl) phenyl ] ethyl } pyrrolidin-3-yl) acetic acid a 14-1.

Methyl (1- {2- [2- (2-oxopiperidinyl-1-yl) phenyl)]Ethyl } pyrrolidin-3-yl) acetate a13-1(500mg, 0.87mmol, 1eq) dissolved in MeOH/H₂O (4ml/1ml) LiOH (47mg, 1.7mmol, 2eq) was added. The reaction mixture was stirred at 30 ℃ for 1 hour and then quenched with HCl1M (100. mu.l). The resulting mixture was diluted with n-butanol (15ml) and stirred at room temperature overnight. After phase separation over Na₂SO₄The organic layer was dried, filtered and the filtrate was concentrated under reduced pressure to give 229mg of (1- {2- [2- (2-oxopiperidin-1-yl) phenyl]Ethyl } pyrrolidin-3-yl) acetic acid a14-1 as a colorless oil that need not be further purifiedIn the next step.

The yield is 80%.

LC-MS(MH⁺):331。

14.2 Synthesis of 1- [2- (2- {3- [ 2-oxo-2- (pyrrolidin-1-yl) ethyl ] pyrrolidin-1-yl } ethyl) phenyl ] piperidin-2-one 86.

(1- {2- [2- (2-Oxopiperidin-1-yl) phenyl ] in dichloromethane (5ml)]Ethyl } pyrrolidin-3-yl) acetic acid a14-1(115mg, 0.348mmol, 1eq) and pyrrolidine (32. mu.l, 0.382mmol, 1.1eq) dicyclohexylcarbodiimide (79mg, 0.82mmol, 1.1eq), hydroxybenzotriazole (52mg, 0.382mmol, 1.1eq) and diisopropylethylamine (131. mu.l, 0.731mmol, 2.1eq) were added. The reaction mixture was stirred at room temperature overnight, then filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (gradient: CH)₃CN/H₂O/NH₄OH from 30/70/0.1 to 60/40/0.1) provides 9mg of 1- [2- (2- {3- [ 2-oxo-2- (pyrrolidin-1-yl) ethyl)]Pyrrolidin-1-yl } ethyl) phenyl]Piperidin-2-one 86 as a yellow oil.

The yield was 7%.

LC-MS(MH⁺):384。

EXAMPLE 15 Synthesis of 1- [3- (2- {3- [6- (2,2, 2-trifluoroethoxy) pyridin-2-yl ] pyrrolidin-1-yl } ethyl) pyridin-2-yl ] piperidin-2-one 108.

15.1 Synthesis of 1- (3- {2- [3- (6-fluoropyridin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one a 15-1.

1- (3- {2- [3- (6-Fluoropyridin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one a15-1 can be prepared according to the procedure described in example 4.4.

LC-MS(MH⁺):369。

15.2 Synthesis of 1- [3- (2- {3- [6- (2,2, 2-trifluoroethoxy) pyridin-2-yl ] pyrrolidin-1-yl } ethyl) pyridin-2-yl ] piperidin-2-one 108.

1- (3- {2- [3- (6-Fluoropyridin-2-Yl) pyrrolidin-1-Yl]Ethyl } pyridin-2-yl) piperidin-2-one a15-1(32mg, 0.087mmol, 1eq), 2,2, 2-trifluoroethanol (13mg, 0.13mmol, 1.5eq) and t-BuOK (48.8mg, 0.43mmol, 5eq) were dissolved in DMSO. The reaction mixture was stirred at room temperature. After 2h, 2,2, 2-trifluoroethanol (8.7mg, 0.087mmol, 1eq) was added and the reaction mixture stirred overnight. Then ethyl acetate and saturated NaCl solution were added, the two phases were separated and the aqueous layer was re-extracted with ethyl acetate (3 times). The organic layers were combined and MgSO₄Dry, filter and concentrate under reduced pressure. The residue was purified by basic reverse phase chromatography (gradient: water/acetonitrile/solvent C from 90/0/10 to 5/85/10 in 10 min; solvent C: acetonitrile/water 1/1+ NH)₄CO₃0.4% w/v and NH₄OH0.05% v/v) provides 11.7mg of 1- [3- (2- {3- [6- (2,2, 2-trifluoroethoxy) pyridin-2-yl]Pyrrolidin-1-yl } ethyl) pyridin-2-yl]Piperidin-2-one 108.

The yield is 30%.

