MXPA06010630A - Novel benzyl(idene)-lactam derivatives - Google Patents

Abstract

The present invention relates to novel benzyl(idene)-lactam derivatives, compounds of the formula (I) wherein R1 is a group of the formula G1 or G2 depicted below, wherein R1, R3, R6,R13, X, a, n and m are as defined herein, their pharmaceutically acceptable salts, and pharmaceutical compositions which include selective antagonists, inverse agonists and partial agonists of serotonin 1 (5-HT1) receptors, specifically, of one or both of the 5-HT1A and 5-HT1B receptors. The compounds of the invention are useful in treating or preventing depression, anxiety, obsessive compulsive disorder (OCD) and other disorders for which a 5-HT1 agonist or antagonist is indicated and have reduced potential for cardiac side effects, in particular QTc prolongation.

Description

NEW BENCIL DERIVATIVES (1DENQ) -LACTAMAS BACKGROUND OF THE INVENTION The present invention relates to new benzyl (ylidene) -lactam derivatives, to intermediates for their preparation, to pharmaceutical compositions containing them and to their use in medicine. The compounds of the present invention include selective antagonists, inverse agonists and partial agonists of serotonin 1 (5-HT ^) receptors, specifically, of one or both of the 5-HT- [alpha] A and 5-HT1 B receptors (previously classified as 5-HT-ID.) They are useful for treating or preventing depression, anxiety, obsessive-compulsive disorder (OCD) and other disorders for which a 5-HT-? agonist or antagonist is indicated and have a reduced potential capacity for cardiac side effects, in particular prolongation of QTC. European patent application 434,561, published on June 26, 1991, refers to 1- (4-substituted-1-piperazinyl) -naphthalenes substituted with 7-alkyl-alkoxy and hydroxy The compounds are referred to as 5-HT? agonists and antagonists useful in the treatment of migraine, depression, anxiety, schizophrenia, stress and pain. European patent application 343,050, published on November 23, 1989, refers to 1 - (4-substituted-1-p¡p erazinyl) -naphthalenes unsubstituted in 7, halogenated and substituted with methoxy as useful therapeutic agents of 5-HT-IA ligands.

PCT application WO 94/21619, published on September 29, 1994, refers to naphthalene derivatives as agonists and antagonists 5- PCT publication WO 96/00720, published January 1, 1996, refers to naphthyl ethers as 5-HT-? Agonists and antagonists. tools. PCT publication WO 97/36867, published October 9, 1997, and WO 98/14433, published April 9, 1998, refer to benzyl- (idene) -lactam related derivatives which have utility as psychotherapeutic agents. European patent publication 701, 819, published on March 20, 1996, refers to the use of 5-HT-? Agonists and antagonists. in combination with a 5-HT reuptake inhibitor. Glennon et al. refer to 7-methoxy-1- (1-piperazinyl) -naphthalene as a 5-HT? useful in their article "5-HT | D Serotonin Receptors", Clinical Drug Res. Dev., 22, 25-36 (1991). Glennon's article "Serotonin Receptors: Clinical Implications", Neuroscience and Behavioral Reviews, 14, 35-47 (1990), refers to the pharmaceutical effects associated with serotonin receptors that include appetite suppression, thermal regulation, cardiovascular / hypotensive effects , drowsiness, psychosis, anxiety, depression, nausea, emesis, Alzheimer's disease, Parkinson's disease and Huntington's disease. PCT publication WO 95/31988, published November 30, 1995, refers to the use of a 5-HT-? D antagonist in combination with a 5-HT-? A antagonist to treat CNS disorders (central nervous system) such as depression, generalized anxiety, panic disorders, agoraphobia, social phobias, obsessive-compulsive disorder, post-traumatic stress disorder, memory disorders, anorexia nervosa and bulimia nervosa, Parkinson's disease, tardive dyskinesias, endocrine disorders such as hyperprolactinemia, vasospasm (particularly in the cerebral vasculature) and hypertension, disorders of the gastrointestinal tract in which changes in mobility and secretion are involved, as well as sexual dysfunction. G. Maura et al., J. Neurochem, 66 (1), 203-209 (1996), have established that the administration of selective agonists for 5-HTIA receptors or for the two receptors 5-HTIA and 5-HT-ID it may represent a great improvement in the treatment of human cerebellar ataxias, a multi-faceted syndrome for which no established therapy is available. European Patent Publication 666,261, published on August 9, 1995, refers to thiazine and thiomorpholine derivatives which are claimed to be useful in the treatment of cataracts.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to benzyl (ylidene) -lactams of formula I wherein R1 is a group of formula G1 or G2 described below, G1 G2 a is zero to eight; m is one to three; R6 is selected from the group consisting of hydrogen, (C -? - C6) alkyl optionally substituted with (C? -C6) alkoxy or one to three fluorine atoms, or ((C? -C) alkyl) - aryl in which the aryl moiety is phenyl, naphthyl or heteroaryl- (CH2) q-, in which the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzizoxazolyl and benzisothiazolyl and q is zero, one, two , three or four, and wherein said aryl and heteroaryl moieties may be optionally substituted with one or more substituents independently selected from the group consisting of chlorine, fluorine, bromine, iodine, (d-C6) alkyl, (C) alkoxy -pCß), trifluoromethyl, cyano and -SOt-alkyl (C Cß), where t is zero, one or two; each R13 is, independently, alkyl of (CrC) or an alkylene bridge of (CC) of one of the ring carbon atoms of the piperazine or piperidine ring of G1 or G2, respectively, at the same or another carbon atom of the ring or a ring nitrogen atom of piperazine or piperidine of G1 or G2, respectively, which has an available binding site, or a carbon atom of the ring of R6, when R6 has a ring structure having a ring available union; X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (d-C6) alkyl, hydroxy, (C? -C6) alkoxy, -SOt-alkyl (CrC6) where t is zero, one or two, -C02R10 or -CONR11R12; each of R10, R11 and R12 is independently selected from hydrogen, (C? -C4) alkyl, phenyl and naphthyl, wherein said phenyl or naphthyl may be optionally substituted with one or more substituents independently selected from chlorine, fluorine, bromine , iodo, alkyl of (C- | -C6), alkoxy of (C -? - C6), trifluoromethyl, cyano and -S-Qralkyl (C- | -C6), where t is zero, one or two; or R11 and R12, together with the nitrogen atom to which they are attached, form a 5 to 7 membered heteroalkyl ring which may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; R3 is vinyl, C (= 0) R, wherein R is straight or branched chain Ci-Ca alkyl, C3-C8 cycloalkyl or aryl, wherein R is preferably tert-butyl, or R3 is - (CH2) gB, where g is zero to three and B is hydrogen, phenyl, naphthyl or a 5- to 6-membered heteroaryl ring containing from one to four heteroatoms in the ring selected from oxygen, nitrogen and sulfur, with the proviso that that said ring can not contain two adjacent oxygen atoms or two adjacent sulfur atoms and wherein each of said phenyl, naphthyl and heteroaryl rings can be optionally substituted with one to three substituents independently selected from hydroxyalkyl of (C C8), (C 1 -C 8) -alkoxy (C Cs), hydroxy (C 3 -C 8) -cycloalkyl, (C 3 -C 8) -cycloalkoxy, (C 1 -C 8) -alkoxy (C 3 -C 8) -cycloalkyl, heterocycloalkyl, hydroxyheterocycloalkyl and (C -? - C8) -heterocycloalkyl alkoxy, wherein each of said cycloalkyl (C3-C8) moieties or heterocycle alkyl can be independently substituted with one to three alkyl groups of (C- | -C6) or benzyl; when B is a phenyl, naphthyl or heteroaryl ring, each of said rings may be optionally substituted with one to three substituents independently selected from phenyl, naphthyl and a 5- to 6-membered heteroaryl ring containing from one to four selected heteroatoms between oxygen, nitrogen and sulfur, with the proviso that said heteroaryl ring can not contain two adjacent oxygen atoms nor two adjacent sulfur atoms, and wherein each independently selected phenyl, naphthyl or heteroaryl substituent can be substituted by itself with one to three alkyl substituents of (Cr C8) or C3-C8 cycloalkyl, and examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl. , indolyl, benzimidazolium, benzofuranyl, cinolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, trivazinyl, pindynyl, purinyl, oxadiazolyl, thiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl and azaindolyl; or when B is a phenyl, naphthyl or heteroaryl ring, each of said rings may be optionally substituted with one to three substituents independently selected from (a) a lactone formed from - (CH2) tOH with an ortho-COOH, where t is one, two or three; (b) -CONR14R15, wherein R14 and R15 are independently selected from (C -? - C8) alkyl and benzyl, or R14 and R15 together with the nitrogen atom to which they are attached form a heteroalkyl ring of from 5 to 7 members which may contain from zero to three heteroatoms selected from nitrogen, sulfur and oxygen in addition to the nitrogen atom of the group -CONR14R15, wherein when any of said heteroatoms is nitrogen, it may be optionally substituted with (Cs) alkyl or benzyl, with the proviso that said ring can not contain two adjacent oxygen atoms or two adjacent sulfur atoms; (c) - (CH2) vNCOR16R17 wherein v is zero, one, two or three and -COR16 and R17 taken together with the nitrogen atom to which they are attached form a lactam ring of 4 to 6 members; and (d) - (C1-C8) -NR18R19 wherein each of R18 and R19 is independently selected from hydrogen and alkyl of (C4), or R18 and R19, together with the nitrogen atom to which they are attached , form a 4- to 7-membered heteroalkyl ring which may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; where the flashing lines indicate optional double links; and n is 1, 2 or 3; or a pharmaceutically acceptable salt or isomer thereof. Other embodiments of the invention relate to a compound according to formula I wherein R3 is (CH2) gB wherein g is zero and B is selected from phenyl or pyridyl. The invention also relates to a compound according to formula I wherein R3 is (CH2) gB wherein g is zero and B is selected from phenyl or pyridyl, wherein said cycloalkyl (C3-C8) - of said substituents hydroxy-cycloalkyl of (C3-C8), alkoxy (CrC8) -cycloalkyl (C3-C8) is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The invention also relates to a compound according to formula I wherein R3 is (CH2) gB in which g is zero and B is selected from phenyl or pyridyl, and wherein said heterocycloalkyl residue having four to eight atoms , of said 1 to 3 optional substituents, is selected from tetrahydropyranyl, morpholinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, thiomorpholinyl, azepinyl, diazepinyl, oxazepinyl, thiazepinyl, oxetanyl and tetrahydrofuranyl. This invention also relates to a compound according to formula I wherein R3 is (CH2) gB wherein g is zero and B is selected from phenyl or pyridyl, wherein said alkoxyheterocycloalkyl moiety is selected from tetrahydropyranoxy, tetrahydrofuranoxy, oxethanoxy, azetidinoxy, pyrrolidinoxy and piperidinoxy. The invention also relates to a compound according to formula I wherein R3 is (CH2) gB in which g is zero and B is selected from phenyl or pyridyl, wherein said 5-6 membered heteroaryl ring, said 1 to 3 optional substituents, is selected from pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, siatyl, oxadiazolyl, thiadiazolyl, pyrimidinyl, pyrazinyl and pyridazinyl. The invention also relates to a compound according to formula I wherein R3 is (CH2) gB in which g is zero and B is selected from phenyl or pyridyl, wherein said groups R14 and R15 of said substituent -CONR14R15 together with the nitrogen atom to which they are attached they form a 5 to 6 membered heteroalkyl ring selected from piperidine, N-alkyi (C0-C6) -piperazine and morpholine. The invention also relates to a compound according to the formula I wherein R3 is (CH2) gB in which g is zero and B is selected from phenyl or pyridyl, wherein said groups -COR16 and R17 of said substituent - (CH2) vNCOR16R17 together with the nitrogen atom to which they are attached together they form a 5- or 6-membered lactam ring, and v is 1. The invention also relates to a compound according to formula I wherein R3 is (CH2) gB wherein g is zero and B is selected from phenyl or pyridyl, wherein a lactone is formed from said substituent -CH2OH with said ortho-COOH substituent. Specific examples of the compounds of the present invention are the following: 3- [5-Fluoro-2- (4-methyl-piperazin-1-yl) -benzyl] -1- [4- (1-hydroxy) -1-methyl-ethyl) -phenyl] -pyrrolidin-2-one, ethyl ester of 4- acid. { 3- [2- (4-methyl-piperazin-1-yl) -benzyl-2-oxo-pyrrolidin-1-yl} -benzoic acid, 3- [2- (4-Methyl-piperazin-1-yl) -benzyl] -1- (6-morpholin-4-yl-pyridin-3-yl) -pyrrolidin-2-one 1- [4- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2- ona, 3- [2- (4-Methyl-piperazin-1-yl) -benzyl] -1- (4-morpholin-4-yl-phenyl) -pyrrolidin-2-one, 1- [4- (1 -Hydroxy-cyclopentyl) -phenyl] -3- [2- (4-methyl-p-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 1- [4- (1-Hydroxy) -cyclohexyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 1- [4- (1-Ethyl -1-hydroxy-propyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 1- [3- (1-Hydroxy-1- methyl-ethyl) -phenyl-3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 1- [4- (2-Hydroxy-2-methyl-propyl) - phenyl-3- (2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 1- [6- (1-Hydroxy-1- methyl-ethyl) -pyridin-3-yl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 1- [4- (1 -Metoxy-1-methyl-ethyl) -phenyl] -3- [2- (4-methyl-p-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 1- [4 - (2-Methoxy-2-methyl-pro pyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 1 - [4- (1-methoxy-cyclobutyl) -phenyl] - 3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 3- [2- (4-Met.lp.perazin-1-yl) -benzyl] -1- (4-pyridin-4-yl-phenyl) -pyrrolidin-2-one, 1- [4- (1-Hydroxy-cyclopentyl) -phenyl] -3- (2-piperazin-1- il-benzyl) -pyrrolidin-2-one, 1- (4- (1-Hydroxy-cyclobutyl) -phenyl] -3- (2-piperazin-1-yl-benzyl) l) -pyrrolidin-2-one, 1- [4- (1-Hydroxy-cyclohexyl) -phenyl] -3- (2-piperazin-1-yl-benzyl) -pyrrolidin-2-one, 1- [4- ( 1-Ethyl-1-hydroxy-propyl) -phenyl] -3- (2-piperazin-1-yl-benzyl) -pyrrolidin-2-one, 1- [4- (1-Hydroxy-1- methyl-ethyl) -phenyl] -3- (2-piperazin-1-yl-benzyl) -pyrrolidin-2-one, 1- [4- (1-Hydroxy-1-methylene-ethyl) - phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzylidene] -pyrrolidin-2-one, 3- [2- (4-Ethyl-piperazin-1-yl) -benzyl] -1- [4- (1-Hydroxy-1-methyl-ethyl) -phenyl] -pyrrolidin-2-one, 3- [2- (2,5-Dimethyl-p-piperazin-1-yl) - benzyl] -1- [4- (1-hydroxy-cyclopentyl) -phenyl] -pyrrolidin-2-one, 3- [2- (4-methyl-piperazine- 1-yl) -benzyl] -1- [6- (tetrahydro-pyrn-4-yloxy) -pyridin-3-yl] -pyrrolidin-2-one, 1- [6- (1-H) Droxy-cyclopentyl) -pyridin-3-yl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl-pyrrolidin-2-one, 1- [4- (1-Hydroxy -cyclobutyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 1- [5- (1-Hydroxy-1-methyl-et; l) -pyridin-2-yl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 1- [5- (1-Hydroxy) -cyclopentyl) -pyridin-2-yl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, and pharmaceutically acceptable salts and optical isomers of the same. Specific optical isomers of the compounds of the invention include: (R) -3- [5-Fluoro-2- (4-methyl-piperazin-1-yl) -benzyl] -1- [4- (1-hydroxy-1-methyl-ethyl) -phenyl] -pyrrolidin-2-one, (R) -4- ethyl ester. { 3- [2 ~ (4-Methyl-piperazin-1-yl) -benzyl] -2-oxo-pyrrolidin-1-yl} -benzoic acid, (R) -3- [2- (4-Methyl-piperazin-1-yl) -benzyl] -1- (6-morpholin-4-yl-pyridin-3-yl) -pyrrolidin -2-one, (R) -1- [4- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] - pyrrolidin-2-one, (R) -3- [2- (4-Methyl-piperazin-1-yl) -benzyl] -1- (4-morpholin-4-yl-phenyl) -pyrrolidin- 2-one, (R) -1- [4- (1-Hydroxy-cyclopentyl) -phenyl] -3- [2- (4-methyl-p-piperazin-1-yl) -benz l] -pyrrolidin-2-one, (R) -1- [4- (1-Hydroxy-cyclohexyl) -phenyl-3- [2- (4-methyl-p-piperazine-1 -yl) -benzyl] -pyrrolidin-2-one, (R) -1- [4- (1-Ethyl-1-hydroxy-propyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin- 2-one, (R) -1- [3- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, (R) -1- [4- (2-Hydroxy-2-methyl-propyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) - benzyl] -pyrrolidin-2-one, (R) -1- [6- (1-Hydroxy-1-methyl-ethyl) -pyridin-3-yl] -3- [2- (4-methyl -piperazin-1-yl) -benzyl] -pyrrolidin-2-one, (S) -3- [5-Fluoro-2- (4-methyl-piperazin-1-yl) -benzyl] -1- [4- (1-Hydroxy-1-methyl-ethyl) -phenyl] -pyrrolidin-2-one, (S) -4- ethyl ester. { 3- [2- (4-Methyl-piperazin-1-yl) -benzyl] -2-oxo-pyrrolidin-1-yl} -benzoic acid, (S) -3- [2- (4-Methyl-piperazin-1-yl) -benzyl] -1- (6-morpholin-4-yl-pyridin-3-yl) -pyrrolidin-2-one, (S) -1- [4- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- [2- (4-methylpiperazin-1- il) -benzyl] -pyrrolidin-2-one, (S) -3- [2- (4-Methyl-piperazin-1-yl) -benzyl] -1- (4-morpholin-4-yl) phenyl) -pyrrolidin-2-one, (S) -1- [4- (1-Hydroxy-cyclopentyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) - benzyl] -pyrrolidin-2-one, (S) -1- [4- (1-Hydroxy-cyclohexyl) -phenyl] -3- [2- (4-methyl-piperazine) 1-yl) -benzyl] -pyrrolidin-2-one, (S) -1- [4- (1-Ethyl-1-hydroxy-propyl) -phenyl] -3- [2- (4-methyl-piperazine -1-yl) -benzyl] -pyrrolidin-2-one, (S) -1- [3- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- [2- (4- methylpiperazin-1-yl) -benzyl-pyrrolidin-2-one, (S) -1- [4- (2-Hydroxy-2-methyl-propyl) -phenyl] -3- [2- (4 -methyl-piperazin-1-l) -benzyl] -pyrrolidin-2-one, (S) -1- [6- (1-Hydroxy-1-methyl-ethyl) -pyridin-3-yl] - 3- [2- (4-Methylpiperazin-1-yl) -benzyl] -pyrrolidin-2-one, and its pharmaceutically acceptable salts. Unless otherwise indicated, the term "halo", as used herein, includes fluorine, chlorine, bromine and iodine. Unless otherwise indicated, the term "alkyl", as used herein, includes linear or branched alkyl groups having one to eight carbon atoms.

Unless otherwise indicated, the term "cycloalkyl", as used herein, includes moieties derived from cyclic hydrocarbons containing from four to seven carbon atoms in the ring, including cyclic hydrocarbon moieties substituted with alkyl moieties. linear or branched. Unless otherwise indicated, the term "heterocycloalkyl", as used herein, includes a cyclic hydrocarbon in which one or more of the ring carbon atoms has been substituted with a nitrogen, oxygen or sulfur atom, or any combination thereof. Examples of these groups are oxetanyl, tetrahydrofuranyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and azepanyl. The term "alkoxy," as used herein, means "alkyl-O-", wherein "alguyl" is defined as above. The term "alkylfen", as used herein, means an alkyl radical having two available binding sites (i.e., -alkyl-), wherein "alkyl" is defined as above. The term "alkenyl" is intended to include hydrocarbon chains of straight or branched configuration comprising one or more unsaturated carbon-carbon bonds that may occur at any stable point along the chain, such as ethenyl and propenyl. The alkenyl groups will usually have two to about twelve carbon atoms, more usually two to about eight carbon atoms. The term "alkynyl" is intended to include hydrocarbon chains of straight or branched configuration comprising one or more triple carbon-carbon bonds, which may occur at any stable point along the chain, such as ethynyl and propynyl. The alkynyl groups will usually have two to about twelve carbon atoms, more usually two to about eight carbon atoms. The term "aryl" is intended to include groups that, according to Hückel's theory, have a system of delocalized pi electrons (4n + 2), cyclic containing from five to about twelve atoms in the ring. Examples of aryl groups include, but are not limited to, free radicals and their substitution products, for example, phenyl, naphthyl and toluyl, among many others. The term "heteroaryl" is intended to include aromatic heterocyclic groups and includes non-limiting examples of thiophenyl, pyridyl, pyrimidyl, pyridazyl, oxazolyl, isooxazolyl, thiazolyl and isothiazolyl, among others. Unless otherwise indicated, the term "one or more substituents", as used herein, refers to from 1 to the maximum number of possible substituents based on the number of available link sites. The compounds of formula I can have chiral centers and, therefore, can be produced in different enantiomeric configurations. The invention includes all enantiomers, diastereomers and other stereoisomers, as well as any possible tautomers of these compounds of formula I, as well as racemic mixtures or other mixtures thereof. The present invention also relates to the pharmaceutically acceptable acid addition salts of the compounds of formula I. Examples of pharmaceutically acceptable acid addition salts of the compounds of formula I are the salts of hydrochloric acid, p-toluenesulfonic acid, acid fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, maleic acid, di-p-toluyl-tartaric acid and mandelic acid. The present invention also relates to all radiolabeled forms of the compounds of formula I. Preferred radiolabelled compounds of formula I are those in which the radiolabels are selected from H3, C11, C14, F18, I123 and I125. These radiolabeled compounds are useful as research and diagnostic tools in pharmacokinetic studies of metabolism and in binding assays in both animals and humans. The present invention also relates to a pharmaceutical composition for treating a disorder or condition in a mammal, including a human being, selected from depression, anxiety, depression with concomitant anxiety, dysthymia, post-traumatic stress disorder, panic, phobias, obsessive-compulsive disorder (OCD), OCD with co-morbid Tourette syndrome, border personality, sleep disorders, psychosis, attacks, dyskinesias, symptoms of Huntington or Parkinson's disease, spasticity, suppression of attacks resulting from epilepsy, cerebral ischemia, anorexia, attacks with fainting, hypokinesia, cranial traumas, chemical dependencies, ejaculation prematurity, mood and appetite disorders associated with premenstrual syndrome (PMS), intestinal inflammation disease, modification of eating behavior, carbohydrate blocking apathetics, late luteal dysphoric disorder, symptoms associated with smoking cessation, panic disorder, bipolar disorder, sleep disturbances, discomfort, dysfunction cognitive, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, chemical dependencies and addictions selected between dependencies or addictions to nicotine or tobacco products, alcohol, benzodiazepines, barbiturates, opiates or cocaine; ludopathies; tricofilomania; migraine, stroke, traumatic brain injury (TBI), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, dementia due to multiple infarctions, epilepsy, senile dementia of Alzheimer's type (AD), Parkinson's disease (PD), disorder of attention deficit hyperactivity (ADHD) and Tourette syndrome, comprising an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The present invention also relates to a method for treating a disorder or condition mentioned above in a mammal, including a human being, which comprises administering to a mammal in need of this treatment an amount of a compound of formula I, or a pharmaceutically salt acceptable of it, that is effective to treat this disorder or condition. The present invention also relates to a pharmaceutical composition for use in the treatment of a disorder or condition mentioned above in a mammal, comprising an amount of a compound according to formula I which is an effective antagonist, inverse agonist or agonist partial of 5-HTIB receptors and a pharmaceutically acceptable carrier. The present invention also relates to a method for treating a disorder or condition mentioned above in a mammal, which comprises administering to a mammal in need of this treatment an amount of a compound of formula I which is an effective antagonist, inverse agonist or partial agonist of 5-HT1B receptors. As used herein, the term "depression" includes depressive disorders, for example, single or recurrent major depressive disorders, and dysthymic disorders, depressive neurosis, and neurotic depression; melancholic depression including anorexia, weight loss, insomnia and waking up early in the morning, and psychomotor retardation; atypical depression (or reactive depression) that includes increased appetite, hypersomnia, psychomotor agitation or irritability, anxiety and phobias, seasonal affective disorder or bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclotinic disorder. Other mood disorders encompassed by the term "depression" include dysthymic disorder with early or late onset and with or without atypical features; dementia of the Alzheimer type, with early or late onset, with depressed mood; vascular dementia with depressed mood, alcohol-induced disorders, amphetamines, cocaine, hallucinogens, inhalants, opiates, phenyclidine, sedatives, hypnotics, anxiolytics and other substances; schizoaffective disorder of the depressed type; and adjustment disorder with depressed mood. As used herein, the term "anxiety" includes anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia with no history of panic disorder, specific phobias, eg, animal-specific phobias, social phobias, obsessive-compulsive disorder. -compulsive, stress disorders that include post-traumatic stress disorder and acute stress disorder, and generalized anxiety disorders. "Generalized anxiety" is usually defined as a prolonged period (for example, at least six months) of excessive anxiety or worry with symptoms on most days of that period. Anxiety and worry are difficult to control and may be accompanied by restlessness, ease of fatigue, difficulty concentrating, irritability, muscle tension and sleep disturbance. "Panic disorder" is defined as the presence of recurrent panic attacks followed by at least one month of persistent restlessness due to having another panic attack. A "panic attack" is a discrete period in which there is a sudden onset of intense apprehension, fear or terror. During a panic attack, the individual may experience a variety of symptoms including palpitations, sweating, tremors, shortness of breath, chest pain, nausea and confusion. Panic disorder can occur with or without agoraphobia. "Phobias" include agoraphobia, specific phobias and social phobias. "Agoraphobia" is characterized by an anxiety to be in places or situations in which it can be difficult or compromised to escape or in which there can be no help available in the case of a panic attack. Agoraphobia can occur without a history of a panic attack. A "specific phobia" is characterized by a clinically significant anxiety caused by a feared object or situation. Specific phobias include the following subtypes: type of animals, triggered by animals or insects; type of natural environment, triggered by objects in the natural environment, for example storms, heights or water; wound type with blood-injection, triggered by the sight of blood or a wound or by observing or receiving an injection or other invasive medical procedure; Situational type, triggered by a specific situation such as public transport, tunnels, bridges, elevators, flights, driving or closed spaces; and another type in which fear is triggered by other stimuli. Specific phobias can also be called simple phobias. A "social phobia" is characterized by a clinically significant anxiety caused by exposure to certain types of social or acting circumstances. Social phobia can also be called social anxiety disorder.

