WO2006106416A1 - PYRIDIL-LACTAMS AND THEIR USE 5 -HTl RECEPTORS LIGAN - Google Patents

Abstract

The present invention relates to novel pyridyl-lactams, compounds of the formula (I), wherein R1 is a group of the formula G1, G2, G3 or G4 depicted below, and R3, Y, R6, R7, R8, R13, a, n and m are as defined herein, their pharmaceutically acceptable salts, pharmaceutical compositions, their preparation and intermediates therefrom, and their use in treating or preventing depression, anxiety, obsessive compulsive disorder (OCD) and other disorders for which a 5-HT1B antagonist is indicated.

Description

PYRIDIL-LACTAMS AND THEIR USE 5-HTl RECEPTORS LIGANDS

Background of the Invention

The present invention relates to novel pyridyl-lactams, to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the present invention include selective antagonists, inverse agonists and partial agonists of serotonin 1 (5-HTi) receptors, specifically the 5-HT_1B (formerly classified

5-HT₁₀) receptors. They 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.

European Patent Publication 434,561 , published on Jun. 26, 1991 , refers to 7-alkyl alkoxy, and hydroxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes. The compounds are referred to as 5-HT₁ agonists and antagonists useful for the treatment of migraine, depression, anxiety, schizophrenia, stress and pain. European Patent Publication 343,050, published on Nov. 23, 1989, refers to

7-unsubstituted, halogenated, and methoxy substituted-1-(4-substituted-1-piperazinyl)- naphthalenes as useful 5-HT-i_A ligand therapeutics.

PCT publication WO 94/21619, published Sep. 29, 1994, refers to naphthalene derivatives as 5-HT₁ agonists and antagonists. PCT publication WO 96/00720, published Jan. 11 , 1996, refers to naphthyl ethers as useful 5-HT₁ agonists and antagonists.

European Patent Publication 701 ,819, published Mar. 20, 1996, refers to the use of 5- HT₁ agonists and antagonists in combination with a 5-HT re-uptake inhibitor.

Glennon et al., refers to 7-methoxy-1-(1-piperaziny!)-naphthalene as a useful 5-HT₁ ligand in their article "5-HT₁₀ 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 pharmacological effects associated with serotonin receptors including appetite suppression, thermoregulation, cardiovascular/hypotensive effects, sleep, psychosis, anxiety, depression, nausea, emesis, Alzheimer's disease, Parkinson's disease and Huntington's disease.

World Patent Application WO 95/31988, published Nov. 30, 1995, refers to the use of a 5-HT-i_D antagonist in combination with a 5-HT_1A antagonist to treat CNS disorders such as depression, generalized anxiety, panic disorder, 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 hyperprolactinaemia, vasospasm (particularly in the cerebral vasculature) and hypertension, disorders of the gastrointestinal tract where changes in motility and secretion are involved, as well as sexual dysfunction.

G. Maura et al., J. Neurochem, 66 (1), 203-209 (1996), have stated that administration of agonists selective for 5-HT_1A receptors or for both 5-HT_1A and 5-HT-i_D receptors might represent a great improvement in the treatment of human cerebellar ataxias, a multifaceted syndrome for which no established therapy is available.

European Patent Publication 666,261 , published Aug. 9, 1995 refers to thiazine and thiomorpholine derivatives which are claimed to be useful for the treatment of cataracts. Other 5HT1B ligands are disclosed in PCT International Pulbication Nos. WO9736867 and WO 98/14433, the contents of which are hereby incorporated by reference.

Summary of the Invention

The present invention relates to pyridyl-piperazine lactams of the formula

wherein R¹ is a group of the formula G¹, G², G³ or G⁴ depicted below,

wherein R is selected from the group consisting of hydrogen, (C_rC₈)alkyl, and (C₃-C₈)cycloalkyl optionally substituted with (CrC₆)alkoxy or one to three fluorine atoms;

R⁷ and R⁸ are independently selected from hydrogen, (CrCβJalkyl, and (C₃-C₈)cycloalkyl; each R¹³ is, independently, hydrogen, (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, or a (C₁-C₄)alkylene bridge wherein the alkylene bridge is from a carbon of G¹, G³, or G⁴ to another carbon of the same group (e.g., same G group) or to a nitrogen of the same group, or to a carbon of R⁶ of the same group, or the alkylene bridge is from a carbon of G² to another carbon of G², or to a carbon of R⁷ or R⁸, wherein the bridge would be formed by a bond replacing a hydrogen atom on the carbon or nitrogen to which the alkylene is bridged; a is zero to four; m is one to three; Y is carbon, nitrogen, sulfur, or oxygen;

R³ is -(CH₂)_gB, wherein g is zero to three and B is hydrogen, phenyl, naphthyl or a 5 to 7 membered heteroaryl ring containing from one to four heteroatoms in the ring selected from oxygen, nitrogen and sulfur, with the proviso that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms and wherein said phenyl, naphthyl and heteroaryl rings may optionally be substituted with one to three substituents independently selected from:

(1) chloro, fluoro, bromo, iodo, trifluoromethyl, trifluoromethoxy, cyano,

wherein t is zero to two, (C_rC₈)alkyl, (Ci-C₈)hydroxyalkyl-, (CrCaJalkoxy, (C₁-C₈)alkoxy-(C₁-C₈)alkyl-, (C₄-C₈)cycloalkyl-, (C₄-C₈)cycloalkyl-O-, and wherein one to three carbon atoms of each of the foregoing (C₄-C₈)cycloalkyl substituents may be replaced with a heteroatom independently selected from nitrogen, oxygen or sulfur to form a heterocycloalkyl substituent having 4 to 8 atoms, with the proviso that said heterocycloalkyl substituent cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms, and wherein each (C₄-C₈)cycloalkyl or heterocycloalkyl substituent may be independently substituted with from zero to three substituents independently selected from hydroxy, (C₁-C₈)BIkOXy, (C_rC₈)alkyl, and (CrC₄)alkyl-aryl wherein said aryl moiety is phenyl or naphthyl; or

(2) phenyl, naphthyl or a 5 to 7 membered heteroaryl ring containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, with the proviso that said heteroaryl ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms, and wherein each independently selected phenyl, naphthyl or heteroaryl substituent may itself be independently substituted with from zero, one, two or three (C_rC₈)alkyl, (C₄-C₈)cycloalkyl or halo substituents; or

(3) hydroxy, -CH₂OH, -COOH or the lactone formed from hydroxy or -CH₂OH with an ortho -COOH; or (4) -CONR¹⁴R¹⁵, wherein R¹⁴ and R¹⁵ are independently selected from

(C-i-Cs)alkyl and benzyl, or R¹⁴ and R¹⁵ together with the nitrogen to which they are attached form a 5 to 7 membered heteroalkyl ring that may contain from zero to three heteroatoms selected from nitrogen, sulfur and oxygen in addition to the nitrogen of the -CONR¹⁴R¹⁵ group, wherein when any of said heteroatoms is nitrogen it may be optionally substituted with (Ci-C₈)alkyl or benzyl, with the proviso that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms; or (5) -(CH₂)vN(R¹⁷)COR¹⁶ wherein v is zero to three and -COR¹⁶ and R¹⁷ taken together with the nitrogen to which they are attached form a 4 to 6 membered lactam ring; or

(6) -(CH₂)_VNR¹⁴R¹⁵, wherein v is zero to three and R¹⁴ and R¹⁵ are independently selected from (C_rC₈)alkyl and benzyl, or R¹⁴ and R¹⁵ together with the nitrogen to which they are attached form a 5 to 7 membered heteroalkyl ring that may contain from zero to three heteroatoms selected from nitrogen, sulfur and oxygen; n is 1 , 2 or 3; each broken line independently indicates an optional double bond; or a pharmaceutically acceptable salt thereof.

The invention also concerns intermediates of formula I, wherein n, and Y have the definitions above;

R¹ is a group of the formula G¹, G², G³ or G⁴ depicted below,

G¹ G² G³ G⁴ wherein R¹³, a and m have the definitions above;

R⁶ is selected from the group consisting of hydrogen, (C_rC₈)alkyl, (C₃-C₈)cycloalkyl optionally substituted with (C_rC₆)alkoxy or one to three fluorine atoms, and -C(O)O-terf-butyl;

R³ is vinyl or C(=O)R, wherein R is (C_rC₈)alkyl, (C₃-C₈)cycloalkyl, CF₃, or aryl, wherein R is preferably tert-butyl, and at least one of R⁷ and R⁸ is aryl optionally substituted with (C₁-C₆JaIkOXy or one to three fluorine atoms and the other is selected from selected from hydrogen, (CrCsJalkyl, (C₃-C₈)cycloalkyl, and aryl optionally substituted with (Ci-C₆)alkoxy or one to three fluorine atoms.

The invention also relates to a compound according to formula I wherein said heterocycloalkyl substituent is selected from any one or more or combination of the following: tetrahydropyranyl, morpholinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, hexahydroazepinyl, diazepinyl, oxazepinyl, thiazepinyl, oxadiazepinyl, thiadiazepinyl, triazepinyl, oxetanyl, or tetrahydrofuranyl. Each such heterocycloalkyl substituent is optionally substituted with one to three (C_rC₈)alkyl, cycloalkyl, alkoxy, or hydroxyl groups. The invention also relates to a compound according to formula I wherein said heteroaryl substituents of B independently include any one or more or combination of the following: pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, and azaindolyl, and preferably include pyridyl, pyrrolyl, pyrimidyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, pyridazinyi and isothiazolyl. Each such heteroaryl substituent is optionally substituted with (Ci-C₈)alkyl, (C₃-C₈)cycloalkyl, alkoxy, or hydroxyl groups.

The invention also relates to a compound according to formula I wherein R⁶ is selected from hydrogen, methyl, and ethyl.

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 and 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, naphthyl and pyridyl, any of which is optionally substituted with -CONR¹⁴R¹⁵ wherein said R¹⁴ and said R¹⁵ groups of said -CONR¹⁴R¹⁵ substituent together with the nitrogen to which they are attached form a 5 to 7 membered heteroalkyl ring selected from piperidine, N-(C₀-C₆)alkylpiperazine and morpholine.

The invention also relates to compounds of formula I wherein R³ is (CH₂)_gB wherein g is zero and B is selected from phenyl, or pyridyl, either of which is substituted with any of the following substituents:

(C_rC₄)alkyl optionally substituted with hydroxyl, (C_rC₄)alkoxy,

(C₄-C₆)cycloalkyl (e.g., cyclobutyl, or cyclopentyl) optionally substituted with hydroxyl or (C₁-C₄)BIkOXy,

(C₄-C₆)cycloalkyl wherein a heterocycloalkyl is formed by 1 to 2 carbon atoms being replaced with oxygen (e.g., tetrahydropyranyl and oxetanyl) and wherein said heterocycloalkyl is optionally substituted with (C_rC₄)alkyl, or oxazolyl optionally substituted with 1 to 2 (C_rC₄)alkyl. Another embodiment of the invention relates to compounds where Y is carbon or oxygen. Another embodiment relates to compounds where n is one or two.

Another embodiment relates to compounds where Y is oxygen or carbon and n is 1 or 2 to give a moiety selected from: morpholin-3-one, pyrrolidin-2-one, and piperidin-2-one.

Another embodiment relates to compounds where R¹ is the group of formula G¹, wherein R⁶ is H or (CVC^alkyl, preferably H or methyl, wherein a is zero to two, wherein m is one, and wherein R¹³ is (Ci-C₄)alkyl, preferably methyl.

The invention includes compounds of formula I that have any variable as discussed herein with any definition for said variable as discussed herein.

Specific examples of the present invention include any one or independently any combination of the following compounds:

2-[3-(4-Methyl-piperazin-1-yl)-pyridin-2-ylmethylene]-4-[4-(tetrahydro-pyran-4-yl)- phenyl]-morpholin-3-one,

4-(4-tert-Butyl-phenyl)-2-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethylene]- morpholin-3-one, 2-[3-(4-Methyl-piperazin-1 -yl)-pyridin-2-ylmethyl]-4-[4-(tetrahydro-pyran-4-yl)-phenyl]- morpholin-3-one,

4-(4-tert-Butyl-phenyl)-2-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-morpholin-3- one,

1-[4-(2-lsopropyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2- ylmethyl]-piperidin-2-one,

1 -[4-(1 -Hydroxy-cyclopentyl)-phenyl]-3-[3-(4-methylpiperazin1 -yl)-pyridin-2-ylmethyl]- pyrrolidin-2-one,

1 -[6-(1 -Hydroxy-1 -methyl-ethyl)-pyridin-3-yl]-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2- ylmethyl]-pyrrolidin-2-one, 1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2- ylmethyl]-pyrrolidin-2-one,

1-(4-tert-Butyl-phenyl)-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-piperidin-2- one,

(+) 1-(4-tert-Butyl-phenyl)-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-piperidin- 2-one,

(-) 1 -(4-tert-Butyl-phenyl)-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2-ylmethyl]-piperidin- 2-one,

3-[3-(4-Methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-1-[4-(tetrahydro-pyran-4-yl)-phenyl]- piperidin-2-one, (+) 3-[3-(4-Methyl-piperazin-1 -yl)-pyridin-2-ylmethyl]-1 -[4-(tetrahydro-pyran-4-yl)- phenyl]-piperidin-2-one, (-)3-[3-(4-Methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-1-[4-(t8trahydro-pyran-4-yl)- phenyl]-piperidin-2-one,

1-[4-(2-tert-Butyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2- ylmethyl]-piperidin-2-one, (+) 1 -[4-(2-tert-Butyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2- ylmethyl]-piperidin-2-one,

(-) 1 -[4-(2-tert-Butyl-oxazol-4-yl)-phenyl]-3-[3-(4-methy!-piperazin-1 -yl)-pyridin-2- ylmethyl]-piperidin-2-one,

1-[4-(2-Methyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]- piperidin-2-one,

(+) 1 -[4-(2-Methyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1 -yl)-pyιidin-2- ylmethyl]-piperidin-2-one,

(-) 1 -[4-(2-Methyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2- ylmethyl]-piperidin-2-one, 1 -[4-(2,5-Dimethyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2- ylmethyl]-piperidin-2-one,

(+) 1 -[4-(2,5-Dimethyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2- ylmethyl]-piperidin-2-one,

(-) 1 -[4-(2,5-Dimethyl-oxazol-4-yl)-phenyl]-3-[3-(4-methy!-piperazin-1 -yl)-pyridin-2- yimethyl]-piperidin-2-one,

1-(6-lsopropyl-pyridin-3-yl)-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]- pyrrolidin-2-one,

6'-Ethoxy-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-3,4,5,6-tetrahydro- [1 ,3']bipyridinyl-2-one, 1-[4-(1-Methoxy-cyclobutyl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]- piperidin-2-one,

(+) 1 -[4-(1 -Methoxy-cyclobutyl)-phenyl]-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2- ylmethyl]-piperidin-2-one,

(-) 1 -[4-(1 -Methoxy-cyciobutyl)-phenyl]-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2- ylmethyl]-piperidin-2-one,

3-[3-(4-Methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-1-(4-oxazol-4-yl-phenyl)-piperidin-2- one,

1-[4-(Tetrahydro-pyran-4-yl)-phenyl]-3-[3-(3,4,5-trimethyl-piperazin-1-yi)-pyridin-2- ylmethyl]-piperidin-2-one, {+) 1 -[4-(Tetrahydro-pyran-4-yl)-phenyl]-3-[3-(3,4,5-trimethyl-piperazin-1 -yl)-pyridin-2- ylmethyl]-piperidin-2-one, (-) 1-[4-(Tetrahydro-pyran-4-yl)-phenyl]-3-[3-(3,4,5-trimethyl-piperazin-1-yl)-pyridin-2- ylmethyl]-piperidin-2-one,