LC-MS(MH⁺):449。

EXAMPLE 16 Synthesis of 1- [3- (2- {3- [6- (difluoromethoxy) pyridin-2-yl ] pyrrolidin-1-yl } ethyl) pyridin-2-yl ] piperidin-2-one 109.

16.1 Synthesis of 1- (3- {2- [3- (6-hydroxypyridin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one a 16-1.

1- (3- {2- [3- (6-hydroxypyridin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one a16-1 can be prepared from 6- (pyrrolidin-3-yl) pyridin-2-ol a16-0 according to the procedure described in example 4.4.

The yield was 46%.

LC-MS(MH⁺):367。

16.2 Synthesis of 1- [3- (2- {3- [6- (difluoromethoxy) pyridin-2-yl ] pyrrolidin-1-yl } ethyl) pyridin-2-yl ] piperidin-2-one 109.

2, 2-difluoro-2- (fluorosulfonyl) acetic acid (9.72mg, 0.054mmol, 1eq) was added slowly to 1- (3- {2- [3- (6-hydroxypyridin-2-yl) pyrrolidin-1-yl]Ethyl } pyridin-2-yl) piperidin-2-one a16-1(20mg, 0.054mmol, 1eq) and anhydrous sodium sulfate (0.78mg, 0.005mmol, 0.1eq) in a mixture of anhydrous acetonitrile (400 μ l). The reaction was stirred at room temperature for 2h, then water (100. mu.l) was added. The resulting solution was concentrated in vacuo. The residue was purified by basic reverse phase chromatography (gradient: H)₂O/acetonitrile/NH₄OH from 50/50/0.1 to 20/80/0.1) provides 9.4mg of 1- [3- (2- {3- [6- (difluoromethoxy) pyridin-2-yl)]Pyrrolidin-1-yl } ethyl) pyridin-2-yl]Piperidin-2-one 109.

The yield was 41%.

LC-MS(MH⁺):417。

EXAMPLE 17 Synthesis of 1- [ 1-methyl-4- (2- {3- [4- (trifluoromethyl) phenyl ] pyrrolidin-1-yl } ethyl) -1H-pyrazol-3-yl ] piperidin-2-one oxalate 111.

17.1 Synthesis of 4- (2-methoxyvinyl) -1-methyl-1H-pyrazol-3-amine a 17-1.

4- (2-methoxyvinyl) -1-methyl-1H-pyrazol-3-amine a17-1 can be prepared from 3-amino-1-methyl-1H-pyrazole-4-carbaldehyde a17-0 according to the method described in example 4.2.

Yield-assumed quantitative.

LC-MS(MH⁺):154。

17.2 Synthesis of 1- [4- (2-methoxyvinyl) -1-methyl-1H-pyrazol-3-yl ] piperidin-2-one a 17-2.

A mixture of 4- (2-methoxyvinyl) -1-methyl-1H-pyrazol-3-amine a17-1(500mg, 3.27mmol, 1eq), 5-bromovaleryl chloride (651.9mg, 3.27mmol, 1eq), potassium hydroxide (550.1mg, 9.80mmol, 3eq), 4-dimethylaminopyridine (39.9mg, 0.33mmole, 0.1eq) and N, N, N-tributylbutane-1-ammonium (aminium) bromide (105.3mg, 0.33mmole, 0.1eq) in toluene (15ml) was heated overnight to reflux. After filtration and evaporation the residue is purified by reverse phase chromatography (basic mode, gradient: H)₂O/acetonitrile/NH₄OH from 80/20/0.1 to 50/50/0.1, within 10 minutes) to provide 1- [4- (2-methoxyvinyl) -1-methyl-1H-pyrazol-3-yl]Piperidin-2-one a 17-2.

LC-MS(MH⁺):236。

17.3 Synthesis of [ 1-methyl-3- (2-oxopiperidin-1-yl) -1H-pyrazol-4-yl ] acetaldehyde a 17-3.

[ 1-methyl-3- (2-oxopiperidin-1-yl) -1H-pyrazol-4-yl ] acetaldehyde a17-3 may be prepared from 1- [4- (2-methoxyvinyl) -1-methyl-1H-pyrazol-3-yl ] piperidin-2-one a17-2 according to the method described in example 4.3.

17.4 Synthesis of 1- [ 1-methyl-4- (2- {3- [4- (trifluoromethyl) phenyl ] pyrrolidin-1-yl } ethyl) -1H-pyrazol-3-yl ] piperidin-2-one oxalate 111.