Other anxiety disorders encompassed by the term "anxiety" include alcohol-induced anxiety disorder, amphetamines, caffeine, cannabis, cocaine, hallucinogens, inhalants, phencyclidine, sedatives, hypnotics, anxiolytics and other substances, and adjustment disorders with anxiety or with combined anxiety and depression.

DETAILED DESCRIPTION OF THE INVENTION Except when otherwise stated, R1, R3, X, G1, G2, R6, R13, a, n and m in the reaction schemes and following expositions are defined as above. Unless otherwise stated, the conditions of the reactions for all reaction schemes They include an inert atmosphere commonly used in the art as nitrogen or argon. The schemes 1 1a to 1d refer to general methods suitable for preparing compounds of formula I in which R1 = G1. In the Step 1 of Scheme 1, a mixture of benzaldehyde V substituted at 2 wherein the substituent at the 2-position, indicated as Z in Scheme 1 is a functional group which has the ability to undergo an oxidative addition as, but not limited to, F, Cl, Br, I and sulfonate, such as 2-fluorobenzaldehyde, and an N-substituted compound of formula IV, are treated in a solvent selected from water, 1,4-dioxane, n-butanol, N, N-dimethe lformamide, dimethyl sulfoxide, acetonitrile or mixtures thereof, preferably water, with a base such as trialkyl amine or an alkali metal carbonate, preferably sodium carbonate, at a temperature of from about 40 ° C to about 150 ° C, preferably from about 90 ° C at about 120 ° C to produce an aldehyde of formula III. A mixture of 2-Z-benzaldehyde and the N-substituted compound of formula IV is treated in a solvent selected from toluene, benzene, DME, of which toluene is preferred, with a base such as sodium or potassium tert-butoxide, sodium or potassium carbonate, potassium phosphonate, preferably sodium tert-butoxide with a palladium source such as tetrakis (triphenylphosphine) palladium, palladium acetate, tris (dibenzylidene acetone) dipalladium, transdichloro-bis (triphenylphosphine) palladium or phosphine ligands optionally added as BINAP or triphenylphosphine when it is palladium acetate, and BINAP is preferred, at a temperature of about 40 ° C to 150 ° C, preferably about 90 ° C to 120 ° C, to produce an aldehyde of formula III. Step 2 of Scheme 1 is an addition reaction of N-substituted lactam II to the aldehyde of formula III, wherein the R3 substituted at N is vinyl or C (= 0) R, wherein R is C | C8 straight or branched chain, C3-C8 cycloalkyl, aryl or CF3, wherein R is preferably tert-butyl, using an amine or a metal hydrous base such as sodium hydride or sodium bis (trimethylsulfonyl), preferably sodium bis (trimethylsilylamide), in a reaction solvent inert to the reaction, preferably an ether solvent selected from diethyl ether, dioxane and tetrahydrofuran, most preferably tetrahydrofuran, at a temperature of about -30 ° C to about 100 ° C, preferably from about -10 ° C to 30 ° C, to produce a compound of formula I, in which the dotted line represents a carbon-carbon double bond, and is designated IB in Scheme 1 (see Sasaki, H et al., J. Med. Chem., 1991, 34, 628-633). In one embodiment, R3 is separated under the conditions of the reaction. In other embodiments, for example, when R3 is vinyl, a separate step of deprotection is required. In this case, R3 can be separated using an aqueous acid treatment such as trifluoroacetic acid or hydrochloric acid, with trifluoroacetic acid being preferred. Step 3 of Scheme 1 is a catalytic reduction of the carbon-carbon double bond of IB to produce a compound of formula I, designated IA in Scheme 1. The reduction of this double bond can be effected with hydrogen gas (H2) in a inert solvent for the reaction as a lower alcohol, THF, dioxane or ethyl acetate, preferably methanol or ethanol, in the presence of a noble metal catalyst on a solid support such as palladium on carbon (Pd / C), palladium on barium sulfate (Pd / BaS04), platinum on carbon (Pt / C) or tris (triphenylphosphine) rhodium chloride (Wilkinson catalyst), preferably about 10% palladium on carbon, at a pressure of from about 1 to about 5 atmospheres, preferably from about 3 to about 4 atmospheres, at a temperature of about 10 ° C to about 100 ° C, preferably 40 ° C to 60 ° C while stirring the reaction mixture. Alternatively, the double bond can be reduced under transfer hydrogenation conditions in which a hydride donor such as cyclohexadiene or ammonium formate is used in place of hydrogen, of which ammonium formate is preferred, in an inert solvent for the reaction as a lower alcohol, THF, dioxane or ethyl acetate, preferably methanol or ethanol, in the presence of a noble metal catalyst on a solid support such as palladium on carbon (Pd / C), palladium on barium sulfate (Pd / BaS0 ), platinum on carbon (Pt / C) or tris (trphenylphosphine) rhodium chloride (Wilkinson's catalyst), preferably about 10% palladium on carbon, at a temperature of about 20 ° C to 150 ° C, preferably 40 ° C to 80 ° C. Alternatively, the reduction of the carbon-carbon double bond of 1B to produce a compound of formula 1, designated 1A in Scheme 1, can be performed using alternative methods known to one skilled in the art. Larock, R. C. Comprehensive Organic Transformations. VCN Publishers, 1989. In cases where R6 is benzyl or another group that is labile under the hydrogenation conditions, the corresponding NH derivative is formed (ie, R6 = H). Step 4 of Scheme 1 discloses the conversion of a compound of formula IA (the compound of formula I in which the optional double bond is absent) in which R3 is hydrogen in a compound of formula IA 'wherein R3 is a aryl or heteroaryl group optionally substituted by means of an N-arylation or N-heteroarylation. The compound of formula IA is treated with an aryl or heteroaryl chloride, bromide, iodide or sulfonate, preferably the bromide, a base such as potassium phosphate, potassium carbonate, sodium carbonate, thallium carbonate, cesium carbonate, tert. potassium butoxide, lithium tert-butoxide or sodium tert-butoxide, preferably potassium carbonate, a diamine, such as 1,2-ethylenediamine, N, N'-dimethylenediamine, N, N-dimethylethylenediamine or cis-1, 2- diaminocyclohexane, preferably N.N'-dimethylethylenediamine, and cuprous chloride, bromide or iodide or other copper (I) salts, preferably cuprous iodide, in the presence of a small amount of water, preferably from about 1% to about 4% water (w / w relative to the compound of formula II) in a solvent inert to the reaction such as 1,2-dimethoxyethane, diglyme, t-buffyl methyl ether, tetrahydrofolate, benzene or toluene, preferably toluene, optionally in the presence of a polar co-solvent as DMF or dimethyl acetamide in the order of 5-15% vol / vol relative to the first solvent, at a temperature from about 40 ° C to about 150 ° C, preferably from about 80 ° C to about 120 ° C to produce the compound of formula IA 'wherein R3 is aryl or optionally substituted heteroaryl. The N-arylation or N-heteroarylation in Step 4 of Scheme 1 can also be performed by treating a compound of formula IA (the compound of formula I in which the optional double bond is absent) in which R3 is hydrogen with a chloride , bromide, iodide or aryl sulfate or heteroaryl, preferably the bromide with a base such as an alkali metal carbonate, an alkali metal amine base, an alkali metal phosphonate, an alkali metal alkoxide, preferably cesium carbonate, a phosphine ligand, preferably 9,9-dimethyl-4,5-bis (diphenylfosine) xanthene (XANTPHOS) and a palladium species, such as acetate of palladium (II) or tris (dibenzyldenoacetone) dipalladium (0) or the corresponding adduct of chloroform, preferably tris (dibenzyldenoacetone) dipaladol (0), in an inert solvent such as 1,4-dioxane or toluene, preferably 1,4-dioxane, at a temperature from about 40 ° C to about 160 ° C, preferably from about 80 ° C to about 120 ° C. For compounds of formula I in which R6 is H, further functionalization of the secondary amine under standard alkylation or reductive amination conditions known to one skilled in the art can be carried out. Alternatively, in Step 3a of Scheme 1, the compound of formula IB can be converted to the N-aryl or N-heteroaryl derivative having formula IB 'using the procedures of Step 4 above. The compound of formula I in which R1 is G1 and R3 is an optionally substituted aryl or heteroaryl group, designated IA 'in Scheme 1 is then prepared in Step 4a of Scheme 1 using the procedures of Step 3 above. In cases where R6 is benzyl or another group that is labile under hydrogenation conditions, the corresponding secondary amine derivative is formed (ie, R6 is H). If R6 is H, an additional functionalization of the secondary amine under standard alkylation or reductive amination conditions known to those skilled in the art can be carried out.

SCHEME 1 Scheme 1a discloses the preparation of a compound of formula I, wherein the optional double bond is present or absent, starting with the N-arylation or N-heteroarylization of lactamyl to form lactam II wherein R3 is a optionally substituted aryl or heteroaryl group. In Step 1 of Scheme 1 the lactam is treated with an aryl or heteroaryl chloride, bromide, iodide or sulfonate, preferably the bromide, a base such as potassium phosphate, potassium carbonate, sodium carbonate, thallium carbonate, cesium carbonate, potassium tert-butoxide, lithium tert-butoxide or sodium tert-butoxide, preferably potassium carbonate, a diamine, such as 1,2-ethylenediamine, N, N'-dimethylenediamine, N, N-dimethylethylenediamine or cis-1, 2-diaminocyclohexane, preferably N, N'-dimethylethylenediamine, and chloride, bromide or cuprous iodide, preferably cuprous iodide, in the presence of a small amount of water, preferably from about 1% to about 4% of water, in an inert solvent for the reaction such as 1,2-dimethoxyethane, digiim, t-butyl methyl ether, tetrahydrofuran, benzene or toluene, preferably toluene, at a temperature of about 40 ° C to about 150 ° C, preferably about 80 ° C a about 120 ° C, to produce the lactam of formula II wherein R 3 is aryl or optionally substituted heteroaryl. The N-arylation or N-heteroarylation of Step 1, Scheme 1 a, can also be carried out by treating a lactam of formula Ia in which R 3 is hydrogen with an aryl or heteroaryl chloride, bromide, iodide or sulfonate, preferably the bromide , with a base such as an alkali metal carbonate, an alkali metal amine base, an alkali metal phosphonate or an alkali metal alkoxide, preferably cesium carbonate, a phosphine ligand, preferably a 9,9-dimetyl! 4,5-bis (diphenylphosphino) xanthene (XANTPHOS) and a palladium species, such as palladium (II) acetate or tris (dibenzylideneacetone) dipalladium (0) or the corresponding chloroform adduct, preferably tris (dibenzylideneacetone) dipalladium (0) , in an inert solvent such as 1,4-dioxane or toluene, preferably 1,4-dioxane, at a temperature of from about 40 ° C to about 160 ° C, preferably from about 80 ° C to about 120 ° C. In Step 2 of the Scheme the compound IB 'is prepared by treating the aldehyde III, prepared as in Scheme I, with the lactam II, wherein R3 is optionally substituted aryl or heteroaryl, using the procedure of Step 2 in the Scheme 1. In Step 2 of Scheme 1a, compound 1B 'can alternatively be prepared by treating aldehyde III, prepared as in Scheme I, with lactam II, wherein R3 is optionally substituted aryl or heteroaryl, in a solvent such as tetrahydrofuran, tert-butyl methyl ether or 1,4-dioxane, preferably tetrahydrofuran, in the presence of an alkali metal base, such as sodium bis (trimethylsilylamide), potassium bis (trimethylsilylamide), lithium bis (trimethylsilylamide) or lithium diisopropylamide, or an alkali metal hydride, such as sodium hydride or potassium hydride, preferably sodium bis (trimethylsilylamide), which is followed by the addition of diethyl chlorophosphonate at a temperature of approx. most preferably -30 ° C to about 100 ° C, preferably from about -10 ° C to about 30 ° C. Step 3 of the Scheme the compound IA 'is prepared by catalytic hydrogenation of the compound IB' using the procedure of Step 3 in Scheme 1.

SCHEME IA Scheme 1 b discloses an alternative preparation of a lactam of formula II in which R 3 is an optionally substituted aryl or heteroaryl group. In Step 1 of Scheme 1b, a compound R3-NH2, wherein R3 is an optionally substituted aryl or heteroaryl group, is treated with a compound of formula VI in which the group A of VI is selected from F, Cl, Br, I or an alkyl- or aryl-sulfonate, preferably Cl, and the group B is selected from F, Cl, Br, I, O-CC alkyl, OH or an activated carboxylic acid group derived from the reaction of the corresponding carboxylic acid with a standard carboxylic acid activating reagent such as, but not limited to, a carbodiimide (dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride salt) or tripropylphosphonic anhydride, preferably Cl, in a solvent such as water, acetonitrile, 1,4-dioxane or tetrahydrofuran, or combinations thereof, preferably tetrahydrofuran, at a temperature of from about 10 ° C to about 120 ° C, preferably from about 50 ° C to about 80 ° C, in the presence or absence of a base, such as triethylamine, diisopropylethylamine, an alkali metal hydroxide or an alkali metal carbonate, preferably cesium carbonate. The compounds IB 'and IA' can then be prepared by the procedures of Scheme la.

IB SCHEME In cases where R6 is benzyl or another group that is labile under hydrogenation conditions, the corresponding secondary amine derivative is formed (ie, R6 is H). If R6 is H, further functionalization of the secondary amine can be carried out under standard alkylation or reductive amination conditions known to those skilled in the art. Scheme 1c still exposes another alternative preparation of the compounds of formula IB 'and IA' wherein R3 is an optionally substituted aryl or heteroaryl group. In Step 1 of Scheme 1 c, a compound of formula VIII is prepared by treating ortho-halo-benzaldehyde VII, wherein D is selected from chlorine, bromine or iodine, preferably bromine, with a lactam of formula II, wherein R3 is an optionally substituted aryl or heteroaryl group, in a solvent such as tetrahydrofuran, tert-butyl methyl ether or 1,4-dioxane, preferably tetrahydrofuran, in the presence of an alkali metal amine base, such as bis (trimethylsilylamide ) of sodium, bis (trimethylsilylamide) of potassium, bis (trimethylsilylamide) of lithium or diisopropylamide of lithium, or an alkali metal hydride, such as sodium hydride or potassium hydride, preferably bis (trimethyl) Lilamide) of sodium. In Step 2 of Scheme 1 c, a compound of formula IB 'is prepared by treating a compound of formula VIII with an N-substituted compound of formula IV in a solvent selected from water, 1,4-dioxane, n-butanol, N , N-dimethylformamide, dimethyl sulfoxide, acetonitrile or mixtures thereof, preferably water, with a base such as trialkyl amine or an alkali metal carbonate, preferably potassium carbonate, at a temperature of about 40 ° C to about 150 ° C, preferably from about 90 ° C to about 120 ° C to produce the compound of formula IB '. Alternatively, this coupling can be facilitated by the use of a transition metal such as palladium and the preferred method is that of Buchwaid as described by Buchwaid et al. J. Org. chem. 2000, 65, p. 1 144-1 157 and pag. 1 158-1174. A mixture of VIII and the N-substituted compound of formula IV is treated in a solvent selected from toluene, benzene and DME, of which toluene is preferred, with a base such as sodium or potassium tert-butoxide, sodium carbonate or potassium, potassium phosphonate, preferably sodium tert-butoxide with a palladium source such as tetrakis (triphenylphosphine) palladium, palladium acetate, tris (dibenzylideneacetone) dipalladium, trans-dichlorobis (triphenylphosphine) palladium or optionally added phosphine ligands that were added as BINAP or triphenylphosphine when palladium acetate and BINAP are preferred at a temperature of about 40 ° C to 150 ° C, preferably about 900 ° C to 120 ° C, to produce a compound of formula IB '. The compound of formula IB 'can then be converted to the compound of formula IA' as described above. Step 3 of Scheme 1c is a catalytic reduction of the carbon-carbon double bond of IB 'to produce a compound of formula I, designated IA' in Scheme 1. The reduction of this double bond can be effected with gashydrogen (H2) in an inert solvent for the reaction as a lower alcohol, THF, dioxane or ethyl acetate, preferably methanol or ethanol, in the presence of a noble metal catalyst on a solid support such as carbon palladium (Pd / C), palladium on sulfate barium (Pd / BaSO4), platinum on carbon (Pt / C) or tris (triphenylphosphine) chloride (Wilkinson's catalyst), preferably about 10% palladium on carbon, at a pressure of about 1 at about 5 atmospheres, preferably from about 3 to about 4 atmospheres, at a temperature of about 10 ° C to about 100 ° C, preferably 40 ° C to 60 ° C while stirring the reaction mixture. Alternatively, the double bond can be reduced under transfer hydrogenation conditions in which a hydride donor such as cyclohexadiene or ammonium formate is used in place of hydrogen, of which ammonium formate is preferred, in a solvent inert to the reaction as a lower alcohol, THF, dioxane or ethyl acetate, preferably methanol or ethanol, in the presence of a noble metal catalyst on a solid support such as palladium on carbon (Pd / C), palladium on barium sulfate (Pd / BaS0), platinum on carbon (Pt C) or tris (triphenylphosphine) rhodium chloride (Wilkinson's catalyst), preferably about 10% palladium on carbon, at a temperature of about 20 ° C to 150 ° C, preferably 40 ° C to 80 ° C. Alternatively, the reduction of the carbon-carbon double bond of 1B to produce a compound of formula 1, designated 1A in Scheme 1, can be performed using alternative methods known to one skilled in the art. Larock, R. C. Comprehensive Organic Transformations. VCN Publishers, 1989.

SCHEME 1C Schemes 2, 2a and 2b refer to general methods suitable for preparing compounds of formula I wherein R1 = G2. Step 1 of Scheme 2 illustrates the preparation of a compound XI by coupling boronic acid or boronic ester IX wherein L is selected from OH and O-alkyl (CC) or wherein the two substituents L together form a derivative of 1 , 3,2-benzodioxazole, preferably L is OH with halopyridine X, wherein the halo group H 1 is selected from chlorine, bromine, iodine or sulfonate, preferably bromine, in the presence of a palladium catalyst, such as palladium tetrakistriphenylphosphine, bistriphenylphosphine dichloropalladium or tris (dibenzylidene acetone) dipalladium, preferably palladium tetrakistriphenylphosphine, and an alkali metal base, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide, preferably sodium carbonate, in a solvent system containing dimethoxyethane and a polar protic solvent such as water, methanol or ethanol, preferably water, at a temperature of about 10 ° C to about 1 50 ° C, preferably from about 70 ° C to about 110 ° C. In Step 2 of Scheme 2, compound XII is prepared by treating compound XI with the N-substituted lactam II, wherein the substituent on NR3 is vinyl or C (= 0) R, wherein R is alkyl straight or branched chain of C C8, C3-C8 cycloalkyl or aryl, CF3, preferably tert-butyl, in the presence of an amine or a metal hydrous metal base such as sodium hydride or sodium bis (trimethylsilylamide), preferably bs (trimethylsilylamide) sodium, in a reaction solvent inert to the reaction, preferably an ether solvent selected from diethyl ether, dioxane and tetrahydrofuran, most preferably tetrahydrofuran, at a temperature of about -30 ° C to about 100 ° C. C, preferably from about -10 ° C to 30 ° C. In the embodiments wherein R3 is vinyl, an aqueous acid, preferably trifluoroacetic acid, is used in the treatment to separate R3. In Step 3 of Scheme 2, compound XIII is prepared by alkylation of the pyridinyl nitrogen of compound XII and partial reduction of the pyridinyl ring. Compound XII is treated with an excess of an alkyl iodide, alkyl methanesulfonate, alkyl arisulfonate or alkyl triflate, in a solvent such as acetonitrile or 1,4-dioxane, preferably acetonitrile, at a temperature of about 20 ° C. about 150 ° C, preferably 70 ° C to 90 ° C, for about 10 minutes to about 60 hours, a period of time sufficient to rent the pyridine nitrogen, followed by separation of the solvent in vacuo and the subsequent addition of a solvent of lower alcohol, preferably methanol, followed by the addition of sodium borohydride. In Step 4 of Scheme 2 a compound of formula I, wherein R1 is G2 and R3 is H, designated IC in Scheme 2, is prepared by the catalytic reduction of the carbon-carbon double bond of XIII. The reduction of this double bond can be effected with hydrogen gas (H2) in an inert solvent for the reaction as a lower alcohol, THF, dioxane or ethyl acetate, preferably methanol or ethanol, in the presence of a noble metal catalyst on a solid support such as palladium on carbon (Pd / C), palladium on barium sulfate (Pd / BaS0), platinum on carbon (Pt / C) or tris (triphenylphosphine) rhodium chloride (Wilkinson's catalyst), preferably about 10% palladium on carbon, at a pressure of about 1 to about 5 atmospheres, preferably of about 3 to about 4 atmospheres, at a temperature of about 10 ° C to about 100 ° C, preferably 40 ° C to 60 ° C while stirring the reaction mixture. Alternatively, the double bond can be reduced under transfer hydrogenation conditions in which a hydride donor such as cyclohexadiene or ammonium formate is used in place of hydrogen, of which ammonium formate is preferred, in a solvent inert to the reaction as a lower alcohol, THF, dioxane or ethyl acetate, preferably methanol or ethanol, in the presence of a noble metal catalyst on a solid support such as palladium on carbon (Pd / C), palladium on barium sulfate (Pd / BaS0), platinum on carbon (Pt / C) or tris (triphenylphosphine) rhodium chloride (Wilkinson's catalyst), preferably about 10% palladium on carbon, at a temperature of about 20 ° C to 150 ° C, preferably 40 ° C to 80 ° C. Alternatively, the reduction of the carbon-carbon double bond of XIII to produce a compound of formula 1, designated 1 C in Scheme 2, can be carried out using alternative procedures known to one skilled in the art. Larock, R. C. Comprehensive Organic Transformations. VCN Publishers, 1989. In Step 5 of Scheme 2 the compound of formula IC, wherein R1 is G2 and R3 is an optionally substituted aryl or heteroaryl group, is prepared from the compound of formula IC in which R1 is G2 and R3 is H by means of an N-arylation or N-heteroarylation. The compound of formula IC is treated with an aryl or heteroaryl chloride, bromide, iodide or sulfonate, preferably the bromide, a base such as potassium phosphate, potassium carbonate, sodium carbonate, thallium carbonate, cesium carbonate, tert. potassium butoxide, lithium tert-butoxide or sodium tert-butoxide, preferably potassium carbonate, a diamine such as 1,2-ethylenediamine, N, N'-dimethylethylenediamine, N, N-dimethylethylenediamine or cis-1,2-diaminocyclohexane , preferably N, N'-dimethylethylenediamine and chloride, bromide or cuprous iodide or other copper (1) sources, preferably cuprous iodide, in the presence of a small amount of water, preferably from about 1% to about 4% of water, in an inert solvent for the reaction such as 1,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran, benzene or toluene, preferably toluene, at a temperature of. about 40 ° C to about 150 ° C, preferably about 80 ° C to about 120 ° C to produce the compound of formula IC wherein R 3 is optionally substituted aryl or heteroaryl. The N-arylation or N-heteroarylation in Step 5 of Scheme 2 can also be carried out by treating a compound of formula IC in which R1 is G2 and R3 is H with an aryl, heteroaryl chloride, bromide, iodide or sulfonate, preferably the bromide with a base such as an alkali metal carbonate, an alkali metal amine base, an alkali metal phosphonate or an alkali metal alkoxide, preferably cesium carbonate, a phosphine ligand, preferably 9,9-dimethyl-4 , 5-bis (diphenylphosphino) xanthene (XANTPHOS) and a palladium species, such as palladium (II) acetate or tris (dibenzylideneacetone) dipalladium (0) or the corresponding chloroform adduct, preferably tris (dibenzylideneacetone) dipalladium (0) ), in an inert solvent such as 1,4-dioxane or toluene, preferably 1,4-dioxane, at a temperature from about 40 ° C to about 160 ° C, preferably from about 80 ° C to about 120 ° C. For compounds of formula IC or IC in which R6 is H, further functionalization of the secondary amine under standard alkylation or reductive amination conditions known to one skilled in the art can be carried out.