1-[4-(2,5-Dimethyl-oxazol-4-yl)-phenyl]-3-[3-(3,4,5-trimethyl-piperazin-1-yl)-pyridin-2- ylmethyl]-piperidin-2-one, 1-[4-(3,5-Dimethyl-isoxazo!-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2- ylmethyl]-piperidin-2-one,

1-[4-(5-Methyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]- piperidin-2-one,

1-(4-lsoxazol-3-yl-phenyl)-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-piperidin- 2-one,

1-[4-(5-Methyl-oxazol-2-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]- piperidin-2-one,

1-[4-(2-Ethyl-5-methyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2- ylmethyl]-piperidin-2-one, (+) 1-[4-(2-Ethyl-5-methyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-

2-ylmethyl]-piperidin-2-one,

(-) 1-[4-(2-Ethyl-5-methyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2- ylmethyl]-piperidin-2-one,

3-[3-(4-Methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-1-[4-(tetrahydro-pyran-4-yl)-phenyl]- pyrrolidin-2-one,

(+) 3-t3-(4-Methyl-piperazin-1 -yl)-pyridin-2-ylmethyl]-1 -[4-(tetrahydro-pyran-4-yl)- phenyi]-pyrrolidin-2-one,

(-) 3-[3-'(4-Methyl-piperazin-1 -yl)-pyridin-2-ylmethyl]-1 -[4-(tetrahydro-pyran-4-yl)- phenyl]-pyrrolidin-2-one, 1-[4-(2,5-Dimethyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2- ylmethyl]-pyrrolidin-2-one,

(+) 1-[4-(2,5-Dimethyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2- ylmethyl]-pyrrolidin-2-one,

(-) 1-[4-(2,5-Dimethyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2- ylmethyl]-pyrrolidin-2-one,

3-[3-(4-Methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-1-[4-(4-methyl-tetrahydro-pyran-4- yl)-phenyl]-piperidin-2-one,

1-(4-lsopropoxy-phenyl)-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-piperidin-2- one, 1-[4-(1-Methoxy-cyclobutyl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]- pyrrolidin-2-one, (+) 1-[4-(1-Methoxy-cyclobutyl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2- ylmethyl]-pyrrolidin-2-one,

(-) 1 -[4-(1 -Methoxy-cyclobutyl)-phenyl]-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2- ylmethyl]-pyrrolidin-2-one, 1 -[4-(3-Methyl-oxetan-3-yl)-phenyl]-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2-ylmethyl]- pyrrolidin-2-one,

1-[4-(3-Methyl-oxetan-3-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]- piperidin-2-one,

4-(2-{2-Oxo-1-[4-(tetrahydro-pyran-4-yl)-phenyl]-piperidin-3-ylmethyl}-pyridin-3-yl)- piperazine-1-carboxylic acid tert-butyl ester,

3-(3-Piperazin-1-yl-pyridin-2-ylmethyl)-1-[4-(tetrahydro-pyran-4-yl)-phenyl]-piperidin- 2-one,

3-[3-(4-lsobutyl-piperazin-1-yl)-pyridin-2-ylmethyl]-1-[4-(tetrahydro-pyran-4-yl)- phenyl]-piperidin-2-one, and 3-[3-(4-Ethyl-piperazin-1 -yl)-pyridin-2-ylmethyl]-1 -[4-(tetrahydro- pyran-4-yl)-phenyl]-piperidin-2-one.

Unless otherwise indicated, the term "halo", as used herein, includes fluoro, chloro, bromo and iodo.

Unless otherwise indicated, the term "alkyl", as used herein, includes straight or branched alkyl containing from 1 to 8 carbon atoms. Unless otherwise indicated the term "cycloalkyl" as used herein includes moieties derived from cyclic hydrocarbons which have a linkage from a ring carbon to another group and includes cyclic hydrocarbon moieties substituted with straight or branched alkyl moieties containing from 4 to 8 carbon atoms.

The term "alkoxy", as used herein, means "alkyl-O-", wherein "alkyl" is defined as above. The term "cycloalkyl-O-" as used herein means "cycloalkyl" as defined above in which the cycloalkyl moiety is linked by a single bond to an oxygen atom with the oxygen atom having an available bonding site for formation of an ether linkage.

The term "alkylene", as used herein, means an alkyl radical having two available bonding sites (Le₁, -alkyl-), wherein "alkyl" is defined as above. The term "alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration comprising one or more unsaturated carbon-carbon bonds which may occur at any stable point along the chain, such as ethenyl and propenyl. Alkenyl groups typically will have 2 to about 12 carbon atoms, more typically 2 to about 8 carbon atoms.

The term "alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration comprising one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. Alkynyl groups typically will have 2 to about 12 carbon atoms, more typically 2 to about 8 carbon atoms.

The term "aryl" is intended to include groups that, in accordance with the theory of Hϋckel, have a cyclic, delocalized (4n + 2) pi-electron system. Examples of aryl groups include, but are not limited to, arenes and their substitution products, e.g. phenyl, naphthyl and toluyl, among numerous others.

The term "heteroaryl" is intended to include aromatic heterocyclic groups and includes the non-limiting examples thiophenyl, pyridyl, pyrimidyl, pyridazyl, oxazolyl, isooxazolyl, thiazolyl and isothiazolyl, among others. 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 replaced with a nitrogen, oxygen or sulfur atom or any combination thereof. Examples of such heterocycloalkyl groups include oxetanyl, tetrahydrofuranyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorphlinyl, piperazinyl, and azapinyl, among others, any of which may be substituted as discussed herein.

The compounds of formula I may have chiral centers and therefore may occur in different enantiomeric configurations. The invention includes all enantiomers, diastereomers, tautomers and other stereoisomers of such compounds of formula I, as well as racemic and 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, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, malate, di-p-toluoyl tartaric acid, and mandelic acid. The present invention also, relates to all radiolabeled forms of the compounds of the formula I. Preferred radiolabeled compounds of formula I are those wherein the radiolabels are selected from as ³H, ¹¹C, ¹⁴C, ¹⁸F, ¹²³I and ¹²⁵I. Such radiolabeled compounds are useful as research and diagnostic tools in metabolism pharmacokinetics studies and in binding assays in both animals and man. The present invention also relates to a pharmaceutical composition for treating a disorder or condition in a mammal, including a human, selected from depression, anxiety, depression with concomitant anxiety, post traumatic stress disorder, panic phobias, obsessive compulsive disorder (OCD), borderline personality disorder, sleep disorder, psychosis, seizures, dyskinesis, symptoms of Huntington's or Parkinson's diseases, spasticity, suppression of seizures resulting from epilepsy, cerebral ischemia, anorexia, faintness attacks, hypokinesia, cranial traumas, chemical dependencies, premature ejaculation, premenstrual syndrome (PMS) associated mood and appetite disorder, inflammatory bowel disease, modification of feeding behavior, blocking carbohydrate cravings, late luteal phase dysphoric disorder, tobacco withdrawal-associated symptoms, panic disorder, bipolar disorder, sleep disorders, jet lag, cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, chemical dependencies and addictions (e.g., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or ***e), headache, stroke, traumatic brain injury (TBI), psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating a disorder or condition in a mammal, including a human, selected from depression, anxiety, depression with concomitant anxiety, post traumatic stress disorder, panic phobias, obsessive compulsive disorder (OCD), borderline personality disorder, sleep disorder, psychosis, seizures, dyskinesis, symptoms of Huntington's or Parkinson's diseases, spasticity, suppression of seizures resulting from epilepsy, cerebral ischemia, anorexia, faintness attacks, hypokinesia, cranial traumas, chemical dependencies, premature ejaculation, premenstrual syndrome (PMS) associated mood and appetite disorder, inflammatory bowel disease, modification of feeding behavior, blocking carbohydrate cravings, late luteal phase dysphoric disorder, tobacco withdrawal- associated symptoms, panic disorder, bipolar disorder, sleep disorders, jet lag, cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, chemical dependencies and addictions (e.g., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or ***e), headache, stroke, traumatic brain injury (TBI), psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome, comprising administering to a mammal in need of such treatment an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition. Detailed Description of the Invention

The compounds of formula I can be prepared according to the methods of Scheme 1. Except where otherwise stated, R¹, R⁶, R⁷, R⁸, R¹³, G¹, G², G³, G⁴, a, m, and n in the reaction scheme and discussion that follow are defined as above. Unless otherwise stated, reaction conditions include an inert atmosphere commonly used in the art such as nitrogen or argon. SCHEME 1

G1 G²

Il

Scheme 1 refers to the preparation of a compound of the formula I wherein Y is carbon, R¹ is G¹ or G², R³ is an optionally substituted aryl or heteroaryl group and n is the integer 1 or 2.

In step 1 of Scheme 1 , aldehyde VIII is prepared from 3-fluoropyridine (Z is F)₁ IX by a) treating a tertiary amine, preferably N,N'-tetramethylethlyenediamine or 1 ,4-diazabicycl[2.2.2]octane (DABCO) with a lithium alkyl base such . as butyl lithium, methyl lithium, tert-butyl lithium, preferably n-butyllithium, in an ethereal solvent such as ethyl ether, tetrahydrofuran or dioxane, preferably ethyl ether at a temperature of about -100⁰C to about -3O⁰C, preferably about -78⁰C and b) quenching the reaction mixture with dimethylformamide (DMF) at a temperature of about -100⁰C to about -3O⁰C, preferably about -78⁰C.

In step 2 of Scheme 1, the aldehyde of formula Vl is prepared by treating 3-fluoro-pyridine-2-carbaldehyde (compound VIlI, Z is F) and an amine corresponding to G¹ or G² (compound VII) in a solvent such as water, 1 ,4-dioxane, tetrahydrofuran, n-butanol, Λ/,Λ/-dimethylformamide, dimethyl sulfoxide, or acetonitrile, or mixtures thereof, preferably water, with a base that is inert towards the reactants and the solvent, such as a trialkylamine or an alkali metal carbonate, preferably potassium carbonate at a temperature of about 4O⁰C to about 15O⁰C, preferably about 9O⁰C to 12O⁰C. An alternative coupling for step 2 is that described in Buchwald, et al. J. Org. Chem. 2000, 65, 1144-1157 and 1158-1174. A mixture of the pyridylaldehyde VIII (Z is Br, Cl, F, or sulfonate, preferably OTf, obtaining the said intermediate VIII using standard procedures known to those of ordinary skill in organic chemistry) and an N-substituted compound of the formula VII are treated in a solvent selected from toluene, benzene, DME wherein 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(dibenzyidene-acetone)dipal!adium, transdichlorobis(triphenylphosphine)pal!adium or optionally added phosphine ligands where added such as BINAP or triphenylphosphine where palladium acetate and BINAP are preferred at a temperature of about 4O⁰C to 15O⁰C, preferably about 9O⁰C to 12O⁰C to yield an aldehyde of the formula Vl.

In step 3 of Scheme 1 , the compound of formula IV is prepared by condensation of the aldehyde of formula Vl with an N-protected lactam of the formula V, wherein protective group P is selected from vinyl or C(=O)R^P, wherein R^p is CF₃, (C_rC₈)alkyl, (C₃-C₈)cycioalkyl, or aryl, preferably P is

(Sasaki, H. et al. J. Med. Chem., 1991, 34, 628-633) or C(=O)CH₃, in a reaction inert solvent such as diethylether, tetrahydrofuran (THF) or dioxane, preferably THF, in the presence of an amine or metal hydride base, such as sodium hydride or sodium bis(trimethylsilylamide), preferably sodium bis(trimethylsilylamide), at a temperature of about -3O⁰C to about 100⁰C, preferably from about -10⁰C to about 3O⁰C.

In an alternative method for step 3 of Scheme 1 , IV can alternatively be prepared by treating aldehyde Vl with lactam V, wherein P is optionally substituted aryl or heteroaryl, in a solvent such as tetrahydrofuran, ferf-butylmethyl ether, or 1 ,4-dioxane, preferably tetrahydrofuran, in the presence of an alkali metal amine 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(hexamethylsilylamide), and more preferably lithium diisopropyl amide which is then followed by the addition of diethylchlorophosphonate at a temperature of about -3O⁰C to about 100⁰C, preferably about -10°C to about 30⁰C.

In step 4 of Scheme 1 , the compound of formula Il is prepared by reducing the double bond of the compound of formula IV, preferably by catalytic hydrogenation using standard techniques that are well known to those skilled in the art. For example, reduction of the double bond may be effected with hydrogen gas (H₂) using catalysts such as palladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSO₄), platinum on carbon (Pt/C), or tris(triphenylphosphine) rhodium chloride(Wilkinson's catalyst), in an appropriate solvent such as methanol, ethanol, THF, dioxane or ethyl acetate, at a pressure from about 1 to about 5 atmospheres and a temperature from about 1O⁰C to about 60⁰C, as described in Catalytic Hydrogenation in Organic Synthesis, Paul Rylander, Academic Press Inc., San Diego, 1979, pp 31-63. The following conditions are preferred: hydrogenation in methanol or ethanol in the presence of a palladium hydroxide/activated carbon catalyst, more preferably about 10% palladium on carbon at about 1 atmosphere (atm) to about 5 atm, more preferably about 3 atm to about 4 atm at about 10°C to about 100°C, more preferably about 40⁰C to about 60°C for about 2.5 hours to about 12 hours, more preferably about 4 hours, while shaking the mixture. When any of R⁶, R⁷ or R⁸ is benzyl or another hydrogenation labile group the compound of formula I wherein R⁶, R⁷ and R⁸ is hydrogen is formed. Alternatively, the double bond may be reduced under transfer hydrogenation conditions where a hydride donor such as cyclohexadiene or ammonium formate is used in place of hydrogen, where ammonium formate is preferred, in a reaction inert solvent such 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/BaSO₄), platinum on carbon (Pt/C), or tris(triphenylphosphine) rhodium chloride (Wilkinson's catalyst), preferably about 10% palladium on carbon, at a temperature of about 2O⁰C to 15O⁰C, preferably 4O⁰C to 8O⁰C. Alternatively, the reduction of the carbon-cabon double bond can be accomplished using alternative procedures known to one skilled in the art. Larock, R. C. Comprehensive Organic Transformations. VCN Publishers , 1989. In step 5 of Scheme 1 , the compound of formula I in which the optional double is absent and R³ is an optionally substituted aryl or heteroaryl group, is prepared by N-arylation or N-heteroarylation of the compound of formula Il (i.e. the compound of formula I wherein R³ is hydrogen). The compound of formula Il is treated with an optionally substituted aryl or heteroaryl chloride, bromide, iodide, or sulfonate, preferably the bromide, exemplified by the compound of formula III in Scheme 1, a base such as potassium phosphate, potassium carbonate, sodium carbonate, thallium carbonate, cesium carbonate, potassium tert-butoxide, lithium tert-butoxide, or sodium terf-butoxide, preferably potassium carbonate, a diamine, such as 1 ,2-ethylenediamine, Λ/,Λ/'-dimethylethylenediamine, or cis-1 ,2-diaminocyclohexane, preferably Λ/,/\r-dimethylethylenediamine, and cuprous chloride, bromide or iodide, preferably cuprous iodide, in the presence of a small amount of water, preferably about 1% to about 4% water, in a reaction inert solvent such as 1 ,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran, benzene or toluene, preferably toluene, at a temperature of about 40⁰C to about 150⁰C, preferably about 8O⁰C to about 120 ⁰C to yield the compound of formula I wherein R³ is optionally substituted aryl or heteroaryl and the optional double bond is absent.