1- [ 1-methyl-4- (2- {3- [4- (trifluoromethyl) phenyl ] pyrrolidin-1-yl } ethyl) -1H-pyrazol-3-yl ] piperidin-2-one oxalate 111 may be prepared from [ 1-methyl-3- (2-oxopiperidin-1-yl) -1H-pyrazol-4-yl ] acetaldehyde a17-3 according to the method described in example 4.4.

Yield 39% from a17-2 (over 2 steps).

LC-MS(MH⁺):421。

EXAMPLE 18 Synthesis of 1- [3- {2- [3- (pyridin-2-yl) pyrrolidin-1-yl ] ethyl } -5- (trifluoromethyl) pyridin-2-yl ] piperidin-2-one 110.

18.1 Synthesis of 1- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] piperidin-2-one a 18-1.

To a solution of 3-chloro-5- (trifluoromethyl) pyridin-2-amine a18-0(700mg, 3.54mmol, 1eq) in anhydrous THF (15ml) cooled to 0 ℃ was added mineral oil containing NaH60% (283mg, 7.08mmol, 2 eq). The reaction mixture was stirred at 0 ℃ for 10 minutes and then at room temperature for 20 minutes. The reaction mixture was then cooled to 0 ℃ and 5-bromovaleryl chloride (707mg, 3.543mmol, 1eq) was added. The reaction mixture was stirred at 70 ℃ for 3 hours and then evaporated to dryness. The residue obtained is redissolved in dichloromethane with NH₄Washed with aqueous Cl (1 time) and saturated NaHCO₃Aqueous wash (1 time). The organic phase is over MgSO₄Dried, filtered and evaporated to dryness. The resulting residue was purified by flash chromatography on silica gel (24g, gradient: dichloromethane/MeOH from 100/0 to 94/6) to provide 480mg of 1- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl]Piperidin-2-one a 18-1.

The yield was 49%.

LC-MS(MH⁺):279/281。

18.2 Synthesis of 1- [5- (trifluoromethyl) -3-vinylpyridin-2-yl ] piperidin-2-one a 18-2.

To 1- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl]To a solution of piperidin-2-one a18-1(260mg, 0.933mmol, 1eq) and vinyl boronic acid pinacol ester (287mg, 1.866mmol, 2eq) in acetonitrile/water (3/2) mixture was added tripotassium phosphate (793mg, 3.732mmol, 2eq), (2, 6-dimethoxy-1, 1' -biphenyl-2-yl) dicyclohexylphosphine (77mg, 0.187mmol, 0.2eq), palladium (II) acetate (21mg, 0.093mmol, 0.1eq), and the reaction mixture was heated at 120 ℃ for 40 min. After evaporation, the residue is redissolved in dichloromethane and the organic phase is passedSaturated NaHCO₃Washed with aqueous solution (2 times) over MgSO₄Dried, filtered and evaporated to dryness. The resulting residue was purified by flash chromatography on silica gel (12 g; gradient: dichloromethane/MeOH from 100/0 to 94/6) to provide 380mg of 1- [5- (trifluoromethyl) -3-vinylpyridin-2-yl]Piperidin-2-one a 18-2.

Yield-assumed quantitative.

LC-MS(MH⁺):271。

18.3 Synthesis of 1- [3- {2- [3- (pyridin-2-yl) pyrrolidin-1-yl ] ethyl } -5- (trifluoromethyl) pyridin-2-yl ] piperidin-2-one 110.

To 1- [5- (trifluoromethyl) -3-vinylpyridin-2-yl]To a solution of piperidin-2-one a18-2(310mg, 1.147mmol, 1eq) and 2-pyrrolidin-3-ylpyridine (221mg, 1.491mmol, 1.3eq) in ethanol (10ml) was added triethylamine (348mg, 479. mu.l, 3.441mmol, 3 eq). The reaction mixture was stirred at 90 ℃ for 7 hours and then heated at 85 ℃ overnight. The reaction mixture was evaporated to dryness and redissolved in dichloromethane. NH for the organic phase₄Washed with aqueous Cl (1 time) and saturated NaHCO₃Washed with aqueous solution (2 times) and then MgSO₄Dried, filtered and evaporated to dryness. The resulting residue was purified by flash chromatography on silica gel (12 g; gradient: from dichloromethane/MeOH 100/0 to 94/6) and dried in vacuo to afford 91.4mg of 1- [3- {2- [3- (pyridin-2-yl) pyrrolidin-1-yl]Ethyl } -5- (trifluoromethyl) pyridin-2-yl]Piperidin-2-one 110.