SCHEME 2 Scheme 2a discloses an alternative route for a compound of formula IC in which R1 is G2. In Step 1 of Scheme 2a, the compound of formula XII is converted to a compound of formula XIV wherein R 3 is an optionally substituted aryl or heteroaryl group, by an N-arylation or N-heteroarylation. The compound of formula XII is treated with an aryl or heteroaryl chloride, bromide, iodide or sulfonate, preferably the bromide, a base such as potassium phosphate, potassium carbonate, sodium carbonate, thallium carbonate, cesium carbonate, tert. potassium butoxide, lithium tert-butoxide or sodium tert-butoxide, preferably potassium carbonate, a diamine such as 1,2-ethylenediamine, N, N'-dimethylethylenediamine, N, N-dimethylethylenediamine or cis-1,2-diaminocyclohexane , preferably N, N'-dimethylethylenediamine, and chloride, bromide or cuprous iodide, preferably cuprous iodide, in the presence of a small amount of water, preferably from about 1% to about 4% of water, in an inert solvent for the reaction as 1,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran, benzene or toluene, preferably toluene, at a temperature of from about 40 ° C to about 150 ° C, preferably from about 80 ° C to about and 120 ° C to produce the compound of formula XIV wherein R 3 is aryl or optionally substituted heteroaryl. The N-arylation or N-heteroarylation in Step 1 of Scheme 2a can also be carried out by treating a compound of formula XII wherein R1 is G2 and R3 is H with an aryl or heteroaryl chloride, bromide, iodide or sulfonate, preferably the bromide with a base such as an alkali metal carbonate, an alkali metal amine base, an alkali metal phosphonate or an alkali metal alkoxide, preferably cesium carbonate, a phosphine ligand, preferably 9,9-dimethyl-4 , 5-bis (diphenylphosphino) xanthene (XANTPHOS) and a palladium species such as palladium (II) acetate or tris (dibenzylideneacetone) dipalladium (0) or the corresponding chloroform adduct, preferably tris (dibenzylideneacetone) dipalladium (0) , in an inert solvent such as 1,4-dioxane or toluene, preferably 1,4-dioxane, at a temperature of from about 40 ° C to about 160 ° C, preferably from about 80 ° C to about 120 ° C. Step 1 a of Scheme 2a discloses an alternative route for the preparation of a compound of formula XIV by treating the compound of formula XI with the compound of formula II (from Scheme 1) wherein R3 is an optionally substituted aryl or heteroaryl group, in a solvent such as tetrahydrofuran, tert-butyl methyl ether or 1,4-dioxane, preferably tetrahydrofuran, with an alkali metal amine base, such as sodium bis (trimethylsilylamide), bs (trimethylsulfonyl) of lithium potassium, bis (trimethylsilylamide) or lithium diisopropylamide, or an alkali metal hydride such as sodium hydride or potassium hydride, preferably sodium bis (trimethylsilylamide). In Step 2 of Scheme 2a the compound of formula XV is prepared by treating the compound of formula XIV with an excess of an alkyl iodide, alkyl methanesulfonate, alkyl arisulfonate or alkyl triflate, in a solvent such as acetonitrile or 1.4. -dioxane, preferably acetonitrile, at a temperature from about 20 ° C to about 150 ° C, preferably 70 ° C to 90 ° C, for about 10 minutes to about 60 hours, a period of time sufficient to rent the pyridine nitrogen, followed by removal of the solvent in vacuo and subsequent addition of a lower alcohol solvent, preferably methanol, followed by the addition of sodium borohydride. In Step 3 of Scheme 2a a compound of formula I, wherein R1 is G2 and R3 is H, designated IC in Scheme 2, is prepared by the catalytic reduction of compound XV in an inert solvent for the reaction as an alcohol lower, preferably methanol or ethanol, with a noble metal catalyst, such as platinum or palladium, suspended in a solid support, preferably 10% palladium on carbon, under a hydrogen pressure of about 1 atmosphere to about 5 atmospheres, preferably of about 3 atmospheres to about 4 atmospheres, at a temperature of about 10 ° C to about 100 ° C, preferably about 40 ° C to about 60 ° C, while stirring the reaction mixture. Alternatively, the double bond can be reduced under transfer hydrogenation conditions in which a hydride donor such as cyclohexadiene or ammonium formate is used in place of hydrogen, of which ammonium formate is preferred, in inert solvent for the reaction as a lower alcohol, THF, dioxane or ethyl acetate, preferably methanol or ethanol, in the presence of a noble metal catalyst on a solid support such as palladium on carbon (Pd / C), palladium on barium sulfate (Pd / BAS0) , platinum on carbon (Pt / C) or tris (triphenylphosphine) rhodium chloride (Wilkinson's catalyst), preferably about 10% palladium on carbon, at a temperature of about 20 ° C to 150 ° C, preferably 40 ° C. ° C to 80 ° C. Alternatively, the reduction of the carbon-carbon double bond of XV to produce a compound of formula 1, designated 1C in Scheme 2a, can be carried out using alternative procedures known to one skilled in the art. Larock, R. C. Comprehensive Organic Transformations. VCN Publishers, 1989.

SCHEME 2A Scheme 2b still exposes another route for the synthesis of compounds of formula I wherein R is G2 and R3 is an optionally substituted aryl or heteroaryl group. In Step 1 of Scheme 2b a compound of formula XVI is prepared in which R1 is G2 by catalytic reduction of compound XIV, wherein R3 is an optionally substituted aryl or heteroaryl group, in a solvent inert to the reaction as an alcohol lower, preferably methanol or ethanol, with a noble metal catalyst, such as platinum or palladium, suspended in a solid support, preferably 10% palladium on carbon, under a hydrogen pressure of about 1 atmosphere to about 5 atmospheres, preferably from about 3 atmospheres to about 4 atmospheres, at a temperature from about 10 ° C to about 100 ° C, preferably from about 40 ° C to about 60 ° C, while stirring the reaction mixture. Alternatively, the double bond can be reduced under transfer hydrogenation conditions in which a hydride donor such as cyclohexadiene or ammonium formate is used in place of hydrogen, of which ammonium formate is preferred, in an inert solvent for the reaction as a lower alcohol, THF, dioxane or ethyl acetate, preferably methanol or ethanol, in the presence of a noble metal catalyst on a solid support such as palladium on carbon (Pd / C), palladium on barium sulfate (PD / BaS0 ), platinum on carbon (Pt / C) or tris (triphenylphosphine) rhodium chloride (Wilkinson catalyst), preferably about 10% palladium on carbon, at a temperature of about 20 ° C to 150 ° C, preferably 40 ° C to 80 ° C. Alternatively, the reduction of the carbon-carbon double bond of XIV to produce a compound of formula XVI can be carried out using alternative methods known to one skilled in the art. Larock, R.C. 1989. In Step 2 of Scheme 2b a compound of formula XVII is prepared by treating the compound of formula XVI with an excess of an alkyl iodide, alkyl methanesulfonate, alkyl arisulfonate or alkyl triflate, in a solvent such as acetonitrile or , 4-dioxane, preferably acetonitrile, at a temperature from about 20 ° C to about 150 ° C, preferably 70 ° C to 90 ° C, for about 10 minutes to about 60 hours, a period of time sufficient to rent the nitrogen from pyridine, followed by removal of the solvent in vacuo and the subsequent addition of a lower alcohol solvent, preferably methanol, followed by the addition of sodium borohydride. In Step 3 of Scheme 2b, the compound of formula I is prepared, wherein R is G2 and R3 is an optionally substituted aryl or heteroaryl group, designated IC in Scheme 2b, by catalytic reduction of compound XVII in an inert solvent for the reaction as a lower alcohol, preferably methanol or ethanol, with a noble metal catalyst, such as platinum or palladium, suspended in a solid support, preferably 10% palladium on carbon, under a hydrogen pressure of about 1 atmosphere at about 5 atmospheres, preferably from about 3 atmospheres to about 4 atmospheres, at a temperature from about 10 ° C to about 100 ° C, preferably from about 20 ° C to about 50 ° C, while stirring the reaction mixture. Alternatively, the double bond can be reduced under transfer hydrogenation conditions in which a hydride donor such as cyclohexadiene or ammonium formate is used in place of hydrogen, of which the ammonium formate is preferred, in an inert solvent for reaction as a lower alcohol, THF, dioxane or ethyl acetate, preferably methanol or ethanol, in the presence of a noble metal catalyst on a solid support such as palladium on carbon (Pd / C), palladium on barium sulfate (Pd / BaS04), platinum on carbon (Pt / C) or tris (triphenylphosphine) rhodium chloride (Wilkinson's catalyst), preferably about 10% palladium on carbon, at a temperature of about 20 ° C to 150 ° C, preferably 40 ° C to 80 ° C. Alternatively, the reduction of the carbon-carbon double bond of XVII to produce a compound of formula 1, designated 1C in Scheme 2b can be carried out using alternative procedures known to one skilled in the art. Larock, R.C., 1989.

SCHEME 2B The general methods for the preparation of aryl halides used in the coupling reactions of N-arylation and N-heteroarylation described herein are provided by Murugusan, N. patent of E.U.A. 5,612,359; Guay, D. et al. Biorg. Med. Chem. Lett. 2002, 12, 1457-1461; Salí, D. J. et al. J. Med. Chem. 2000, 43, 649-663; Olah, G. A .; Porter, R. D. J. Amer. Chem. Soc. 1971, 93, 6877-6887; Brown, H.C. et al. J. Amer. Chem. Soc. 1957, 79, 1906-1909; Nenitzescu, C; Necsoiu, I. J. Amer. Chem. Soc. 1950, 72, 3483-3486; Muci, A. R .; Buchwaid, S. L. Top. Curr. Chem .; Springer-Verlag: Berlin Heidelberg, 2002; Vol. 219, p. 131-209; Schefczik, E. DE 19650708; Howard, H. R .; Sarges, R. EP 104860; Wang, X et al.

Tetrahedron Lett., 2000, 41, 4335-4338, all of which are incorporated by reference herein in their entirety. Those skilled in the art will recognize that, when appropriate, the hydroxyl groups on the aryl or heteroaryl halides may be etherified by standard methods known in the art as a treatment with an alkali metal hydride or alkali metal hydroxide, such as hydride sodium, potassium hydride, sodium hydroxide, potassium hydroxide or cesium hydroxide, preferably sodium hydride, in a solvent such as tetrahydrofuran, N, N-dimethylformamide or dimethisulfoxide, preferably tetrahydrofuran, at a temperature of about -20 a 50 ° C, followed by the addition of an alkyl halide or tosylate, preferably an alkyl iodide. The compounds of formula I and their pharmaceutically acceptable salts (hereinafter "the active compounds") can be administered orally, transdermally (for example, by the use of a patch), intranasally, sublingually, rectally, parenterally or topically . Transdermal and oral administration are preferred. The compounds are administered, most desirably, in dosages ranging from about 0.25 mg to about 1500 mg per day, preferably from about 0.25 to about 300 mg per day in single or divided doses, although variations will necessarily occur depending on the weight and the condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of about 0.01 mg to about 10 mg per kg of body weight per day is most desirably employed. However, variations may occur depending on the weight and condition of the persons being treated and their individual responses to said medication, as well as the type of pharmaceutical formulation chosen and the period of time and interval during which it is carried out. this administration. In some cases, dosage levels below the lower limit of the aforementioned range may be more suitable, although in other cases even higher doses may be employed without causing harmful side effects, provided that these higher doses are first divided into several doses. small doses for one administration throughout the day. The active compounds can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the various routes previously indicated. More particularly, the active compounds can be administered in a wide variety of different dosage forms, for example, they can be combined with various inert pharmaceutically acceptable carriers in the form of tablets, capsules, transdermal patches, troches, lozenges, hard candies, powders. , sprays, creams, ointments, suppositories, gelatins, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like. These vehicles include diluents or solid fillers, sterile aqueous media and various non-toxic organic solvents. further, the oral pharmaceutical compositions can be suitably sweetened and / or can be given a flavor. In general, the active compounds are present in these dosage forms at concentration levels ranging from about 5.0% to about 70% by weight. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine can be used with various disintegrants such as starch (preferably corn starch, potato or tapioca), alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc can be used for tabletting purposes. Solid compositions of a similar type can also be used as filling materials in gelatin capsules; preferred materials in this regard also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening agents or for flavoring, coloring matter and, if desired, emulsifying and / or suspending agents, together with diluents such as water. , ethanol, propylene glycol, glycerin and various combinations thereof. For parenteral administration, a solution of an active compound in sesame or peanut oil or in aqueous propylene glycol can be employed. The aqueous solutions must be suitably regulated in their pH (preferably a pH greater than 8), if necessary, and the liquid diluent must first be made isotonic. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is easily accomplished by standard pharmaceutical techniques well known to those skilled in the art. It is also possible to administer the active compounds topically and this can be done by means of creams, a patch, gelatins, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.

BIOLOGICAL ASSAY All compounds tested had IC50 values of 1000 nM or less. The activity of the compounds of the present invention with respect to the binding capacity of 5HTIB (formerly 5HT1D) can be determined using standard radioligand binding assays as described in the literature. The affinity of 5-HT1A can be measured using the procedure of Hoyer et al (Brain Res., 376, 85 (1986)). The affinity of 5-HT-ID can be measured using the procedure of Heuring and Peroutka (J. Neurosci., 7, 894 (1987)).

The in vitro activity of the compounds of the present invention at the 5-HT-ID binding site can be determined according to the following procedure. Bovine caudal tissue is homogenized and suspended in 20 volumes of a pH buffer containing 50 mM TRIS hydrochloride (tris (hydroxymethyl) ammonium hydrochloride) at a pH of 7.7. The homogenate is then centrifuged at 45,000 g for 10 minutes. The supernatant is then discarded and the resulting pellet is resuspended in approximately 20 volumes of 50 mM TRIS hydrochloride pH buffer at a pH of 7.7. The suspension is then pre-incubated for 15 minutes at 37 ° C, after which the suspension is again centrifuged at 45,000 g for 10 minutes and the supernatant is discarded. The resulting pellet (approximately 1 gram) is resuspended in 150 ml of a 15 mM TRIS hydrochloride pH buffer containing 0.01 percent ascorbic acid with a final pH of 7.7 and also containing 10 μM pargyline and calcium chloride (CaCl2) 4 mM. The suspension is kept on ice at least 30 minutes before being used. The inhibitor, control or vehicle is then incubated according to the following procedure. To 50 μl of a 20 percent dimethylsulfoxide solution (DMSOV80 percent distilled water solution) add 200 μl of tritiated 5-hydroxytryptamine (2 nM) in a 50 mM TRIS hydrochloride pH regulator containing 0.01 percent of ascorbic acid at pH 7.7 and also containing 10 μM pargyline and 4 μM calcium chloride, plus 100 nM 8-hydroxy-DPAT (dipropylaminotetralin) and 100 nM mesulergine To this mixture 750 μl of bovine caudal tissue and suspension are added. The resulting suspension is stirred to ensure a homogeneous suspension.The suspension is then incubated in a shaking water bath for 30 minutes at 25 [deg.] C. After completion of the incubation, the suspension is filtered using glass fiber filters (e.g. Whatman GF-B®) The pellet is then washed three times with four ml of a pH regulator of 50 mM TRIS hydrochloride at pH 7.7 The pellet is then placed in a scintillation flask with 5 ml of fluid of cent. elleo (Aquasol 2®) and let it settle overnight. The percentage of inhibition can be calculated for each dose of the compound. An IC50 value can then be calculated from the values of the inhibition percentage. The activity of the compounds of the present invention as regards the binding capacity of 5-HT 1A can be determined according to the following procedure. Rat cerebral cortex tissue is homogenized and divided into 1-gram batch samples and diluted with 10 volumes of 0.32 M sucrose solution. The suspension is then centrifuged at 900 g for 10 minutes and the supernatant is separated and dried. centrifuge at 70,000 g for 15 minutes. The supernatant is discarded and the pellet is resuspended in 10 volumes of 15 mM TRIS hydrochloride at pH 7.5. The suspension is allowed to incubate for 15 minutes at 37 ° C. After completing the pre-incubation, the suspension is centrifuged at 70,000 g for 15 minutes and the supernatant is discarded. The resulting fabric pellet is resuspended in a pH regulator of 50 mM TRIS hydrochloride pH 7.7 containing 4 mM calcium chloride and 0.01 percent ascorbic acid. The tissue is stored at -70 ° C until you are ready for an experiment. The fabric can be thawed immediately before use, diluted with 10 μm pargyline and kept on ice. The tissue is then incubated according to the following procedure. 50 microliters of control, inhibitor or vehicle (final concentration of 1 percent in DMSO) are prepared at various dosages. To this solution is added 200 μl of tritiated DPAT at a concentration of 1.5 nM in a pH regulator of 50 mM TRIS hydrochloride at pH 7.7 containing 4 mM calcium chloride, 0.01% ascorbic acid and pargyline. To this solution is then added 750 μl of tissue and the resulting suspension is stirred to ensure homogeneity. The suspension is then incubated in a shaking water bath for 30 minutes at 37 ° C. The solution is then filtered, washed twice with 4 ml of 10 mM TRIS hydrochloride at pH 7.5 containing 154 mM sodium chloride. The percent inhibition is calculated for each dose of the compound, control or vehicle. The CI5o values are calculated from the percentage inhibition values. The agonist and antagonist activities of the compounds of the invention at 5-HT1A and 5-HT-ID receptors can be determined using a single saturation concentration according to the following procedure. Male Hartley guinea pigs are decapitated and 5-HT-? A receptors are removed and dried from the hippocampus, while 5-HT1D receptors are obtained by cutting slices at 350 mM in a Mcllwain tissue chopper and the black substance is extracted and dried. the appropriate slices. The individual tissues are homogenized in pH buffer of 5 mM HEPES which confers 1 mM EGTA (pH 7.5) using a hand-held Teflon® glass homogenizer and centrifuged at 35,000 g for 10 minutes at 4 ° C. The pellets are resuspended in pH buffer of 100 mM HEPES containing 1 mM EGTA (pH 7.5) to a final protein concentration of 20 mg (hippocampus) or 5 mg (substantia nigra) of protein per tube. The following agents are added so that the reaction mixture in each tube contains 2.0 mM MgCl2, 0.5 mM ATP, 1.0 mM cAMP, 0.5 mM IBMX, 10 mM phosphocreatine, 0.31 mg / ml creatine phosphokinase, 100 μM GTP, and 0.5 -1 microcuries of [P32] -ATP (30 Ci / mmol: NEG-033-New England Nuclear). Incubation is initiated by adding tissue to siliconized microcentrifuge tubes (in triplicate) at 30 ° C for 15 minutes. Each tube receives 20 μl of tissue, 10 μl of drug or pH regulator (at a final concentration of 10x), 10 μl of agonist or pH regulator 32 nM (at a concentration of 10x), 20 μl of forskolin (final concentration) 3 μM) and 40 μl of the preceding reaction mixture. Incubation is terminated by the addition of 100 μl of 2% SDS, 1.3 mM cAMP, 45 mM solution of ATP containing 40,000 dpm of [H3] -cAMP (30 Ci / mmol: NET-275-New England Nuclear) for verify the recovery of cAMP from the columns. The separation of [P] -ATP and [P] -cAMP is performed using the method of Solomon et al., Analytical Biochemistry, 1974, 58, 541-548. The radioactivity is quantified by liquid scintillation counting. Maximum inhibition is defined by 10 μM (R) -8-OH-DPAT for 5-HT1A receptors, and 320 nM 5-HT for 5-HT- receptors | . The percentages of inhibition by the test compounds are then calculated in relation to the inhibitory effect of (R) -8-OH-DPAT for 5-HT1A or 5-HT receptors for 5-HT1D receptors. The inversion of inhibition induced agonist of the adenylate cyclase activity stimulated by forskolin is calculated in relation to the 32 nM agonist effect. The in vitro activity of the compounds of the present invention in the potassium channel of the human ether-a-go-go related gene (hERG) can be determined according to the following procedure. HEK-293 cells expressing the human ERG channel are grown according to standard cell culture techniques. The cells are collected, centrifuged and the resulting pellet is frozen for future use. On the day of the experiment, the concentrated cell pellet is weighed (100 mg per 96-well assay plate) and homogenized in 20 volumes of cold 50 mM Tris base containing 10 mM KCl and 1 M MgCl 2 (pH up to 7.4 to 4). ° C). The homogenate is then centrifuged at 45.degree., 000 g for 10 minutes. The supernatant is separated by decanting and the membrane pellet is resuspended in Polytron in cold 50 mM Tris base containing 10 mM KCl and 1 mM MgCl 2 (pH 7.4 at 4 ° C) at a concentration of 20 mg / ml. PVT WGA SPA granules (type A treated with PEI) are weighed and added to diluted tissue, also at a concentration of 20 mg / ml. The membrane / granule solution is then rotated gently (speed 2, high) in a cold room (4 ° C) for 2 hours in a Roto-Torque device (Cole-Palmer Model 7637). After this preincubation, the granule suspension is then centrifuged at 1000 rpm for 5 minutes at 4 ° C. The supernatant is separated by decanting and the pellet is resuspended to 5 mg / ml concentration of membranes and granules in 50 mM Tris base containing 10 mM KCl and 1 mM MgCl 2 (pH up to 7.4 at 22 ° C) . The newly suspended slurry of SPA granules / membranes is used immediately in the test. Granules and membranes are used at a final concentration of 1 mg / well and 25 micrograms of protein / well, respectively. Dilutions of compounds are made in 10% DMSO / 50 mM Tris pH buffer (pH 7.4) (at a final concentration of 10 x, such that the final concentration of DMSO is 1%). To 96-well SPA plates containing drug dilutions, radioligand (3H-dofetilide to a final concentration of 5 nM) is added. Incubation is initiated by the addition of tissue / granule suspension. The assay plates are incubated for one hour and then the radioactivity is quantified using a MicroBeta scintillation counter. The percentage of specific binding inhibition can then be calculated. The compounds of the invention can be tested for in vivo activity for the antagonism of hypothermia induced by HTD agonists in guinea pigs according to the following procedure. Male Hartley guinea pigs from Charles River, weighing 250-275 grams on arrival and 300-600 grams in the trial, served as subjects in the experiment. The guinea pigs were housed under standard laboratory conditions in a lighting model of 7 a.m. to 7 p.m. for at least seven days before experimentation. Food and water were available ad libitum until the time of the trial. The compounds of the invention can be administered in the form of solutions in a volume of 1 ml / kg. The used vehicle varies depending on the solubility of the compound. The test compounds are normally administered sixty minutes orally (po) or zero minutes subcutaneously (sc) before a 5-HT- | D agonist, such as [3- (1-methylpyrrolidin-2-ylmethyl) -1H-indoi-5-yl] - (3-nitropyridin-3-yl) -amine, which can be prepared as described in PCT application WO 93/11106, published June 10, 1993, which is administered at a dose of 5.6 mg / kg sc Before a first reading of the temperature is taken, each guinea pig is placed in a transparent plastic shoe box containing pieces of wood and a metal grid floor and allowed to acclimate to the surroundings for 30 minutes. The animals were then returned to the same shoe box after each reading of the temperature. Before each temperature measurement, each animal was held firmly with one hand for a period of 30 seconds. A digital thermometer with a small animal probe is used for temperature measurements. The probe is made of semi-flexible nylon with an epoxy tip. The temperature probe is inserted 6 cm into the rectum and held there for 30 seconds until a stable record is obtained. Then the temperatures are recorded. In po selection experiments, a reading of the baseline temperature of "pre-drugs" is done at a time value of -90 minutes, the test compound is given at -60 minutes and an additional reading is taken at -30 minutes. Then the 5-HT-ID agonist is administered at 0 minutes and the temperatures are taken 30, 60, 120 and 240 minutes later. In subcutaneous selection experiments, a pre-drug baseline temperature is read at -30 minutes. The test compound and the 5-HT-ID agonists are provided concurrently and the temperatures are taken 30, 60, 120 and 240 minutes later. The data are analyzed with two-way analysis of the variants with repeated measurements in Newman-Keuls post-hoc analysis. The active compounds of the invention can be evaluated as anti-migraine agents by testing the extent to which they mimic sumatriptan in the contraction of the dog saphenous vein isolated from the dog (P. Humphrey et al., Br. J. Pharmacol., 94, 1 128 (1988)). This effect can be blocked by means of metiotepine, a known serotonin antagonist. Sumatriptan is known to be useful in the treatment of migraine and produces a selective increase in carotid vascular resistance in an anesthetized dog. The pharmacological basis of sumatriptan efficacy has been reported by W. Fenwick et al., Br. J. Pharmacol., 96, 83 (1989). The 5-HT- agonist activity of serotonin can be determined by in vitro receptor binding assays, as described for the 5-HT1A receptor using rat cortex as the receptor source and [H3] -8-OH-DPAT as the radioligand (D. Hoyer et al. ., Eivr. J. Pharm., 18, 13 (1985)) and as described for the 5-HT? D receptor using bovine caudal as the receptor source and [H3] -serotonin as the radioligand (RE Heuring and SJ Peroutka, J. Neuroscience, 7, 894 (1987)). The following experimental preparations and examples They illustrate this invention, but they do not limit its scope.

PREPARATION 1 2- (4-Methylpiperazinyl) -benzaldehyde A solution of 1-methylpiperazine (139.5 ml, 1.26 moles), potassium carbonate (145 g, 1.05 moles) and 2-fluorobenzaldehyde (73.7 ml, 0.7 moles) in water (700 ml) was heated to reflux for 18 hours. The solution was cooled to room temperature, extracted with methylene chloride (2 x 700 ml) and the combined organic layers were washed with water (2 x 700 ml). The organic layer was dried (MgSO), filtered and the solvent removed in vacuo to provide 140 g of a dark oil. H1 NMR (400 MHz, CDCl3) d 7.79 (dd, J = 1.2, 7.9 Hz, 1 H), 7.52 (td, J = 1.5, 7.5 Hz, 1 H), 7.11 (m, 2H), 3.12 ( t, J = 4.8 Hz, 4H), 2.63 (brs, 4H), 2.39 (s, 3H); C13 NMR (100 MHz, CDCl 3) d 191.6, 155.8, 135.2, 130.0, 128.9, 122.8, 119.2, 55.3, 54.1, 46.3.

PREPARATION 2 2- (4-Benzyl-piperazin-1-yl) -benzaldehyde The title compound was prepared using a method analogous to that used in Preparation 1. C13 NMR (100 MHz, CDCl 3) d 191.7, 156.0, 138.1, 135.2, 129.9, 129.5, 128.9, 128.6, 127.5, 122.8, 119.2; MS (AP / CI) 281.2 (M + H) +.

PREPARATION 3 5-Methoxy-2- (4-methyl-piperazin-1-yl) -benzaldehyde The title compound was prepared using a method analogous to that used in Preparation 1. H1 NMR (400 MHz, CDCl3) d 2.36 (s, 3H), 2.61 (brs, 1 H), 3.03 (m, 4Hz), 3.78 (s, 3H), 7.06-7.12 (m, 2H), 7.28 (m, 2H), 10.37 (s, 1 H).

PREPARATION 4 2- (2,5-Dimethyl-piperazin-1-yl) -benzaldehyde The title compound was prepared using an analogous method to that used in Preparation 1. H1 NMR (400 MHz, CDCl3) d 0.83 (d, 1H, J = 5.8 Hz), 1.04 (d, 1H, J = 6.6 Hz), 2.20-2.30 (brs, 1H), 2.52 (dd, 1H, J = 11.6 and 10.0 Hz), 2.72 (dd, 1H, J = 13.2 and 10.8 Hz), 2.89 (dd, 1H, J = 11.6 and 2.8 Hz), 3.05-3.64 (m, 3H), 7.21-7.27 (m, 1H), 7.33 (d, 1H, J = 5.5 Hz), 7.56-7.60 (m, 1H), 7.84 (dd, 1H, J = 8.0 and 1.6 Hz), 10.6 (s) , 1H): MS (AP / CI) 219.2 (M + H) +.