The N-arylation or N-heteroarylation in step 5 of Scheme 1 may also be accomplished by treating a compound of formula Il (the compound of formula I wherein the optional double is absent and R³ is hydrogen) with an optionally substituted 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 phoshpine 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 about 40⁰C to about 16O⁰C,- preferably about 80⁰C to about 120⁰C. For compounds of formula I wherein any of R⁶, R⁷ or R⁸ is H further functionalization of the amine can be carried out under standard alkylation or reductive animation conditions known to one skilled in the art.

In step 5a of Scheme 1 , the compound of formula I in which the optional double is present and R³ is an optionally substituted aryl or heteroaryl group is prepared by treating the compound of formula IV with an optionally substituted aryl or heteroaryl chloride, bromide, iodide, or sulfonate, preferably the bromide, exemplified by the compound of formula III in scheme 1 , in the manner described in step 5. The compound of formula I in which the optional double is absent and R³ is an optionally substituted aryl or heteroaryl group, is prepared by catalytic hydrogenation as described in step 4 of Scheme 1. When any of R⁶, R⁷ or R⁸ is benzyl or another hydrogenation labile group the compound of formula I wherein R⁶, R⁷ and R⁸ is hydrogen is formed. For such compounds of formula I further functionalization of the resultant amine can be carried out under standard alkylation or reductive amination conditions known to one skilled in the art.

Scheme 1a refers to an alternative preparation of a compound of the formula I wherein Y is carbon, R¹ is G¹ or G² or G³, R³ is an optionally substituted aryl or heteroaryl group, n is the integer 1 or 2 and the optional double bond is either present or absent, beginning with N-arylation or N-heteroarylation of lactam Va to form lactam Vb wherein R³ is an optionally substituted aryl or heteroaryl group.

Step 1 of Scheme 1a uses conditions as discussed for step 5a in Scheme 1 , making minor changes as needed for the different intermediates. In step 1 of Scheme 1a lactam Vb, N-substituted with optionally substituted aryl or heteroaryl group R³, is prepared by treating lactam Va with a compound L-R³ which is an optionally substituted 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 terf-butoxide, lithium ferf-butoxide, or sodium fe/f-butoxide, preferably potassium carbonate, a diamine, such as 1 ,2-ethylenediamine, Λ/./V-dimethylethylenediamine, or cis- 1 ,2-diaminocyclohexane, preferably Λ/.Λ/'-dimethylethylenediamine, and cuprous chloride, bromide or iodide, preferably cuprous iodide, in the presence of a small amount of water, preferably about 1% to about 4% water, in a reaction inert solvent such as 1 ,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran, benzene or toluene, preferably toluene, at a temperature of about 40⁰C to about 15O⁰C, preferably about 8O⁰C to about 12O⁰C.

The N-arylation or N-heteroarylation of step 1, Scheme 1a may also be accomplished by treating a lactam of formula Va with a compound L-R³ which is an optionally substituted 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 phoshpine 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(dibenzylidene-acetone)dipalladium (0), in an inert solvent such as 1 ,4-dioxane or toluene, preferably 1 ,4-dioxane, at a temperature of about 40⁰C to about 160⁰C, preferably about 80⁰C to about 120⁰C.

In an alternative preparation of compound Vb, depicted in step 1a of Scheme 1a, a compound R³-NH2, wherein R³ is an optionally substituted aryl or heteroaryl group, is treated with a compound of the formula X wherein, group A of X is selected from F, Cl, Br, I or an alkyl or aryl sulfonate, preferably Cl, and group B is selected from F, Cl, Br, I, O(C_rC₄)alkyl, OH, or an activated carboxylic acid group derived from reaction of the corresponding carboxylic acid with a standard carboxylic acid activating reagent such as, but not limited to, a carbodiimide (dicyclohexyl carbodiimide, 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 about 10⁰C to about 120°C, preferably about 5O⁰C to about 80°C, in the presence or absence of a base, such as triethylamine, diisopropylethyl amine, an alkali metal hydroxide or an alkali metal carbonate, preferably cesium carbonate.

In step 2 of Scheme 1a, compound IA is prepared by treating aldehyde Vl, prepared as in Scheme I, with lactam Vb, wherein R³ is optionally substituted aryl or heteroaryl, in a solvent such as tetrahydrofuran, ferf-butylmethyl ether, or 1 ,4-dioxane, preferably tetrahydrofuran, in the presence of an alkali metal amine 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(hexamethylsilylamide), and more preferably lithium diisopropyl amide when followed by the optional addition of diethylchlorophosphonate, at a temperature of about -3O⁰C to about 100⁰C, preferably about -10⁰C to about 3O⁰C.

In step 3 of Scheme 1a compound I is prepared by catalytic hydrogenation of compound Ia using the procedure of step 4 in Scheme 1.

SCHEME 1a

Scheme 1b refers to an alternative preparation of a compound of the formula I wherein Y is carbon, R¹ is G¹ or G², R³ is an optionally substituted aryl or heteroaryl group, n is the integer 1 or 2 and the optional double bond is either present or absent, beginning with pyridylaldehyde Villa, wherein D is fluoro or chloro.

In step 1 of Scheme 1b a compound of the formula Xl is prepared by treating pyridylaldehyde Villa, wherein D is selected from fluoro or chloro, preferably fluoro, with a lactam of the formula Vb, wherein R³ is an optionally substituted aryl or heteroaryl group, in a solvent such as tetrahydrofuran, terf-butylmethyl ether, or 1 ,4-dioxane, preferably tetrahydrofuran, in the presence of an alkali metal amine 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(hexamethylsilylamide), and more preferably lithium diisopropyl amide when followed by the optional addition of diethylchlorophosphonate at a temperature of about -30°C to about 100⁰C, preferably about -1O⁰C to about 30°C.

In step 2 of Scheme 1b, a compound of the formula Ia is prepared by treating a compound of the formula Xl with a cyclic secondary amine of the formula R¹H, wherein R¹ is G¹ or G², in a solvent selected from water, 1 ,4-dioxane, n-butanol, W,Λ/-dimethylformamide, dimethyl sulfoxide, acetonitrile or mixtures thereof, preferably water, with a base such as a trialkyl amine or an alkali metal carbonate, preferably potassium carbonate, at a temperature of about 40°C to about 150°C, preferably about 9O⁰C to about 120⁰C to yield a compound of the formula II. This coupling can also be facilitated by use of a transition metal such as palladium and the preferred method is that of Buchwald as described in Buchwald, et al., J. Org. Chem. 2000, 65, 1144-1157 and 1158-1174. A mixture of the Xl and R¹-H is treated in a solvent selected from toluene, benzene, DME wherein toluene is preferred with a base such as sodium or potassium tert-butoxide, sodium or potassium carbonate, or potassium phosphonate where sodium tert-butoxide is preferred with a palladium source such as tetrakis(triphenylphosphine)palladium, palladium acetate, tris(dibenzyidene- acetone)dipalladium, transdichlorobis(triphenylphosphine)palladium and optionally added phosphine ligands, e.g., BINAP or triphenylphosphine where palladium acetate and BINAP are preferred at a temperature of about 40⁰C to 150⁰C, preferably about 9O⁰C to 120⁰C to yield an aldhedyde of the formula Ia. In step 3 of Scheme 1b compound I is prepared by catalytic hydrogenation of compound Ia using the procedure of step 4 in Scheme 1.

SCHEME Ib

Villa

Scheme 2 refers to the preparation of a compound of the formula Ia wherein Y is oxygen, R¹ is G¹ or G², R³ is an optionally substituted aryl or heteroaryl group and n is the integer 1 or 2.

For the preparation of intermediate Vl in steps 1 and 2 of Scheme 2 please refer to the previous discussion of steps 1 and 2 of Scheme 1.

In step 3 of Scheme 2, the compound of formula XIII is prepared by condensation of the aldehyde of formula Vl with an N-protected lactam of the formula XII, wherein protective group P is selected from vinyl, CF₃, or C(=O)R^P, wherein R^p is (C_rC₈)alkyl, (C₃-C₈)cycloalkyl, or aryl, preferably C(=O)- terf-butyl (Sasaki, H. et al. J.Med. Chem., 1991 , 34, 628-633) or C(=O)CH₃, in a reaction inert solvent such as diethylether, tetrahydrofuran (THF) or dioxane, preferably THF, in the presence of an amine or metal hydride base, such as sodium hydride or sodium bis(trimethylsiiylamide), preferably sodium bis(trimethylsilylamide) at a temperature of about -30⁰C to about 100⁰C, preferably from about -1O⁰C to about 30⁰C. In step 4 of Scheme 2, the compound of formula Ha is prepared by reducing the double bond of the compound of formula XIII, preferably by catalytic hydrogenation, using the procedure described in step 4 of Scheme 1. When any of R⁶, R⁷ or R⁸ is benzyl or another hydrogenation labile group, the compound of formula I wherein R⁶, R⁷ and R⁸ is hydrogen is formed.

In step 5 of Scheme 2, the compound of formula Ia wherein the optional double is absent, Y is oxygen and R³ is an optionally substituted aryl or heteroaryl group, is prepared by N-arylation or N-heteroarylation of the compound of formula Ha (i.e. the compound of formula I wherein R³ is hydrogen) using either of the procedures of step 5, Scheme 1. For compounds of formula Ia wherein any of R⁶, R⁷ or R⁸ is H, further functionalization of the amine can be carried out under standard alkylation or reductive amination conditions known to one skilled in the art.

In step 5a of Scheme 2, the compound of formula Ia in which the optional double is present, Y is oxygen and R³ is an optionally substituted aryl or heteroaryl group is prepared by treating the compound of formula XIII with an optionally substituted aryl or heteroaryl chloride, bromide, iodide, or sulfonate, preferably the bromide, R³-L (formula III) using either of the procedures of step 5, Scheme 1. The compound of formula Ia in which the optional double is absent, Y is oxygen and R³ is an optionally substituted aryl or heteroaryl group, is prepared by catalytic hydrogenation as described in step 4 of Scheme 1. When any of R⁶, R⁷ or R⁸ is benzyl or another hydrogenation labile group the compound of formula I wherein R⁶, R⁷ and R⁸ is hydrogen is formed. For such compounds of formula I further functionalization of the resultant amine can be carried out under standard alkylation or reductive amination conditions known to one skilled in the art.

SCHEME 2

Scheme 2a refers to an alternative preparation of a compound of the formula I wherein Y is oxygen, R¹ is G¹ or G², R³ is an optionally substituted aryl or heteroaryl group, n is the integer 1 or 2 and the optional double bond is either present or absent, beginning with N-arylation or N-heteroarylation of lactam XIIa to form lactam XIIb wherein R³ is an optionally substituted aryl or heteroaryl group. In step 1 of Scheme 2a lactam XIIb, N-substituted with optionally substituted aryl or heteroaryl group R³, is prepared by N-arylation or N-heteroarylation of lactam XIIa by treating with a compound L-R³ which is an optionally substituted aryl or heteroaryl chloride, bromide, iodide, or sulfonate, preferably the bromide, using either of the procedures of step 5, Scheme 1.

In an alternative route depicted in step 1a of Scheme 2a, compound XIIa (for n=2, see: Lehn, J.-M.; Montavon, F., HeIv. Chim. Acta, 59, 1976, 1566-1583. Heyns; Buchholz; Chem. Ber., 109, 1976, 3707,3713, 3725. Vieles; Seguin; Bull. Soc. Chim. Fr. 1953, 287) is prepared from a compound of the formula XIV wherein B is selected from F, Cl, Br, I, O(C_rC₄)alkyl, OH, or an activated carboxylic acid group derived from reaction of the corresponding carboxylic acid with a standard carboxylic acid activating reagent such as, but not limited to, a carbodiimide (dicyclohexyl carbodiimide, 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride salt) or tripropylphosphonic anhydride, preferably Cl, and wherein R⁹ and R¹⁰ are hydrogen or together with the nitrogen form a carbamate, a phthalimide or another appropriately designed protective group known in the art, preferably the phthalimide, which may be removed by standard methods such as treatment with hydrazine. Compound XIV is cyclized to compound XIIa, in a solvent such as water, acetonitrile, 1 ,4-dioxane, or tetrahydrofuran, preferably tetrahydrofuran, at a temperature of about 1O⁰C to about 120 ⁰C, preferably about 5O⁰C to about 8O⁰C in the presence or absence of a base, preferably in the presence of a base, with the base selected from triethylamine, diisopropylethylamine, an alkali metal hydroxide or an alkali metal carbonate, preferably cesium carbonate.

In yet another alternate route depicted in step 1b of Scheme 2b compound XIIb wherein n is the integer 2 and R³ is optionally substituted aryl or heteroaryl is prepared by treatment of compound XV, wherein n is the integer 2 and R³ is optionally substituted aryl or heteroaryl, with an appropriate oxidation reagent such as potassium permanganate, sodium periodate/ruthenium oxide, mercury oxide/EDTA (ethylenediaminetetraacetic acid), dimethyldioxirane wherein potassium permanganate is preferred with a quaternary ammonium salt preferably benzyltrimethylammonium chloride, in a chlorinated solvent such as methylene chloride, dichloroethane or chloroform, preferably methylene chloride, or when mercury oxide is used in a non chlorinated solvent such as acetone at a temperature of about 25⁰C to about 16O⁰C, preferably about 3O⁰C to about 6O⁰C. For the case where Y = O and n = 1 , see Kricheldorf, Makromol.Chem. 176, 1975, 57,75,76.

Step 1c of Scheme 2a depicts preparation of compound XV wherein n is the integer 2 and R³ is optionally substituted aryl or heteroaryl by treating morpholine, XVI, 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 terf-butoxide, lithium terf-butoxide, or sodium ferf-butoxide, preferably sodium ferf-butoxide, a phosphine ligand, preferably BINAP or triphenylphosphine, a palladium species, such as palladium (II) acetate or tris(dibenzylideneacetone)dipalladium (0) or the corresponding chloroform adduct, preferably tris(dibenzylidene-acetone)dipalladium (0), in an inert solvent such as 1 ,4-dioxane or toluene, preferably 1 ,4-dioxane, at a temperature of about 4O⁰C to about 16O⁰C, preferably about 8O⁰C to about 120⁰C.

In step 2 of Scheme 2a, the compound of formula Ia in which the optional double is present, Y is oxygen and R³ is an optionally substituted aryl or heteroaryl group is prepared by treating lactam XIIb with pyridylaldehyde Vl using the procedure described in step 2 of Scheme 1a.

In step 3 of Scheme 2a the compound of formula I wherein the optional double bond is absent, Y is oxygen and R³ is an optionally substituted aryl or heteroaryl group is prepared by catalytic hydrogenation of compound Ia using the procedure of step 4 in Scheme 1. When any of R⁶, R⁷ or R⁸ is benzyl or another hydrogenation labile group the compound of formula I wherein R⁶, R⁷ and R⁸ is hydrogen is formed. For such compounds of formula I further functionalization of the resultant amine can be carried out under standard alkylation or reductive amination conditions known to one skilled in the art.

SCHEME 2a

Scheme 2b refers to an alternative preparation of a compound of the formula I wherein Y is oxygen, R¹ is G¹ or G², R³ is an optionally substituted aryl or heteroaryl group, n is the integer 1 or 2 and the optional double bond is either present or absent, beginning with pyridylaldehyde Villa, wherein D is fluoro or chloro.