The yield was 19%.

LC-MS(MH⁺):419。

EXAMPLE 19 Synthesis of 1- (5-fluoro-3- {2- [3- (pyridin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one (mixture of 80/20 enantiomers) 112.

19.1 Synthesis of 5-fluoro-2- (2-oxopiperidinyl-1-yl) nicotinaldehyde a 19-1.

5-fluoro-2- (2-oxopiperidinyl-1-yl) nicotinaldehyde a19-1 can be prepared from 2-bromo-5-fluoronicotinaldehyde a19-0 according to the procedure described in example 4.1.

Yield-assumed quantitative.

LC-MS(MH⁺):223。

19.2 Synthesis of 1- [ 5-fluoro-3- (2-methoxyvinyl) pyridin-2-yl ] piperidin-2-one a 19-2.

1- [ 5-fluoro-3- (2-methoxyvinyl) pyridin-2-yl ] piperidin-2-one a19-2 can be prepared from 5-fluoro-2- (2-oxopiperidinyl-1-yl) nicotinaldehyde a19-1 according to the procedure described in example 4.2.

The yield is 80%.

LC-MS(MH⁺):251。

19.3 Synthesis of 1- (5-fluoro-3- {2- [3- (pyridin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one (mixture of 80/20 enantiomers) 112.

To 1- [ 5-fluoro-3- (2-methoxyvinyl) pyridin-2-yl at 0 deg.C]To a solution of piperidin-2-one a19-2(620mg, 2.477mmol, 1eq) in acetonitrile (25ml) was added sodium iodide (557mg, 3.716mmol, 1.5eq) and trimethylsilyl chloride (404mg, 3.716mmol, 1.5eq) and the reaction mixture was stirred at room temperature for 16 hours to form [ 5-fluoro-2- (2-oxopiperidin-1-yl) pyridin-3-yl in situ]Acetaldehyde a 19-3. In parallel, 2- (pyrrolidin-3-yl) pyridine enantiomer 2 dihydrochloride a1-67(654mg, 2.973mmol, 1.2eq) was dissolved in acetonitrile, loaded onto a carbonate resin, the resin washed with dichloromethane, and the combined filtrates evaporated to dryness to provide 2- (pyrrolidin-3-yl) pyridine enantiomer 2 as the free base. The resulting residue was added to intermediate a 19-3. Addition of NaBH (OAc)₃(1050mg, 4.954mmol, 2eq), the reaction mixture was stirred overnight and the reaction was still not completed. Adding racemic 2- (pyrrolidin-3-yl) pyridine (0.4eq), heating the reaction mixture at 90 ℃ overnight andthe evaporation to dryness. The evaporated residue was redissolved in dichloromethane. The organic phase was washed with saturated NaHCO₃The aqueous solution was washed (2 times) over MgSO₄Dried, filtered and evaporated to dryness. The resulting residue was dissolved in acetonitrile (12ml), HCl5M (ca. 4ml) was added, and the mixture was stirred at 40 ℃ for 3 hours. Dichloromethane was then added and the organic phase was saturated NaHCO₃Washed with aqueous solution (2 times) over MgSO₄Dried, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (12 g; gradient: from CH)₂Cl₂MeOH100/0 to 94/6), and then by reverse phase chromatography (basic conditions: gradient: acetonitrile/H)₂O/NH₄OH from 20/80/0.1 to 50/50/0.1) provides 38mg of 1- (5-fluoro-3- {2- [3- (pyridin-2-yl) pyrrolidin-1-yl)]Ethyl } pyridin-2-yl) piperidin-2-one 112 as a mixture of the 80/20 enantiomers.

The yield was 4.2%.

LC-MS(MH⁺):369。

Table (I) shows the IUPAC name of the compound, the ion peak found in the mass spectrum, the 1HNMR description, the melting point or onset temperature of DSC, and α D.

Table I: physical characteristics of the compounds of the examples.

Example 20 [³H]-5-carboxytryptamine (5-CT) binding assay.

Cell culture conditions and cell membrane preparation:

stable expression of human 5-HT₇Flp-In cells of the D receptor HEK293 were produced internally. Cells were subcultured in DMEM supplemented with 10% dialyzed FBS, 100IU/ml penicillin, 100. mu.g/ml streptomycin and 200. mu.g/ml hygromycin. The cells contained 5% CO at 37 deg.C₂In a humid atmosphere. Cell membranes were prepared as described in gillardetal, eur.j.pharmacol. (2006)536, 102-108.