PREPARATION 5 5-Fluoro-2- (4-methyl-piperazin-1-yl) -benzaldehyde The title compound was prepared using a method analogous to that used in Preparation 1. H1 NMR (400 MHz, CDCl3) d 2.35 (s, 3H), 2.55-2.65 (m, 4H), 3.00-3.10 (m, 4H) , 7.11 (d, 1H, J = 9.2 and 4.8 Hz), 7.19-7.25 (m, 1H), 7.46 (d, 1H, J = 8.8 and 3.6Hz); 10.38 (s, 1H), PREPARATION 6 2-Fluoro-6- (4-methyl-p¡perazin-1-yl) -benzaldehyde The title compound was prepared using a method analogous to that used in Preparation 1. H1 NMR (400 MHz, CDCl3) d 2.37 (s, 3H), 2.62-2.64 (m, 4H), 3.1 1-3.14 (m, 4H ), 6.74 (dd, 1 H, J = 10.4 and 8.4 Hz), 6.84 (d, 1 H, J = 8.4 Hz), 7.41-7.46 (m, 1 H), 10.25 (s, 1 H); MS (AP / CI) 223.3 (M + H) +.

PREPARATION 7 5-Methyl-2- (4-methyl-piperazin-1-yl) -benzaldehyde The title compound was prepared using a method analogous to that used in Preparation 1. H1 NMR (400 MHz, CDCl3) d 2.32 (s, 3H), 2.38 (s, 3H), 2.55-2.65 (m, 4H), 3.05 -3.09 (m, 4H), 7.04 (d, 1 H, J = 8.0 Hz), 7.32-7.34 (m, 1 H), 7.61 (d, 1 H, J = 2.0 Hz) 10.30 (s, 1 H); MS (AP / CI) 219.2 (M + H) +.

PREPARATION 8 2- (3,5-Dimethyl-piperazin-1-yl) -benzaldehyde The title compound was prepared using a method analogous to that used in Preparation 1. H1 NMR (400 MHz, CDCl3) d 1.09 (d, 6H, J = 6.4 Hz), 2.51 (t, 2H, J = 11.2 Hz), 3.10-3.18 (rn, 4H), 7.08 (dd, 1H, J = 3.2 and 0.8 Hz), 7.48-7.51 (m, 1 H), 7.78 (d, 1 H, J = 8.0 and 2.0 Hz), 10.30 ( s, 1 H). MS (AP / CI) 219.2 (M + H) +.

PREPARATION 9 2- (3,4,5-Trimethyl-piperazin-1-yl) -benzaldehyde The title compound was prepared using a method analogous to that used in Preparation 1. H1 NMR (400 MHz, CDCl3) d 1.12 (d, 6H, J = 6.4 Hz), 2.33 (s, 3H), 2.46-2.51 (m , 2H), 2.79 (dd, 2H, J = 10.8 and 11.6 Hz), 3.06-3.09 (m, 2H), 7.07-7.11 (m, 1 H), 7.48-7.53 (m, 1 H), 7.78 (dd) , 1 H, J = 7.6 and 1.6 Hz), 10.32 (s, 1 H).

PREPARATION 10 2- (4-Methyl-ri, 4] diazepan-1-yl) -benzaldehyde The title compound was prepared using a method analogous to that used in Preparation 1. H1 NMR (400 MHz, CDCl3) d 1.95 (p, 5.6 Hz. 2H), 2.38 (s, 3H), 2.67 (t, J = 5.4 Hz, 2H), 2.73 (d, J = 4.8 Hz, 2H), 3.45 (t, J = 5.8 Hz, 2H), 3.50-3.52 (m, 2H), 6.92 (t, J = 7.3 Hz, 1 H) , 7.02 (d, J = 8.3 Hz. 1 H), 7.39 (dt, J = 7.1, 1.7 Hz, 1 H), 7.70 (dd, J = 7.9, 1.7 Hz, 1 H), 10.15 (s, 1 H) ).

PREPARATION 11 2- (4-Ethyl-piperazin-1-yl) -benzaldehyde The title compound was prepared using a method analogous to that used in Preparation 1. H1 NMR (400 MHz, CDCl3) d 1.11 (t, J = 7.3 Hz, 3H), 2.59 (q, J = 7.2 Hz, 2H), 2.65 (br s, 4H), 3.12 (t, J = 4.8 Hz, 4H), 7.06-7.10 (m, 2H), 7.50 (dt, J = 7.7, 1.7 Hz, 1 H), 7.77 (dd, J = 8.3, 1.9 Hz. 1 H), 10.29 (s, 1 H).

PREPARATION 12 General procedure of aldoles 3- [5-Fluoro-2- (4-methyl-piperazin-1-yl) benzylidene-1-pyrrolidin-2-one A solution of 9.0 g (40.5 mmol) of 5-fluoro-2- (4-methyl-piperazin-1-yl) -benzaldehyde and 5.1 g (40.5 mmol) of N-acetylpyrrolidinone in 80 ml of tetrahydrofuran was slowly added to a solution at 0 ° C of 5.4 g (133.6 mmol) of sodium hydride in 80 ml of tetrahydrofuran for a period of 2 hours, After 2.5 hours at 0 ° C, the reaction was quenched with saturated ammonium chloride and extracted with methylene chloride. The organic layer was dried magnesium sulfate and concentrated to give a yellow solid. Recrystallization from ethyl acetate and diisopropyl ether gave 3.92 g (33%) of 3- [5-fluoro-2- (4-methyl-piperazin-1-yl) -benzylidene] -pyrrolidin-2-one as a a white solid. C13 NMR (100 MHz, CDCI3) d diagnostic 26.4, 39.9, 46.1, 52. 9, 55.3, 1 15.2, 1 15.5, 1 15.8, 116.0, 120.2, 120.3, 126.7, 131.1, 148.9, 157.3, 159.7, 172.8; MS m / z 290.3 (M + 1), PREPARATION 13 General procedure 2 of aldoles 3-r2- (4-Methyl-piperazin-1-yl) -benzylidene-1-pyrrolidin-2-one To a solution of 1.0 M NaHMDS in anhydrous THF (30 ml, 30 mmol) at 0 ° C under N2 was added through an addition funnel a mixture of the aldehyde of Preparation 1 (2.02 g, 9.90 mmol) and pyrrolidinone II (R3 = tert-butyl) (5.02 g, 29.6 mmol) in anhydrous THF (20 ml. + 5 ml of rinsing), After the addition was complete, the reaction mixture was warmed to room temperature and stirred at room temperature for 18 hours. Water (30 ml) was added to the reaction mixture. The mixture was extracted with CH2Cl2 (30 ml), the aqueous phase was extracted with additional CH2Cl2 (2 x 20 ml). The combined organic extracts were washed with brine, dried (Na2SO) and concentrated to give a brown solid. The solid was triturated with ethyl acetate and hexanes for 3 hours and then filtered to yield the desired product as beige solids (2.54 g, 95%). C13 NMR (100 MHz, CDCl 3) d 173.3, 152.1, 129.7, 129.0, 128.0, 122.5, 1 18.9, 55.4, 52.5, 46.2, 39.9, 26.6; MS (AP / CI) 272.2 (M + H) +.

PREPARATION 14 3-f2- (4-Benzyl-piperazin-1-yl) -benzylidene-1-pyrrolidin-2-one The title compound was prepared by an analogous procedure to that described in Preparation 13. C13 NMR (100 MHz, CDCl 3) d 173.3, 152.8, 138.4, 129.7, 129.63, 129.57, 129.0, 128.5, 128.0, 127.3, 122.3, 1 18.8 , 63.3, 53.6, 52.7, 40.0, 26.6; MS (AP / CI) 348.1 (M + H) +.

PREPARATION 15 3-r5-Methoxy-2- (4-methyl-piperazin-1-yl) -benzylidene-pyrrolidin-2-one The title compound was prepared by an analogous procedure to that described in Preparation 13. C13 NMR (100 MHz, CDCl 3) d 26.5, 40.0, 46.2, 53.0, 55.5, 55.7, 1 14.1, 114.9, 120.0, 127.5, 130.3, 131.2, 146.5, 155.1, 173.1; MS (APICI) 302.3 (M + H) +.

PREPARATION 16 3-f2- (4-Methyl-piperazin-1-yl) -benzylidene-1-piperidin-2-one The title compound was prepared by an analogous procedure to that described in Preparation 13. C13 NMR (100 MHz, CDCl 3) d 23.3, 26.6, 42.4, 46.2, 52.2, 55.5, 118. 2, 121.8, 128.4, 129.3, 129.4, 130.3, 134.3, 152.4, 167.2; MS (AP / CI) 286.3 (M + H) +.

PREPARATION 17 3-f2- (2,5-Dimethyl-piperazin-1-yl) -benzylidene-pyrrolidin-2-one The title compound was prepared by an analogous procedure to that described in Preparation 13. C13 NMR (100 MHz, CDCl 3) d 17.5, 19.6, 26.6, 40.0, 51.1, 53.8, 53.9, 63.8, 123.4, 124.3, 127.3, 128.9, 129.2, 130.4, 133.6, 151.6, 173.4; MS (AP / CI) 286.3 (M + H) +.

PREPARATION 18 3-f5-Fluoro-2- (4-methyl-piperazin-1-yl) -benzylidene-piperidin-2-one The title compound was prepared by an analogous procedure to that described in Preparation 13. C13 NMR (100 MHz, CDCl 3) d 23.3, 26.5, 42.4, 46.2, 52.5, 55.5, 1 15.4, 1 15.6, 1 16.6, 116.8, 1 19.5, 1 19.6, 129.4, 131.2, 131.2, 133.1, 148.7, 1 59.1, 166.7; MS (AP / CI) 304.2 (M + H) +.

PREPARATION 19 3- [2-Fluoro-6- (4-methyl-piperazin-1-yl) -benzyl-deno] -pyrrolidin-2-one The title compound was prepared by an analogous procedure to that described in Preparation 13. C13 NMR (100 MHz, CDCl 3) d 25.2, 27.3, 40.7, 41.4, 46.2, 53.0, 55.7, 1 1.5, 1 1 1.7, 1 16.6 , 1 16.6, 123.0, 123.2, 127.8, 127.9, 153.8, 153.9, 160.9, 163.4, 180.7; MS (AP / CI) 292.3 (M + H) +.

PREPARATION 20 3- [2- (3,4,5-Trimethyl-piperazin-1-yl) -benzylidene-1-pyrrolidin-2-one The title compound was prepared by an analogous procedure to that described in Preparation 13. C13 NMR (100 MHz, CDCl 3) d 18.3, 26.6, 29.9, 38.0, 39.9, 58.1, 60.2, 118.8, 122.4, 127.8, 129.0, 129.6, 152.2, 173.1.

PREPARATION 21 3- [5-Methyl-2- (4-methyl-piperazin-1-yl) benzylidene-pyrrolidin-2-one) The title compound was prepared by an analogous procedure to that described in Preparation 13. C13 NMR (100 MHz, CDCl 3) d 23.0, 26.6, 39.9, 46.1, 52.7, 55.4, 1 18.8, 128.0, 129.3, 129.5, 129.6, 130.2, 131.8, 150.4, 173.0; MS (AP / CI) 286.3 (M + H) +.

PREPARATION 22 3-f2- (4-Methyl-ri, 41diazepan-1-iQbenzylidene-pyrrolidin-2-one) The title compound was prepared by an analogous procedure to that described in Preparation 13. H1 NMR (400 MHz, CDCl3) d 1.93 (p, J = 5.9 Hz, 2H), 2.41 (s, 3H), 2.72-2.76 (m, 4H), 3.03 (dt, J = 6.6, 2.8 Hz, 2H), 3.22-3.30 (m, 4H), 3.49 (t, J = 6.4 Hz, 2H), 6.44 (s, 1 H), 6.95 (t, J = 7.5 Hz, 1 H), 7.05 (dd, J = 7.9, 1.0 Hz, 1 H), 7.20-7.24 (m, 1 H), 7.35 (dd, J = 7.9, 1.2 Hz, 1H), 7.60 (t, J = 2.9 Hz, 1 H); MS (AP / CI) 286.2 (M + H) +.

PREPARATION 23 3-f2- (4-Ethyl-piperazin-1-yl) -benzylidene-1-pyrrolidin-2-one The title compound was prepared by an analogous procedure to that described in Preparation 13. H1 NMR (400 MHz, CDCl3) d 1.09 (t, J = 7.1 Hz, 3H), 2.48 (q, J = 7.2 Hz, 2H), 2.64 (br s, 4H), 2.98 (t, J = 4.6 Hz, 4H), 3.07-3.11 (m, 2H), 3.49 (t, J = 6.6 Hz, 2H), 6.50 (br s, 1 H), 7.00-7.04 (m, 2H), 7.27 (t, J = 8.5 Hz, 1 H), 7.38 (d, J = 7.9 Hz, 1 H), 7.62 (t, J 2.7 Hz, 1H); MS (AP / CI) 286.2 (M + H) +.

PREPARATION 24 3-f5-Fluoro-2- (4-methyl-piperazin-1-yl) -benzyl-pyrrolidin-2-one To a solution of 3.9 g (13.5 mmol) of 3- [5-fluoro-2- (4-methyl-piperazin-1-yl) benzylidene] -pyrrolidin-2-one in 150 ml of methanol was added 1.0 g. of Pd / C. A hydrogenation at 3.4 atmospheres with heating at 50 ° C was complete after 24 hours. The reaction was filtered over Celite® using methanol and concentrated. The resulting residue was purified by chromatography on silica gel to provide 3.8 g (98% yield) of 3- [5-fluoro-2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2- ona C13 NMR (100 MHz, CDCl 3) d of diagnosis 27.3, 31.7, 40.5, 42.1, 46.2, 53.0, 55.8, 1 13.7, 1 13.9, 1 16.6, 1 16.8, 122.3, 122.4, 137.9, 148.0, 161.0; MS m / z 292.2 (M + 1), PREPARATION 25 3- [2- (4-Methyl-piperazin-1-yl) -benzyl-pyrrolidin-2-one In a round bottom flask under N2 were introduced 10% Pd / C (0.99 g) and ethyl alcohol (50 ml) followed by 3- [2- (4-methylpiperazin-1-yl) -benzylidene] -pyrrolidin-2 -one (3.00 g, 1.1 mmol) and ammonium formate (6.97 g, .6 mmol). The reaction mixture was stirred at room temperature during 1 hour and then heated to 50 ° C for 3 hours. The reaction mixture was cooled to room temperature and filtered through Celite® under N2. The Celite® cartridge was washed with ethyl alcohol (25 ml) and water (10 ml). The filtrate was evaporated to give white solids which were partitioned between ethyl acetate (25mml) and H20 (10ml). The aqueous layer was extracted with additional ethyl acetate (2 x 25 ml). The combined organic extracts were washed with brine, dried (Na2SO) and concentrated to a white solid (2.90 g, 96%). The material could be used raw or triturated with ethyl acetate (5 volumes) to provide an 80% recovery of improved purity of the title compound. C13 NMR (100 MHz, CDCl 3) d 180.6, 152.1, 135.5, 130.4, 127.5, 124. 5, 120.8, 55.9, 52.9, 46.4, 42.4, 40.6, 31.8, 27.3; MS (AP / CI) 274.3 (M + H) +.

PREPARATIONS 26-34 3- [5-Methoxy-2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one 3- [2- (4-Met.l-piperazin-1-yl) -benzyl] -piperidin-2-one 3- [2- (2,5-D-methyl-p-piperazin-1-yl) -benzyl] -pyrrolidin-2-one 3- [5 -Fluoro-2- (4-methyl-piperazin-1-yl) -benzyl] -piperidin-2-one 3- [2-Fluoro-6- (4-methyl-piperazin-1-yl) -benzyl) ] -pyrrolidin-2-one 3- [5-Methyl-2- (4-methyl-p-piperazin-1-yl) -benzyl] -pyrrolidin-2-one 3- [2- (3,4,5-Trimethyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one 3- [2- (4-Methyl- [1,4] diazepan-1-yl) - benzyl] -pyrrolidin-2-one 3- [2- (4-Ethyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one The title compounds were prepared by an analogous procedure to that described in Preparation 25.

PREPARATION 35 3- (2-Piperazin-1-yl-benzyl) -pyrrolidin-2-one A suspension of 3- [2- (4-Benzyl-piperazin-1-yl) benzylidene] -pyrrolidin-2-one (Preparation 15, 6.3 g, 18 mmol) and 10% palladium on carbon (1.5 g) in methanol (100 ml) was placed under a hydrogen atmosphere (3.4 atmospheres) and heated at 50 ° C for 24 hours. The mixture was filtered through Celite®, 10% palladium on fresh carbon (2.0 g) was added and the mixture was placed under hydrogen (3.4 atmospheres) and heated at 60 ° C for 7 hours. The mixture was filtered through Celite®, the solvent was removed in vacuo and the residue was purified by chromatography on silica gel (20: 1 chloroform-methanol by weight / 1% ammonium hydroxide) to provide 3.8 g ( 82% yield) of the title compound. C13 NMR (100 MHz, CDCl 3) d 180.7, 152.6, 135.5, 130.4, 127.5, 124.5, 120.8, 54.3, 46.8, 42.4, 40.7, 31.9, 27.3; MS (APICI) 260.1 (M + H) +.

PREPARATION 36 2- (4-Bromo-phenyl) -propan-2-ol A solution of methyl p-bromobenzoate (3 g, 13.2 mmol) in tetrahydrofuran (14 ml) cooled to -30 ° C was treated dropwise with methyl magnesium bromide (1 M in diethyl ether, 105.5 mmol, 105.5 ml). After the addition was complete, the resulting suspension was allowed to warm to room temperature and was stirred for 5 hours. Saturated aqueous ammonium chloride (100 ml) was added slowly and the mixture was diluted with ethyl acetate (100 ml). The organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by chromatography on silica gel (10: 1 hexanes-ethyl acetate) provided 2.2 g (79% yield) of 2- (4-bromo-phenyl) -propan-2-ol. C13 NMR (100 MHz, CDCl 3) d 148.4, 131.4, 126.6, 120.8, 72.5, 31. 9; MS (AP / CI) 1971. 199.1 (M + H) +.

PREPARATIONS 37-40 2- (3-Bromo-phenyl) -propan-2-o! 1- (4-Bromo-pheny1) -2-methyl-propan-2-ol 2- (5-Bromo-pyridin-2-yl) -propan-2-ol 3- (5-Bromo-pyridin-2) -yl) -pentan-3-ol The title compounds were prepared using mephyl 3-bromobenzoate, mephyl 4-bromophenyl-acetate, ethyl-5-bromo-2-carboxypyridine or ethyl-5-bromo-2-carboxy. -pyridine and ethyl-magnesium bromide with methylene chloride as solvent, respectively, but otherwise following the procedure detailed in Preparation 36.

PREPARATION 41 1- (5-Bromo-pyridin-2-yl) -cyclopentanol The title compound was prepared using ethyl-5-bromo-2-carboxypyridine, 1,4-bis (bromomagnesium) butane and diethyl ether as the solvent, but otherwise following the general procedure of Preparation 36. C13 NMR (100 MHz, CDCl 3) d 164.1, 148.9, 139.5, 120.9, 118.8, 83.2, 42.7, 24.9; MS (AP / CI) 242.1, 244.1 (M + H) +.

PREPARATION 42 2- (6-Bromo-pyridin-3-yl) -propan-2-ol The title compound was prepared using ethyl-5-bromo-2-carboxypyridine, but otherwise the general procedure of Preparation 36 was followed.

C13 NMR (100 MHz, CDCl 3) d 147.2, 144.1, 140.4, 135.8, 127.8, 21.3, 31.9; MS (AP / CI) 216.2. 218.2 (M + H) +.

PREPARATION 43 1- (6-Bromo-pyridin-3-yl) -cyclopentanol The title compound was prepared using ethyl-5-bromo-2-carboxypyridine, 1,4-bis (bromomagnesium) -butane and diethyl ether as the solvent, but otherwise the general procedure of Preparation 36 was followed. C13 NMR (100 MHz, CDCI3) d 147.5, 142.2, 140.3, 136.4, 127.8, 81.8, 42.3, 24.0; MS (APICI) 242.2. 244.2 (M + H) +.

PREPARATION 44 1 - (4-Bromo-phenyl) -cyclohexanol 4-Bromo-1-iodobenzene (5 g, 17.7 mmol) in tetrahydrofuran (20 ml) was treated dropwise at -40 ° C with isopropyl-magnesium chloride (2 M solution in tetrahydrofuran, 23 mmol, 1.5 ml). and after the addition was stirred 1 hour. Cyclohexanone (1.5 ml, 14.75 mmol) in tetrahydrofuran (5 ml) was added and the solution allowed to warm slowly to room temperature for 3 hours. Saturated aqueous ammonium chloride solution was added and the mixture was then diluted with ethyl acetate. The aqueous and organic layers were separated and the organic layer was washed with water (1x) and brine (1x). The combined aqueous layers were extracted with ethyl acetate (3 x 10 ml), the combined organic layers were dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by chromatography on silica gel (20: 1 hexanes-ethyl acetate) to provide 3 g (67% yield) of 1- (4-bromo-phenyl) -cyclohexanol. C13 NMR (100 MHz, CDCl 3) d 148.8, 131.4, 126.8, 120.8, 73.2, 38.9, 25.6, 22.3.

PREPARATION 45 3- (4-Bromo-phenyl) -pentan-3-ol The title compound was prepared using the detailed procedure for Preparation 44 with 3-pentanone in place of cyclohexanone. H1 NMR (400 MHz, CDCl3) d 7.45 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 8.7 Hz, 2H), 1.8 (m, 4H), 1.59 (s, 1 H), 0.74 ( t, J = 7.5 Hz, 6H); C 3 NMR (100 MHz, CDCl 3) d 145.0, 131.3, 127.7, 120.4, 77.5, . 2, 8.0.

PREPARATION 46 1- (4-Bromo-phenyl) -cyclopentanol The title compound was prepared using the procedure detailed for Preparation 44 with cyclopentanone in place of cyclohexanone. H1 NMR (400 MHz, CDCl3) d 7.44 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 1.9 (m, 6H), 1.8 (m, 2H), 1.75 (s) , 1 HOUR); C13 NMR (100 MHz, CDCl 3) d 146.4, 131.4, 127.2, 120.8, 83.4, 42.2, 24.1.

PREPARATION 47 1 - (4-Bromo-phenyl) -cyclobutanol In a flame-dried flask under N2, 1,4-dibromobenzene (7.52 g, 31.9 mol) and anhydrous THF (50 ml) were introduced. The reaction mixture was cooled to -78 ° C and 2.5 M n-BuLi in hexanes (12.8 ml, 32 mmol) was added keeping the temperature below 60 ° C. The reaction mixture was stirred at -78 ° C for 30 minutes and then cyclobutanone (2 ml, 26.8 mmol) was slowly added keeping the temperature below -60 ° C. After one hour, the reaction was poured into saturated NH CI solution (40 ml). The salts were filtered through Celite® and washed with EtOAc (2 x 20 ml). The layers were separated and the aqueous phase was extracted with additional EtOAc (20 ml). The combined organic layers were washed with brine, dried (Na2SO) and concentrated to a pale yellow oil (5.51 g). The material could be used without further purification. C13 NMR (400 MHz, CDCl 3) d 145.5, 131.7, 127.1, 121.3, 76.8, 37. 2, 13.2; MS (AP / CI) 209.0. 21 1.0 (M + H-H20) +.

PREPARATION 48 4- (4-Bromo-phenyl) -tetrahydro-pyran-4-ol The title compound was prepared using the procedure detailed for Preparation 44 with 4-oxopyran in place of cyclohexanone. C13 NMR (100 MHz, CDCl 3) d 38.8, 63.9, 70.6, 121.3, 126.6, 131.7, 147.4.

PREPARATION 49 1-Bromo-4- (1-methoxy-1-methyl-ethyl) -benzene 2- (4-bromo-phenyl) -propan-2-ol (Preparation 39, 1.77 g, 8.2 mmol) and methyl iodide (0.5 mL, 8.2 mmol) in tetrahydrofuran (100 mL) were treated with sodium hydride. (60% dispersion in mineral oil, 328 mg, 8.2 mmol). The mixture was stirred for 24 hours at room temperature, poured into 0.5 M aqueous hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by chromatography on silica gel (200: 1 hexanes-ethyl acetate) to provide 500 mg (27% yield) of the title compound. C13 NMR (100 MHz, CDCl 3) d 145.4, 131.5, 127.9, 121.0, 76.7, 50. 9, 28.1; MS (AP / CI) 197.0, 199.0 (M + H-OMe) +.

PREPARATION 50 1-Bromo-4- (1-methoxy-cyclobutyl) -benzene The title compound was prepared using the detailed procedure for Preparation 51 over the corresponding hydroxyl compound prepared above. C13 NMR (100 MHz, CDCl 3) d 142.5, 131.6, 128.4, 121.4, 81.3, 50.8, 33.0, 13.1; MS (AP / CI) 209.1, 21 1.1 (M + H-OMe) +.

PREPARATION 51 1-Bromo-4- (2-methoxy-2-methyl-propyl) -benzene The title compound was prepared using the detailed procedure for Preparation 51 over the corresponding hydroxyl compound above. C13 NMR (100 MHz, CDCl 3) d 137.6, 132.4, 131.1, 120.3, 75.2, 49.7, 45.9, 24.9; MS (APICI) 21 1.1. 213.1 (M + H-OMe) +.