In step 1 of Scheme 2b a compound of the formula XVII is prepared by treating pyridylaldehyde Villa, wherein D is selected from fluoro or chloro, preferably fluoro, with a lactam of the formula XIIb, wherein Y is oxygen and R³ is an optionally substituted aryl or heteroaryl group, in a solvent such as tetrahydrofuran, terf-butylmethyl ether, or 1 ,4-dioxane, preferably tetrahydrofuran, in the presence of an alkali metal amine 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(hexamethylsilylamide) followed by the optional addition of diethylchlorophosphonate, and more preferably lithium diisopropyl amide when followed by the optional addition of diethylchlorophosphonate, at a temperature of about -30⁰C to about 100⁰C, preferably about -10⁰C to about 30°C.

In step 2 of Scheme 2b, a compound of the formula Ia wherein R¹ is G¹ or G², Y is oxygen and R³ is an optionally substituted aryl or heteroaryl group, is prepared by treating a compound of the formula XVII with a cyclic secondary amine of the formula R¹H, wherein R¹ is G¹ or G², in a solvent selected from water, 1 ,4-dioxane, n-butanol, Λ/,Λ/-dimethylformamide, dimethyl sulfoxide, acetonitrile or mixtures thereof, preferably water, with a base such as a trialkyl amine or an alkali metal carbonate, preferably potassium carbonate, at a temperature of about 40°C to about 150°C, preferably about 90⁰C to about 12O⁰C to yield a compound of the formula II.

In step 3 of Scheme 2b compound I is prepared by catalytic hydrogenation of compound Ia using the procedure of step 4 in Scheme 1. When any of R⁶, R⁷ or R⁸ is benzyl or another hydrogenation labile group the compound of formula I wherein R⁶, R⁷ and R⁸ is hydrogen is formed. For such compounds of formula I further functionalization of the resultant amine can be carried out under standard alkylation or reductive amination conditions known to one skilled in the art.

SCHEME 2b

Villa

SCHEME 3:

Scheme 3 illustrates preparation of a compound 1 by coupling boronic acid or boronic ester XX wherein L is selected from OH and O(C_rC₄)alkyl or wherein both L substituents together form a 1,3.2-benzodioxaboroie derivative, preferably L is OH with XIX, wherein the Z group is selected from chloro, bromo or iodo or sulfonate, preferably bromo, in the presence of a palladium catalyst, such as palladium tetrakistriphenylphosphine, dichloropalladium bistriphenylphosphine, or tris(dibenzylideneacetone)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 from about 10⁰C to about 150⁰C, preferably about 7O⁰C to about 110°C. The preparation of compound XIX is detailed in schemes 1 to 2.

General methods for the preparation of aryl halides used in the N-arylation and N-heteroarylation coupling reactions described herein are given in US Patent No. 5,612,359; Guay, D. et al. Biorg.Med. Chem. Lett. 2002, 12, 1457-1461; Sail, D. J. et al. J. Med. Chem. 2000, 43, 649-663; Olah, G. A.; Porter, R. D. JAmer. Chem. Soc. 1971 , 93, 6877-6887; Brown, H.C.; Okamoto, Y.; Ham, G. JAmer. Chem. Soc. 1957, 79, 1906-1909; Nenitzescu, C; Necsoiu, I. JAmer. Chem. Soc. 1950, 72, 3483-3486; Muci, A. R.; Buchwald, S. L. Top. Curr. Chem.; Springer-Verlag: Berlin Heidelberg, 2002; Vol. 219, pp. 131-209; DE 19650708; EP 104860; Wang, X et al. Tetrahedron Lett., 2000, 41, 4335-4338, the contents of which are herein incorporated by reference in their entirety. Those skilled in the art will recognize that, where appropriate, hydroxyl groups on aryl or heteroaryl halides can be etherified by standard methods known in the art such as treatment with an alkali metal hydride or alkali metal hydroxide, such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, or cesium hydroxide, preferably sodium hydride, in a solvent such as tetrahydrofuran, Λ/,Λ/-dimethylformamide, or dimethylsulfoxide, preferably tetrahydrofuran, at a temperature from about -20 to 5O⁰C, followed by addition of an alkyl halide or tosylate, preferably an alkyl iodide.

The compounds of the formula I and their pharmaceutically acceptable salts (hereafter "the active compounds") can be administered via either the oral, transdermal (e.g., through the use of a patch), intranasal, sublingual, rectal, parenteral or topical routes. Transdermal and oral administration are preferred. These compounds are, most desirably, administered in dosages ranging from about 0.25 mg up 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 upon the weight and 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. Variations may nevertheless occur depending upon the weight and condition of the persons being treated and their individual responses to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval during which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day.

The active compounds can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the several routes previously indicated. More particularly, the active compounds can be administered in a wide variety of different dosage forms, OQ., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, transdermal patches, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. In addition, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the active compounds are present in such 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 may be employed along with various disintegrants such as starch (preferably com, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc can be used for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials, in this connection 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 or flavoring agents, coloring matter and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

For parenteral administration, a solution of an active compound in either sesame or peanut oil or in aqueous propylene glycol can be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8), if necessary, and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily 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 way of creams, a patch, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.

The activity of the compounds of the present invention with respect to 5HT₁₆ (formerly 5HT₁₀) binding ability can be determined using standard radioligand binding assays as described in the literature. The 5-HT_1A affinity can be measured using the procedure of Hoyer et al. (Brain Res., 376, 85 (1986)). The 5-HT₁₀ affinity 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-HT₁₀ binding site may be determined according to the following procedure. Bovine caudate tissue is homogenized and suspended in 20 volumes of a buffer containing 50 mM TRIS.hydrochloride (tris[hydroxymethyl]aminomethane 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 resuspended in approximately 20 volumes of 50 mM TRIS.hydrochloride buffer at pH 7.7. This suspension is then pre-incubated for 15 minutes at 37°C, after which the suspension is centrifuged again at 45,000 G for 10 minutes and the supernatant discarded. The resulting pellet (approximately 1 gram) is resuspended in 150 ml of a buffer of 15 mM TRIS.hydrochloride containing 0.01 percent ascorbic acid with a final pH of 7.7 and also containing 10 μM pargyline and 4 mM calcium chloride (CaCI₂). The suspension is kept on ice at least 30 minutes prior to use.

The inhibitor, control or vehicle is then incubated according to the following procedure. To 50 μl of a 20 percent dimethylsulfoxide (DMSO)/80 percent distilled water solution is added 200 μl of tritiated 5-hydroxytryptamine (2 nM) in a buffer of 50 mM TRIS.hydrochloride containing 0.01 percent ascorbic acid at pH 7.7 and also containing 10 μM pargyline and 4 μM calcium chloride, plus 100 nM of 8-hydroxy-DPAT (dipropylaminotetraline) and 100 nM of mesulergine. To this mixture is added 750 μl of bovine caudate tissue, and the resulting suspension is vortexed to ensure a homogenous suspension. The suspension is then incubated in a shaking water bath for 30 minutes at 25°C. After incubation is complete, the suspension is filtered using glass fiber filters (e.g., Whatman GF/B-filters.TM.). The pellet is then washed three times with 4 ml of a buffer of 50 mM TRIS.hydrochloride at pH 7.7. The pellet is then placed in a scintillation vial with 5 ml of scintillation fluid (aquasol 2™) and allowed to sit overnight. The percent inhibition can be calculated for each dose of the compound. An IC₅₀ value can then be calculated from the percent inhibition values.

The activity of the compounds of the present invention for 5-HT_1A binding ability can be determined according to the following procedure. Rat brain cortex tissue is homogenized and divided into samples of 1 gram lots and diluted with 10 volumes of 0.32 M sucrose solution. The suspension is then centrifuged at 900G for 10 minutes and the supemate separated and recentrifuged at 70,000 G for 15 minutes. The supemate is discarded and the pellet re-suspended 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 pre-incubation is complete, the suspension is centrifuged at 70,000 G for 15 minutes and the supemate discarded. The resulting tissue pellet is resuspended in a buffer of 50 mM TRIS.hydrochloride at pH 7.7 containing 4 mM of calcium chloride and 0.01 percent ascorbic acid. The tissue is stored at -70° C until ready for an experiment. The tissue can be thawed immediately prior to use, diluted with 10 μm pargyline and kept on ice.

The tissue is then incubated according to the following procedure. Fifty microliters of control, inhibitor, or vehicle (1 percent DMSO final concentration) is prepared at various dosages. To this solution is added 200 μl of tritiated DPAT at a concentration of 1.5 nM in a buffer of 50 mM TRIS.hydrochloride at pH 7.7 containing 4 mM calcium chloride, 0.01 percent ascorbic acid and pargyline. To this solution is then added 750 μl of tissue and the resulting suspension is vortexed 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 of sodium chloride. The percent inhibition is calculated for each dose of the compound, control or vehicle. IC₅₀ values are calculated from the percent inhibition values.

The agonist and antagonist activities of the compounds of the invention at 5-HT-|_A and 5-HT₁₀ receptors can be determined using a single saturating concentration according to the following procedure. Male Hartley guinea pigs are decapitated and 5-HT_1A receptors are dissected out of the hippocampus, while 5-HTi_D receptors are obtained by slicing at 350 mM on a Mcllwain tissue chopper and dissecting out the substantia nigra from the appropriate slices. The individual tissues are homogenized in 5 mM HEPES buffer containing 1 mM EGTA (pH 7.5) using a hand-held glass-Teflon^® homogenizer and centrifuged at 35,000xg for 10 minutes at 4°C. The pellets are resuspended in 100 mM HEPES buffer 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 mix in each tube contained 2.0 mM MgCI₂, 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 [³²P]-ATP (30 Ci/mmol: NEG-003--New England Nuclear). Incubation is initiated by the addition of tissue to siliconized microfuge tubes (in triplicate) at 30° C. for 15 minutes. Each tube receives 20 μl_ tissue, 10 μL drug or buffer (at 10x final concentration), 10 μL 32 nM agonist or buffer (at 10x final concentration), 20 μL forskolin (3 μM final concentration) and 40 μL of the preceding reaction mix. Incubation is terminated by the addition of 100 μL 2% SDS, 1.3 mM cAMP, 45 mM ATP solution containing 40,000 dpm [³H]-CAMP (30 Ci/mmol: NET- 275~New England Nuclear) to monitor the recovery of cAMP from the columns. The separation of [³²P]-ATP and [³²P]-CAMP is accomplished using the method of Salomon et al., Analytical Biochemistry, 1974, 58, 541-548. Radioactivity is quantified by liquid scintillation counting. Maximal inhibition is defined by 10 μM (R)-δ-OH-DPAT for 5-HT_1A receptors, and 320 nM 5-HT for 5-HT₁₀ receptors. Percent inhibitions by the test compounds are then calculated in relation to the inhibitory effect of (R)-8-OH-DPAT for 5-HT_1A receptors or 5-HT for 5-HT_1D receptors. The reversal of agonist induced inhibition of forskolin-stimulated adenylate cyclase activity is calculated in relation to the 32 nM agonist effect.

The in vitro activity of the compounds in the present invention at the human ether-a-go-go-related gene potassium channel (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. Cells are collected, spun down and the resulting pellet is frozen for future use. On the day of the experiment, frozen 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 KCI and 1 mM MgCI2 (pH to 7.4 at 4 degrees C). The homogenate is then centrifuged at 45,000 G for 10 minutes. The supernatant is decanted and the membrane pellet resuspended by Poiytron in cold 50 mM Tris base containing 10 mM KCI and 1 mM MgCI2 (pH to 7.4 at 4 degrees C) to a 20 mg/mL concentration. PVT WGA SPA beads (PEI treated type A) are weighed out and added to diluted tissue, also to concentration of 20 mg/mL. The membrane / bead solution is then gently rotated (speed 2, high) in a cold room (4°C) for 2 hours on a Roto-Torque (Cole-Palmer Model 7637). Following this preincuabation, the bead slurry is then centrifuged at 1000 rpm for 5 min at 4°C. The supernatant is decanted and the pellet is resuspended to 5 mg/ml membrane and bead concentration in 50 mM Tris base containing 10 mM KCI and 1 mM MgCI2 (pH to 7.4 at 22 degrees C). The resuspended SPA beads / membrane mixture is immediately used in the assay. Beads and membranes are used at a final concentration of 1 mg/well and 25 microgram protein/well, respectively. Dilutions of compounds are made in 10% DMSO / 50 mM Tris buffer (pH 7.4) (at 10 x final concentration - so that the final DMSO concentration is 1 %). To 96 well SPA plates containing drug dilutions, radioligand is added (5 nM final concentration 3H-dofetilide). The incubation is initiated by the addition of tissue/bead slurry. Assay plates incubate for one hour and then radioactivity is quantified using a MicroBeta scintillation counter. The percent inhibition of specific binding can then be calculated.

The compounds of the invention can be tested for in vivo activity for antagonism of 5- HTi_D agonist-induced hypothermia 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 at testing, serve as subjects in the experiment. The guinea pigs are housed under standard laboratory conditions on a 7 a.m. to 7 p.m. lighting schedule for at least seven days prior to experimentation. Food and water are available ad libitum until the time of testing.

The compounds of the invention can be administered as solutions in a volume of 1 ml/kg. The vehicle used is varied depending on compound solubility. Test compounds are typically administered either sixty minutes orally (p.o.) or 0 minutes subcutaneously (s.c.) prior to a 5-HT_1D agonist, such as

[3-(1-methylpyrrolidin-2-ylmethyl)-1H-indol-5-yl]-(3-nitropyridin-3-yl)-amine, which can be prepared as described in PCT publication WO93/11106, published Jun. 10, 1993 which is administered at a dose of 5.6 mg/kg, s.c. Before a first temperature reading is taken, each guinea pig is placed in a clear plastic shoe box containing wood chips and a metal grid floor and allowed to acclimate to the surroundings for 30 minutes. Animals are then returned to the same shoe box after each temperature reading. Prior to each temperature measurement each animal is firmly held with one hand for a 30-second period. 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 or until a stable recording is obtained. Temperatures are then recorded. In p.o. screening experiments, a "pre-drug" baseline temperature reading is made at

-90 minutes, the test compound is given at -60 minutes and an additional -30 minute reading is taken. The 5-HT₁₀ agonist is then administered at 0 minutes and temperatures are taken 30, 60, 120 and 240 minutes later. In subcutaneous screening experiments, a pre-drug baseline temperature reading is made at -30 minutes. The test compound and 5-HT-i_D agonists are given concurrently and temperatures are taken at 30, 60, 120 and 240 minutes later.

Data are analyzed with two-way analysis of variants with repeated measures 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 contracting the dog isolated saphenous vein strip (P.P.A. Humphrey et al., Br. J. Pharmacol., 94, 1128 (1988)). This effect can be blocked by methiothepin, 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 the anesthetized dog. The pharmacological basis of sumatriptan efficacy has been discussed in W. Fenwick et al., Br. J. Pharmacol., 96, 83 (1989).

The serotonin 5-HT-ι agonist activity can be determined by the in vitro receptor binding assays, as described for the 5-HT_1A receptor using rat cortex as the receptor source and [³H]-S-OH-DPAT as the radioligand (D. Hoyer et al. Eur. J. Pharm., 118, 13 (1985)) and as described for the 5-HT_1D receptor using bovine caudate as the receptor source and [³H]serotonin as the radioligand (R. E. Heuring and S. J. Peroutka, J. Neuroscience, 7, 894 (1987)).

All of the exemplified compounds that were tested exhibited a Ki of about 100 nM or less.