[³H]-5-carboxytryptamine (5-CT) binding assay:

compounds for human 5-HT₇The affinity of the D receptor is in the range of³H]5-CT in a competitive assay. This binding assay was adapted from plateatetic (1993). Briefly, human 5-HT was expressed₇Cell membranes of HEK293Flp-In of the D receptor (1-5. mu.g protein per assay) at 25 ℃ In the presence of 2mM MgCl₂，0.3-0.4nM[³H]5-CT and increasing concentrations of test compounds in 0.2ml50mM Tris-HCl buffer (pH7.4) in culture for 180min non-specific binding (NSB) is defined as the residual binding found in the presence of 10. mu.M 5-hydroxytryptamine (5-HT). bound cell membranes and free radioligand were separated by rapid filtration through a glass fiber filter pre-soaked in 0.1% polyethylenimine the samples and filters were rinsed with ice cold 50mM Tris-HCl buffer (pH 7.4). the radioactivity trapped on the filter was calculated by liquid scintillation in a β -counter.

The compounds of formula I according to the invention exhibit a pKi value of at least 7.0.

Example 21 measurement of intracellular cAMP concentration.

Evaluation of test Compounds for human 5-HT in cAMP assay by measuring the rightward shift of the concentration-response curve for 5-CT and the decrease in the maximal effect of 5-CT_7DAntagonism of the disease. Briefly, human 5-HT was performed_7DHEK293Flp-In cells were pre-cultured at 750 cells per well for 60min at 25 ℃ In 40. mu.l HBSS buffer (pH7.4) containing 20 nHEPES, 0.1mMIBMX and test compound. 5-CT was added at increasing concentrations and the samples were incubated for an additional 60 min. Termination of culture and measurement of cAMP concentration were performed by HTRF according to the guidelines provided by the kit (HTRFcAMP dynamic kit-62 AM2PEC, CisBioInternational, France). Control 5-HT₇The antagonist compound is mianserin.

The best compounds of formula I according to the invention have a non-overriding effect, i.e. they inhibit the maximal effect induced by 5-CT.

Example 22 epidural extravasation model of migraine.

In an established model of epidural extravasation, the reduction of compound-induced extravasation of plasma proteins into the dura mater is thought to be predictive of activity against dural inflammation found in migraine (Johnson, Neuroreport, 1997, 8, 2237-. Sprague-dawley rats (280-350g) (pentobarbital 60mg/kgi. p.) were anesthetized, and then the femoral vein was catheterized (PE50ID0.58mm, OD0.965mm) for fluorescein isocyanate-bovine serum albumin (FITC-BSA) perfusion and drug injection, and a tracheotomy was performed to reduce respiration. The rat body temperature was maintained at 37 ℃.

The rats were then placed on a stereotaxic frame (Kopf instrument); the anteroposterior position reference (0) is placed on the interaural rod (interaural). Two craniotomies (with a 2.2mm strawberry-shaped manual probe; position +5.4mm from the interaural line and +3.8mm from the medial suture) were performed by hand after a midline pinnate three-spoke spicule scalp incision. Two stimulation electrodes (A-M system stainless steel insulated electrodes 0.10 diameter, 12M Ω, tilt angle 8 °, inter-electrode width: 1.6mm) (9.1 mm depth from the cranial surface) were then introduced into the left trigeminal ganglion. The position was confirmed by blinking in the left eye after stimulation (1 pulse 60 μ a).

Test compound (1ml/kg) was administered intravenously; approximately 5min after injection, FITC-BSA (prepared at 50mg/kg in phosphate buffer solution SigmaP 4417) was infused via the femoral venous catheter (0.3ml/2 min).

At the end of perfusion, the trigeminal ganglion (60 μ A, 200ms, 4Hz) was electrically stimulated for 3 min.

Alternatively, the compound is administered orally prior to anesthesia approximately 45min before electrical stimulation as described above.

Immediately after stimulation, rats were sacrificed by exsanguination, the skull removed, and the left (ipsilateral to stimulation) and right (contralateral to stimulation) dura mater collected and placed in filtered water and then placed on a glass slide and allowed to dry (30 ° protected from light for a minimum of 3 h).

Electrode positions in the trigeminal ganglia (anteroposterior and dorsal/ventral) were confirmed under a microscope (x 16).