PREPARATION 52 5-Bromo-2- (tetrahydro-pyran-4-yloxy) -pyridine A solution of 2,5-dibromopyridine (9.5 g, 40 mmol) in N, N-dimethylformamide (10 ml) was treated with sodium hydride (60% dispersion in mineral oil, 2.4 g, 60 mmol). The mixture was cooled to 4 ° C and 4-hydroxypyran (3.8 ml, 40 mmol) was slowly added. The resulting mixture was stirred at room temperature for 24 hours, then dilute brine solution was added and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by chromatography on silica gel (40: 1 hexanes-ethyl acetate) to provide 9.0 g (87% yield) of the title compound. C13 NMR (100 MHz, CDCl 3) d 162.0, 147.6, 141.5, 1 13.5, 1 1 1.7, 70. 3, 65.7, 32.1; MS (APICI) 258.2. 260.2 (M + H) +.

PREPARATION 53 4- (5-Bromo-pyridin-2-yl) -morpholine Heating at 120 ° C for 24 hours 2,5-dibromopyridine (7.1 g, 30 mmol), morpholine (1.74 ml, 20 mmol), cesium carbonate (9.1 g, 2.8 mmol), tris (dibenzylideneacetone) dipalladium (0) (183 mg, 0.2 mmol) and racemic 2,2'-bis (diphenphosphino) -1,1 '-dinaphthyl (374 mg, 0.6 mmol) in toluene (20 ml). After cooling to room temperature, the mixture was filtered through Celite® and the Celite® cartridge was washed with chloroform. The solution was concentrated in vacuo and purified by chromatography on silica gel (200: 1 chloroform-methanol) to provide 2.9 g (60% yield) of the title compound. C13 NMR (100 MHz, CDCl 3) d 158.3, 148.7, 140.0, 108.4, 66.8, 45.7; MS (APICI) 243.0. 245.0 (M + H) +.

PREPARATION 54 4- (4-Bromo-phenyl) -morpholine The title compound was prepared using 1,4-dibromobenzene, but otherwise the procedure of Preparation 55 was followed. H1 NMR (400 MHz, CDCl3) d 7.35 (d, J = 9.1 Hz, 2H), 6.77 (d , J = 9.1 Hz, 2H), 3.85 (t, J = 5.0 Hz, 4H), 3.12 (t, J = 4.8 Hz, 4H); MS (AP / CI) 242.1. 244.0 (M + H) +.

GENERAL COUPLING PROCEDURE MEASURED BY PALLADIUM The following general procedure illustrates the method used for the Pd-mediated N-arylation of the pyrrolidin-2-one moiety with the corresponding aryl bromide: To a sealed tube was added 3- [5-fluoro-2- (4- methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one (Preparation 13), aryl bromide (1.2 equivalents), tris (dibenzylideneacetone) dipalladium (0.05 equivalents), 9.9-dimethyl-4 , 5-bis (diphenylphosphino) xanthene (XANTPHOS) (0.15 equivalents), cesium carbonate (1.5 equivalents) and dioxane (7 volumes). The mixture was heated at 100 ° C for 12 to 24 hours. After cooling to room temperature, the mixture was concentrated in vacuo and purified by chromatography on silica gel. The following compounds were prepared by the above general procedure: EXAMPLE 1 3-r5-Fluoro-2- (4-methyl-piperazin-1-iD-benzyl-1 - [4- (1-hydroxy-1-methyl-ethyl) -phenyl] -pyrrolidin-2-one: 3 - [5-Fluoro-2- (4-methyl-piperazin-1-yl) -bendl] -1- [4- (1-hydroxy-1-methyl-ethyl) -phenyl] -pyrrolidin-2-one: C13 NMR (100 MHz, CDCl 3) d 24.8, 31.9, 32.5, 44.7, 46.0, 46.9, 52.9, 55.7, 72.4, 113.9, 114.1, 116.8, 117.1, 119.7, 1222.4, 122.5, 125.2, 137.8, 137.9, 138.2, 145.6 , 147.9, 158.6, 161.1, 175.5; MS (APICI) 426.3 (M + H) +. The enantiomers were separable by HPLC (90/10 heptane / ethanol; Chiracel OD, 10 cm x 50 cm; 275 ml / minute). Approximate retention times: t1 = 12.7 minutes; t2 = 14.8 minutes.

EXAMPLE 2 Ethyl ester of 4- acid. { 3-r2- (4-Methyl-piperazin-1-yl) -benzyl] -2 -oxo-pyrrolidin-1-yl) -benzoic acid Ethyl ester of 4- acid. { 3- [2- (4-methyl-piperazin-1-yl) -benzyl] -2-oxo-pyrrolidin-1-yl} -benzoic acid: C13 NMR (100 MHz, CDCl 3) d 176.46, 166.86, 152.14, 143.83, 134. 97, 130.70, 130.55, 127.73, 125.58, 124.55, 120.86, 118.68; Anal. cale, for C25H31N3? 3: C, 71.2; H, 7.4; N, 10.0; Found: C, 70.9; H, 7.4; N, 10.1.

EXAMPLE 3 3-r2- (4-Methyl-piperazin-1-it) -benzin-1- (6-morpholin-4-yl-pyridin-3-yl) -pyrrolidin-2-one 3- [2- (4-Methyl-p-piperazin-1-yl) -benzyl] -1- (6-morpholin-4-yl-pyridin-3-yl) -pyrrolidin-2-one: C13 NMR (100 MHz, CDCl 3) d 175.90, 156.93, 152.14, 139.17, 135.15, 130.75, 130.52, 128.27, 127.64, 124.53, 120.79, 107.02, 66.93, 55.91, 52.96, 46.82, 46.36, 46.18, 44.34, 32.40, 24.75; MS (APICI) 436.2 (M + H) +. The enantiomers were separable by HPLC (70/30 heptane / ethanol with 0.025% diethylamine, Chiracel OD, 4.6 mm x 25 cm, 1 ml / minute). Retention times: t1 = 9.8 minutes; t2 = 12.3 minutes.

EXAMPLE 4 1 - | 4- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl-1-pyrrolidin-2-one 1- [4- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- [2- (4-methyl-p-piperazin-1-yl) -benzyl] -pyrrolid N-2-one: C 3 NMR (100 MHz, CDCl 3) d 175.99, 152.05, 145.55, 138.33, 135.23, 130.54, 127.62, 125.16, 124.56, 120.83, 119.64, 72.38, 55.84, 52.80, 47.01, 46.27, 44.89 , 32.51, 32.01, 24.71; MS (APICI) 408.4 (M + H) +, 390.3 (M + H-H20) +. The enantiomers were separable by HPLC (95/5 acetonitrile / methanol, Chiralpak AD, 10 cm x 50 cm, 250 ml / minute). approximate retention times: t1 = 25 minutes; t2 = 40 minutes.

EXAMPLE 5 3-f2- (4-Methyl-piperazin-1-yl) -bencip-1- (4-morpholin-4-yl-phenyl) -pyrrolidin-2-one 3- [2- (4-Methyl-piperazin-1-yl) -benzyl] -1- (4-morpholin-4-yl-phenyl) -pyrrolidin-2-one: C13 NMR (100 MHz, CDCl 3) d 175.57 , 152.04, 148.43, 135.35, 132.70, 130.55, 127.58, 124.54, 121.18, 120.79, 116.29, 67.10, 55.84, 52.82, 49.89, 47.19, 46.26, 44.76, 32.54, 24.73; MS (AP / CI) 435.2 (M + H) +.

EXAMPLE 6 1 - [4- (1-Hydroxy-cyclopentyl) -fenin-3-f2- (4-methyl-piperazin-1-yl) -benzifl-pyrrolidin-2-one: 1- [4- (1-Hydroxy-cyclopentyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one: C13 NMR (100 MHz, CDCI3) d 175.94, 152.15, 143.44, 138.45, 135.25, 130.36, 127.47, 125.83, 124.51, 120.79, 119.63, 83.11, 55.91, 52.94, 47.00, 46.37, 44.90, 42.04, 32.46, 24.69, 24.03; MS (AP / CI) 416.1 ((M + H) -H20) +; 434.1 (M + H) +. The enantiomers were separable by HPLC (85/15 acetonitrile / methanol, Chiralpak AD 2.1 cm x 25 cm, 20 ml / minute). Retention times: t1 = 7 minutes; t2 = 1 1 minutes.

EXAMPLE 7 1 - | - (1-Hydroxy-cyclohexyl) -fenin-3-r2- (4-methyl-piperazin-1-yl) -benzyl-pyrrolidin-2-one 1- [4- (1-Hydroxy-cyclohexyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one: H1 NMR (400 MHz, CDCl3) d 7.63 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 9.1 Hz, 2H), 7.2 (m, 2H), 7.14 (dd, J = 1.2, 7.9 Hz , 1 H), 7.05 (m, 1 H), 3.7 (m, 2H), 3.38 (m, 1 H), 3.06 (m, 1 H), 2.94 (m, 4H), 2.78 (dd, J = 10.6 , 13.5 Hz, 1 H), 2.60 (brs, 4H), 2.35 (s, 3H), 2.06 (m, 1 H), 1.9-1.6 (m, 10H), 1.3 (m, 1 H); MS (AP / CI) 448.2 (M + H) +, 430.2 (M + H-H20) +.

EXAMPLE 8 1-f4- (1-Ethyl-1-hydroxypropyl) -fenin-3-r2- (4-methyl-piperazin-1-yl) -benzyl-pyrrolidin-2-one 1- [4- (1-Ethyl-1-hydroxy-propyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl-pyrrolidin-2-one: C13 NMR (100 MHz , CDCI3) d 175.91, 152.15, 141.99, 138.08, 135.29, 130.55, 127.59, 126.22, 124.50, 120.77, 119.28, 76.98, 55.91, 52.95, 46.96, 46.38, 44.97, 35.21, 32.53, 24.75, 8.06; MS (AP / CI) 436.1 (M + H) +, 418.1 (M + H-H20) +. The enantiomers were separable by HPLC (methanol, Chiralpak AD 10 cm x 50 cm, 250 ml / minute). Approximate retention times: t1 = 35 minutes; t2 = 68 minutes (flow rate increased to 290 ml / minute after 46 minutes).

EXAMPLE 9 s1 -f3- (1-Hydroxy-1-methyl-ethyl) -phenyl-1-3-r2- (4-methyl-piperazin-1-yl) -benzyl-pyrrolidin-2-one 1- [3- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] - pyrrolidin-2-one: C13 NMR (100 MHz, CDCl 3) d 176.0, 152.0, 150.3, 139.7, 135.2, 130. 6, 128.9, 127.6, 124.6, 120.8, 118.3, 116.4, 72.7, 55.8, 52.8, 47.1, 46.2, 44. 9, 32.6, 32.0, 24.8; MS (AP / CI) 408.1 (M + H) +.

EXAMPLE 10 1-r4- (2-Hydroxy-2-methyl-propyl) -fenip-3-r2- (4-methyl-piperazin-1-yl) -benzyl-pyrrolidin-2-one 1- [4- (2-Hydroxy-2-methyl-propyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2 -one: C13 NMR (100 MHz, CDCl 3) d 175.9, 152.0, 138.3, 135.2, 134.1, 131.0, 130.6, 127.6, 124.6, 120.8, 1 19.7, 71.0, 55.8, 52.8, 49.4, 47.0, 46.2, 44.9, 32.6 , 29.4, 24.7; MS (APICI) 422.5 (M + H) +. The enantiomers were separable by HPLC (methanol; Chiralpak AD, 10 cm x 50 cm; 250 ml / minute). Approximate retention times: t1 = 20 minutes; t2 = 38 minutes.

EXAMPLE 11 1-f &- (1-Hydroxy-1-methyl-ethyl) -pyridin-3-n-3-r 2 - (4-methyl-piperazin-1 -iQ-benzyl) -pyrrolidin-2-one 1- [6- (1-Hydroxy-1-methyl-ethyl) -pyridin-3-yl] -3- [2- (4-methyl-p¡perazin-1-yl) -benzyl] -pyrrolidin-2-one : C13 NMR (100 MHz, CDCl 3) d 176.5, 161.9, 152.1, 138.2, 124.9, 134.9, 130.5, 128.2, 127.8, 124.6, 120.9, 118.7, 71.9, 55.9, 52.9, 46.3, 44.4, 32.4, 30.9, 24.7; MS (APICI) 409.4 (M + H) +.

The enantiomers were separable by HPLC (95/5 acetonitrile / methanol, Chiralpak AD, 10 cm x 50 cm, 250 ml / minute). Approximate retention times: t1 = 26 minutes; t2 = 37 minutes.

EXAMPLE 12 2.2-Dimethyl-3- (4-3- [2- (4-methyl-p-piperazin-1-yl) -bencip-2-oxo-pyrrolidin-1-yl) -phenyl) -propionitrile 2. 2-Dimethyl-3- (4-. {3- [2- (4-methyl-piperazin-1-yl) -benzyl] -2-oxo-pyrrolidin-1-yl} - phen.l) -proponitrile: C13 NMR (100 MHz, CDCl 3) d 176.0, 152.1, 139.1, 135.2, 130.6, 127. 6, 125.0, 124.5, 120.8, 119.6, 55.9, 53.0, 46.9, 46.37, 46.30, 45.0, 33.8, 32. 5, 26.7, 24.7; MS (APICI) 431.3 (M + H) +.

EXAMPLE 13 1-f4- (1-Methoxy-1-methyl-ethyl) -fenin-3-r2- (4-methyl-piperazin-1-yl) -bencip-pyrrolidin-2-one 1- [4- (1-Methoxy-1-methyl-ethyl) -phenyl] -3- [2- (4-methyl-p-piperazin-1-yl) -benzyl] -pyrrolidin-2- ona: C13 NMR (100 MHz, CDCl 3) d 175.9, 152.1, 142.1, 138.6, 135.3, 130.5, 127.6, 126.6, 124.5, 120.8, 1 19.6, 76.7, 55.9, 53.0, 50.9, 47.0, 46.4, 44.9, 32.5, 28.2, 24.7; MS (APICI) 422.2 (M + H) +.

EXAMPLE 14 1-r4- (2-Methoxy-2-methyl-propyl) -phenn-3-r2- (4-methyl-piperazin-1-yl) -benzin-pyrrolidin-2-one 1- [4- (2-Methoxy-2-methyl-propyl) -phenyl] -3- [2- (4-methylpiper-1-yl) -benzyl] -p rrolidin-2-one: C13 NMR (100 MHz, CDCl 3) d 175.8, 152.1, 138.0, 135.3, 131.0, 130.5, 129.0, 127.6, 124.5, 120.8, 119.3, 75.5, 55.9, 53.0, 49.6, 47.0, 46.4, 45.9 , 45.0, 32.5, 24.9, 24.7; MS (AP / CI) 436.4 (M + H) +.

EXAMPLE 15 1-r4- (1-Methoxy-cyclobutyl) -fenin-3-r2- (4-methyl-piperazin-1-yl) -benzyl-pyrrolidin-2-one 1- [4- (1-Methoxy-cyclobutyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one: C13 NMR (100 MHz, CDCI3) d 176.0, 152.1, 139.2, 138.8, 135.2, 130.5, 127.6, 127.1, 124.5, 120.8, 119.6, 81.3, 55.9, 53.0, 50.7, 47.0, 46.4, 44.9, 33.1, 32.5, 24.7, 13.1; MS (AP / CI) 434.4 (M + H) +.

EXAMPLE 16 3- [2- (4-Met.l-p.perazin-1-yl) -benzin-1- (4-pyridin-4-yl-phenyl) -pyrrolidin-2-one 3- [2- (4-Methyl-piperazin-1-yl) -benzyl] -1- (4-pyridin-4-yl-phenyl) -pyrrolidin-2-one: C 3 NMR (100 MHz, CDCl 3) d 176.2, 152.1, 150.5, 147.7, 140.7, 135.1, 133.7, 130.6, 127.7, 127.6, 124.6, 121.4, 120.9, 120.0, 55.9, 52.9, 46.8, 46.3, 45.0, 32.5, 24.6; MS (AP / CI) 427.3 (M + H) +.

EXAMPLE 17 1 -f 4 - (1-Hydroxy-cyclopentyl) -phenyl-1,3- (2-piperazin-1-ylbenzyl) -pyrrolidin-2-one 1- [4- (1-Hydroxy-cyclopentyl) -phenyl] -3- (2-pperazin-1-ylbenzyl) -pyrrolidin-2-one: C13 NMR (100 MHz, CDCl 3) d 176.0 , 152.4, 143.5, 138.3, 135.2, 130.6, 127.6, 125.8, 124.6, 120.9, 1 19.7, 83.3, 54.1, 47.1, 46.6, 44.9, 42.0, 32.44, 24.7, 24.0; MS (AP / CI) 420.1 (M + H) +.

EXAMPLE 18 1-f4- (1-Hydroxy-cyclobutyl) -phenyl] -3- (2-piperazin-1-yl-benzyl) -pyrrolidin-2-one 1- [4- (1-Hydroxy-cyclobutyl) -phenyl] -3- (2-p¡perazin-1-yl-benzyl) -pyrrolidin-2-one: C13 NMR (100 MHz, CDCl 3) d 176.0 , 152.4, 142.7, 138.8, 135.2, 130.6, 127.6, 124.6, 120.9, 119.8, 76.7, 54.0, 47.0, 46.6, 45.0, 37.2, 32.5, 24.7, 13.2; MS (AP / CI) 406.2 (M + H) +.

EXAMPLE 19 1 -f 4 - (1-Hydroxy-cyclohexyl) -phenyl-3- (2-piperazin-1-yl-benzyl) -pyrrolidin-2-one 1- [4- (1-Hydroxy-cyclohexyl) -phenyl] -3- (2-pperazin-1-yl-benzyl) -pyrrolidin-2-one: C13 NMR (100 MHz, CDCl 3) d 175.9, 152.6, 145.8, 138.3, 135.3, 130.5, 127.6, 125.3, 124.5, 120.9, 119.7, 73.1, 54.2, 47.0, 46.8, 45.0, 39.1, 32.4, 25.7, 24.7, 22.4; MS (AP / CI) 434.3 (M + H) +, 416.3 (M + H-H20) +.

EXAMPLE 20 1 - | 4- (1-Ethyl-1-hydroxy-propyl) -phenyl] -3- (2-piperazin-1 -M-benzyl) -pyrrolidin-2-one 1- [4- (1-Ethyl-1-hydroxy-propyl) -phenyl] -3- (2-piperazin-1-yl-benzyl) -pyrrolidin-2-one: C13 NMR (100 MHz, CDCl 3) d 175.9, 152.6, 141.9, 138.1, 135.3, 130.6, 127.6, 126.2, 124.5, 120.8, 119.3, 77.4, 54.2, 47.0, 46.8, 45.0, 35.2, 32.5, 24.7, 8.1; MS (AP / CI) 422.3 (M + H) +, 404.3 (M + H-H20) +.

EXAMPLE 21 1-r4- (1-Hydroxy-1-methyl-ethyl) -fenin-3- (2-piperazin-1-yl-benzyl) -pyrrolidin-2-one 1- [4- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- (2-piperazin-1-yl-benzyl) -pyrrolidin-2-one: C13 NMR (100 MHz , CDCl 3) d 176.0, 152.6, 145.5, 138.4, 135.3, 130.6, 127.6, 125.1, 124.5, 120.9, 119.7, 72.5, 54.1, 47.0, 46.7, 45.0, 32.5, 32.0, 24.7; MS (AP / CI) 394.2 (M + H) +, 376.2 (M + H-H20) +.

EXAMPLE 22 1 - [4- (1-Hydroxy-1-methyl-ethyl) -phenn-3-f2- (4-methyl-piperazin-1-yl) -benzylidene-1-pyrrolidin-2-one 1- [4- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzylidene] -pyrrolidin-2 -one: C13 NMR (100 MHz, CDCl 3) d 168.8, 152.9, 145.6, 138.5, 129.8, 129.5, 129.1, 128.9, 125.2, 122.4, 1 19.5, 1 19.0, 72.4, 55.5, 52.7, 46.2, 45.8, 32.0, 24.3; MS (AP / CI) 406.1 (M + H) +.

EXAMPLE 23 3-r5-Fluoro-2- (4-methyl-piperazin-1-yl) -benzin-1 - [4- (1-hydroxy-cyclopentyl) -phenip-Pyrrolidin-2-one 3- [5-Fluoro-2- (4-methyl-piperazin-1-yl) -benzyl] -1- [4- (1-hydroxy-cyclopentyl) -phenyl] -pyrrolidin-2-one : C13 NMR (100 MHz, CDCl 3) d 24.0, 24.7, 32.4, 42.1, 44.7, 46.2, 46.9, 53.0, 55.8, 1 13.8, 1 14.0, 1 16.8, 1 17.0, 1 19.6, 122.3, 122.4, 125.8, 137.7 , 1 38.3, 143.5, 148.0, 158.6, 175.0; MS (AP / CI) 452.3 (M + H) +. The enantiomers were separable by HPLC (90/10 heptane / ethanol: Chiralcel OD, 10 cm x 50 cm, 275 ml / minute.

Approximate retention times: t1 = 13.7 minutes; t2 = 16.2 minutes.

EXAMPLE 24 1 - [4- (1-Hydroxy-cyclopentyl) -phenn-3-r5-methyl-2- (4-methyl-p-piperazin-1-yl) -bencip-pyrroiidin-2-one 1- [4- (1-Hydroxy-cyclopentyl) -phenyl] -3- [5-methyl-2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidine n-2-one: C13 NMR (100 MHz, CDCl 3) d 21.1, 24.0, 24.6, 32.4, 41.7, 42.0, 45. 0, 46.2, 47.0, 52.8, 55.9, 83.3, 119.6, 120.7, 125.8, 128.2, 131.2, 134.0, 135.1, 138.4, 143.3, 149.5, 176.0; MS (AP / CI) 448.4 (M + H) +.

EXAMPLE 25 1-r4- (1-Hydroxy-1-methyl-ethyl) -fenin-3-r5-methyl-2- (4-methyl-piperazin-1-yl) -benzin-pyrrolidin-2-one 1- [4- (1-Hydroxy-1-methyl-ethyl] -phenyl] -3- [5-methyl-2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one. "C13 NMR (100 MHz, CDCl 3) d 21.1, 24.6, 31.9, 32.4, 45.0, 46.2, 47.0, 52.9, 55.9, 72.4, 119.6, 120.7, 125.1, 128.1, 131.2, 134.0, 135.1, 138.3, 145.5, 149.5, 176.0; MS (AP / CI) 422.3 (M + H) +.

EXAMPLE 26 1 -f4- (1-Hydroxy-cyclopentyl) -phenin-3-r2- (4-methyl-p-piperazin-1-yl) -benzyl] -piperidin-2-one 1- [4- (1-Hydroxy-cyclopentyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -piperidin-2-one: C13 NMR (100 MHz, CDCl 3 ) d 22.1, 24.0, 25.8, 33.1, 42.0, 43.2, 46.2, 51.9, 52.7, 55.8, 83.3, 120.7, 124.4, 126.0, 126.1, 127.3, 130.9, 135.8, 142.3, 145.7, 152.2, 173.0; MS (AP / CI) 448.3 (M + H) +. The enantiomers were separable by HPLC (60/40 heptane / ethanol, Chiralpak AD, 10 cm x 50 cm, 275 ml / minute). Approximate retention times: t1 = 8.3 minutes; t2 = 10.7 minutes.

EXAMPLE 27 1-f4- (1-Hydroxy-1-methyl-ethyl) -femT | -3-r2- (4-met? 'L-piperazin-1 -iQ-benzyl] -piperidin-2-one 1- [4- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- [2- (4-methyl-piperazin-1-l) -benzyl] -piper-d-n-2 -ona: C13 NMR (100 MHz, CDCl 3) d 22.1, 25.8, 31.9, 33.1, 43, 2, 46, 2, 51, 9, 52, 7, 55, 8, 72.4, 120.8, 124.4, 125.5, 126.0, 127.3, 130.9 , 135.9, 142.2, 147.7, 152.2, 173.0: MS (AP / CI) 422.3 (M + H) +. The enantiomers were separable by HPLC (60/40 heptane / ethanol, Chiralpak AD, 10 cm x 50 cm, 275 ml / minute). Approximate retention times: t1 = 6.9 minutes; t2 = 10.3 minutes.

EXAMPLE 28 1 - [4- (1-Hydroxy-1-methyl-ethyl) -phenn-3-f5-methoxy-2- (4-methyl-piperazin-1-yl) -benzin-pyrrolidin-2-one 1- [4- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- [5-methoxy-2- (4-methyl-piperazin-1-yl) -benzyl] -p Rrolidin-2-one: C13 NMR (100 MHz, CDCl 3) d 24.5, 31.9, 32.4, 45.0, 46.2, 47.0, 53.1, 55.5, 55.8, 72.3, 112.3, 115.9, 119.6, 122.1, 125.1, 136.9, 138.2, 145.2, 145.7, 156.5, 175.9; MS (AP / CI) 438.3 (M + H) +.

EXAMPLE 29 1-r4- (1-HydroxS-cyclopentyl) -feu'n-3-f5-methoxy-2- (4-methyl-piperazin-1-yl) -benzyl-pyrrolidin-2-one 1- [4- (1-Hydroxy-cyclopentyl) -feuyl] -3- [5-methoxy-2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one: C13 NMR (100 MHz, CDCl 3) d 24.0, 24.5, 32.4, 42.0, 45.0, 46.0, 47.0, 52.9, 55.5, 55.8, 83.2, 112.2, 115.9, 119.6, 122.1, 125.8, 136.9, 138.2, 143.6, 145.1, 156.6 175.9; MS (AP / CI) 464.4 (M + H) +.

EXAMPLE 30 3-r2-Fluoro-6- (4-methyl-piperazin-1-yl) -benzyl-1-f4- (1-hydroxy-cyclopentyl) -phenyl-pyrrolidin-2-one 3- [2-Fluoro-6- (4-methyl-piperazin-1-yl) -benzyl] -1- [4- (1-hydroxy-cyclopentyl) -phenyl] -pyrrolidin-2 -one: C13 NMR (100 MHz, CDCl 3) d 24.0, 24.9, 25.7, 42.0, 43.9, 46.2, 46.8, 53.0, 55.7, 83.2, 111.5, 111.7, 116.6, 119.5, 122.7, 122.9, 125.8, 128.0, 128.1, 138.4, 143.4, 153.9, 153.9, 161.0, 163.4, 175.6; MS (AP / CI) 464.3 (M + H) +.