The following experimental preparations and examples illustrate, but do not limit the scope of, this invention. Preparation 1

3-(4-Methyl-piperazin-1-vO-pyridine-2-carbaldehvde

A solution of 1-methylpiperazine (54.2 mL, 0.48 moles), potassium carbonate (60 g,

0.43 moles), and 3-fluoro-pyridine-2-carbaldehyde (36.2 g, 0.28 moles) in water (340 mL) and 1 ,4-dioxane (150 mL) was heated at reflux for 2 hours. The solution was cooled to room temperature, poured into water (1000 mL) and extracted with methylene chloride (2 x 700 mL). The combined organic layers were washed with water (2 x 900 mL). The organic layer was dried (MgSO₄), filtered, and the solvent was removed in vacuo to afford 58.5 g of an oil.

MS (AP/CI) 206.3 (M+1). ¹³C NMR (100 MHz, CDCI₃) 46.3, 52.4, 55.1 , 126.7, 128.0, 142.9, 143.7, 150.2, 191.9.

Preparation 2

3-(3,5-Dimethyl-piperazin-1-yl)-pyridine-2-carbaldehvde

The title compound was prepared using the method analogous to that used for Preparation 1. MS (AP/CI) 220.3 (M+H). ¹³C NMR (100 MHz, CDCI₃) 19.7, 50.7, 59.4, 126.7, 127.9, 142.6, 143.6, 150.1, 191.8.

Preparation 3

4-(2-Formyl-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester The title compound was prepared using the method analogous to that used for Preparation 1. MS (AP/CI) 292.3 (M+H). ¹³C NMR (100 MHz, CDCI₃) 28.6, 42.0, 52.3, 80.2, 126.6, 128.0, 143.0, 143.7, 149.7, 154.9, 192.0.

Preparation 4

3-(3,4,5-Trimethyl-piperazin-1-yl)-pyridine-2-carbaldehvde

Formic acid (900 uL, 24 mmol) and 38% formalin (1.05 mL, 14 mmol) were added to a solution of 3-(3,5-dimethyl-piperazin-1-yl)-pyridine-2-carbaldehyde (2.6g, 12mmol) in tetrahydrofuran (13OmL) and water (13mL). After heating at 80° C for 18 hours the cooled reaction mixture was quenched into aqueous sodium bicarbonate and extracted three times with dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated to 2.7 g of gold colored oil (96% yield). MS (AP/CI) 234.3 (M+H). ¹³C NMR (100 MHz, CDCI₃) 18.0, 38.0, 58.0, 59.4, 112.5, 126.5, 128.0, 142.7, 143.5, 192.0. Preparation 5

3-r3-f4-Methyl-piperazin-1-yl)-pyridin-2-ylmethylene1-piperidin-2-one

A solution of 1.5 g (7.1 mmol) of 3-(4-methyl-piperazin-1-yl)-pyridine-2-carbaldehyde and 1.2 g (8.3 mmol) of Λ/-acetylpiperidinone in 10 mL of tetrahydrofuran was slowly added to a 0 ⁰C suspension of 1.2 g (30.0 mmol) of sodium hydride in 10 mL of tetrahydrofuran over a 30 minute period. After 2.5 hours at O⁰C, the reaction was stirred at room temperature for 18 hours. The reaction was then quenched with water and extracted with methylene chloride. The organic layer was dried with sodium sulfate and concentrated to provide a yellow solid. Recrystallization from ethyl acetate and dispropylether provided 960 mg (47% yield) of the title compound as a white solid. MS (AP/CI) 287.3 (M+H). ¹³C NMR (100 MHz₁ CDCI₃) 23.2,

26.5, 42.6, 46.2, 52.2, 55.3, 123.1, 125.4, 131.0, 132.5, 142.6, 149.2, 149.6, 170.0. Preparation 6

3-f3-(4-Methyl-piperazin-1-yl)-pyridin-2-ylmethylene1-pyrrolidin-2-one The title compound was prepared in a procedure analogous to that described in Preparation 5. MS (AP/CI) 273.3 (M+H). ¹³C NMR (100 MHz, CDCI₃) 27.3, 40.3, 46.1 , 52.4, 55.2, 123.1 , 124.7, 125.9, 135.1 , 143.4, 149.0, 149.9, 173.1. Preparation 7

3-f3-(3,4,5-Trimethyl-piperazin-1-ylVpyhdin-2-ylmethylene1-piperidin-2-one The title compound was prepared in a procedure analogous to that described in Preparation 5. MS (AP/CI) 315.4 (M+H). ¹³C NMR (100 MHz, CDCI₃) 18.3, 23.3, 26.6, 38.0,

42.6, 58.0, 59.7, 123.1 , 125.3, 131.0, 132.5, 142.6, 148.7, 149.6, 166.9. Preparation 8

4-|^"2-(2-Oxo-piperidin-3-ylidenemethyl)-pyridin-3-vn-piperazine-1 -carboxylic acid tert-butyl ester

The title compound was prepared in a procedure analogous to that described in Preparation 5. MS (AP/CI) 373.3 (M+H). ¹H NMR (400 MHz, CDCI₃) 1.46 (s, 9H), 1.83-1.93 (m, 2H), 2.91-2.97 (m, 4H), 3.38-3.45 (m, 4H), 3.55 (m, 4H), 7.30-7.33 (m, 1 H), 7.53 (dd, 1 H, J = 5.3 and 1.2 Hz), 7.86 (s, 1h), 8.26 (dd, 1 H, J = 4.9 and 1.2 Hz).

Preparation 9

4-r4-(Tetrahvdro-pyran-4-yl)-phenvπ-morpholin-3-one

4-[4-(Tetrahydro-pyran-4-yl)-phenyl]-morpholine was prepared in a procedure analogous to that described in Buchwald, S. L. Topics in Current Chemistry, Springer-Verlag: Berlin Heidelberg, 2002; Vol. 219, pp. 131-209. MS (APCI) 248.2 (M+H). Diagnostic ¹³C NMR (100 MHz, CDCI₃) 34.3, 40.8, 49.8, 67.2, 68.7, 116.1 , 127.6.

The resultant 4-[4-(Tetrahydro-pyran-4-yl)-phenyl]-morpholine (2.37g, 9.6 mmol), potassium permanganate (4.54g, 29 mmol ) and benzyltriethylammonium chloride (6.59g, 29 mmol) were combined in dichloromethane (60 ml). After heating 4 hours at 45⁰C, the cooled reaction mixture was quenched with aqueous sodium bisulfite and extracted three times with dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated to an oil. Purification by silica gel chromatography provided the title compound as a white foam

(600mg, 24% yield). MS (APCI) 262.2 (M+H). ¹³C NMR (100 MHz, CDCI₃) 34.0, 41.4, 49.9, 64.3, 68.5, 68.8, 125.8, 127.9, 139.7, 145.0, 166.9. Preparation 10

3-r3-(4-Methyl-piperazin-1 -vD-p yridin-2-ylmethvn-piperidin-2-one General Hydrogenation procedure

To a solution of 5.0 g (17.5 mmol) 3-[3-(4-methyl-piperazin-1-yl)-pyridin-2- ylmethylene]-piperidin-2-one in 200 mL of ethanol was added 1.26 g of 10% Pd/C. Hydrogenation at 45 psi with heating to 50 ⁰C was complete after 24 hours. The reaction was filtered over celite using ethanol and concentrated to 5.0 g of oil (99% yield) of the title compound. MS (AP/CI) 289.3 (M+H). ¹³C NMR (100 MHz, CDCI₃) 21.9, 26.2, 34.4, 40.4, 42.6, 46.3, 52.3, 55.6, 121.7, 127.0, 144.0, 148.1 , 156.0, 175.5. Preparation 11

3-f3-(4-Methyl-pipera2in-1-yl)-pyridin-2-ylmethyl]-Pyrrolidin-2-one The title compound was prepared in a procedure analogous to that described in Preparation 10. MS (AP/CI) 275.3 (M+H). ¹³C NMR (100 MHz, CDCI₃) 28.0, 34.0, 40.5, 40.7, 46.0, 52.0, 55.4, 121.9, 127.2, 144.1 , 147.7, 155.7, 181.2. Preparation 12

3-F3-(3,4,5-Trimethyl-piperazin-1-yl)-pyridin-2-ylmethvn-piperidin-2-one The title compound was prepared in a procedure analogous to that described in Preparation 10. MS (AP/CI) 317.4 (M+H). ¹³C NMR (100 MHz, CDCI₃) 18.2, 18.3, 21.9, 26.2, 34.3, 38.0, 40.5, 42.6, 58.4, 59.3, 60.5, 121.7, 126.8, 144.0, 147.7, 156.0, 175.5. Preparation 13

4-f2-(2-Oxo-piperidin-3-ylrnethvO-pyridin-3-yl1-piperazine-1 -carboxylic acid tert-butyl ester

The title compound was prepared in a procedure analogous to that described in Preparation 10. MS (AP/CI) 375.4 (M+H). ¹³C NMR (100 MHz, DMSO) 22.6, 26.6, 28.7, 32.0, 34.0, 42.0, 52.2, 79.6, 123.2, 146.6, 154.4, 173.3. Preparation 14

2-(4-Bromo-phenyl)-propan-2-ol

A solution of methyl p-bromobenzoate (3g, 13.2 mmol) in tetrahydrofuran (14 mL) cooled to -30⁰C was treated dropwise with methyl magnesium bromide (1 M in diethyl ether,

105.5 mmol, 105.5 mL). Upon completion of addition, 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, were filtered, and the solvent was removed in vacuo. Purification by silica gel chromatography (10:1 hexanes - ethyl acetate) gave 2.2 g (79% yield) of 2-(4-bromo-phenyl)- propan-2-ol. ¹³C NMR (100 MHz, CDCI₃) 148.4, 131.4, 126.6, 120.8, 72.5, 31.9; MS (AP/CI) 197.1 , 199.1 (M+H)+.

Preparation 15

2-(5-Bromo-pyridin-2-yl)-propan-2-ol The title compound was prepared using ethyl-5-bromo-2-carboxypyridine, but otherwise followed the general procedure for Preparation 14. ¹³C NMR (100 MHz, CDCI₃) 165.1 , 148.9, 139.7, 120.4, 118.9, 72.2, 30.7; MS (AP/CI) 216.0, 218.1 (M+H)+.

Preparation 16

1-(4-Bromo-phenyl)-cvclopentanol 4-Bromo-1-iodobenzene (5g, 17.7 mmol) in tetrahydrofuran (20 ml.) at -40⁰C was treated dropwise with isopropyl magnesium chloride (2 M solution in tetrahydrofuran, 23 mmol, 11.5 mL) and following addition was stirred 1 hour. Cyclopentanone (1.5 mL, 14.75 mmol) in tetrahydrofuran (5 mL) was added and the solution was allowed to slowly warm to room temperature over 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, were filtered, and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (20:1 hexanes-ethyl acetate) to provide 1-(4-bromo-phenyl)-cyclopentanol. ¹H NMR (400 MHz, CDCI₃) 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, 1H); ¹³C NMR (100 MHz, CDCI₃) d 146.4, 131.4, 127.2, 120.8, 83.4, 42.2, 24.1.

Preparation 17

1-(4-Bromo-phenyl)-cvclobutanol The title compound was prepared using the procedure detailed for Preparation 16 with cyclobutanone in place of cyclopentanone ¹³C NMR (400 MHz, CDCI₃) 145.5, 131.7, 127.1 , 121.3, 76.8, 37.2, 13.2; MS (AP/CI) 209.0, 211.0 (M+H-H2O)+.

Preparation 18

4-(4-Bromo-phenvO-tetrahvdro-pyran-4-ol The title compound was prepared using the procedure detailed for Preparation 16 with 4-oxopyran in place of cyclopentanone. ¹³C NMR (100 MHz, CDCI₃) 38.8, 63.9, 70.6, 121.3, 126.6, 131.7, 147.4.

Preparation 19

4-(4-Bromo-phenyl)-tetrahvdro-pyran A solution of 4-(4-bromo-phenyl)-tetrahydro-pyran-4-ol (859 mg, 3.3 mmol) and triethylsilane (596 uL, 3.7 mmol) in 12 mL dichloromethane was chilled in an ice bath. Trifiuoroacetic acid (2.54 mL, 33 mmol) was added in a dropwise manner over 20 minutes. After 1 hour at 0° C the reaction mixture was stirred at room temperature for 3 hours. 1N aqueous NaOH was added until the aqueous pH remained basic, and the mixture was extracted three times with dichloromethane. The organic extracts were combined, dried over Na₂SO₄ and concentrated to an oily solid. Purification by silica gel chromatography (5:95, ethyl acetate: hexanes) provided the title compound as a white solid (640mg, 80% yield). ¹³CNMR (100 MHZ₁ CDCI₃) 34.0, 41.3, 68.5, 120.2, 128.7, 131.8, 145.0.

Preparation 21

1-bromo-4-(1-methoxy-cvclobutyl)-benzene The title compound was prepared using the procedure detailed for Preparation 20 on the corresponding hydroxyl compound prepared above. ¹³C NMR (100 MHz, CDCI₃) 142.5,

131.6, 128.4, 121.4, 81.3, 50.8, 33.0, 13.1; MS (AP/CI) 209.1 , 211.1 (M+H-OMe)+.

Preparation 22 5-Bromo-2-ethoxy-pyrid ine A solution of freshly prepared sodium ethoxide (sodium, 4.9g, 210 mmol; absolute ethanol, 100 mL, room temperature) was treated with 2,5-dibromopyridine (10g, 42 mmol) and was heated at reflux for 18 hours. After cooling to room temperature, the mixture was poured into aqueous saturated sodium bicarbonate solution, was extracted with diethyl ether, and the ether layer was washed with brine, was dried over magnesium sulfate, was concentrated in vacuo. Purification by silica gel chromatography (100:1 hexanes-ethyl acetate) gave 7.5 g (88% yield) of the title compound. ¹³C NMR (100 MHz, CDCI₃) d 162.9,

147.7, 141.2, 112.9, 111.6, 62.3, 14.7; MS (AP/CI) 202.1 , 204.1 (M+H)+.

Preparation 23

4-(4-Bromo-phenyl)-4-methyl-tetrahydro-pyran The title compound was prepared in an analogous fashion to that found in EP

0501579A1 ¹³C NMR (100 MHz, CDCI₃) 29.2, 35.8, 37.7, 37.8, 64.6, 119.9, 127.7, 127.8, 131.7.

Preparation 24

3-(4-Bromo-phenvD-3-methyl-oxetane Step 1 : 2-(4-Bromo-phenyl)-2-methyl-malonic acid diethyl ester

Sodium methoxide (5.96g, 110.4 mmol) was added to a 0° C solution of 2-(4-bromo- phenyOmalonic acid diethyl ester (29g, 92mmol) in ethanol (200 mL). After 15 minutes iodomethane (6.9ml, 110.4 mmol) was added slowly. The reaction mixture was warmed to room temperature and stirred 18 hours. Additional portions of iodomethane (1.1ml, 22 mmol) and sodium methoxide (1.0g, 22 mmol) were added and the mixture was stirred 66 hours. After quenching into water the mixture was extracted three times with ethyl acetate. The combined organic extracts were dried overMgS0₄ and concentrated to provide 16.8g of the title compound as an oil (55% yield). ¹H NMR (400 MHz, CDCI₃) 1.23-1.25 (m, 6H), 1.83 (s, 3H), 4.19-4.25 (m, 4H), 7.25 (d, 1H, J = 7.4 Hz), 7.46 (d, 1 H, J = 7.4 Hz).