The fluorescence concentration in the dura mater ipsilateral-and contralateral to trigeminal ganglion stimulation was quantified using a digital camera (hamamatsu c4742-98 filter for FITC purpose nikon 2.8x) and analytical software (WIT5.3, logistic).

Preferred compounds are those that effectively prevent ipsilateral fluorescence from trigeminal ganglion stimulation, thus preventing extravasation.

Claims

1. 2-oxo-piperidinyl derivatives according to formula I, their geometric isomers, enantiomers, diastereomers and mixtures, or pharmaceutically acceptable salts thereof,

wherein

X is CH or N; y is-NR⁴-or-CH ═ CH-; with the proviso that when Y is-NR⁴-when, X is N;

n is an integer selected from 1,2 or 3; m is 1 or 2;

R¹is benzyl, 2-bromobenzyl, tert-butyl, 2-methylpropyl, 2-fluoro-2-methylpropyl, 2-chloro-2, 2-difluoroethyl, 2-oxo-2- (pyrrolidin-1-yl) ethyl, 2,2, 2-trifluoroethyl, propyl, phenyl, 2-carbamoylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3, 4-difluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2- (methylcarbamoyl) phenyl, 2- (3-methyl-1, 2, 4-oxadiazol-5-yl) phenyl, 2- (pyrrolidin-1-ylcarbonyl) phenyl, 2- (trifluoromethyl) phenyl, 3- (trifluoromethyl) phenyl, 4- (trifluoromethyl) phenyl, cyclohexyl, 4, 4-difluorocyclohexyl, pyridin-2-yl, 6-cyanopyridin-2-yl, 3-fluoropyridin-2-yl, 5-fluoropyridin-2-yl, 6-methoxy-pyridin-2-yl, 6-methylpyridin-2-yl, 6- (4-fluorophenyl) pyridin-2-yl, 6- (propan-2-yloxy) pyridin-2-yl, 6- (1H-pyrazol-1-yl) pyridin-2-yl, 6-trifluoromethylpyridin-2-yl, 6- (cyclo-butyloxy) pyridin-2-yl, 6- (difluoromethoxy) pyridin-2-yl, 6- (2,2, 2-trifluoroethoxy) pyridin-2-yl, pyridin-3-yl, 2-fluoropyridin-3-yl, pyridin-4-yl, 4-methoxypyrimidin-2-yl, 4-methyl-1, 3-thiazolyl-5-yl, 1-acetylpiperidin-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydrofuran-2-yl; or

R¹is-O-R²Group, wherein R²Is benzyl, phenyl, 5-bromo-2-methoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-methoxy-phenyl, 3-methoxyphenyl or 5-fluoropyridin-2-yl

R³Is hydrogen, fluoro or trifluoromethyl; and

R⁴is hydrogen or methyl.

2. A compound according to claim 1, having the formula I-A,

wherein

X is CH or N.

3. A compound according to claim 1, having the formula I-B,

4. a compound according to claim 1, having the formula I-C,

wherein

X is CH or N.

5. A compound according to claim 1, having the formula I-D,

wherein

X is CH or N.

6. A compound according to claim 1, having the formula I-E,

wherein

X is CH or N.

7. A compound selected from the group comprising:

1- {2- [2- (3-phenylpyrrolidin-1-yl) ethyl ] phenyl } piperidin-2-one;

1- {2- [2- (3-phenylazetidin-1-yl) ethyl ] phenyl } piperidin-2-one oxalate;

1- {2- [2- (3-phenylpiperidin-1-yl) ethyl ] phenyl } piperidin-2-one oxalate;

1- {2- [2- (3-benzylpyrrolidin-1-yl) ethyl ] phenyl } piperidin-2-one oxalate;

1- {2- [2- (3-benzylazetidin-1-yl) ethyl ] phenyl } piperidin-2-one;

1- (2- {2- [3- (2-bromobenzyl) azetidin-1-yl ] ethyl } phenyl) piperidin-2-one;

1- {2- [2- (3-phenoxyazetidin-1-yl) ethyl ] phenyl } piperidin-2-one oxalate;

1- {2- [2- (3-tert-butylpyrrolidin-1-yl) ethyl ] phenyl } piperidin-2-one;

1- (5-fluoro-3- {2- [3- (pyridin-2-yl) pyrrolidin-1-yl ] ethyl } pyridin-2-yl) piperidin-2-one.

8. The use of a compound according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment of migraine.

9. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 7 in combination with a pharmaceutically acceptable diluent or carrier.