EXAMPLE 31 1 - | 4- (1-Hydroxy-cyclopentyl) -phenyl] -3-f2- (3,4,5-trimethyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one 1- [4- (1-Hydroxy-cyclopentyl) -phenyl] -3- [2- (3,4,5-trimethyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one: H1 NMR (400 MHz, CDCl3) d 1.13 (s, 6H), 1.51-1.69 (m, 2H), 1.80-1.89 (m, 4H), 1.98 (s, 3H), 2.31-2.51 (m, 4H), 2.60-2.71 (m, 2H), 2.79 (dd, 1 H, J = 10.4 and 13.6 Hz), 2.84-2.95 (m, 2H), 3.03-3.04 (m, 1 H), 3.36 (dd, 1 H, J = 13.6 and 4.0 Hz), 3.676-3.71 (m, 2H), 7.05 (dd, 1 H, J = 7.6 and 7.2 Hz); 7.1 1 (d, 1 H, J = 7.6 HzO, 7.19-7.23 (m, 2h), 7.49 (d, 2H, J = 9.2 Hz), 7.61 (d, 2H, J = 8.8 Hz); MS (AP / CI) 462.4 (M + H) +.

EXAMPLE 32 1- [4- (1-Hydroxy-1-methyl-ethyl] -phenyl] -3-f2- (3,4,5-trimethyl-p-piperazin-1-yl) -benz N-pyrrolidin-2-one 1- [4- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- [2- (3,4,5-trimethyl-piperazin-1-yl) -benzyl] -pyrrolidin-2 -one: C13 NMR (100 MHz, CDCl 3) d 18.1, 24.7, 31.9, 32.4, 38.0, 44.9, 47.0, 58.7, 60.4, 60.7, 72.5, 1 19.6, 120.5, 124.5, 125.1, 127.6, 130.5, 1 35.1. 138.3, 145.3, 151.6, 175.9; MS (AP / CI) 436.2 (M + H) +.

EXAMPLE 33 1-f4- (4-Hydroxy-tetrahydro-pyran-4-ip-phenyl1-3-r2- (3,4,5-trimethyl-p-eperazin-1-yl) -benzyl-pyrrolidin-2-one 1- [4- (4-Hydroxy-tetrahydro-pyran-4-yl) -phenyl] -3- [2- (3,4,5-trimethyl-piperazin-1-yl) -benzyl] - pyrrolidone-2-one: C13 NMR (100 MHz, CDCl 3) d 24.6, 39.0, 44.9, 46.9, 64.1, 119.8, 125.2, 127.7, 130.5; MS (AP / CI) 478.4 (M + H) +.

EXAMPLE 34 1-r4- (4-Hydroxy-tetrahydro-pyran-4-yl) -fenip-3-r2- (4-methyl-piperazin-1-yl) -bencip-piperidin-2-one 1- [4- (4-Hydroxy-tetrahydro-pyrn-4-yl) -phenyl] -3- [2- (4-methyl-p-piperazin-1-yl) -benzyl] -piperdin-2-one: C13 NMR (100 MHz, CDCl 3) d 22.1, 25.8, 33.1, 38.9, 43.2, 46.2, 51.8, 52.7, 55.8, 64.1, 70.6, 120.8, 124.4, 125.6, 126.3, 127.4, 130.9, 135.8, 142.7, 146.7, 152.2, 173.0; MS (AP / CII) 464.4 (M + H) +. The enantiomers were separable by HPLC (75/25 heptane / ethanol with 2% diethylamine, Chiralpak OJ, 10 cm x 50 cm, 275 ml / minute). Approximate retention times: t1 = 6.8 minutes; t2 = 10.6 minutes.

EXAMPLE 35 1-f4- (1-Hydroxy-1-methyl-ethyl) -fenin-3-r2- (3,4,5-trimethyl-piperazin-1-N) -benzyl-piperidin-2-one 1- [4- (1-Hydroxy-1-methyl-ethyl] -phenyl] -3- [2- (3,4,5-trimethyl-piperazin-1-yl) -benzyl] - piperidin-2-one: C13 NMR (100 MHz, CDCl 3) d 18.2, 18.3, 22.2, 25.8, 31.9, 33.0, 38. 0, 43.3, 51.9, 58.7, 60.3, 60.9, 72.5, 120.4, 124.4, 125.5, 126.1, 127.3, 130. 9, 135.8, 142.3, 147.6, 151.9, 173.0 MS (AP / CI) 450.5 (M + H) +.

EXAMPLE 36 1 -f 4 - (1-Hydroxy-cyclopentyl) -phenyl-3-f 2 - (3,4,5-trimethyl-piperazin-1-yl) -benzyl-T-piperidin-2-one 1- [4- (1-Hydroxy-cyclopentyl) -phenyl] -3- [2- (3,4,5-trimethyl-p-piperazin-1-yl) -benzyl] -piperidin-2-one: C13 NMR (100 MHz, CDCl 3) d 18.1, 18.2, 22.2, 24.0, 25.8, 33.0, 38.0, 42.1, 43.3, 51.9, 58.7, 58.8, 60.3, 60.9, 83.4, 120.4, 124.4, 126.1, 126.2, 127.3, 130.9 , 135.8, 142.4, 145.6, 151.9, 173.0; MS (AP / CI) 476.5 (M + H) +.

EXAMPLE 37 3-r5-Fluoro-2- (3,4,5-trimethyl-piperazin-1-yl) -benzyl] -1 - [4- (1-hydroxy-1-methyl-ethyl) -phenylHP-P-pyridine- 2-one 3- [5-Fluoro-2- (3,4,5-trimethyl-p-piperazin-1-yl) -benzyl] -1- [4- (1-hydroxyl-1-methyl-ethyl) ) -phenyl] -piperidin-2-one: C13 NMR (100 MHz, CDCl 3) d 18.1, 22.3, 25.9, 31.9, 32.9, 37.9, 43.2, 51.8, 58.8, 60.6, 61.0, 72.5, 113.5, 113.7, 117.1, 117.3, 121.9, 125.5, 126.0, 138.5, 142.2, 147.7, 147.8, 172.6; MS (AP / CI) 468.5 (M + H) +.

EXAMPLE 38 3-r5-Fluoro-2- (3,4,5-trimethyl-piperazin-1-yl) -bencip-1-f4- (1-hydroxy-cyclopentyl) -phenyl] -pyridin-2-one 3- [5-Fluoro-2- (3,4,5-trimethyl-p-piperazin-1-yl) -benzyl] -1- [4- (1-hydroxy-cyclopentyl) -phenyl) ] -peridin-2-one: C13 NMR (100 MHz, CDCl 3) d 18.1, 18.2, 22.3, 24.0, 25.9, 32.8, 38.0, 42.1, 43.2, 51.8, 58.7, 58.8, 60.6, 61.1, 83.3, 113.5 , 113.7, 117.0, 1 17.2, 121.9, 122.0, 126.0, 126.1, 126.4, 129.3, 138.4, 138.5, 142.2, 145.7, 147.9, 158.5, 160.9, 172.6; MS (AP / CI) 494.5 (M + H) +.

EXAMPLE 39 3-f2- (4-Methyl-piperazin-1-yl) -benzin-1-f4- (2-oxo-pyrrolidin-1-ylmethyl) -phenin-piperidin-2-one 3- [2- (4-Met.lp.-piperazin-1-yl) -benzyl] -1- [4- (2-oxo-pyrrolidin-1-methylmet) -phenol ] -peridin-2-one: C 3 NMR (100 MHz, CDCl 3) d 17.9, 22.2, 25.8, 31.1, 33.1, 43.2, 46.2, 46.3, 46.8, 51.8, 52.8, 55.8, 120.8, 124.4, 126.6, 127.4, 129.0, 130.9, 135.0, 135.8, 143.2, 152.2, 173.0, 175.2; MS (AP / CI) 461.5 (M + H) +.

EXAMPLE 40 3- [2- (4-Methyl-piperazin-1-yl) -benzyl-1 - (3-oxo-1,3-dihydro-isobepzofuran-5-yl) -piperidin-2-one 3- [2- (4-Methyl-piperazin-1-yl) -benzyl] -1- (3-oxo-1,3-dihydro-isobenzofuran-5-yl) -p -peridin-2-one: C13 NMR (100 MHz, CDCI3) d 22.1, 25.8, 33.0, 43.3, 46.3, 51.8, 52.2, 52.8, 55.5, 55.9, 69.8, 120.8, 122.7, 122.8, 124.6, 127.6, 127.6, 127.5, 127.5, 127.5, 127.5, 135.5, 144.5, 144.9 , 12.2, 170.7, 173.3; MS (AP / CI) 420.5 (M + H) +.

EXAMPLE 41 3-f5-Fluoro-2- (4-methyl-piperazin-1-yl) -benzin-1-r4- (1-hydroxy-cyclobutyl) -phenyl] -piperidin-2-one 3- [5-Fluoro-2- (4-methyl-piperazin-1-yl) -benzyl] -1- [4- (1-hydroxyl-cyclobutyl) -phenyl] -piperidin-2 -one: C13 NMR (100 MHz, CDCl 3) d 13.1, 22.2, 26.0, 33.0, 37.1, 43.2, 46. 0.51.8, 52.9, 55.7, 113.6, 113.9, 117.1, 117.4, 122.3, 122.4, 126.1, 126.3, 142.7, 161.0, 172.6; MS (AP / CI) 452.5 (M + H) +.

EXAMPLE 42 3-r2- (4-Methyl-piperazin-1-yl) -benzin-1- (3-p, 3,41-oxadiazol-2-yl-phenyl) -pyrrolidin-2-one 3- [2- (4-Methyl-piperazin-1-yl) -benzyl] -1- (3- [1, 3,4] -oxadiazol-2-yl-phenyl) -pyrrolidin-2-one: C13 NMR (100 MHz, CDCI3) d 24.6, 32.6, 44.9, 46.1, 46.8, 52.7.53.0, 55.7, 112.4, 117.6, 120.9, 122.9, 123.2, 124.6, 127.8, 129.9, 130.5, 134.9, 140.6, 151.9, 152.9, 164.8 , 176.3; MS (AP / CI) 418.3 (M + H) +.

EXAMPLE 43 6 '- (1-Hydroxy-1-methyl-ethyl) -3-r2- (4-methyl-piperazin-1-yl) -benzipa-3,4,5,6-tetrahydro- [1, 3'1-bipyridinyl-2-one Hydroxy-l-methyl-ethyl-J-S - ^^ - methyl-piperazin-li-benzyl] -3,4,5,6-tetrahydro- [1,3 '] bipyridyl -2-one: C13 NMR (100 MHz, CDCI3) d 22.1, 25.8, 30.8, 30.9, 33.1, 43.2, 46.2, 51.7, 52.8, 55.9, 118.9, 120.8, 124.5, 127.5, 130.9, 135.0, 135.5, 138.6, 1 14.9, 152.2, 163.9, 173.4; MS (AP / CI) 423.4 (M + H) +. The enantiomers were separable by HPLC (70/30 heptanol / ethanol, Chiralpak AD, 10 cm x 50 cm 85 ml / minute, Approximate retention times: t1 = 1.8 minutes, t2 = 14.6 minutes.

EXAMPLE 44 3- [5-Fluoro-2- (4-methyl-piperazin-1-yl) -benzyl-1-rß- (1-hydroxy-1-methyl-ethyl) -pyridin-3-yl-1-pyrrolid N-2-one 3- [5-Fluoro-2- (4-methyl-piperazin-1-yl) -benzyl] -1- [6- (1-hydroxy-1-methyl-ethyl) -pyridin-3- il] -pyrrolidin-2-one: C13 NMR (100 MHz, CDCl 3) d 24.8, 30.8, 32.2, 44.3, 46.2, 53.1, 55.8, 71.9, 1 14.0, 1 14.2, 1 16.8; 117.0, 118.7, 122.4, 122.5, 128.3, 134.9, 137.3, 137.4, 138.1, 148.0, 148.1, 158.5, 160.9, 161.8, 176.0; MS (AP / CI) 464.3 (M + H) +. The enantiomers were separable by HPLC (85/15 heptane / isopropanol; Chiralcel AD, 10 cm x 50 cm; 85 ml / minute). Approximate retention times: t1 = 16.1 minutes; t2 = 18.0 minutes.

EXAMPLE 45 3-f2-Fluoro-β- (4-methyl-piperazin-1-tl) -bencW-1-fß- (1-hydroxy-1-methyl-ethyl) -pyridin-3-n-Pyrrolidin -2-one 3- [2-Fluoro-6- (4-methyl-p¡perazin-1-yl) -benzyl] -1- [6- (1-hydroxy-1-methylene-ethyl) -pyr Din-3-yl] -pyrrolidin-2-one: C 3 NMR (100 MHz, CDCl 3) d 24.9, 25.5, 30.8, 43.4, 46.2, 53.0, 55.6, 71.9, 111.5, 111.7, 116.7, 118.7, 122.3, 122.5, 128.1, 128.2, 134.9, 138.1, 153.8, 153.9, 160.9, 161.8, 163.3, 176.1; MS (AP / CI) 427.3 (M + H) +. The enantiomers were separable by HPLC (70/30 heptane / ethanol, Chiralpak AD, 10 cm x 50 cm, 250 ml / minute). Approximate retention times: t1 = 8.4 minutes; t2 = 12.9 minutes.

EXAMPLE 46 1-rß- (1-Hydroxy-1-methyl-etin-pyridin-3-yn-3-r 2 - (3,4,5-trimethyl-piperazin-1-yl) -benzin-pyrrolidin-2 -one 1- [6- (1-Hydroxy-1-methyl-ethyl) -pyridin-3-yl] -3- [2- (3,4,5-tr'methyl-piperazin-1-yl) - benzyl] -pyrrolidin-2-one: H1 NMR (400 MHz, CDCl3) d 1.10 (d, 3H, J = 6.4 Hz), 1.12 (d, 3H, J = 6.4 Hz), 1.54 (s, 6H), 1.86-1.95 (m, 1H), 2.07-2.15 (m, 1 H), 2.32 (s, 3H), 2.35-2.42 (m, 1 H), 2.62-2.68 (m, 1 H), 2.79 -2.85 (m, 2H), 2.90 (dt, 1 H, J = 1.2 and 2.4 Hz), 3.08 (ddd, 1 H, J = 14.4, 10.4, and 4.0 Hz), 3.86 (dd, 1H, J = 14.0 and 4.0 Hz), 3.68-3.73 (m, 2H), 7.04 (dt, IH, J = 7.6 and 1.2 Hz), 7.10-7.13 (m, 1h), 7.20-7.24 (m, 2H), 8.29 (dd, 1 H, J = 8.8 and 2.8 Hz), 8.59 (d, 1 H, J = 2.4 Hz); MS (AP / CI) 437.4 3 (M + H) +.

EXAMPLE 47 6 '- (1-Hydroxy-1-methyl-ethyl) -3-r 2 - (3,4,5-trimethyl-piperazin-1-yl) -bencip-3, 4,5,6 - tetrahydro-l, 3'1bi-pyridin-2-one 6 '- (1-Hydroxy-1-methyl-ethyl) -3- [2- (3,4,5-trimethyl-piperazin-1-yl) -benzyl] -3,4,5 , 6-tetrahydro- [1,3 '] bi-pyridinyl-2-one: C13 NMR (100 MHz, CDCl 3) d 18.1, 22.2, 25.8, 30.8, 33.1, 38.0, 43.3, 51.7, 58.8, 58.9, 60.3, 60.7, 72.0, 118.9, 120.6, 124.4, 127.5, 130.9, 135.0, 135.4, 138.6, 144.9, 151.8, 163.8, 173.4; MS (AP / CI) 451.3 (M + H) +.

EXAMPLE 48 3-r5-Fluoro-2- (3,4,5-trimethyl-piperazin-1-yl) -benzin-6 '- (1-hydroxy-1-methyl-ethyl) -3,4,5,6 -tetrahydro-n, 3 bipyridinyl-2-one 3- [5-Fluoro-2- (3,4,5-tr'methyl-piperazin-1-yl) -benzyl] -6 '- (1-hydroxy-1-methyl-ethyl) l) -3,4,5,6-tetrahydro- [1,3 '] - bipyridinium-2-one: C13 NMR (100 MHz, CDCl 3) d 18.0, 21.5, 22.2, 25.9, 30.8, 32.9 , 37.8, 43.2, 51.7, 58.9, 59.0, 60.6, 60.9, 72.0, 113.7, 113.9, 117.1, 118.9, 122.1, 122.2, 135.0, 1338.0, 138.1, 138.5, 144.9, 147.7, 158.5, 160.9, 164.0, 173.0; MS (AP / CI) 469.5 (M + H) +.

EXAMPLE 49 3-r5-Fluoro-2- (4-methyl-piperazin-1-yl) -benzyl-1-6 '- (1-hydroxy-1-methyl-ethyl) -3,4,5,6-tetrahydro- | , 3'1-bipyridinyl-2-one 3- [5-Fluoro-2- (4-methyl-piperazin-1-yl) -benzyl] -6 '- (1-hydroxy-1-methyl-ethyl) -3,4,5,6-tetrahydro- [ 1, 3 '] bipyridinyl-2-one: C13 NMR (100 MHz, CDCl 3) d 22.2, 25.8, 30.8, 32.8, 43.1, 46.2, 46.3, 51.6, 53.1, 55.8, 72.0, 113.7, 113.9, 117.0, 117.2, 118.9, 122.3, 122.4, 134.9, 138.1, 138.2, 138.4, 144.9, 148.2, 148.3, 160.9, 164.0, 173.0; MS (AP / CI) 441.5 (M + H) +. The enantiomers were separable by HPLC (50/50 heptane / ethanol with 1% TFA, Chiralpak AD, 5 cm x 50 cm, 100 ml / minute, Approximate retention times: t1 = 12.1 minutes, t2 = 16.1 minutes.

EXAMPLE 50 1 - | 4- (1-Hydroxy-cyclopentyl) -phenyl] -3-f2- (4-methyl-ri, 41-diazepan-1-yl) -benzyl] -pyrrolidin-2-one 1- [4- (1-Hydroxy-cyclopentyl) -phenyl] -3- [2- (4-methyl- [1,4] diazepan-1-yl) -benzyl] -pyrrolidin-2-one : H1 NMR (400 MHz, CDCl3) d 1.80-1.89 (m, 1 H), 1.96 (br s, 8H), 2.03-2.20 (m, 2H), 2.55-2.64 (m, 4H), 2.80-3.40 ( m, 10H), 3.50 (dd, J = 13.3, 2.9 Hz, 1 H), 3.71 (dd, J = 8.3, 5.6 Hz, 2H), 7.03 (dt, J = 7.3, 1.2 Hz, 1 H), 7.13 -7.22 (m, 3H), 7.48 (d, J = 9.1 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H); MS (AP / CI) 448.3 (M + H) +.

EXAMPLE 51 1 -f4- (1-Hydroxy-1-methyl-ethyl) -fenip-3-f2- (4-methyl-p, 41-diazepane-1-Q-benzyl-pyrrolidin-2-one) 1- [4- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- [2- (4-methyl- [1,4] diazepan-1-yl) -benzyl] - pyrrolidin-2-one: H1 NMR (400 MHz, CDCl3) d 1.55 (s, 6H), 1.80-1.88 (m, 1 H), 1. 97-2.11 (m, 3H), 2.44 (s, 3H), 2.68 (dd, J = 13.3, 10.6 Hz, 1 H), 2.75-2.90 (m, 4H), 2.95-3.25 (m, 5H), 3.45 (cid, J = 13.7, 3.7 Hz, 1 H), 3.68-3.72 (m, 2H), 6.99 (dt, J = 7.3, 1.2 Hz, 1 H) , 7.11-7.20 (m, 3H), 7.47 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8. 7 Hz, 2H); MS (AP / CI) 422.3 (M + H) +.

EXAMPLE 52 3-r2- (4-Ethyl-piperazin-1-yl) -benzyl-1-r4- (1-hydroxy-1-methyl-ethyl) -phenin-pyrrolidin-2-one 3- [2- (4-Ethyl-piperazin-1-yl) -bencll] -1- [4- (1-hydroxyl-1-methyl-ethyl) -phenyl] -pyrrolidin-2-one : H1 NMR (400 MHz, CDCl3) d 1.15-1.20 (m, 3H), 1.55 (s, 6H), 1. 77-1.87 (m, 1 H), 2.03-2.11 (m, 1 H), 2.30-2.90 (br m, 7H), 2.93-3.15 (m, 5H), 3.37 (dd, J = 13.3, 5.5 Hz, 1 H), 3.62-3.72 (m, 2H), 7.04 (dt, J = 7.5, 1.6 Hz, 1 H), 7.14 (dd, J = 7.9, 1.5 Hz, 1 H), 7.18-7.22 (m, 2H ), 7.47 (d, J = 9.1 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H); p.f. 135-137 ° C.

EXAMPLE 53 3-f2- (2.5-D-methyl-piperazin-1-di-benzyl-1-f4- (1-hydroxy-cyclopentyl) -phenyl-1-pyrrolidin-2-one) 3- [2- (2,5-D-methyl-piperazin-1-yl) -bendl] -1- [4- (1-hydroxy-cyclopentyl) -phenyl] -p Rrolidin-2-one: C13 NMR (100 MHz, CDCl 3) d 17.4, 19.5; 19.6, 24.0, 24.9, 31.1, 33.0, 42.0, 44.2, 45.2, 46.9, 47.0, 51.5, 51.6, 54.1, 54.3, 54.5, 83.1, 119.5, 123.4, 123.5, 125.2, 125.8, 127.2, 127.5, 129.8, 130.8, 137.3, 137.5, 138.3, 143.5, 143.6, 150.3, 150.4, 175.9, 176.0; MS (AP / CI) 448.4 (M + H) +.

EXAMPLE 54 General procedure for copper-mediated coupling A mixture of 3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 1 equivalent of the aryl bromide corresponding to the aryl group of the N-arylated product, iodide of copper (I) (0.1 equivalent), potassium carbonate (1.5 equivalents) and N.N'-dimethylethylenediamine (0.1 equivalent) in toluene (5 volumes) containing water (0.05-0.5 volumes) was stirred at reflux until a HPLC analysis showed the disappearance of the starting aryl bromide. The mixture was cooled to room temperature and filtered through a Celite® cartridge and washed with toluene. The filtrate was washed with water and the organic extracts were washed with brine and concentrated to provide the crude arylated product. The following compounds (Examples 55-64) were prepared using the same general procedure as in Example 62.

EXAMPLE 55 1-f6- (1-Ethyl-1-hydroxy-propyl) -pyridin-3-yl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one 1- [6- (1-Ethyl-1-hydroxy-propyl) -pyridin-3-yl] -3- [2- (4-methyl-p-piperazin-1-yl) -benzyl ] -pyrrolidin-2-one: C13 NMR (100 MHz, CDCl 3) d 176.5, 159.0, 152.0, 137.5, 134.9, 1 30.6, 128.2, 127.8, 124.6, 120.9, 1 19.6, 76.6, 55.9, 52.9, 46.3 , 44.6, 34.95, 34.89, 32.5, 24.8, 8.0; MS (AP / CII) 437.3 (M + H) +. The enantiomers were separable by HPLC (92/8 acetonitrile / methanol; Chiralpak AD, 10 cm x 50 cm; 275 ml / minute). Approximate retention times: t1 = 25 minutes; t2 = 50 minutes.

EXAMPLE 56 3-r2- (4-Methyl-piperazin-1-yl) -benzp-1-f6- (tetrahydro-pyran-4-yloxy) -pyridin-3-yl-pyrrolidin-2-one 3- [2- (4-Methyl-piperazin-1-yl) -benzyl] -1- [6- (tetrahydro-prann-4-yloxy) -pyridin-3-yl] -pyrrolidin-2-one: C13 NMR (100 MHz, CDCl 3) d 176.0, 159.9, 152.0, 137.8, 135.0, 132.0, 130.7, 130.5, 127.7, 124.6, 120.9, 111.6, 69.9, 65.8, 55.8, 52.8, 46.8, 46.2, 44.3, 32.5, 32.2 , 24.8; MS (AP / CI) 451.5 (M + H) +.

EXAMPLE 57 1 -f-d-Hydroxy-cyclopentyl) -pyridin-3-ill-3-f2- (4-methyl-piperazin-1-di-benzyl-pyrrolidin-2-one) 1- [6- (1-Hydroxy-cyclopentyl) -pyridin-3-yl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one: C13 NMR (100 MHz, CDCl 3) d 176.5, 160.7, 152.0, 138.1, 134.9, 130.5, 128.2, 127.8, 124.6, 120.9, 119.2, 82.9, 55.8, 46.4, 46.3, 44.5, 42.8, 32.5, 25.0, 24.8; MS (AP / CI) 435.5 (M + H) +.

EXAMPLE 58 1 - [4- (1-Hydroxy-cyclobutyl) -fenin-3-r2- (4-methyl-piperazin-1 -D-benzyl-pyrrolidin-2-one 1- [4- (1-Hydroxy-cyclobutyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one: C13 NMR (100 MHz, CDCI3) d 176.00, 152.08, 142.59, 138.82, 135.22, 130.54, 127.63, 125.79, 124.55, 120.83, 1 19.81, 76.76, 55.85, 52.84, 47.00, 46.27, 44.91, 37.20, 32.51, 24.70, 13.13; MS (AP / CI) 420.3 (M + H) +. The enantiomers were separable by HPLC (92/8 acetonitrile / methanol: Chiralpak AD, 10 cm x 50 cm, 275 ml / minute, Approximate retention times: t1 = 30 minutes, t2 = 49 minutes.

EXAMPLE 59 1-f5- (1-Hydroxy-1-methyl-ethyl) -pyridin-2-n-3-r2- (4-methyl-piperazin-1-yl) -benzyl-1-pyrrolidin-2 -one 1- [5- (1-Hydroxy-1-methyl-ethyl) -pyridin-2-yl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2- ona: C13 NMR (100 MHz, CDCl 3) d 176.7, 152.0, 150.8, 144.2, 140.3, 135.2, 134.6, 130.5, 127.7, 124.6, 120.9, 1 14.2, 71.2, 55.8, 52.7, 46 2, 45.8, 45.6, 32.5 , 31.9, 24.5; MS (AP / CI) 409.5 (M + H) +.

EXAMPLE 60 1-r 5 - (1-Hydroxy-cyclopentyl) -pyridin-2-yl-3-r 2 - (4-methyl-piperazin-1-yl) -benzyl-pyrrolidin-2-one 1- [5- (1-Hydroxy-cyclopentyl) -pyridin-2-yl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one: C13 NMR (100 MHz, CDCl 3) d 176.7, 152.0, 150.9, 144.7, 138.3, 135.22, 135.18, 130.5, 127.7, 124.6, 120.9, 114.2, 81.9, 55.8, 52.7, 46.2, 45.7, 45.6, 41.9, 32.5, 24.5 , 23.9; MS (APICI) 435.4 (M + H) +.

EXAMPLE 61 3-r2- (4-Methyl-p¡perazin-1-yl) -benzin-1- (4-oxazol-4-yl-phenyl) -piperidin-2-one 3- [2- (4-Methyl-piperazin-1-yl) -benzyl] -1- (4-oxazol-4-yl-pheny] -piperidin-2-one: C13 NMR (100 MHz, CDCl 3 ) d 22.2, 25.8, 33.0, 43.3, 46.3, 51.7, 52.9, 55.9, 120.7, 124.4, 126.4, 126.7, 127.7, 127.3, 129.0, 130.9, 134.0, 135.8, 140.1, 143.7, 151.5, 152.3, 173.0; MS (AP / CI) 431.3 (M + H) +.

EXAMPLE 62 3-r2- (4-Methyl-piperazin-1-yl) -benzyl-1- (4-pyrazol-1-yl-phenyl) -piperidin-2-one 3- [2- (4-Methyl-piperazin-1-yl) -benzyl] -1- (4-pyrazol-1-yl-phenyl) -piperidn-2-one: C13 NMR (100 MHz, CDCI3) d 22.2, 25.6, 25.8, 33.0, 43.3, 46.3, 51.8, 52.9, 55.9, 107.9, 119.9, 120.7, 124.4, 127.0, 127.3, 127.4, 130.4, 130.9, 135.8, 138.4, 141.3, 142.0, 152.3, 173.1; MS (AP / CI) 430.3 (M + H) +.

EXAMPLE 63 1-f4- (2-Methyl-oxazol-4-yl) -fenip-3-r2- (4-methyl-piperazin-1-yl) -benzyl-piperidin-2-one 1- [4- (2-Methyl-oxazol-4-yl) -phenyl] -3- [2- (4-methyl-p-piperazin-1-yl) -benzyl] -piperidin-2- ona: C13 NMR (100 MHz, CDCI3) d 14.2, 22.2, 25.8, 33.0, 43.3, 46.3, 51.7, 52.8, 55.9, 120.7, 124.4, 126.2, 126.6, 127.3, 129.5, 130.9, 133.4, 135.8, 143.3, 152.2 , 173.0; MS (AP / CI) 445.3 (M + H) +.

EXAMPLE 64 3-f2- (4-Methyl-p¡perazin-1-yl) -benzyl-1- (4-oxazol-5-yl-phenyl) -piperidin-2-one C 3 NMR (100 MHz, CDCl 3) d 22.2, 25.8, 29.9, 33.0, 43.3, 46.4, 51.6, 52.9, 55.9, 120.7, 121.7, 124.4, 125.2, 126.0, 126.8, 127.4, 130.9, 135.8, 144.0, 150.7, 152.4, 173.1; MS (AP / CI) 431.5 (M + H) +.

EXAMPLE 65 3-r2-f4-Methyl-p¡perazin-1-yl) -bencill-1-r4- (morpholine-4-carbonyl) -phen p-pyrrolidin-2-one Trimethyl aluminum (2 M in toluene, 700 μl, was added dropwise, 1. 4 mmol) was added to a solution of morpholine (124 μl, 1.4 mmol) in 1,2-dichloroethane (4 ml) at 0 ° C. After completing the addition, the cold bath was removed and the solution was stirred 30 minutes at 23 ° C. Then a solution of ethyl ester of acid 4 was added. { 3- [2- (4-methy1-piperazin-1-l) -benzyl] -2-oxo-pyrrolidi-1-yl} -benzoic acid (Example 2, 150 mg, 0.36 mol) in 1,2-dichloroethane (2 ml) and the solution was heated at 70 ° C for about 18 hours. The solution was cooled to room temperature, methanol was added carefully to inactivate the excess species of methyl aluminum and the mixture was then treated with sodium sulfate decahydrate (1.5 g). The mixture was stirred rapidly for 3 hours, the salts were separated by filtration, the solvent was removed in vacuo and the residue was purified by chromatography on silica gel (20: 1 chloroform: methanol by weight / 1% ammonium hydroxide) to provide 160 mg (96% yield) of the title compound. C13 NMR (100 MHz, CDCl 3) d 176.28, 170.23, 152.12, 141.26, 135.00, 130.88, 130.52, 128.25, 127.71, 124.54, 120.84, 1 19.35, 67.14, 67.09, 55.90, 54.36, 52.97, 46.81, 46.36, 44.91, 32.48, 24.58; MS (AP / CI) 463.2 (M + H) +. The enantiomers were separable by HPLC (60/40 heptane / ethanol, Chiralcel OJ, 10 cm x 50 cm, 27.5 ml / minute). Approximate retention times: t1 = 45 minutes, t2 = 60 minutes. The following compounds (examples 66-67) were prepared in an analogous manner.

EXAMPLE 66 1 -f4- (4-Methyl-piperazino-1 -carbonyl) -phenn-3-r2- (4-methyl-piperazin-1-yl) -benzin-pyrrolidin-2-one 1- [4- (4-Methyl-piperazino-1-carbonyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one: C13 NMR (100 MHz, CDCI3) d 176.24, 170.1 1, 152.03, 141.05, 135.03, 131.48, 130.54, 128.28, 127.71, 124.59, 120.86, 119.33, 77.52, 55.85, 55.21, 52.86, 46.83, 46.27, 44.91, 32.52, 24.62; MS (AP / CI) 476.2 (M + H) +.

EXAMPLE 67 3-f2- (4-Methyl-piperazin-1-yl) -benzyl] -1-F4- (piperidino-1-carbonyl) -phenyl-pyrrolidin-2-one 3- [2- (4-Methyl-piperazin-1-yl) -benzyl] -1- [4- (p -peridin-1-carbonyl) -phenyl] -pyrrolidin-2-one: C13 NMR (100 MHz, CDCI3) d 176.2, 170.1, 152.0, 140.8, 135.1, 132.3, 130.6, 128.0, 127.7, 124.6, 120.9, 119.3, 55.8, 52.8, 49.1, 46.9, 46.2, 44.9, 43.5, 32.5, 26.8, 25.9 , 24.8, 24.6; MS (AP / CI) 461.2 (M + H) +. The enantiomers will be separable by HPLC (5/95 acetonitrile / methanol, Chiralpak AD, 4.6 mmx 25 cm, 1 ml / minute). Retention times: t1 = 8.9 minutes; t2 = 19.1 minutes.

EXAMPLE 68 3- (2-Pyridin-4-yl-benzylidene) -pyrrolidin-2-one The title compound was prepared through a reaction between 2-pyridin-4-yl-benzaldehyde and N-acetylpyrrolidinone using the general procedure of aldoles 1. C C13 NMR (100 MHz, CDCl 3) d 172.6, 149.9, 148.5, 140.0, 133.7, 132.8, 130.3, 128.9, 128.7 , 128.4, 124.8, 40.0, 26.4; MS (AP / CI) 252.1 (M + H) +.

EXAMPLE 69 3- [2- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -benzylidene-1-pyrrolidin-2-one) A solution of 3- (2-pyridin-4-yl-benzylidene) -pyrrolidin-2-one (Example 77, 500 mg, 2 mmol) and methyl iodide (150 μL, 2.4 mmol) in acetonitrile (5 mL) was stirred at room temperature for 1 hour. Methanol (5 ml) was added to improve the solubility and then 10 equivalents of methyl iodide were added. The mixture was heated at 40 ° C for 18 h, then heated at 75 ° C for 18 hours. The solvent was removed in vacuo, methanol was added and the procedure was repeated three times (to remove methyl iodide). The residue was dissolved in methanol (20 ml), cooled to 0 ° C and sodium borohydride (151 mg, 4.0 mmol) was added in small portions. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo, water was added and the mixture was extracted with diethyl ether (5x). The organic layer was dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (50: 1 chloroform-methanol by weight / 1% ammonium hydroxide) to provide 313 mg (58% yield) of the title compound. C13 NMR (100 MHz, CDCl 3) d 172.9, 144.4, 135.8, 133.4, 130.9, 129.5, 128.8, 128.5, 128.3, 127.0, 126.1, 54.8, 52.2, 45.9, 40.0, 31.5, 26.5; MS (AP / CI) 269.2 (M + H) +.

EXAMPLE 70 3- [2- (1 -Met-1-piperidin-4-yl) -benzyl-pyrrolidin-2-one A mixture of 3- [2- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -benzylidene] -pyrrolidin-2-one (Example 78) (308 mg, 1.15 mmol ) and 10% palladium on carbon (300 mg) in methanol (20 ml) was placed under 3.4 atmospheres of hydrogen and heated at 50 ° C for 8 hours. The mixture was cooled to room temperature, filtered through Celite® and the solvent was removed in vacuo to provide 310 mg (99% yield) of the title compound. C13 NMR (100 MHz, CDCl 3) d 180.1, 144.5, 136.8, 129.9, 127.1, 126.6, 126.2, 56.7, 46.7, 42.7, 40.6, 37.2, 33.9, 33.6, 33.5, 27.7; MS (AP / CI) 273.2 (M + H) +. The compounds of Examples 70-73 were prepared from the corresponding N-arylated 3- (2-pyridin-4-yl-benzylodene) -pyrrolidin-2-one using nalalogic procedures to those used for the general conditions of palladium-mediated coupling of examples 1-55.

EXAMPLE 71 1-r4- (1-Hydroxy-cyclobutyl) -fenin-3-r2- (1-methyl-piperidin-4-yl) -bencip-pyrrolidin-2-one 1- [4- (1-Hydroxy-cyclobutyl) -phenyl] -3- [2- (1-methyl-p -peridin-4-yl) -benzyl] -pyrrolidin-2-one: C13 NMR (100 MHz, CDCI3) d 175.3, 144.4, 142.9, 138.6, 136.7, 130.0, 127.2, 126.8, 126.2, 125.8, 119.8, 76.6, 56.6, 46.9, 46.5, 45.4, 37.2, 34.0, 33.8, 33.3, 25.1, 13.2; MS (AP / CI) 419.3 (M + H) +.

EXAMPLE 72 1-r4- (1-Hydroxy-cyclohexyl) -fenin-3-r2- (1-methyl-piperidin-4-yl) -benzyl-1-pyrrolidin-2-one 1- [4- (1-Hydroxy-cyclohexyl) -phenyl] -3- [2- (1-methyl-piperidin-4-yl) -benzyl] -pyrrolidin-2-one: C13 NMR (100 MHz, CDCl 3) d 175.3, 146.0, 144.4, 138.1, 136.7, 130.0, 127.2, 126.8, 126.2, 125.4, 119.6, 73.1, 56.6, 46.9, 46.6, 45.4, 37.2, 34.0, 33.8, 33.3, 25.72, 25.1, 22.4; MS (AP / CI) 447.3 (M + H) +, 429.3 (M + H-H20) +.

EXAMPLE 73 1-r4- (1-Hldroxy-1-methyl-etin-phenin-3-r2- (1-methyl-piperidin-4-yl) -benzyl-pyrrolidin-2-one 1- [4- (1-Hldroxy-1-methyl-etl) -phenyl] -3- [2- (1-methyl-piperidin-4-yl) -benzyl] -pyrrolidine -2-one: C13 NMR (100 MHz, CDCI3) d 175.3, 145.7, 144.4, 138.2, 126.7, 130.0, 127.2, 126.8, 126.2, 125.2, 119.7, 72.4, 56.6, 46.9, 46.6, 45.4, 37.2, 34.0, 33.8, 33.3, 25.1; MS (AP / CI) 407.3 (M + H) +, 389.3 (M + H-H20) +.

EXAMPLE 74 1- [4- (1-Hydroxy-cyclopentyl) -phenyl] -3- [2- (1-methyl-piperidin-4-yl) -benzyl] -pyrrolidin-2-one: C13 NMR (100 MHz, CDCI3) d 175.3, 144.4, 143.6, 138.3, 136.7, 130. 0, 127.2, 126.8, 126.2, 125.8, 119.7, 56.6, 46.9, 46.6, 45.4, 42.1, 37.2, 34.0, 33.8, 33.3, 25.1, 24.0; MS (AP / CI) 433.3 (M + H) +, 415.3 (M + H-H20) +.

Claims (17)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula I wherein R1 is a group of formula G1 or G2 described below,

G G2 a is zero to eight; m is one to three; R is selected from the group consisting of hydrogen, (C -? - C6) alkyl optionally substituted with (CrC6) alkoxy or one to three fluorine atoms, or (C1-C) alkyl-aryl wherein the aryl portion is phenyl, naphthyl or heteroaryl- (CH) q-, wherein the heteroaryl portion is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzizoxazolyl and benzisothiazolyl and q is zero, one, two, three or four , and wherein said aryl and heteroaryl moieties may be optionally substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, (C- | -C6) alkyl, (d-C6) alkoxy ), trifluoromethyl, cyano and -SOr alkylCalk C), where t is zero, one or two; each R 13 is, independently, (C C 4) alkyl or an alkylene bridge (C 1 -C 4) of one of the ring carbon atoms of the piperazino or piperidino ring of G 1 or G 2, respectively, at the same or another atom of carbon of the ring or to an annular nitrogen atom of the piperazino or piperidino ring of G1 or G2, respectively, having an available binding site, or to a carbon atom of the ring of R6, when R6 has an annular structure having a ring available union; X is hydrogen, chlorine, fluorine, bromine, iodine, cyano, alkyl of (C Ce), hydroxy, alkoxy of (CrC ^, -SOt-alkyl (C C6) where t is zero, one or two, -C02R1 ° or -CONR11R12; each of R10, R11 and R12 is independently selected from hydrogen, (C -? - C4) alkyl, phenyl and naphthyl, wherein said phenyl or naphthyl may be optionally substituted with one or more substituents independently selected from chlorine, fluorine, bromine, iodine, alkyl of (CrC6), alkoxy of (C? -C6), trifluoromethyl, cyano and -SOt-alkyl (C? -C6), where t is zero, one or two; or R11 and R12, together with the nitrogen atom to which they are attached, form a 5 to 7 membered heteroalkyl ring which may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; R3 is - (CH2) gB, wherein g is zero to three and B is hydrogen, phenyl, naphthyl or a 5- to 6-membered heteroaryl ring containing from one to four heteroatoms in the ring selected from oxygen, trogen and sulfur, with the proviso that said ring can not contain two adjacent oxygen atoms nor two adjacent sulfur atoms and wherein each of the above rings of phenyl, naphthyl and heteroaryl can be optionally substituted with one to three substituents independently selected from hydroxyalkyl of (C -? - C8), (C? - C8) alkoxy - (C? - 8) alkyl, hydroxy - cycloalkyl (C3 - C8), (C3 - C8) cycloalkoxy, (C? - alkoxy) C8) -cycloalkyl (C3-C8), heterocycloalkyl, hydroxyheterocycloalkyl and alkoxy (CrC8) -heterocycloalkyl, wherein each of said cycloalkyl (C3-C8) or heterocycloalkyl portions can be independently substituted with one to three alkyl groups of (C? -C6) or benzyl; when B is a phenyl, naphthyl or heteroaryl ring, each of said rings may be optionally substituted with one to three substituents independently selected from phenyl, naphthyl and a 5- to 6-membered heteroaryl ring containing from one to four selected heteroatoms between oxygen, nitrogen and sulfur, with the proviso that said heteroaryl ring can not contain two adjacent oxygen atoms or two adjacent sulfur atoms, and wherein each independently selected phenyl, naphthyl or heteroaryl substituent can be substituted by itself with one to three alkyl substituents of (C 8) or C 3 -C 8 cycloalkyl; or when B is a phenyl, naphthyl or heteroaryl ring, each of said rings may be optionally substituted with one to three substituents independently selected from (a) a lactone formed from - (CH2) tOH with an ortho-COOH, where t is one, two or three; (b) -CONR1 R15, wherein R14 and R15 are independently selected from alkyl of (C Cs) and benzyl, or R14 and R15 together with the nitrogen atom to which they are attached form a heteroalkyl ring of 5-7 members which may contain from zero to three heteroatoms selected from nitrogen, sulfur and oxygen in addition to the nitrogen atom of the group -CONR14R15, wherein when any of said heteroatoms is nitrogen, it may be optionally substituted with (C? -8) alkyl or benzyl, with the proviso that said ring can not contain two adjacent oxygen atoms or two adjacent sulfur atoms; (c) - (CH2) vNCOR16R17 wherein v is zero, one, two or three and -COR16 and R17 taken together with the nitrogen atom to which they are attached form a lactam ring of 4 to 6 members; and (d) - (d-C8) NR 8 R19 wherein each of R18 and R19 is independently selected from hydrogen and (C4) alkyl, or R8 and R19, together with the nitrogen atom to which they are attached. united, they form a 4- to 7-membered heteroalkyl ring which may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; where the flashing lines indicate optional double links; n is one, two, or three; and a pharmaceutically acceptable salt or pharmaceutically acceptable isomer thereof. 2 - The compound according to claim 1, further characterized in that R 3 is (CH 2) g B wherein g is zero and B is selected from phenyl and pyridyl.

3. The compound according to claim 2, further characterized in that said cycloalkyl portion of (C3-C8) of said hydroxy-cycloalkyl substituent of (C3-C8), (C3-C8) cycloalkoxy or alkoxy (Cr C8) -cycloalkyl (C3-C8) is selected from cyclobutyl, cyclopentyl and cyclohexyl.

4. The compound according to claim 2, further characterized in that said heterocycloalkyl portion having 4 to 8 atoms, said one to three optional substituents, is selected from tetrahydropyranyl, morpholinyl, azetidyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, hexahydroazepinyl, diazepinyl, oxazepinyl, thiazepinyl, oxetanyl and tetrahydrofuranyl.

5. The compound according to claim 2, further characterized in that said heteroaryl ring of 5 to 6 members of said one to three optional substituents is selected from pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazole and oxadiazolyl.

6. The compound according to claim 2, further characterized in that said groups R14 and R15 of said substituent - CONR14R15 together with the nitrogen atom to which they are attached form a 6-membered heteroalkyl ring selected from piperidino, N-alkyl ( C0- C6) -piperazine and morpholino.

7. The compound according to claim 2, further characterized in that said groups -COR16 and R17 of said substituent - (CH2) vNCOR16R17 together with the nitrogen atom to which they are attached form a 5- or 6-membered lactam ring, and v is 1.

8. The compound according to claim 2, further characterized in that a lactone is formed from said substituent -CH OH, with said ortho-COOH substituent.

9. The compound according to claim 1, further characterized in that R6 is selected from hydrogen, methyl, ethyl and benzyl, R13 is methyl, X is fluorine, methyl or methoxy, a is 1 or 2, m is 1 or 2 and n is 1 or 2.

10. The compound according to claim 1, further characterized in that it is selected from the group consisting of: 3- [5-Fluoro-2- (4-methyl-piperazin-1- il) -benzyl] -1- [4- (1-hydroxy-1-methyl-ethyl) -phenyl] -pyrrolidin-2-one, 3- [2- (4-Methyl-piperazin-1-yl) -benzyl] ] -1- (6-morfoyl-4-yl-pyridin-3-yl) -pyrrolidin-2-one, 1- [4- (1-Hydroxy-1-methyl-ethyl) -phenyl] - 3- [2- (4-Methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 3- [2- (4-Methyl-piperazin-1-yl) -benzyl-1 - (4-morpholin-4-yl-phenol) -pyrrolidin-2-one, 1- [4- (1-Hydroxy-cyclopentyl) -phenyl] -3- [2- (4-methyl) -piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 1- (4- (1-Hydroxy-cyclohexyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) - benzyl] -pyrrolidin-2-one, 1- (4- [1-Ethyl-1-hydroxy-propyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] - pyrrolidin-2-one, 1- [3- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] - pyrrolidin-2-one, 1- [4- (2-Hydroxy-2-methyl-propyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl ] -pyrrolidin-2-one, 1 - [6- [1-Hydroxy-1-methyl-ethyl) -pyridin-3-yl] -3- [2- (4-methyl-piperazin-1-yl) ) -benzyl] -pyrrolidin-2-one, 1- [4- (1-Methoxy-1-methyl-ethyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benz l] -pyrrolidin-2-one, 1 - [4- (2-Methoxy-2-methyl-propyl) -phenyl] -3- [2- (4-methyl-piperazine-1-yl) -benzyl] -pyrrolidin-2-one, 1- [4- (1-Methoxy-cyclobutyl) -phenyl] -3- [2- (4-methy-p-piperazine-1) -yl) -benzyl] -pyrrolidin-2-one, 3- [2- (4-Met.l.p.-piperazin-1-yl) -benzyl] -1- (4-pyridin-4-yl- phenyl) -pyrrolidin-2-one, 1- [4- (1-Hydroxy-cyclopentyl) -phenyl] -3- (2-piperazin-1-yl-benzyl) -pyrrolidin-2-one, 1- [ 4- (1-Hydroxy-cyclobutyl) -phenyl] -3- (2-piperazin-1-yl-benzyl) -pyrrolidin-2-one, 1- [4- (1-Hydroxy-) cyclohexyl) -phenyl] -3- (2-piperazin-1-yl-benzyl) -pyrrolidin-2-one, 1- [4- (1-Ethyl-1-h -droxy-propyl) -phen l] -3- (2-piperazin-1-i l-benzyl) -pyrrolidin-2-one, 1- [4- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- (2-pyridin-1-yl-benz L) -pyrrolidin-2-one, 1- [4- (1-Hydroxy-1-methyl-ethyl] -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzylidene] -pyrrolidin-2-one, 1 [4- (1-Hydroxy-cyclopentyl) -phenyl] -3- [5-methyl-2- (4-methyl-p-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 1- [4- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- [5-methyl-2- (4- methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 3- [5-Fluoro-2- (4-methyl-piperazin-1-yl) -benzyl] -1 - [4- (1-hydroxy-cyclopentyl) -phenyl] -pyrrolidin-2-one, 1- [4- (1-Hydroxy-cyclopentyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -piperidin-2-one, 1- [4- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- [2- (4 -met.lp.perazin-1-yl) -benzyl] -p.peridin-2-one, 1- [4- (1-Hydroxy-1-methyl-ethyl) - phenyl] -3- [5-methoxy-2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 1- [4- (1-Hydroxy-cyclopentyl) l) -phenyl] -3- [5-methoxy-2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 3- [2-Fluoro-6-] (4-methyl-piperazin-1-yl) -benzyl] -1- [4- (1-hydroxyl) -cyclopentyl) -phenyl] -pyrrolidin-2-one, 1- [4- (1-Hydroxy-cyclopentyl) -phenyl] -3- [2- (3,4,5-trimethyl- pperazin-1-yl) -bencll] -pyridin-idin-2-one, 1- [4- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- [2- (3,4,5-trimethy1-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 1- [4- (4-Hydroxy-tetrahydro-pyran-4-yl) ) -phenyl] -3- [2- (3,4,5-tr'methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 1- [4- (4 -H-hydroxy-tetrahydro-pyran-4-yl) -phenyl] -3- [2- (4-methyl-p-piperazin-1-yl) -benzyl] -piperidin-2-one, 1- [ 4- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- [2- (3,4,5-trimethyl-piperazin-1-yl) -benzyl) -piperdin-2-one, 1- [4- (1-Hydroxy-cyclopentyl) -phenyl] -3- [2- (3,4,5-trimethyl-p-piperazin-1-yl) -benzyl] -p, per-dinate 2-one, 3- [5-Fluoro-2- (3,4,5-tr'methyl-piperazin-1-yl) -benzyl] -1- [4- (1-hydroxy-1- methyl-ethyl) -phenyl] -p, pyridn-2-one, 3- [5-Fluoro-2- (3,4,5-tr'met-piperazin-1-) L) -bencll] -1- [4- (1-hydroxy-cyclopentyl) -phenyl] -piperidin-2-one, 3- [2- (4-Methyl-piperazin-1-l) -benz L] -1- [4- (2-Oxo-pyrrolidin-1-ylmethyl) -phenyl] -p-per-d-n-2- ona, 3- [2- (4-Methyl-piperazin-1-yl) -benzyl] -1 - (3-0X0-1, 3-dihydro-isobenzofuran-5-yl) -p¡perdin-2 -one, 3- [5-Fluoro-2- (4-methyl-piperazin-1-yl) -benzyl] -1- [4- (1-hldroxy-cyclobutyl) -phenyl] - piper¡d¡n-2-one, 3- [2- (4-Methyl-piperazin-1-yl) -benzyl] -1- (3- [1, 3,4] -oxadiazol-2-yl-phenyl) -pyrrolidin-2-one , 6 '- (1-Hydroxy-1-methyl-ethyl) -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -3,4,5,6-tetrahydro- [1, 3 '] bipyridin-2-one, 3- [5-Fluoro-2- (4-methyl-piperazin-1-yl) -benzl] -1- [6- (1-Hydroxy-1-methyl-ethyl) -pyridin-3-yl] -pyrrolidin-2-one, 3- [2-Fluoro-6- (4-methyl-piperazin-1-yl); l) -benzyl] -1- [6- (1-hydroxy-1-methyl-ethyl) -pyridin-3-yl] -pyrrolidin-2-one, 1- [6- (1- Hydroxy-1-methyl-ethyl) -pyridin-3-yl] -3- [2- (3,4,5-trimethyl-piperazin-1-l) -benzyl] -p rrolidin-2-one, e'-l-Hydroxy-l-methyl-eti -S- ^ S ^ .d -trimethyl-piperazin-l-yl) -benzyl] -3,4,5,6-tetrahydro - [1, 3 '] bi-pyridyl-2-one, 3- [5-Fluoro-2- (3,4,5-trimethyl-p-piperazin-1-yl) -benzyl] -6 '- (1-hydroxy-1-methyl-ethyl) -3,4,5,6-tetrahydro- [1,3'] - bipyridinyl-2-one, 3- [5-Fluoro-2 - (4-methyl-piperazin-1-yl) -benzyl] -6 '- (1-hydroxy-1-methyl-ethyl) -3,4,5,6-tetrahydro- [1 , 3 '] bipyridinyl-2-one, 1- [4- (1-Hldroxy-cyclopentyl) -phenyl] -3- (2- (4-methyl- [1,4] dlazepan-1-yl) -benzyl] -pyrrolidin-2-one, 1- [4- (1-Hydroxy-1-methyl-ethyl] -phenyl] -3- [2- (4-methyl- [1,4] ] diazepan-1-yl) -benzyl] -pyrrolidin-2-one, 3- [2- (4-Ethyl-piperazin-1-yl) -benzyl] -1- [4- (1-hydroxy) 1-methyl-ethyl) -phenyl] -pyrrolidin-2-one, 3- [2- (2,5-D-methyl-piperazin-1-yl) -benzyl] -1- [ 4- (1-hydroxy-cyclopentyl) -phenyl] -pyrrolidin-2-one, 1- [6- (1-Ethyl-1-hydroxy-propyl) -p Ridin-3-yl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 1- [6- (1-Hydroxy-cyclopentyl) ) -pyridin-3-yl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 1- [4- (1-H) droxy-cyclobutyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 1- [5- (1-Hydroxy-1-methyl) l-ethyl) -pyridin-2-yl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 1- [5- (1-Hydroxy) cyclopentyl) -pyridin-2-yl] -3- [2- (4-methyl-p-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 3- [2- (4- Methyl-piperazin-1-yl) -benzyl] -1- (4-oxazol-4-yl-phenyl) -p -peridin-2-one, 3- [2- (4-Methyl-piperazin-1- il) -benzyl] -1- (4-pyrazol-1-yl-phenyl) -piperdin-2-one, 1- [4- (2-Methyl-oxazol-4-yl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -piperdin-2-one, 3- [2 - (4-Methyl-pperazin-1-yl) -benzyl] -1- (4-oxazol-5-yl-phenyl) -piperidin-2-one, 3- [2- ( 4-Methyl-piperazin-1-yl) -benzyl] -1- [4- (morpholin-4-carbonyl) -phenyl] -pyrrolidin-2-one, 1- [4- (4-Met. 1-piperazino-1-carbonyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, 3- [2- (4-Methyl- piperazin-1-yl) -benzyl] -1- [4- (piperidin-1-carbonyl) -phenyl] -pyrrolidin-2-one, and its pharmaceutically acceptable salts and optical isomers acceptable

11. The compound according to claim 1, further characterized in that it is selected from the group consisting of: (R) -3- [5-Fluoro-2- (4-methyl-piperazin-1-yl) - benzyl] -1- [4- (1-hydroxy-1-methyl-ethyl) -phenyl] -pyrrolidin-2-one, (R) -3- [2- (4-Methyl-p-piperazin-1- L) -benzyl] -1- (6-morpholin-4-yl-pyridin-3-yl) -pyrrolidin-2-one, (R) -1- [4- (1-Hydroxy) 1-methylene-3-phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, (R) -3- [2- ( 4-Methyl-piperazin-1-yl) -benzyl] -1- (4-morpholin-4-yl-phenyl) -pyrrolidin-2-one, (R) -1- [4- (1-Hydroxy) cyclopentyl) -phenyl] -3- [2- (4-methyl-p-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, (R) -1- [4- ( 1-Hydroxy-cyclohexyl) -phenyl-3- [2- (4-methyl-piperazin-1-yl) -benzyl] pyrrolidin-2-one, (R) -1- [4- (1- Ethyl-1-hydroxy-propyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, (R) -1- [ 3- (1-Hydroxy-1-methylene-ethyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidine -2-one, (R) -1- [4- (2-Hydroxy-2-methyl-propyl) -phenyl] -3- [2- (4-methyl-p-piperazin-1-yl) ) -benzyl] -pyrrolidin-2-one, (R) -1- [6- (1-Hydroxy-1-methylene-ethyl) -pyridin-3-yl] -3- [2- (4-Methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, (R) -3- [5-Fluoro-2- (4-methyl-piperazin-1-yl ) -benzyl] -1- [4- (1-hydroxy-cyclopentyl) -phenyl] -pyrrolidin-2-one, (R) -1- [4- (1-Hydroxy-cyclopentyl) ) -fenl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -piperidin-2-one, (R) -1- [4- (1-Hydrox) -1-methyl-ethyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -p -peridin-2-one, (R) - 1- [4- (4-Hydroxy-tetrahydro-pyran-4-yl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -p.perid N-2-one, (R) -1- [6- (1-Hydroxy-1-methyl-etl) -3- [2- (4-methyl-piperazin-1-yl) -benzyl ] -piperidin-2-one, (R) -3- [5-Fluoro-2- (4-methyl-piperazin-1-yl) -benzyl] -1 - [6- (1-hydroxy-1-methyl-et-1) -p Rdin-3-yl] -pyrrolidin-2-one, (R) -3- [2-Fluoro-6- (4-methyl-piperazin-1-yl) -benzyl] -1- [6 - (1-hydroxy-1-methyl-ethyl) -pyridin-3-yl] -pyrrolidin-2-one, (R) -1- [6- (1-Hydroxy-1- methyl-ethyl) -pyridin-3-yl] -3- [2- (3,4,5-trimethyl-p-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, (R ) -3- [5-Fluoro-2- (4-methyl-piperazin-1-yl) -benzyl] -6 '- (1-hydroxy-1-methyl-ethyl) -3,4, 5,6-tetrahydro- [1,3 '] bipyridinyl-2-one, (R) -1- [6- (1-Ethyl-1-hydroxy-propyl) -pyridin-3-yl] - 3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, (R) -1 - [4- (1-Hydroxy-cyclobutyl) -phenyl) ] -3- [2- (4-methy1-piperazin-1-yl) -bencll] -pyrrolidin-2-one, (R) -3- [2- (4-Methyl-p, perazin-1-yl) -bencll] -1- [4- (p.peridino-1-carbonyl) -phenyl] -pyrrolidin-2-one, (S) - 3- [5-Fluoro-2- (4-methyl-piperazin-1-yl) -benzyl] -1- [4- (1-hydroxy-1-methyl-ethyl) -phenyl] -pyrrolidine -2-one, (S) -3- [2- (4-Methyl-piperazin-1-yl) -benzyl] -1- (6-morpholin-4-yl-pyridin-3-yl) -pyrrolidin-2-one, (S) -1- [4- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -bencll] -pyrrolidin-2 ona, (S) -3- [2- (4-Methyl-piperazin-1-l) -benzyl] -1- (4-morpholin-4-yl-phenyl) -pyrrolidin-2 -one, (S) -1- [4- (1-Hydroxy-cyclopentyl) -phenyl] -3- [2- (4-methyl-plperazin-1-yl) -benzyl] -pyrrolidin-2-one, ( S) -1- [4- (1-Hydroxy-cyclohexyl) -phenyl] -3- [2- (4-methyl-piperazin-1-l) -benzyl] -pyrrolidin-2-one, (S) -1- [4- (1-Ethyl-1-hydroxy-propyl) -fenii] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin- 2-one, (S) -1- [3- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- [2- (4-methyl-p-piperazin-1-yl) -benzyl ] -pyrrolidin-2-one, (S) -1- [4- (2-Hydroxy-2-methyl-propyl) -phenyl] -3- [2- (4-methyl-piperazine-1 - il) -benzyl] -pyrrolidin-2-one, (S) -1- [6- (1-Hydroxy-1-methyl-ethyl) -pyridin-3-yl] -3- [2 - (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, (S) -3- [5-Fluoro-2- (4-methyl-piperazin-1-yl) ) -benzyl] -1 - [4- (1-hydroxy-cyclopentyl) -phenyl] -pyrrolidin-2-one, (S) -1- [4- (1 -H-hydroxy-cyclopentyl) -phenyl] -3- [2- (4-methy-piperazin-1-yl) -benzyl] -piper id-2-one, (S) -1- [4- (1-Hydroxy-1-methyl-ethyl) -phenyl] -3- [2- (4-methyl-piperazin-1) -yl) -benzyl] -piperidn-2-one, (S) -1- [4- (4-Hydroxy-tetrahydro-pyran-4-yl) -phenyl] -3- [2- (4 -methyl-piperazin-1-yl) -benzyl] -p, peridn-2-one, (S) -1- [6- (1-Hydroxy-1-methyl-etl) -3- [2- (4-methyl-piperazin-1-yl) -benzyl] piperidin-2-one, (S) -3- [5-Fluoro-2- (4-methyl-p-piperazin- 1-yl) -benzyl] -1- [6- (1-hydroxy-1-methyl-ethyl) -pyridin-3-yl] -pyrrolidin-2-one, (S) -3- [2 -Fluoro-6- (4-methyl-piperazin-1-yl) -benzyl] -1- [6- (1-hydroxy-1-methyl-ethyl) -pyridin-3- il] -pyrrolidin-2-one, (S) -1- [6- (1-Hydroxy-1-methyl-ethyl) -pyridin-3-yl] -3- [2- (3,4,5 -trimethyl-piperazin-1-l) -benzyl] -pyrrolidin-2-one, (S) -3- [5-Fluoro-2- (4-methyl-piperazin-1- il) -benzyl] -6 '- (1-hydroxy-1-methyl-ethyl) pyridin-3-yl] pyridin-2-one, (S) -1- [6- (1-Ethyl-1-hydroxy-propyl) -pyridin-3-yl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, (S ) -1- [4- (1-Hydroxy-cyclobutyl) -phenyl] -3- [2- (4-methyl-piperazin-1-yl) -benzyl] -pyrrolidin-2-one, (S) - 3- [2- (4-Meti l-Piperazin-1-yl) -benzyl] -1- [4- (piperidino-1 -carbonyl) -phenyl] -pyrrolidin-2-one, and its pharmaceutically acceptable salts.

12. A pharmaceutical composition for use in the treatment of a disorder or condition in a mammal selected from depression, anxiety, depression with concomitant anxiety, dysthymia, post-traumatic stress disorder, panic, phobias, obsessive-compulsive disorder (OCD) , OCD with co-morbid Tourette syndrome, borderline personality disorder, sleep disorders, psychosis, attacks, dyskinesias, symptoms of Huntington's or Parkinson's disease, spasticity, suppression of seizures resulting from epilepsy, cerebral ischemia, anorexia, attacks with fainting, hypokinesia, cranial traumas, chemical dependencies, premature ejaculation, mood and appetite disorders associated with premenstrual syndrome (PMS), intestinal inflammation disease, modification of eating behavior, carbohydrate blocking apathetic, luteal phase dysphoric disorder late, symptoms associated with quitting, p disorder nico, bipolar disorder, sleep disorders, hourly discomfort, cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, chemical dependencies and addictions selected among dependencies or addictions to nicotine or tobacco products, alcohol, benzodiazepines, barbiturates, opiates or cocaine; ludopathies; trichotillomania; migraine, stroke, traumatic brain injury (TBI), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, dementia due to multiple infarctions, epilepsy, senile dementia of Alzheimer's type (AD), Parkinson's disease (PD), disorder of attention deficit hyperactivity disorder (ADHD) and Tourette syndrome, which comprises an amount of a compound according to any of claims 1 to 11, or a pharmaceutically acceptable salt thereof, which is effective to treat said disorder or condition and a pharmaceutically acceptable vehicle.

13. The use of a compound according to any of claims 1 to 11, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder or condition in a mammal selected from depression, anxiety, depression with concomitant anxiety, dysthymia, post-traumatic stress disorder, panic, phobias, obsessive-compulsive disorder (OCD), OCD with co-morbid Tourette syndrome, borderline personality disorder, sleep disorders, psychosis, seizures, dyskinesias, symptoms of diseases of Huntington or Parkinson, spasticity, suppression of attacks resulting from epilepsy, cerebral ischemia, anorexia, attacks with fainting, hypokinesia, cranial traumas, chemical dependencies, premature ejaculation, mood and appetite disorders associated with premenstrual syndrome (PMS) , disease of intestinal inflammation, modification of feeding behavior, carcinogenicity bohydrates, dysphoric disorder of late luteal phase, symptoms associated with smoking cessation, panic disorder, bipolar disorder, sleep disorders, hourly discomfort, cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, chemical dependencies and selected addictions among dependencies or addictions to nicotine or tobacco products, alcohol, benzodiazepines, barbiturates, opiates or cocaine; ludopatlas; trichotillomania; migraine, stroke, traumatic brain injury (TBI), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, dementia due to multiple infarctions, epilepsy, senile dementia of Alzheimer's type (AD), Parkinson's disease (PD), disorder of hyperactivity due to attention deficit (ADHD) and Tourette syndrome.

14. A process for preparing a compound having the formula IA ': where a is zero to eight, m is one to three; R is selected from the group consisting of hydrogen, (CrCß) alkyl optionally substituted with (CrC6) alkoxy or one to three fluorine atoms, or (alkyl (CrC)) - aryl wherein the aryl portion is phenyl, naphthyl or heteroaryl- (CH2) q-, wherein the heteroaryl portion is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzizoxazolyl and benzisothiazolyl and q is zero, one, two, three or four, and wherein said portions aryl and heteroaryl may be optionally substituted with one or more substituents independently selected from the group consisting of chlorine, fluorine, bromine, iodine, (CrCß) alkyl, (d-Cß) alkoxy, trifluoromethyl, cyano and -SOt-alkyl (C C6), where t is zero, one or two; each R 13 is, independently, alkyl of (CrC) or an alkylene bridge (CC) of one of the ring carbon atoms of the piperazine ring or piperidine of G1 or G2, respectively, at the same or another carbon atom of the ring or a nitrogen atom of the piperazine or piperidine ring ring of G1 or G2, respectively, having an available binding site, or a carbon atom of the ring of R6, when R6 has a ring structure having a ring available union; X is hydrogen, chlorine, fluorine, bromine, iodine, cyano, alkyl of (CrC6), hydroxy, alkoxy of (CrC6), -SOt-alkyl (CrC6) where t is zero, one or two, -C02R10 or -CONR11R12; each of R10, R11 and R12 is independently selected from hydrogen, (CrC4) alkyl, phenyl and naphthyl, wherein said phenyl or naphthyl may be optionally substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, alkyl (CrCe), alkoxy of (CrC6), trifluoromethyl, cyano and -SOt-alkyl (CrCe), where t is zero, one or two; or R11 and R12, together with the nitrogen atom to which they are attached, form a 5 to 7 membered heteroalkyl ring which may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; R3 is optionally substituted aryl or heteroaryl; and n is one, two or three; or a pharmaceutically acceptable salt or pharmaceutically acceptable isomer thereof; which comprises (a) preparing a compound having the formula 1 B ': wherein a, n, m, X R6 and R13 are as defined above; and (b) treating the compound prepared in step (a) with hydrogen gas in a solvent inert to the reaction selected from the group consisting of a lower alcohol, THF, dioxane, ethyl acetate, methanol or ethanol, in the presence of a noble metal catalyst on a solid support selected from the group consisting of palladium on carbon (Pd / C), palladium on barium sulfate (Pd / BaS04), platinum on carbon (Pt / C), tris (triphenylphosphine), rhodium chloride (Wilkinson's catalyst) and 10% palladium on carbon, at a pressure of about 1 to about 5 atmospheres, preferably about 3 to about 4 atmospheres, at a temperature of about 10 ° C to about 100 ° C, under suitable conditions to form the compound having the formula 1A; or treating the compound prepared in step (a) under hydrogenation transfer conditions with a hydride donor selected from the group consisting of cyclohexadiene and ammonium formate, in an inert solvent for the reaction selected from a lower alcohol, THF, dioxane, ethyl acetate, methanol and ethanol, in the presence of a noble metal catalyst on a solid support selected from the group consisting of palladium on carbon (Pd / C), palladium on barium sulfate (Pd / BaS0), platinum on carbon (Pt C), tris (triphenylphosphine) rhodium chloride (Wilkinson's catalyst) and 10% palladium on carbon, at a temperature of about 20 ° C to about 150 ° C, under suitable conditions to form the compound having the formula 1A '.

15. - A process for preparing a compound having the formula 1 B ': where a is zero to eight; m is one to three; R6 is selected from the group consisting of hydrogen, (d-Cß) alkyl optionally substituted with (CrCe) alkoxy or one to three fluorine atoms, or (alkyl (CrC)) -aryl wherein the aryl portion is phenyl , naphthyl or heteroaryl- (CH2) q-, wherein the heteroaryl portion is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzizoxazolyl and bencisothiazole and q is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may be optionally substituted with one or more substituents independently selected from the group consisting of chlorine, fluorine, bromine, iodine, (CrCß) alkyl, (d-Cß) alkoxy, trifluoromethyl, cyano and -SOr alkyl (CrCe), where t is zero, one or two; each R13 is, independently, alkyl of (CrC) or an alkylene bridge (CrC4) of one of the ring carbon atoms of the piperazino or piperidino ring of G1 or G2, respectively, at the same or another carbon atom of the ring or an annular nitrogen atom of the piperazino or piperidino ring of G1 or G2, respectively, having an available binding site, or a carbon atom of the ring of R6, when R6 has an annular structure having an available binding site; X is hydrogen, chlorine, fluorine, bromine, iodine, cyano, (d-Cß) alkyl, hydroxy, (CrC6) alkoxy, -SOt-alkyl (CrC6) where t is zero, one or two, - C02R10 or -CONR11R12; each of R 0, R 11 and R 12 is independently selected from hydrogen, (dC) alkyl, phenyl and naphthyl, wherein said phenyl or naphthyl may be optionally substituted with one or more substituents independently selected from chlorine, fluorine, bromine, iodine , (d-Cß) alkyl, (d-Cß) alkoxy, trifluoromethyl, cyano and -SOralkyl (CrC6), wherein t is zero, one or two; or R11 and R12, together with the nitrogen atom to which they are attached, form a 5 to 7 membered heteroalkyl ring which may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; R3 is optionally substituted aryl or heteroaryl; and n is one, two or three; or a pharmaceutically acceptable salt or pharmaceutically acceptable isomer thereof; comprising (a) preparing a compound having the formula 1 B: wherein a, n, m, X, R6 and R13 are as defined above; and (b) treating the compound prepared in step (a) with aryl or heteroaryl chloride, bromide, fluoride, iodide or sulfonate, in the presence of (1) a base selected from the group consisting of potassium phosphate, carbonate potassium, sodium carbonate, thallium carbonate, cesium carbonate, potassium tert-butoxide, lithium tert-butoxide, sodium tert-butoxide or a diamine selected from the group consisting of 1,2-ethylenediamine, N, N '-dimethylenediamine, N, N-dimethylenediamine or cis-1,2-diaminocyclohexane, (2) a copper (I) salt selected from the group consisting of cuprous chloride, cuprous bromide and cuprous iodide, and (3) an amount of water comprising from about 1% to about 4% w / w, in a solvent inert to the reaction selected from the group consisting of 1,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran, benzene or toluene, optionally in the presence of a polar co-solvent selected from the group consisting of N, N-dimethylformamide, N, N-dimethylacetamide in the order of 5-15% v / v in relation to the first solvent, at a temperature of about 40 ° C to about 150 ° C, under suitable conditions for forming the compound having the formula 1 B '.

16. A process for preparing a compound having the formula 1A: where a is zero to eight; m is one to three; R6 is selected from the group consisting of hydrogen, (d-C6) alkyl optionally substituted with (CrC6) alkoxy or one to three fluorine atoms, or (alkyl (d-C4)) - aryl wherein the aryl portion is phenyl, naphthyl or heteroaryl- (CH2) q-, wherein the heteroaryl portion is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzizoxazolyl and benzisothiazolyl and q is zero, one, two, three or four, and wherein said aryl and heteroaryl portions may be optionally substituted with one or more substituents independently selected from the group consisting of chlorine, fluorine , bromine, iodine, (d-Cß) alkyl, (d-Cß) alkoxy, trifluoromethyl, cyano and -SOt-alkyl (CrCe), where t is zero, one or two; each R13 is, independently, alkyl of (d-C4) or an alkyiene bridge (CrC4) of one of the ring carbon atoms of the piperazino or piperidino ring of G1 or G2, respectively, at the same or another carbon atom of the ring or an annular nitrogen atom of the piperazino or piperidino ring of G1 or G2, respectively, having an available binding site, or to a carbon atom of the ring of R6, when R6 has an annular structure having a binding site available; X is hydrogen, chlorine, fluorine, bromine, iodine, cyano, (d-Cß) alkyl, hydroxy, (d-C6) alkoxy, -SOt-alkyl (CrCß) where t is zero, one or two, -C02R1 ° or -CONR11R12; each of R10, R11 and R12 is independently selected from hydrogen, (C4) alkyl, phenyl and naphthyl, wherein said phenyl or naphthyl may be optionally substituted with one or more substituents independently selected from chlorine, fluorine, bromine, iodine , (d-Cß) alkyl, (CrCe) alkoxy, trifluoromethyl, cyano and -SOralkyl (CrCe), wherein t is zero, one or two; or R11 and R12, together with the nitrogen atom to which they are attached, form a 5 to 7 membered heteroalkyl ring which may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; R3 is optionally substituted aryl or heteroaryl; and n is one, two or three; or a pharmaceutically acceptable salt or pharmaceutically acceptable isomer thereof; comprising (a) preparing a compound having the formula 1 B: wherein a, n, m, X, R6 and R13 are as defined above; and (b) treating the compound prepared in step (a) with hydrogen gas in a solvent inert to the reaction selected from the group consisting of a lower alcohol, THF, dioxane, ethyl acetate, methanol or ethanol, in the presence of a noble metal catalyst on a solid support selected from the group consisting of palladium on carbon (Pd / C), palladium on barium sulfate (Pd / BaS0), platinum on carbon (Pt / C), tris (triphenylphosphine), rhodium chloride (Wilkinson's catalyst) and 10% palladium on carbon, at a pressure of about 1 to about 5 atmospheres, preferably of about 3 to about 4 atmospheres, at a temperature of about 10 ° C to about 100 ° C, under suitable conditions to form the compound having the formula 1A; or treating the compound prepared in step (a) under hydrogenation transfer conditions with a hydride donor selected from the group consisting of cyclohexadiene and ammonium formate, in an inert solvent for the reaction selected from a lower alcohol, THF, dioxane, ethyl acetate, methanol and ethanol, in the presence of a noble metal catalyst on a solid support selected from the group consisting of palladium on carbon (Pd / C), palladium on barium sulfate (Pd / BaS0), platinum on carbon (Pt / C), tris (triphenylphosphine) rhodium chloride (Wilkinson's catalyst) and 10% palladium on carbon, at a temperature of about 20 ° C to about 150 ° C, under suitable conditions to form the compound which has the formula 1A.

17. A process for preparing a compound having the formula 1A ': where a is zero to eight; m is one to three; R6 is selected from the group consisting of hydrogen, (d-Cß) alkyl optionally substituted with (d-Cß) alkoxy or one to three fluorine atoms, or (alkyl (d-C4)) -aryl wherein the aryl portion is phenyl, naphthyl or heteroaryl- (CH2) q-, wherein the heteroaryl portion is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzizoxazolyl and benzisothiazolyl and q is zero, one, two, three or four , and wherein said aryl and heteroaryl moieties may be optionally substituted with one or more substituents independently selected from the group consisting of chlorine, fluorine, bromine, iodine, (d-Ce) alkyl, (CrC6) alkoxy, trifluoromethyl, cyano and -SOt-alkyl (CrCe), where t is zero, one or two; each R 3 is, independently, alkyl of (dd) or an alkylene bridge (d-C4) of one of the ring carbon atoms of the piperazino or piperidino ring of G1 or G2, respectively, at the same or another carbon atom of the ring or to an annular nitrogen atom of the piperazino or piperidino ring of G1 or G2, respectively, having an available binding site, or to a carbon atom of the ring of R6, when R6 has an annular structure having a union available; X is hydrogen, chlorine, fluorine, bromine, iodine, cyano, alkyl of (d-Ce), hydroxy, alkoxy of (dd), -SOralkyl (CrC6) where t is zero, one or two, -C02R10 or -CONR11R12; each of R10, R11 and R12 is independently selected from hydrogen, (dC) alkyl, phenyl and naphthyl, wherein said phenyl or naphthyl may be optionally substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (dd) alkyl, (dd) alkoxy, trifluoromethyl, cyano, and -SOt-alkyl (CrCe), wherein t is zero, one or two; or R11 and R12, together with the nitrogen atom to which they are attached, form a 5 to 7 membered heteroalkyl ring which may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; R3 is optionally substituted aryl or heteroaryl; and n is one, two or three; or a pharmaceutically acceptable salt or pharmaceutically acceptable isomer thereof; comprising (a) preparing a compound having the formula 1A: wherein a, n, m, X, R6 and R13 are as defined above; and (b) treating the compound prepared in step (a) with aryl or heteroaryl chloride, bromide, fluoride, iodide or sulfonate, in the presence of (1) a base selected from the group consisting of potassium phosphate, potassium, sodium carbonate, thallium carbonate, cesium carbonate, potassium tert-butoxide, lithium tert-butoxide, sodium tert-butoxide or a diamine selected from the group consisting of 1,2-ethylenediamine, N, N '-dimethylenediamine, N, N-dimethylethylenediamine or cis-1,2-diaminocyclohexane, (2) a copper (I) salt selected from the group consisting of cuprous chloride, cuprous bromide and cuprous iodide, and (3) an amount of water comprising from about 1% to about 4% w / w, in a solvent inert to the reaction selected from the group consisting of 1,2-dimethoxyethane, diglyme, t-butymethyl ether, tetrahydrofurane, benzene or toluene, optionally in the presence of a polar co-solvent selected from the group or consisting of N, N-dimethylformamide, N, N-dimethylacetamide in the order of 5-15% v / v in relation to the first solvent, at a temperature of about 40 ° C to about 150 ° C, under suitable for forming the compound having the formula 1A '.