Step 2: 2-(4-Bromo-phenyl)-2-methyt-propane-1 ,3-diol A solution of 2-(4-bromo-phenyl)-2-methyl-malonic acid diethyl ester (10g, 30.3 mmol) in 100 mL diethyl ether was added in a dropwise fashion to a 0° C solution of 1.0 M lithium aluminum hydride (45mL, 45mmol) in 200 mL diethyl ether. After 30 minutes the reaction was warmed to 4O⁰C and heated for 4 hours. After cooling to O⁰C and quenching with aqueous saturated sodium sulfate, the reaction mixture was filtered through Celite and concentrated to a thick oil. Purification by silica gel chromatography (1 :1 , ethyl acetate: hexanes) provided 3.94g of the title compound (53% yield). ¹³C NMR (100 MHz, CDCI₃) 20.9, 44.3, 69.6, 120.8, 126.8, 128.8, 128.9, 131.8, 142.6.

Step 3: 3-(4-Bromo-phenyl)-3-methyl-oxetane

Triphenylphosphine (3.6g, 13.8mmol) was added to a solution of 2-(4-bromo-phenyl)- 2-methyl-propane-1 ,3-diol (1.69g, 6.89 mmol) in 57mL toluene. After stirring 5 minutes, N,N-dimethyldithiacarbonate (3.16g, 10.34mmol) and diethyl azodicarboxylate (2.17 mL, 13.79mmol) were added and the resulting mixture was stirred at room temperature for 18 hours. After filtering through Celite the mixture was concentrated to a solid. The crude product was purified by silica gel chromatography (1 :19-, ethyl acetate: hexanes) to afford 1.26g of the title compound (81 % yield). ¹³C NMR (100 MHz, CDCI₃) 27.8, 43.3, 83.6, 120.3, 127.1 , 131.8, 145.7.

Example 1

2-r3-(4-Methyl-piperazin-1-yl)-pyridin-2-ylmethylene^'|-4-r4-(tetrahvdro-pyran-4-yl)- phenyli-morpholin-3-one A solution of 3-(4-methyl-piperazin-1-yl)-pyridine-2-carbaldehyde (427 mg, 2.1 mmol) and 4-[4-(tetrahydro-pyran-4-yl)-phenyl]-morpholin-3-one (600 mg, 2.3 mmol) in 20 ml tetrahydrofuran was added to a suspension of 252 mg of NaH (6.3 mmol, 60% by weight) in 10 ml tetrahydrofuran. The resulting mixture was heated at 65⁰C for 18 hours. After quenching with water, the mixture was extracted three times with dichloromethane. The combined organic extracts were dried with Na₂SO₄ and concentrated to an oil. Recrystallization from ethyl acetate/ ether provided 427 mg of the title compound as a tan solid (45% yield). MS (AP/CI) 449.4 (M+H). ¹³C NMR (100 MHz, CDCI₃) 34.09, 41.4, 46.2, 49.2, 52.3, 55.4, 65.1, 68.5, 109.4, 122.6, 125.3, 125.8, 127.8, 140.2, 143.6, 144.9, 146.5, 148.5, 160.0. Example 2

4-(4-tert-Butyl-phenyl)-2-r3-(4-methyl-pipera2in-1-yl)-pyridin-2-ylmethylene1- morpholin-3-one

The title compound was prepared in a procedure analogous to that described in Example 1. MS (AP/CI) 421.4 (M+H). Diagnostic ¹³C NMR (100 MHz, CDCI₃) 31.5, 34.7, 46.4, 49.2, 51.4, 55.7, 65.1 , 116.3, 122.5, 124.7, 125.3, 125.8, 126.1 , 143.7, 150.1.

Example 3

2-f3-(4-Methyl-piperazin-1-yl)-pyridin-2-ylmethvn-4-f4-(tetrahvdro-pyran-4-yl)-phenvπ- morpholin-3-one General hvdrogenation procedure for morpholinones

To a solution of 2-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethylene]-4-[4-(tetrahydro- pyran-4-yl)-phenyl]-morpholin-3-one (427 mg, 0.95 mmol) in 50 mL of ethanol was added 427 mg of 10% Pd/ C. Hydrogenation at 40 psi was complete after 24 hours. The mixture was filtered over Celite™ using ethanol and concentrated to an oil. Purification by silica gel flash column chromatography (9:1 , dichloromethane: methanol) provided 126 mg of the title compound as an oil (29% yield). MS (AP/CI) 451.4 (M+H). ¹³C NMR (100 MHz, CDCI₃) 34.1 , 35.6, 41.4, 46.4, 50.4, 52.2, 55.7, 63.4, 68.6, 76.9, 122.1 , 125.9, 127.2, 127.7, 140.6, 143.9, 144.6, 148.0, 153.9, 170.1.

Example 4 4-(4-tert-Butyl-phenyl)-2-|^'3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethvπ-morpholin-3- one

The title compound was prepared in a procedure analogous to that described in Example 3. MS (AP/CI) 423.4 (M+H). ¹³C NMR (100 MHz, CDCI₃) 23.0, 31.5, 34.7, 35.7, 46.1, 50.4, 51.9, 55.5, 63.3, 122.1 , 125.2, 126.3, 127.3, 139.6, 144.1 , 149.9, 154.0 Example 5

H4-(2-lsopropyl-oxazol-4-ylVphenvfl-3-[3-(4-methyl-piperazin-1-v0-pyridin-2- ylmethyli-piperidin-2-one.

The following is a general procedure for copper-mediated coupling used to provide compounds of formula I: A mixture of 3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-piperidin-2-one (250 mg, 0.87 mmol), 4-(4-bromo-phenyl)-2-isopropyl-oxazole (461 mg, 1.74 mmol), copper (I) iodide (66 mg, 0.35 mmol), potassium carbonate (240 mg, 1.74 mmol), and N-N¹- dimethylethylendiamine (74 ul, 0.70 mmol) in toluene (1.5 mL) was stirred at 100⁰C for 24 hours. Copper (I) iodide (66mg, 0.35 mmol) and N-N'-dimethylethylendiamine (74 ul, 0.70 mmol) were added and the reaction mixture was heated at 100⁰C for an additional 24 hours. The mixture was cooled to room temperature, poured into water and extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated to provide 600 mg crude product. Purification by silica gel chromatography (1 :9, methanol : dichloromethane) afforded 135 mg (33% yield) of the title compound. MS (AP/CI) 474.4 (M+H). ¹³C NMR (100 MHz, CDCI₃) 20.7, 22.8, 26.7, 28.8, 34.8, 41.2, 46.3, 51.6, 52.2, 55.7, 121.7, 126.3, 126.5, 127.0, 129.6, 133.0, 140.1 , 143.6, 143.9, 148.1 , 156.0, 169.5, 173.3.

The following compounds were made using the same general procedure as Example 5 using the corresponding lactam derivative and the corresponding N-aryl or N-heteroaryl bromide. Example 6

1-f4-(1-Hvdroxy-cvclopentyl)-phenvπ-3-[3-(4-methylpiperazin1-yl)-pyridin-2-ylmethvn- pyrrolidin-2-one

MS (AP/CI) 435.3 (M+H). ¹³C NMR (100 MHz, CDCI₃) 24.0, 25.3, 34.5, 42.0, 42.9, 46.2, 47.0, 52.2, 55.5, 83.2, 119.5, 122.2, 125.8, 127.4, 138.5, 143.4, 144.0, 147. 9, 155.5, 176.2.

Example 7 1-r6-(1-Hvdroxy-1-methyl-ethyl)-pyridin-3-vπ-3-r3-(4-methyl-piperazin-1-yl)-pyridin-2- ylmethvπ-pyrrolidin-2-one

MS (AP/CI) 410.3 (M+H). ¹³C NMR (100 MHz, CDCI₃) 25.4, 30.9, 34.3, 42.5, 46.1 , 46.4, 52.1 , 55.5, 71.9, 118.7, 122.2, 127.4, 128.4, 135.1 , 138.1 , 144.2, 147.8, 155.1 , 177.0.

Example 8 1 -f4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl1-3-f3-(4-methyl-piperazin-1 -yl)-pyridin-2- ylmethvn-pyrrolidin-2-one

MS (AP/CI) 409.3 (M+H). ¹³C NMR (100 MHz, CDCI₃) 21.9, 25.4, 32.0, 34.6, 43.0, 46.1, 47.0, 52.0, 55.5, 119.6, 122.2, 125.1 , 127.4, 138.5, 144.2, 145.4, 176.3.

Example 9 1-(4-tert-Butyl-phenyl)-3-|^'3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethvn-piperidin-2- one

MS (AP/CI) 421.5 (M+H). ¹³C NMR (100 MHz, CDCI₃) 22.7, 26.3, 31.6, 34.7, 34.9, 41.2, 46.3, 51.8, 52.2, 55.6, 121.8, 125.8, 126.1 , 127.1, 141.3, 143.9, 148.0, 149.4, 156.1 , 173.3. The enantiomers were separable by HPLC: 50/50 heptane/ ethanol; Chiralpak AD, 5 cm x 50 cm; 90 mL/minute. Approximate retention times: t1 = 16 minutes; t2 = 34 minutes. Example lO

3-r3-(4-Methyl-piperazin-1-ylVpyridin-2-ylmβthvn-1-f4-(tetrahvdro-pyran-4-ylVphenvn- piperidin-2-one

MS (AP/CI) 449.4 (M+H). ¹³C NMR (100 MHz, CDCI₃) 22.8, 26.7, 34.1, 35.0, 41.2, 41.4, 46.1 , 51.9, 55.6, 68.6, 121.9, 126.5, 127.0 127.3, 127.6, 128.7, 142.2, 144.1, 144.2,

147.8, 156.1 , 173.3. The enantiomers were separated by HPLC: 95/ 5 Methanol/

Acetonitrile; Chiralpak AD, 10 cm x 50 cm; 275 mL/minute. Approximate retention times: t1 =

17 minutes; t2 = 26 minutes.

Example 11 1-r4-(2-tert-Butyl-oxazol-4-yl)-phenyll-3-f3-(4-methyl-piperazin-1-yl)-pyridin-2- ylmethvπ-piperidin-2-one MS (APCI) 488.3 (M+H). ¹³C NMR (100 MHz, CDCI₃) 22.8, 26.8, 28.8, 34.0, 34.8,

41.2, 46.3, 51.7, 52.2, 55.7, 121.8, 126.3, 126.5, 127.1, 129.7, 133.0, 140.0, 143.5, 143.9, 148.0, 156.0, 171.7, 173.3. The enantiomers were separated by HPLC: 85/15 Heptane/ Ethanol; Chiralpak AD, 5 cm x 50 cm; 85 mL/minute. Approximate retention times: t1 = 19 minutes; t2 = 25 minutes.

Example 12 1-r4-(2-Methyl-oxazol-4-yl)-phenvn-3-f3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethvn- piperidin-2-one MS (AP/CI) 446.3 (M+H). ¹³C NMR (100 MHz, CDCI₃) 14.2, 22.8, 26.7, 34.8, 41.2,

46.3, 51.6, 52.2, 55.7, 121.8, 126.1 , 126.6, 127.0, 129.3, 133.4, 140.5, 143.6, 143.9, 148.0, 156.0, 162.0, 173.3. . The enantiomers were separated by HPLC: 70/30 Heptane/ Ethanol; Chiralpak AD, 5 cm x 50 cm; 85 mL/minute. Approximate retention times: t1 = 19 minutes; t2 = 31 minutes. Example 13

1-f4-(2,5-Dimethyl-oxazol-4-v0-phenyl1-3-[3-(4-metriyl-piperazin-1-yl)-pyridin-2- ylmethyli-piperidin-2-one

MS (AP/CI) 460.2 (M+H). ¹³C NMR (100 MHz, CDCI₃) 11.9, 14.0, 22.8, 26.7, 34.8,

41.2, 46.3, 51.7, 52.2, 55.6, 121.7, 126.4, 127.0, 127.3, 130.7, 134.1 , 142.8, 143.6, 143.9, 148.0, 156.0, 159.2, 173.3. The enantiomers were separated by HPLC: 85/15 heptane/ ethanol; Chiralpak AD, 5 cm x 50 cm; 85 mL/minute. Approximate retention times: t1 = 24 minutes; t2 = 32 minutes.

Example 14

1-(6-lsopropyl-pyridin-3-vn-3-r3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethvn-pyrrolidin-2-one This compound was prepared via an alternative route starting from 140 mg (0.34 mmol) of 1-[6-(1-Hydroxy-1-methyl-ethyl)-pyridin-3-yl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2- ylmeth-yl]-pyrrolidin-2-one (example 7) and treating with 318 mg (2.7 mmoi) of thionyl chloride for 6hrs at room temperature. The solvent was removed and the residue dissolved in 50 mL of ethanol and 500mg of palladium on carbon was added. The mixture was hydrogenated at 40 psi for 5 hrs. The reaction was filtered through celite , the solvent removed and the residue purified by silica gel chromatography to provide the title compound: MS (AP/CI) 394.3 (M+H). ¹³C NMR (100 MHz, CDCI₃) 22.8, 25.4, 34.4, 36.0, 42.5, 46.3, 46.4, 52.3, 55.6, 120.5, 122.1, 127.3, 128.1, 134.3, 139.7, 144.1, 147.9, 155.3, 163.2, 176.8.

Example 15

6'-Ethoxy-3-r3-(4-methyl-piperazin-1-vn-pyridin-2-ylmβthvn-3.4,5,6-tetrahvdro-f1 ,3'1bipyridinyl- 2-one

MS (AP/CI) 410.3 (M+H). ¹³C NMR (100 MHz, CDCI₃) 14.9, 22.9, 26.7, 34.7, 41.0, 46.3, 52.1 , 52.2, 55.7, 62.1, 111.2, 121.8, 127.0, 134.3, 137.7, 143.9, 144.2, 148.0, 155.8, 162.1, 173.8.

Example 16 1-[4-(1-Methoxy-cvclobutyl)-phenvπ-3-r3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethvπ- piperidin-2-one

MS (AP/CI) 449.3 (M+H). ¹³C NMR (100 MHz, CDCI₃) 13.1 , 22.8, 26.7, 33.0. 33.1 ,

34.9, 41.1 , 46.3, 50.7, 51.7, 52.2, 55.7, 81.4, 121.7, 126.1 , 127.0, 127.1, 141.2, 143.0, 143.9,

148.0, 156.0, 173.2. The enantiomers were separated by HPLC: , 65/35 Heptane/ Isopropanol; Chiralpak AD, 5 cm x 50 cm; 75 mL/minute. Approximate retention times: t1 =

18 minutes; t2 = 34 minutes.

Example 17 3-f3-(4-Methyl-piperazin-1-yl)-pyridin-2-ylmethvπ-1-(4-oxazol-4-yl-phenyl)-piperidin-2- one MS (AP/CI) 432.4 (M+H). ¹³C NMR (100 MHz, CDCI₃) 22.8, 26.7, 34.8, 41.2, 46.3,

51.6, 52.2, 55.7, 121.8, 126.4, 126.7, 127.1, 133.9, 140.2, 144.0, 148.0, 151.5, 156.0, 173.4.

Example 18 1-r4-(Tetrahydro-pyran-4-yl)-phβnyl]-3-)^'3-(3,4.5-trimethyl-piperazin-1-vπ-pyridin-2- ylmethyli-piperidin-2-one MS (AP/CI) 477.4 (M+H). ¹³CNMR (100 MHz, CDCI₃) 18.2, 18.3, 22.9, 26.7, 34.1 ,

34.8,

38.0, 41.2, 41.4, 51.8, 58.4, 58.5, 59.6, 60.1 , 68.6, 121.7, 126.5, 126.9, 127.6, 142.2, 143.9, 144.1 , 147.6, 156.0, 173.3. The enantiomers were separated by HPLC: 90/ 10 Heptane/ Ethanol; Chiralpak AD, 5 cm x 50 cm; 85 mL/minute. Approximate retention times: t1 = 31 minutes; t2 = 36 minutes. Example 19

1-)^"4-(2,5-Dimethyl-oxazol-4-ylVphenvn-3-r3-(3,4,5-trinnethyl-piperazin-1-ylVpyridin-2- ylmethvπ-piperidin-2-one

MS (APCI) 488.4 (M+H). ¹³C NMR (100 MHz, CDCI₃) 11.9, 14.1, 18.1, 18.2, 22.8, 26.7, 34.8, 38.0, 41.3, 51.7, 58.6, 59.5, 60.0, 121.8, 126.4, 126.9, 127.3, 130.7, 134.2, 142.9, 143.6, 144.0, 147.6, 156.0, 159.3, 173.3.

Example 20 1-r4-(3,5-Dimethyl-isoxazQl-4-yl)-phenvn-3-f3-(4-methyl-piperazin-1-yl)-pyridin-2- ylmethvπ-piperidin-2-one Step 1 : 1-(4-lodo-phenyl)-piperidin-2-one prepared via the procedure (WO 0349681

A2 20030619) (1.1g, 3.7mmol), potassium phosphate (1.57g, 7.4mmol), tetrakis (triphenylphosphine)palladium (0) (214mg, 0.19mmol) and 3,5-dimethyloxazole-4-boronic acid (780mg, 5.5mmol) were combined in 25ml_ dioxane. After heating at 90° C for 18h, the coooled reaction mixture was poured in aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated to an oil. Purification by silica gel chromatography (4:96, methanol: dichloromethane) afforded 340mg of the title compound as an oil (34% yield). MS (APCI) 271.2 (M+1 ); ¹H NMR^>(400 MHz, CDCI₃) 1.88-1.94 (m, 4H), 2.23 (s, 3H), 2.36 (s, 3H), 2.53 (t, 2H, J = 6.2Hz), 3.62-3.65 (m, 2H), 7.22 (d, 2H, J = 8.4 Hz), and 7.29 (d, 2H, J = 8.4 Hz). Step 2: 1-[4-(3,5-Dimethyl-isoxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)- pyridin-2-ylmethylene]-pipe ridin-2-one was prepared in a procedure analogous to that described in Preparation 5 using 1-[4-(3,5-Dimethyl-isoxazol-4-yl)-phenyl]-piperidin-2-one and 3-(4-Methyl-piperazin-1- yl)-pyridine-2-carbaldehyde. MS (AP/CI) 458.4 (M+H). ¹³C NMR (100 MHz, CDCI₃) 11.1 , 11.8, 23.5, 27.0, 46.1 , 51.7, 52.2, 55.3, 116.4, 123.1 , 125.5, 126.6, 128.2, 129.8, 131.3,

132.9, 138.2, 142.6, 143.4, 149.3, 149.7, 158.9, 165.6

Step 3: The title compound was prepared in a procedure analogous to that described in Prepartion 10. MS (AP/CI) 460.4 (M+H). ¹³C NMR (100 MHz, CDCI₃) 22.6, 23.6, 27.1 , 29.6, 45.5, 51.5, 51.8, 54.9, 109.6, 123.1 , 125.7, 126.1 , 130.8, 132.7, 133.5, 138.8, 142.7, 143.0, 148.8, 149.8, 160.3, 165.5, 196.9.

Example 21 1-r4-(5-Methyl-oxazol-4-yl)-phenvn-3-r3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethvn- piperidin-2-one

MS (AP/CI) 446.4 (M+H). ¹³C NMR (100 MHz, CDCI₃) 11.3, 22.8, 26.6, 34.7, 41.2, 46.3, 51.4, 52.2, 55.6, 121.8, 124.4, 125.7, 126.4, 126.7, 127.0, 143.9, 145.4, 148.0, 155.8, 160.5, 173.4. Example 22

1-(4-lsoxazol-3-yl-phenyl)-3-r3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethvπ-piperidin- 2-one

MS (AP/CI) 432.4 (M+H). ¹³C NMR (100 MHz, CDCI₃) 22.8, 26.6, 34.8, 41.2, 46.3, 51.5, 52.1, 55.6, 102.7, 121.9, 126.7, 126.8, 127.2, 127.7, 144.0, 145.6, 148.0, 155.9, 159.2, 161.2, 173.5.

Example 23 1-r4-(5-Methyl-oxazol-2-vπ-phenvn-3-f3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethvn- piperidin-2-one MS (AP/CI) 446.4 (M+H). ¹³C NMR (100 MHz, CDCI₃) 12.0, 22.9, 26.7, 34.8, 41.2,

46.3, 51.7, 52.2, 55.7, 121.8, 126.5, 127.1 , 127.5, 130.3, 134.0, 143.2, 143.9, 144.4, 148.0, 149.1 , 156.0, 173.4.

Example 24

1-r4-(2-Ethyl-5-methyl-oxazol-4-v0-phenvπ-3-f3-(4-methyl-piperazin-1-vπ-pyridin-2- ylmethvπ-piperidin-2-one

MS (AP/CI) 474.4 (M+H). ¹³C NMR (100 MHz, CDCI₃) 11.7, 11.9, 21.9, 22.8, 26.7,

34.8, 41.2, 46.3, 51.7, 52.2, 55.7, 121.7, 126.4, 127.1 , 127.4, 130.8, 134.0, 142.8, 143.4,

144.0, 148.0, 156.0, 163.6, 173.3. The enantiomers were separated by HPLC: 85/ 15 heptane/ethanol; Chiralpak AD, 2.1 cm x 25 cm; 16 mL/minute. Approximate retention times: t1 = 11 minutes; t2 = 16 minutes.

Example 25

3-f3-(4-Methyl-piperazin-1-vπ-pyridin-2-ylmethyl1-1-r4-(tetrahvdro-pyran-4-yl)-phenvn- pyrrolidin-2-one

MS (AP/CI) 435.4 (M+H). ¹³C NMR (100 MHz, CDCI₃) 25.5, 34.2, 34.6, 41.2, 42.9, 46.3, 47.1 , 52.3, 55.6, 68.6, 120.1 , 122.1 , 127.3, 138.2, 142.1 , 144.1 , 147.9, 155.6, 176.2.

The enantiomers were separated by HPLC: 60/40 heptane/isopropanol/ 0.1% diethylamine;

Chiralpak AD, 10 cm x 25 cm; 275 mL/minute. Approximate retention times: t1 = 11.8 minutes; t2 = 22.4 minutes.

Example 26 1-[4-(2,5-Dimethyl-oxazol-4-yl)-phβnyπ-3-f3-(4-methyl-piperazin-1-yl)-pyridin-2- ylmethvπ-pyrrolidin-2-one

MS (AP/CI) 446.4 (M+H). ¹³C NMR (100 MHz, CDCI3) 12.0, 14.0, 25.3, 34.5, 43.0,

46.2, 46.9, 52.2, 55.5, 119.7, 122.1 , 127.0, 127.3, 128.5, 134.0, 138.8, 143.3, 144.1 , 147.9,

155.5, 159.2, 176.3.The enantiomers were separated by HPLC: 95/5 Methanol/ Acetonitrile; Chiralpak AD, 5 cm x 50 cm; 85 mL/minute. Approximate retention times: t1 = 20 minutes; t2

= 39 minutes. Example 27

3-r3-(4-Methyl-piperazin-1-ylVpyridin-2-ylmethyl1-1-f4-(4-nnethyl-tetrahvdro-pyran-4- yl)-phenyl1-piperidin-2-one

MS (AP/CI) 463.4 (M+H). ¹³C NMR (100 MHz, CDCI₃) 22.8, 26.7, 29.3, 34.9, 35.7, 37.8, 37.9, 41.1, 46.3, 51.7, 52.2, 55.7, 64.6, 121.7, 126.2, 126.4, 127.0, 141.7, 143.9, 147.0, 148.0, 156.0, 173.3.

Example 28 1-(4-lsopropQxy-phenyl)-3-|^'3-(4-nnethyl-piperazin-1-ylVpyridin-2-ylmethyl1-piperidin-2- one MS (AP/CI) 423.4 (M+H). ¹³C NMR (100 MHz, CDCI₃) 22.2, 22.3, 22.8, 26.7, 34.9,

41.1, 46.3, 52.1 , 52.2, 55.7, 70.3, 116.5, 121.7, 127.0, 127.6, 136.8, 143.9, 148.0, 156.1 ,

156.4, 173.3.

Example 29

1-r4-(1-Methoxy-cvclobutyl)-phenvn-3-f3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethvn- pyrrolidin-2-one

MS (AP/CI) 435.4 (M+H). ¹³C NMR (100 MHz, CDCI₃) 13.1 , 25.4, 33.1 , 34.6, 43.0,

46.3, 47.0, 50.6, 52.3, 55.6, 81.3, 119.6, 122.1, 127.1 , 127.2, 139.0, 139.1 , 144.1 , 147.9,

155.5, 176.3. The enantiomers were separated by HPLC: 70/30 heptane/isopropanol/0.1% diethylamine; Chiralpak AD, 10 cm x 25 cm; 275 mL/minute. Approximate retention times: t1 = 6.9 minutes; t2 = 10.6 minutes.

Example 30 1-r4-(3-Methyl-oxetan-3-yl)-phenvn-3-f3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethvn- pyrrolidin-2-one

MS (AP/CI) 421.4 (M+H). ¹³C NMR (100 MHz, CDCI₃) 25.4, 27.9, 34.5, 42.8, 43.1 , 43.2, 46.3, 46.9, 52.3, 55.6, 83.9, 120.0, 122.0, 125.6, 127.2, 138.2, 142.4, 144.0, 147.9, 155.4, 176.2.

Example 31 1-r4-(3-Methyl-oxetan-3-yl)-phenvπ-3-r3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethvπ- piperidin-2-one MS(APCI) 435.5 (M+H). ¹³C NMR (I OO MHZ₁ CDCI₃) 22.8, 26.7, 28.0, 34.8, 41.1,

43.4, 46.3, 51.8, 52.2, 55.7, 83.9, 121.8, 126.0, 126.5, 127.1 , 142.3, 143.9, 144.7, 148.0, 156.0, 173.4. Example 32

4-(2-(2-Oxo-1-r4-(tetrahvdro-pyran-4-yl)-phenvπ-piperidin-3-ylmethyl)-pyridin-3-yl)- piperazine-1-carboxylic acid tert-butyl ester

MS (AP/C!) 535.5 (M+H). ¹³C NMR (100 MHz, CDCI₃) 22.7, 26.8, 28.6, 34.1, 35.0, 41.1 , 41.3, 51.8, 68.6, 80.0, 1 ^*21.9, 126.4, 127.6, 127.7, 142.1 , 144.2, 155.1 , 156.1, 173.1.

The following is a general procedure for deprotection.

Example 33

3-(3-Piperazin-1-yl-pyridin-2-ylmethvπ-1-[4-(tetrahvdro-pyran-4-vlVphenyl^'|-piperidin- 2-one

Trifluoroacetic acid (2.2 mL) was added to a solution of 4-(2-{2-oxo-1-[4-(tetrahydro- pyran-4-yl)-phenyl]-piperidin-3-ylmethyl}-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (800 mg, 1.5 mmol) in 1OmL dichloromethane. After stirring for 13 hours, the mixture was poured into aqueous sodium bicarbonate and extracted three times with dichloromethane. The combined organic extracts were dried with magnesium sulfate and concentrated to an oil. Purification by silica gel chromatography provided 291 mg of the title compound as an oil (45% yield). MS (AP/CI) 435.4 (M+H). ¹³C NMR (100 MHz, CD₃OD)

21.9, 26.0, 33.9, 34.6, 41.1 , 41.3, 45.4, 52.1 , 68.1 , 122.4, 126.5, 127.4, 128.4, 141.9, 143.6,

144.9, 148.5, 155.8, 173.8. The following is a general procedure for alkylation.

Example 34 3-r3-(4-lsobutyl-piperazin-1-ylVpyridin-2-ylmethvπ-1-r4-(tetrahydro-pyran-4-yl)- phenyli-piperidin-2-one

3-(3-Piperazin-1-yl-pyridin-2-ylmethyl)-1-[4-(tetrahydro-pyran-4-yl)-phenyl]-piperidin- 2-one (75 mg, 0.17 mmol) was dissolved in 0.5 mL acetic acid. After addition of isobutyraldehyde (17 uL, 0.19 mmol) the reaction mixture was stirred for 20 minutes. Sodium triacetoxyborohydride (79 mg, 0.38mmol) was added and the resulting mixture was stirred at room temperature for 18 hours. After quenching into aqueous sodium bicarbonate, the mixture was extracted three times with dichloromethane, dried over Na₂SO₄ and concentrated to an oil. Purification by silica gel chromatography provided the title compound (30 mg, 36% yield) as an oil. MS (AP/CI) 491.4 (M+H). ¹³C NMR (100 MHz, CDCI₃) 21.2, 22.8, 25.6, 26.7,

34.1, 41.1 , 41.4, 51.8, 52.3, 54.1, 67.1, 68.6, 121.7, 126.5, 126.9, 127.5, 142.3, 143.7, 144.1,

148.3, 156.0, 173.4. Example 35

3-f3-(4-Ethyl-piperazin-1-vπ-pyridin-2-ylmethyl1-1-f4-(tetrahvdro-pyran-4-ylVDhenvπ- piperidin-2-one

The title compound was prepared in a procedure analogous to that used for Example 34. MS (AP/CI) 463.5 (M+H). ¹³C NMR (100 MHz. CDCI₃) 12.2, 22.8, 26.7, 34.1 , 34.9, 41.1, 41.4, 51.8, 52.2, 52.6, 53.4, 68.6, 121.8, 126.5, 127.1 , 127.6, 142.2, 143.9. 156.1 , 173.3.

Example 36 1-(4-tert-Butyl-phenyl)-3-r3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethylene1-piperidin-

2-one The title compound was prepared in a procedure analogous to that described in

Preparation 5 using 1-(4-tert-Butyl-phenyl)-piperidin-2-one and 3-(4-Methyl-piperazin-1-yl)- pyridine-2-carbaldehyde. MS (AP/CI) 419.5 (M+H). ¹³C NMR (200 MHz. CDCI₃) 23.6, 27.1 , 31.6, 34.8, 46.1 , 51.8, 52.2, 55.4, 123.0, 125.5, 125.7, 126.2, 130.8, 133.3, 141.5, 142.6, 149.2, 149.5, 150.0, 165.5.

Claims

What is claimed:

1. A compound pyridyl-piperazine lactams of the formula

wherein R¹ is a group of the formula G¹, G², G³ or G⁴ depicted below,

wherein R⁶ is selected from the group consisting of hydrogen, (Ci-C₈)alkyl, and (C₃-C₈)cycloalkyl optionally substituted with (C_rC₆)alkoxy or one to three fluorine atoms;

R⁷ and R⁸ are independently selected from hydrogen, (Ci-C₈)alkyl, and (C₃-C₈)cycloalkyl; each R¹³ is, independently, hydrogen, (Ci-C₄)alkyl, (C₃-C₈)cycloalkyl, or a (C^C^alkylene bridge wherein the alkylene bridge is from a carbon of G¹, G³, or G⁴ to another carbon of the same group or to a nitrogen of the same group, or to a carbon of R⁶ of the same group, or the alkylene bridge is from a carbon of G² to another carbon of G², or to a carbon of R⁷ or R⁸, wherein the bridge would be formed by a bond replacing a hydrogen atom on the carbon or nitrogen to which the alkylene is bridged; a is zero to four; m is one to three;

Y is carbon, nitrogen, sulfur, or oxygen;

R³ is -(CH₂)_gB, wherein g is zero to three and B is hydrogen, phenyl, naphthyl or a 5 to 7 membered heteroaryl ring containing from one to four heteroatoms in the ring selected from oxygen, nitrogen and sulfur, with the proviso that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms and wherein said phenyl, naphthyl and heteroaryl rings may optionally be substituted with one to three substituents independently selected from: (1) chloro, fluoro, bromo, iodo, trifluoromethyl, trifluoromethoxy, cyano, -SO_t(C₁ -C₆)alkyl wherein t is zero to two, (Ci-C₈)alkyl, (C₁-C₈)hydroxyalkyl-, (C_rC₈)alkoxy, (C_rC₈)alkoxy-(CrC₈)alkyl-, (C₄-C₈)cycloalkyl-, (C₄-C₈)cycloalkyl-0-, and wherein one to three carbon atoms of each of the foregoing (C₄-C₈)cycloaikyl substituents may be replaced with a heteroatom independently selected from nitrogen, oxygen or sulfur to form a heterocycloalkyl substituent having 4 to 8 atoms, with the proviso that said heterocycloalkyl substituent cannot contain two adjacent oxygen atoms , or two adjacent sulfur atoms, and wherein each (C₄-C₈)cycloalkyl or heterocycloalkyl substituent may be independently substituted with from zero to three substituents independently selected from hydroxy, (C_rC₈)alkoxy, (CrC₈)alkyl, and (CrC^alkyl-aryl wherein said aryl moiety is phenyl or naphthyl; or

(2) phenyl, naphthyl or a 5 to 7 membered heteroaryl ring containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, with the proviso that said heteroaryl ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms, and wherein each independently selected phenyl, naphthyl or heteroaryl substituent may itself be independently substituted with from zero, one, two or three (CrCaJalkyl, (C₄-C₈)cycloalkyl or halo substituents; or

(3) hydroxy, -CH₂OH, -COOH or the lactone formed from hydroxy or -CH₂OH with an ortho -COOH; or

(4) -CONR¹⁴R¹⁵, wherein R¹⁴ and R¹⁵ are independently selected from (C_rC₈)alkyl and benzyl, or R¹⁴ and R¹⁵ together with the nitrogen to which they are attached form a 5 to 7 membered heteroalkyl ring that may contain from zero to three heteroatoms selected from nitrogen, sulfur and oxygen in addition to the nitrogen of the -CONR¹⁴R¹⁵ group, wherein when any of said heteroatoms is nitrogen it may be optionally substituted with (CrCsJalkyl or benzyl, with the proviso that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms; or

(5) -(CH₂)_vN(R¹⁷)COR¹⁶ wherein v is zero to three and -COR¹⁶ and R¹⁷ taken together with the nitrogen to which they are attached form a 4 to 6 membered lactam ring; or

(6) -(CH₂)_VNR¹⁴R¹⁵, wherein v is zero to three and R¹⁴ and R¹⁵ are independently selected from (C_rC₈)alkyl and benzyl, or R¹⁴ and R¹⁵ together with the nitrogen to which they are attached form a 5 to 7 membered heteroalkyl ring that may contain from zero to three heteroatoms selected from nitrogen, sulfur and oxygen; n is 1 , 2 or 3; each broken line independently indicates an optional double bond; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein R³ is (CH₂)_gB wherein g is zero and B is selected from phenyl and pyridyl.

3. The compound of any of claims 1 to 2 wherein B is selected from phenyl or pyridyl each of which is substituted with (C_rC₄)alkyl optionally substituted with hydroxyl, (Ci-C₄)a!koxy/ (C₄-C₆)cycloalkyl optionally substituted with hydroxyl or (Ci-C₄)alkoxy, (C₄-C₆)cycloalkyl wherein a heterocycloalkyl is formed by 1 to 2 carbon atoms being replaced with oxygen and wherein said heterocycloalkyl is optionally substituted with (C₁-C₄)alkyl, or oxazolyl optionally substituted with 1 to 2 (C₁-C₄)alkyl.

4. The compound of claim 3 wherein said heterocycloalkyl is tertrahydropyranyl and oxetanyl each of which is optionally substituted with 1 to 2 (C₁-C₄)alkyl.

5. The compound according to claim 1 wherein said heterocycloalkyl substituent is selected from tetrahydropyranyl, morpholinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, hexahydroazepinyl, diazepinyl, oxazepinyl, thiazepinyl, oxadiazepinyl, thiadiazepinyl, triazepinyl, oxetanyl, or tetrahydrofuranyl, wherein said heterocycloalkyl substituent is optionally substituted with one to three (CrC₈)alkyl, cycloalkyl, alkoxy, or hydroxyl groups.

6. The compound according to claim 1 wherein said heteroaryl is pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, and azaindolyl, wherein said heteroaryl is optionally substituted with (C_rC₈)alkyl, (C₃-C₈)cycloalkyl, alkoxy, or hydroxyl groups.

7. The compound of any of claims 1 to 6 wherein Y is oxygen or carbon and n is 1 or 2 to give a moiety selected from morpholin-3-one, pyrrolidin-2-one, and piperidin-2-one.

8. The compound of claim 1 wherein R⁶ is selected from hydrogen, or methyl, R¹³ is (C_rC₄)alkyl, a is zero to two and m is one.

9. The compound of claim 1 selected from the group consisting of 2-[3-(4-Methyl-piperazin-1-yl)-pyridin-2-ylmethylene]-4-[4-(tetrahydro-pyran-4-yl)- phenyl]-morpholin-3-one,

4-(4-tert-Butyl-phenyl)-2-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethylene]- morpholin-3-one, 2-[3-(4-Methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-4-[4-(tetrahydro-pyran-4-yl)-phenyl]- morpholin-3-one,

4-(4-tert-Butyl-phenyl)-2-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-morpholin-3- one, 1 -[4-(2-lsopropyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2- y!methyl]-piperidin-2-one,

1 -[4-(1 -Hydroxy-cyclopentyl)-phenyl]-3-[3-(4-methylpiperazin1 -yl)-pyridin-2-ylmethyl]- pyrrolidin-2-one,

1 -[6-(1 -Hydroxy-1 -methyl-ethyl)-pyridin-3-yl]-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2- ylmethyl]-pyrrolidin-2-one,

1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2- ylmethyl]-pyrrolidin-2-one,

1-(4-tert-Butyl-phenyl)-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-piperidin-2- one, (+) 1-(4-tert-Butyl-phenyl)-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-piperidin-

2-one,

(-) 1 -(4-tert-Butyl-phenyl)-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2-ylmethyl]-piperidin- 2-one,

3-[3-(4-Methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-1-[4-(tetrahydro-pyran-4-yl)-phenyl]- piperidin-2-one,

(+) 3-[3-(4-Methyl-piperazin-1 -yl)-pyridin-2-ylmethyl]-1 -[4-(tetrahydro-pyran-4-yl)- phenyl]-piperidin-2-one,

(-)3-[3-(4-Methyl-piperazin-1-yi)-pyridin-2-ylmethyl]-1-[4-(tetrahydro-pyran-4-yl)- phenyl]-piperidin-2-one, 1-[4-(2-tert-Butyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2- ylmethyl]-piperidin-2-one,

(+) 1 -[4-(2-tert-Butyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2- ylmethyl]-piperidin-2-one,

(-) 1 -[4-(2-tert-Butyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2- ylmethyl]-piperidin-2-one,

1-[4-(2-Methyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]- piperidin-2-one,

(+) 1 -[4-(2-Methyl-oxazol-4-y!)-phenyl]-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2- ylmethyl]-piperidin-2-one, (-) 1 -[4-(2-Methyl-oxazol-4-yi)-phenyl]-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2- ylmethyl]-piperidin-2-one, 1-[4-(2,5-Dimethyl-oxazol-4-yl)-phenyl]-3-[3-(4-methy!-piperazin-1-yl)-pyridin-2- ylmethyl]-piperidin-2-one,

(+) 1-[4-(2,5-Dimethyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2- ylmethyl]-piperidin-2-one, (-) 1-[4-(2,5-Dimethyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2- ylmethyl]-piperidin-2-one,

1-(6-lsopropyl-pyridin-3-yl)-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]- pyrrolidin-2-one,

6'-Ethoxy-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-3₎4,5,6-tetrahydro- [1 ,3']bipyridinyl-2-one,

1-[4-(1-Methoxy-cyclobutyl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]- piperidin-2-one,

(+) 1-[4-(1-Methoxy-cyclobutyl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2- ylmethyl]-piperidin-2-one, (-) 1-[4-(1-Methoxy-cyclobutyl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2- ylmethyl]-piperidin-2-one,

3-[3-(4-Methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-1-(4-oxazol-4-yl-phenyl)-piperidin-2- one,

1-[4-(Tetrahydro-pyran-4-yl)-phenyl]-3-[3-(3,4,5-trimethyl-piperazin-1-yl)-pyridin-2- ylmethyl]-piperidin-2-one,

(+) 1-[4-(Tetrahydro-pyran-4-yl)-phenyl]-3-[3-(3,4,5-trimethyl-piperazin-1-yl)-pyridiπ-2- ylmethyl]-piperidin-2-one,

(-) 1 -[4-(Tetrahydro-pyran-4-yl)-phenyl]-3-[3-(3,4,5-trimethyl-piperazin-1 -yl)-pyridin-2- ylmethyl]-piperidin-2-one, 1-[4-(2,5-Dimethyl-oxazol-4-yl)-phenyl]-3-[3-(3,4,5-trimethyl-piperazin-1-yl)-pyridin-2- ylmethyl]-piperidin-2-one,

1-[4-(3,5-Dimethyl-isoxazol-4-yl)-phenyl]-3-[3-(4-methy!-piperazin-1-yl)-pyridin-2- ylmethyl]-piperidin-2-one,

1-[4-(5-Methyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]- piperidin-2-one,

1-(4-lsoxazol-3-yl-phenyl)-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-piperidin- 2-one,

1-[4-(5-Methyl-oxazol-2-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]- piperidin-2-one, 1 -[4-(2-Ethyl-5-methyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2- ylmethyl]-piperidin-2-one, (+) 1-[4-(2-Ethyl-5-methyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin- 2-ylmethyl]-piperidin-2-one,

(-) 1 -[4-(2-Ethyl-5-methyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2- ylmethyl]-piperidin-2-one, 3-[3-(4-Methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-1-[4-(tetrahydro-pyran-4-yl)-phenyl]- pyrrolidin-2-one,

(+) 3-[3-(4-Methyl-piperazin-1 -yl)-pyridin-2-ylm8thyl]-1 -[4-(tetrahydro-pyran-4-yl)- phenyl]-pyrro!idin-2-one,

(-) 3-t3-(4-Methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-1-[4-(tetrahydro-pyran-4-yl)- phenyl]-pyrrolidin-2-one,

1-[4-(2,5-Dimethyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2- y!methyl]-pyrrolidin-2-one,

(+) 1-[4-(2,5-Dimethyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2- ylmethyl]-pyrrolidin-2-one, (-) 1 -[4-(2,5-Dimethyl-oxazol-4-yl)-phenyl]-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2- y!methyl3-pyrrolidin-2-one,

3-[3-(4-Methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-1-[4-(4-methyl-tetrahydro-pyran-4- yl)-phenyl]-piperidin-2-one,

1-(4-lsopropoxy-phenyl)-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]-piperidin-2- one,

1-[4-(1-Methoxy-cyclobutyl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]- pyrrolidin-2-one,

(+) 1 -[4-(1 -Methoxy-cyclobutyl)-phenyl]-3-[3-(4-methyl-piperazin-1 -yl)-pyridin-2- ylmethyl]-pyrrolidin-2-one, (-) 1-[4-(1-Methoxy-cyclobutyl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2- yimethyl]-pyrrolidin-2-one,

1-[4-(3-Methyl-oxetan-3-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]- pyrrolidin-2-one,

1-[4-(3-Methyl-oxetan-3-yl)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-pyridin-2-ylmethyl]- piperidin-2-one,

4-(2-{2-Oxo-1-[4-(tetrahydro-pyran-4-yl)-phenyl]-piperidin-3-ylmethyl}-pyridin-3-yl)- piperazine-1-carboxylic acid tert-butyl ester,

3-(3-Piperazin-1-yl-pyridin-2-ylmethyl)-1-[4-(tetrahydro-pyran-4-yl)-phenyl]-piperidin- 2-one, 3-[3-(4-lsobutyl-piperazin-1 -yl)-pyridin-2-ylmethyl]-1 -[4-(tetrahydro-pyran-4-yl)- phenyl]-piperidin-2-one, 3-[3-(4-Ethyl-piperazin-1-yl)-pyridin-2-ylmethyl]-1-[4-(tetrahydro-pyran-4-yl)-phenyl]- piperidin-2-one, and pharmaceutically acceptable salts and optical isomers thereof.

10. A pharmaceutical composition for use in treating a disorder or condition in a mammal selected from depression, anxiety, depression with concomitant anxiety, post traumatic stress disorder, panic phobias, obsessive compulsive disorder (OCD), borderline personality disorder, sleep disorder, psychosis, seizures, dyskinesis, symptoms of Huntington's or Parkinson's diseases, spasticity, suppression of seizures resulting from epilepsy, cerebral ischemia, anorexia, faintness attacks, hypokinesia, cranial traumas, chemical dependencies, premature ejaculation, premenstrual syndrome (PMS) associated mood and appetite disorder, inflammatory bowel disease, modification of feeding behavior, blocking carbohydrate cravings, late luteal phase dysphoric disorder, tobacco withdrawal-associated symptoms, panic disorder, bipolar disorder, sleep disorders, jet lag, cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, chemical dependencies and addictions selected from dependencies on, or addictions to nicotine or tobacco products, alcohol, benzodiazepines, barbiturates, opioids or ***e; headache, stroke, traumatic brain injury (TBI), psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome, comprising an amount of a compound of any of claims 1 to 9, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition and a pharmaceutically acceptable carrier.

11. A method of treating a disorder or condition in a mammal selected from depression, anxiety, depression with concomitant anxiety, post traumatic stress disorder, panic phobias, obsessive compulsive disorder (OCD), borderline personality disorder, sleep disorder, psychosis, seizures, dyskinesis, symptoms of Huntington's or Parkinson's diseases, spasticity, suppression of seizures resulting from epilepsy, cerebral ischemia, anorexia, faintness attacks, hypokinesia, cranial traumas, chemical dependencies, premature ejaculation, premenstrual syndrome (PMS) associated mood and appetite disorder, inflammatory bowel disease, modification of feeding behavior, blocking carbohydrate cravings, late luteal phase dysphoric disorder, tobacco withdrawal-associated symptoms, panic disorder, bipolar disorder, sleep disorders, jet lag, cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, chemical dependencies and addictions selected from dependencies on, or addictions to nicotine or tobacco products, alcohol, benzodiazepines, barbiturates, opioids or ***e; headache, stroke, traumatic brain injury (TBI), psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome, comprising administering to a mammal in need of such treatment an amount of a compound of any of claims 1 to 9, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition.