WO2008026046A1

WO2008026046A1 - Morpholine d3 dopamine antagonists

Info

Publication number: WO2008026046A1
Application number: PCT/IB2007/002492
Authority: WO
Inventors: Travis T. Wager; Ramalakshmi Yegna Chandrasekaran; Todd William Butler
Original assignee: Pfizer Products Inc.
Priority date: 2006-08-30
Filing date: 2007-08-20
Publication date: 2008-03-06

Abstract

The present invention relates to compounds of the formula (I) wherein R1, R2, R3, R4, R5 and R6 are as defined in the specification, to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use as modulators of the dopamine D3 receptor, particularly as psychotherapeutic agents.

Description

D3 Dopamine Antagonists

Background of the Invention

The present invention relates to novel morpholine compounds. The compounds possess valuable therapeutic properties and are suitable, in particular, for treating diseases that respond to modulation of the dopamine D₃ receptor.

Neurons obtain their information by way of G protein-coupled receptors, inter alia. A large number of substances exert their effect by way of these receptors. One of them is dopamine. Confirmed findings exist with regard to the presence of dopamine and its physiological function as a neurotransmitter. Disorders in the dopaminergic transmitter system result in diseases of the central nervous system which include, for example, schizophrenia, depression and Parkinson's disease. These diseases, and others, are treated with drugs which interact with the dopamine receptors.

Up until 1990, two subtypes of dopamine receptor had been clearly defined pharmacologically, namely the D₁ and D₂ receptors. More recently, a third subtype was found, namely the D₃ receptor which appears to mediate some effects of antipsychotics and antiparkinsonians (J. C. Schwartz et a]., The Dopamine D₃ Receptor as a Target for Antipsychotics, in Novel Antipsychotic Drugs, H.Y. Meltzer, Ed. Raven Press, New York 1992, 135-144; M. Dooley et al., Drugs and Aging 1998, 12, 495-514, J.N. Joyce, Pharmacology and Therapeutics. 2001 , 90, 231-59 "The Dopamine D₃ Receptor as a Therapeutic Target for Antipsychotic and Antiparkinsonian Drugs").

Since then, the dopamine receptors have been divided into two families. On the one hand, there is the D₂ group, consisting of D₂, D₃ and D₄ receptors, and, on the other hand, the D₁ group, consisting of D₁ and D₅ receptors. Whereas D₁ and D₂ receptors are widely distributed, D₃ receptors appear to be expressed regioselectively. Thus, these receptors are preferentially to be found in the limbic system and the projection regions of the mesolimbic dopamine system, especially in the nucleus accumbens, but also in other regions, such as the amygdala. Because of this comparatively regioselective expression, D₃ receptors are regarded as being a target having few side-effects and it is assumed that while a selective D₃ ligand would have the properties of known antipsychotics, it would not have their dopamine D₂ receptor-mediated neurological side-effects (P. Sokoloff et al.. Localization and Function of the D₃ Dopamine Receptor, M/45293 Arzneim. Forsch./Drug Res. 42(1 ). 224 (1992); P. Sokoloff et al. Molecular Cloning and Characterization of a Novel Dopamine Receptor (D₃) as a Target for Neuroleptics, Nature, 347. 146 (1990)).

WO 99/58499 discloses phenylsulfonamide substituted phenethylamines having an affinity for the dopamine D₃ receptor. The phenyl ring of the phenylsulfonamide moiety preferably carries a radical selected from C^Cralkyl, halogen, OCH₃, OCF₃, CF₃, CN, SCH₃ or NHCOCH₃. These compounds are selective for the Dopamine D₃ receptor and possess only modest affinities for the dopamine D₂ receptor. They have therefore been proposed as being suitable for treating diseases of the central nervous system. Unfortunately, their affinity for the D₃ receptor or their pharmacological profile is not satisfactory. Consequently there is an ongoing need to provide new compounds, which have either high affinity or improved selectivity. The compounds should also have good pharmacological profile, e.g. a high brain plasma ratio, a high bioavailability, metabolic stability or a decreased inhibition of the mitochondrial respiration.

Summary of the Invention

The present invention relates to a pharmaceutical composition for the treatment of depression or anxiety in a mammal, including a human, comprising: (a) a dopamine D₃ receptor antagonist of the formula I, as depicted and defined below,

I or a pharmaceutically acceptable salt thereof, wherein: R¹ is hydrogen or d-C₈-alkyl optionally substituted with 1 to 3 halogens;

R² is selected from the group consisting of hydrogen, C<ι-C₆-alkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₃-C₆-cycloalkyl, CVCβ-alkoxy, fluorinated C-i-Cβ-alkyl, fluorinated C₃- C₆-cycloalkyl, fluorinated CrCβ-alkoxy, CrCβ-hydroxyalkyl, d-Ce-alkoxy-d-C^alkyl, C₁- C₆-hydroxyalkoxy, d-Ce-alkoxy-d-C^alkoxy, COOH, NR⁷R⁸, CH₂NR⁷R⁸, ONR⁷R⁸, NHC(O)NR⁷R⁸, C(O)NR⁷R⁸, SO₂NR⁷R⁸, C_rC₆-alkylcarbonyl, fluorinated C_rC₆-alkylcarbonyl, d-Ce-alkylcarbonylamino, fluorinated CrCβ-alkylcarbonyl- amino, CrCβ-alkylcarbonyloxy, fluorinated CrCβ-alkylcarbonyloxy, d-Ce-alkoxycarbonyl, d-Cβ-alkylthio, fluorinated C₁-C₆- alkylthio, d-Cβ-alkylsulfinyl, CrC₆-alkylsulfonyl, fluorinated d-Cβ-alkylsulfinyl, fluorinated C₁- C₆-alkylsulfonyl, phenylsulfonyl, phenyl, phenoxy, benzyloxy, and a 3- to 7-membered heterocyclic ring, wherein said phenylsulfonyl, phenyl, phenoxy, benzyloxy, and heterocyclic ring may be optionally substituted with 1 to 4 substituents selected from halogen, cyano, OH, oxo, and cyano;

R³ is selected from hydrogen, halogen, cyano, nitro, OH, methyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy and trifluoromethoxy; or optionally, when R² and R³ are bound to two adjacent carbon atoms, R² and R³ together with the two carbons to which they are attached, form a 5- or 6-membered heterocyclic or carbocylic ring; wherein said ring is optionally substituted with 1 to 4 substituents selected from halogen, NO₂, NH₂, OH, cyano_, Ci-C₆-alkyl, C₃-C₆-cycloalkyl, C₁- C₆-alkoxy, fluorinated C_rC₆-alkyl, fluorinated C₃-C₆-cycloalkyl, fluorinated CrC₆-alkoxy, C₁- C₆~hydroxyalkyl, C₁-C₄-alkoxy-C₂-C₄-alkyl, d-C₆-hydroxyalkoxy, d-C₄-alkoxy-C₂-C₄-alkoxy, d-C₆-alkylcarbonyl, d-C₆-alkylamino, di- d-C₆-alkylamino, d-Cβ-alkylaminocarbonyl, di-d- C₆-alkylaminocarbonyl, fluorinated d-Cβ-alkylcarbonyl, d-Cβ-alkylcarbonylamino, fluorinated d-Cβ-alkylcarbonylamino, d-Cε-alkylcarbonyloxy, fluorinated d-Cβ-alkylcarbonyloxy, C₁-C₆- alkoxycarbonyl, d-Cβ-alkylthio, fluorinated d-Cβ-alkylthio, d-C₆-alkylsulfinyl, C₁-C₆- alkylsulfonyl, fluorinated d-C₆-alkylsulfinyl, and fluorinated d-C₆-alkylsulfonyl;

R⁴ is hydrogen, d-C₈-alkyl, or a 5-6-membered aryl optionally substituted with 1 to 3 substituents selected from halo, -OCH₃, -OCF₃, -CF₃, and cyano; or

R¹ and R⁴ may be combined to form a 5 to 7 member carbocyclic ring;

R⁵ is hydrogen or d-C₈-alkyl;

R⁶ is selected from hydrogen, halo, d-C₈-alkyl, -OCH₃, -OCF₃, -CF₃, and cyano; and

R⁷ and R⁸ are independently selected from H, d-C₃-alkyl, d-C₃-alkoxy and fluorinated C_rC₃-alkyl.

This invention also relates to a method of treating schizophrenia in a mammal, especially in a human, comprising administering to said mammal a pharmaceutical composition comprising: (a) a dopamine D₃ receptor antagonist, or pharmaceutically acceptable salt thereof, of the formula I as defined above; and (b) a pharmaceutically acceptable carrier; wherein the active agent is present in an amount effective in treating schizophrenia.

The present invention also relates to a pharmaceutical composition for the treatment of schizophrenia in a mammal, especially in a human, comprising administering to said mammal a pharmaceutical composition comprising: (a) a dopamine D₃ receptor antagonist, or pharmaceutically acceptable salt thereof, of the formula I as defined above; and (b) a pharmaceutically acceptable carrier; wherein the active agent is present in an amount effective in treating schizophrenia.

Unless otherwise indicated, the term "halo", as used in the compounds of formula I, includes fluoro, chloro, bromo and iodo.

Unless otherwise indicated, the term "alkyl", as used in the compounds of formula I, may be straight, branched or cyclic, and may include straight and cyclic moieties as well as branched and cyclic moieties.

Unless otherwise indicated, the term "alkenyl", as used in the compounds of formula I, includes unsaturated hydrocarbon radicals having one or more double bonds connecting two carbon atoms, wherein said hydrocarbon radical may have straight, branched or cyclic moieties or combinations thereof. Examples of "alkenyl" groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl and dimethylpentenyl, and include E and Z forms where applicable. Unless otherwise indicated, the term "alkynyl", as used in the compounds of formula I, includes unsaturated hydrocarbon radicals having one or more triple bonds connecting two carbon atoms, wherein said hydrocarbon radical may have straight, branched or cyclic moieties or combinations thereof. Unless otherwise indicated, the term "heteroaryl", as used in the compounds of formula I, refers to aromatic groups containing one or more heteroatoms (O, S, or N), preferably from one to four heteroatoms. Unless otherwise indicated, a multicyclic group containing one or more heteroatoms wherein at least one ring of the group is aromatic is also a "heteroaryl" group for purposes of the present invention. The heteroaryl groups of the compounds of this invention can also include ring systems substituted with one or more oxo moieties. Examples of heteroaryl groups are pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thiophenyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrrolopyrimidinyl and azaindolyl.

Unless otherwise indicated, the term "heterocyclic", as used in the compounds of formula I, refers to non-aromatic cyclic groups containing one or more heteroatoms, preferably from one to four heteroatoms, each selected from O, S and N. Unless otherwise indicated, "heterocyclic" includes heterobicyclic groups. "Heterobicyclic" refers to non-aromatic two-ringed cyclic groups, wherein said rings share one or two atoms, and wherein at least one of the rings contains a heteroatom (O, S, or N). Unless otherwise indicated, for purposes of the present invention, heterobicyclic groups include spiro groups and fused ring groups. In one embodiment, each ring in the heterobicyclic group contains up to four heteroatoms (i.e., from zero to four heteroatoms, provided that at least one ring contains at least one heteroatom). The heterocyclic groups of this invention can also include ring systems substituted with one or more oxo moieties. Examples of heterocyclic groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, 1 ,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinyl, morpholino, thiomorpholino, thiazolidinyl, thioxanyl, pyrrolinyl, indolinyl, 2H- pyranyl, 4H-pyranyl, dioxanyl, 1 ,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[4.1.0]heptanyl, quinolizinyl, quinuclidinyl, 1 ,4-dioxaspiro[4.5]decyl, 1 ,4- dioxaspiro[4.4]nonyl, 1 ,4-dioxaspiro[4.3]octyl and 1 ,4-dioxaspiro[4.2]heptyl. The foregoing groups, heteroaryl or heterocyclic, may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N- attached) or pyrrol-3-yl (C-attached). The terms referring to the groups also encompass all possible tautomers. Preferred embodiments of the invention are those in which:

R¹ is independently H or a C₁-C₈ alkyl including isomeric forms thereof, optionally substituted with 1 to 3 halogens (preferable F);

R² is H, CrC₃ alkyl including isomeric forms thereof, halogens (preferably, Cl, F and Br), OCH₃ , OCF₃ , CF₃ , CN, SCH₃ or NHCOCH₃; R³ is H₁ C₁-C₃ alkyl including isomeric forms thereof, halogens (preferably, Cl, F and

Br), OCH₃ , OCF₃ , CF₃ , CN, SCH₃ or NHCOCH₃;

R⁴ is H, or a C₁-C₈ alkyl, aryl optionally substituted with 1 to 3 groups selected from, but not limited to halogens, 0CH3, OCF3, CF3, or CN;

R⁵ is H, or C₁-C₃ alkyl; R⁶ is H or a C₁-C₈ alkyl, halogens, OCH₃, OCF₃, CF₃, or CN.

In Formula I, the sulfonamide is depicted to be at either the meta or para position relative to the point of attachment of the heterocyclic morpholine ring to the benzene ring.

More preferred embodiments of the invention are those in which:

R¹ is independently H or a C₁-C₄ alkyl including isomeric forms thereof, optionally substituted with 1 to 3 halogens (preferable F);

R² is H, C₁-C₃ alkyl including isomeric forms thereof, halogens (preferably, Cl, F and Br), CF₃ or CN;

R³ is H, C₁-C₃ alkyl including isomeric forms thereof, halogens (preferably, Cl, F and Br); R⁴ is H, or a C₁-C₈ alkyl;

R⁵ is H;

R⁶ is H or a C₁-C₃ alkyl, fluoro, OCH₃, CF₃, or CN.

In Formula I, the sulfonamide is depicted to be at either the meta or para position relative to the point of attachment of the heterocyclic morpholine ring to the benzene ring. Exemplary compounds of formula I in accordance with the present invention are the following:

4-lsopropyl-N-(4-(octahydropyrido[2,1-c][1 ,4]oxazin-3-yl)phenyl)benzenesulfonamide;

N-(4-(4-Ethylmorpholin-2-yl)phenyl)-4-isopropylbenzenesulfonamide;

N-(4-(4-Ethylmorpholin-2-yl)phenyl)-4-isopropyl-N-methylbenzenesulfonamide; N-(4-(4-Ethylmorpholin-2-yl)-3-methoxyphenyl)-4-isopropylbenzenesulfonamide;

N-(4-(4-Ethylmorpholin-2-yl)-2-methoxyphenyl)-4-isopropylbenzenesulfonamide;

N-(4-(4-Ethylmorpholin-2-yl)-2-fluorophenyl)-4-isopropylbenzenesulfonamide; N-(4-(4-Ethylmorpholin-2-yl)-3-fluorophenyl)-4-isopropylbenzenesulfonamide;

N-(4-(4-Ethylmorpholin-2-yl)-2-methylphenyl)-4-isopropylbenzenesulfonamide;

N-(4-(4-Ethylmorpholin-2-yl)-2-methyphenyl)-pyrrolidine-1 -sulfonamide;

N-(4-(4-Ethylmorpholin-2-yl)-3-methylphenyl)-4-isopropylbenzenesulfonamide; N-(4-(4-Ethylmorpholin-2-yl)-3-methylphenyl)-1 ,2-dimethyl-1 H-imidazole-4-sulfon- amide;

N-(4-((2S,5S-4-Ethyl-5-methylmorpholin-2-yl)-phenyl)-4- isopropylbenzenesulfonamide;

N-(4-((2R,5S-4-Ethyl-5-methylmorpholin-2-yl)-phenyl)-4- isopropylbenzenesulfonamide;

[4-(4-Ethylmorpholin-2-yl)-phenyl]-4-isopropyl-benzenesulfonamide;

[4-(4-Ethylmorpholin-2-yl)-phenyl]-3-fluoro-4-methoxybenzenesulfonamide;

3-{4-[4-(4-Ethylmorpholin-2-yl)-phenylsulfamoyl]-phenyl}-propionic acid methyl ester;

2-Oxo-2H-chromene-6-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide; C-(3,4-Dichlorophenyl)-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-methanesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-C-(4-trifluoromethylphenyl)-methanesulfon- amide;

4-Methylthiophene-2-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

Benzo[b]thiophene-2-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide; C-(3,5-Dichlorophenyl)-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-methanesulfonamide;

C-(4-Chlorophenyl)-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-methanesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-C-(3-trifluoromethyl-phenyl)-methanesulfon- amide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2,4-dimethoxy-benzenesulfonamide; C-(3-Chlorophenyl)-N-[4-(4-ethyl-morpholin-2-yl)-phenyl]-methanesulfonamide;

2-Ethoxy-N-[4-(4-ethyl-morpholin-2-yl)-phenyl]-4-methylbenzenesulfonamide;

5-Methylthiophene-2-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

2,5-Dimethylthiophene-3-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

S-Methylthiophene^-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide; 4-[4-(4-Ethylmorpholin-2-yl)-phenylsulfamoyl]-2,5-dimethylfuran-3-carboxylic acid methyl ester;

4-Methyl-3,4-dihydro-2H-benzo[1 ,4]oxazine-7-sulfonic acid [4-(4-ethylmorpholin-2-yl)- phenyl]-amide;

5-Methyl-2-trifluoromethylfuran-3-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]- amide;

5-[4-(4-Ethylmorpholin-2-yl)-phenylsulfamoyl]-2-methylfuran-3-carboxylic acid methyl ester; Benzo[b]thiophene-3-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide; β-Morpholin^-ylpyridine-S-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

N-[4-(4-Ethyl-morpholin-2-yl)-phenyl]-4-fluoro-2-methyl-benzenesulfonamide; i-^-^-Ethyl-morpholin^-ylJ-phenylsulfamoyll-piperidine-S-carboxylic acid ethyl ester; δ-Methyl-i-phenyl-I H-pyrazole^-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]- amide;

2,4-Dimethyl-thiazole-5-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

5-Pyridin-2-yl-thiophene-2-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

1-[4-(4-Ethylmorpholin-2-yl)-phenylsulfamoyl]-piperidine-4-carboxylic acid ethyl ester; Piperidine-1 -sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

Benzothiazole-6-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2-methylbenzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2,5-dimethylbenzenesulfonamide;

5-Bromo-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-2-methoxybenzenesulfonamide; N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide;

3,5-Dimethylisoxazole-4-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2,5-dimethoxybenzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-5-fluoro-2-methylbenzenesulfonamide;

5-Chloro-1 ,3-dimethyl-i H-pyrazole-4-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]- amide;

5-Chloro-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-2-methoxy-benzenesulfonamide;

4-Bromo-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-2-methyl-benzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-3,4-difluorobenzenesulfonamide;

3-Chloro-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-4-methylbenzenesulfonamide; N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-3-fluorobenzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2-trifluoromethoxy-benzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-benzenesulfonamide;

Naphthalene-2-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-4-methylbenzenesulfonamide; 4-Chloro-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-benzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2,4-dimethyl-benzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-3-methylbenzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-4-fluorobenzenesulfonamide;

4-tert-Butyl-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-benzenesulfonamide; N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2-methoxy-5-methylbenzenesulfonamide;

2-Bromo-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-benzenesulfonamide;

Naphthalene-1 -sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide; 3-Chloro-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-benzenesulfonamide;

3-Chloro-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-2-methylbenzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2,4-difIuoro-benzenesulfonamide;

2-Chloro-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-4-fluoro-benzenesulfonamide; N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-4-propyl-benzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2-fluorobenzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2-methoxy-4-methyl-benzenesulfonamide;

4-Ethyl-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-benzenesulfonamide;

Thiophene-2-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide; 3-Chloro-propane-1 -sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2,4,6-trimethyl-benzenesulfonamide;

4-Butoxy-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-benzenesulfonamide;

Benzo[1 ,2,5]oxadiazole-4-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

(E)-2-Phenyl-ethenesulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide; N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-4-vinyl-benzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-4-fluoro-3-trifluoromethyl-benzenesulfonamide;

1 ,2-Dimethyl-1 H-imidazole-4-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-4-formyl-benzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-3-trifluoromethoxy-benzenesulfonamide; and 4-Acetyl-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-benzenesulfonamide.

Most preferred compounds of the invention include:

N-(4-(4-Ethylmorpholin-2-yl)phenyl)-4-isopropylbenzenesulfonamide;

N-(4-(4-Ethylmorpholin-2-yl)-2-methoxyphenyl)-4-isopropylbenzenesulfonamide;

N-(4-(4-Ethylmorpholin-2-yl)-2-fluorophenyl)-4-isopropylbenzenesulfonamide;

N-(4-(4-Ethylmorpholin-2-yl)-3-fluorophenyl)-4-isopropylbenzenesulfonamide;

N-(4-(4-Ethylmorpholin-2-yl)-2-methylphenyl)-4-isopropylbenzenesulfonamide; and N-(4-(4-Ethylmorpholin-2-yl)-3-methylphenyl)-4-isopropylbenzenesulfonamide.

The present invention also relates to novel intermediates of the formula III,

wherein: R¹, R⁵ and R⁶ are as previously defined;

R⁴ is C_rC₈-alkyl, or a 5-6-membered aryl optionally substituted with 1 to 3 substituents selected from halo, -OCH₃, -OCF₃, -CF₃, and cyano;

R⁹ is hydrogen or OH; and Z is NH₂ or NO₂.

Examples of specific compounds of the formula III are: (5S)-4-Ethyl-5-methyl-2-(4-nitrophenyl)morpholin-2-ol; (5S)-4-Ethyl-5-methyl-2-(4-nitrophenyl)morpholine; 4-((5S)-4-Ethyl-5-methylmorpholin-2-yl)benzenamine; 4-((2R,5S)-4-Ethyl-5-methylmorpholin-2-yl)benzenamine; and

4-((2S,5S)-4-Ethyl-5-methylmorpholin-2-yl)benzenamine.

The term "treating", as used herein, refers to reversing, alleviating, or inhibiting the progress of the disease, disorder or condition, or one or more symptoms of such disease, disorder or condition, to which such term applies. Depending on the condition of the patient, as used herein, this term also refers to preventing a disease, disorder or condition, and includes preventing the onset of a disease, disorder or condition, or preventing the symptoms associated with a disease, disorder or condition. As used herein, this term also refers to reducing the severity of a disease, disorder or condition or symptoms associated with such disease, disorder or condition prior to affliction with the disease, disorder or condition. Such prevention or reduction of the severity of a disease, disorder or condition prior to affliction refers to administration of the composition of the present invention, as described herein, to a subject that is not at the time of administration afflicted with the disease, disorder or condition.

"Preventing" also refers to preventing the recurrence of a disease, disorder or condition or of symptoms associated with a disease, disorder or condition. The terms "treatment" and "therapeutically" refer to the act of treating, as defined above.

The term "mammal", as used herein, refers to any member of the class "Mammalia", including, but not limited to, humans, dogs and cats.

The pharmaceutical compositions and methods of this invention comprise, or comprise administering, dopamine D₃ receptor antagonists of formulae I which may have chiral centers and therefore may exist in different enantiomeric forms. This invention includes methods and pharmaceutical compositions, as described above, wherein the dopamine D₃ receptor antagonists of formulae I that are employed are optical isomers, tautomers or stereoisomers of the compounds of formulae I, as defined above, or mixtures thereof.

The present invention also relates to pharmaceutical compositions and methods comprising, or comprising administering, pharmaceutically acceptable acid addition salts of dopamine D₃ receptor antagonists of formulae I. The compounds of the formula I which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to a mammal, preferably a human, it is often desirable in practice to initially isolate a compound of the formula I from the reaction mixture as a pharmaceutically acceptable salt and then covert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts are prepared in a customary manner by mixing the free base of the compound of formula I with a substantially equivalent amount of the corresponding inorganic or organic acid, where appropriate, in an aqueous solvent medium or in a solution in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, an ether such as methyl tert-butyl ether or diisopropyl ether, a ketone, such as acetone or methyl ethyl ketone, or an ester, such as ethyl acetate. The desired salt may then be isolated by filtration of the precipitated solid or by careful evaporation of the solvent used in the salt formation.

The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the basic compounds of this invention are those which form non-toxic addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, malate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e., 1 ,1 '-methylenebis-(2- hydroxy-3-naphthoate)] salts.

Those compounds of the formula I which are also acidic in nature, e.g., which contain a carboxylate group, are capable of forming base addition salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and, in particular, the sodium or potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the herein described acidic compounds of formula I. Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine (meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

These salts can be easily prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds of formula I and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, approximately stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum product yields.

Those dopamine D₃ receptor antagonists of formulae I that contain acidic groups can form base addition salts with certain bases. The present invention also relates to pharmaceutical compositions and methods comprising, or comprising administering, pharmaceutically acceptable base addition salts of dopamine D₃ receptor antagonists of formulae I. The chemical bases that may be used as reagents to prepare the pharmaceutically acceptable base salts of the acidic active agents that are employed in the methods and pharmaceutical compositions of this invention are those that form non-toxic base salts with such compounds.

The present invention also relates to pharmaceutical compositions and methods of treatment or prevention that employ isotopically-labeled compounds that are identical to those recited in formulae I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the dopamine D₃ receptor antagonists of formulae I, that are employed in the pharmaceutical compositions and methods of the present invention, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹¹C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶CI, respectively. The dopamine D₃ receptor antagonists of formulae I employed in the pharmaceutical compositions and methods of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of such compounds or of such prodrugs which contain the aforementioned isotopes and/or other isotopes are within the scope of this invention. Such compounds may be useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays. Certain isotopically-labeled dopamine D₃ receptor antagonists of formulae I, for example, those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically-labeled dopamine D₃ receptor antagonists of formulae I and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and discussion of the schemes below and substituting a readily available isotopically-labeled reagent for a nonisotopically-labeled reagent.

The compounds of formula I may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antipsychotic agents (e.g., clozapine, olanzapine, quetiapine, risperidone, ziprasidone, haloperidol, aripiprazole), antidepressant agents such as tricyclic antidepressants (e.g., amitriptyline, dothiepin, doxepin, trimipramine, butriptyline, clomipramine, desipramine, imipramine, iprindole, lofepramine, nortriptyline or protriptyline), monoamine oxidase inhibitors (e.g., isocarboxazid, phenelzine or tranylcyclopramine), 5-HT re-uptake inhibitors (e.g., fluvoxamine, sertraline, fluoxetine or paroxetine), serotonin-1 B antagonists (e.g., elzasonan), serotonin-2A antagonists (e.g., eplivanserin, MDL-100907), histamine-3 antagonists or agonists (e.g., cipralisant, ABT239, TISQ, GSK-189254A) and / or with antiparkinsonian agents such as dopaminergic antiparkinsonian agents (e.g., levodopa, preferably in combination with a peripheral decarboxylase inhibitor e.g., benserazide or carbidopa, or with a dopamine agonist e.g., bromocriptine, lysuride or pergolide). It is to be understood that the present invention covers the use of a compound of general formula I or a physiologically acceptable salt or solvate thereof in combination with one or more other therapeutic agents.

The present invention relates to pharmaceutical compositions and methods of treatment or prevention of disorders, the treatment or prevention of which is facilitated by dopamine D₃ receptor inhibition in a mammal, comprising: a) a pharmaceutically acceptable carrier; b) a compound of the formula I or a pharmaceutically acceptable salt thereof; and c) a serotonin reuptake inhibitor (SRI), wherein the amounts of each of the active compounds (i.e., the compound of formula

I and the SRI) are such that the combination is effective in treating or preventing such condition.

The present invention also relates to pharmaceutical compositions and methods of treatment or prevention of disorders, the treatment or prevention of which is facilitated by dopamine D₃ receptor inhibition in a mammal, comprising: a) a pharmaceutically acceptable carrier; b) a compound of the formula I or a pharmaceutically acceptable salt thereof; and c) a serotonin-2A (5HT_2A) receptor antagonist, wherein the amounts of each of the active compounds (i.e., the compound of formula I and the serotonin-2A (5HT_2A) receptor antagonist) are such that the combination is effective in treating or preventing such condition.

The present invention also relates to pharmaceutical compositions and methods of treatment or prevention of disorders, the treatment or prevention of which is facilitated by dopamine D₃ receptor inhibition in a mammal, comprising: a) a pharmaceutically acceptable carrier; b) a compound of the formula I or a pharmaceutically acceptable salt thereof; and c) a serotonin-1B (5HT_1B) receptor antagonist, wherein the amounts of each of the active compounds (i.e., the compound of formula I and the serotonin-1B (5HT_1B) receptor antagonist) are such that the combination is effective in treating or preventing such condition.

The present invention also relates to pharmaceutical compositions and methods of treatment or prevention of disorders, the treatment or prevention of which is facilitated by dopamine D₃ receptor inhibition in a mammal, comprising: a) a pharmaceutically acceptable carrier; b) a compound of the formula I or a pharmaceutically acceptable salt thereof; and c) a serotonin-2C (5HT₂c) receptor antagonist, wherein the amounts of each of the active compounds (i.e., the compound of formula

I and the serotonin-2C (5HT₂c) receptor antagonist) are such that the combination is effective in treating or preventing such condition.

The present invention also relates to pharmaceutical compositions and methods of treatment or prevention of disorders, the treatment or prevention of which is facilitated by dopamine D₃ receptor inhibition in a mammal, comprising: a) a pharmaceutically acceptable carrier; b) a compound of the formula I or a pharmaceutically acceptable salt thereof; and c) a histamine-3 (H₃) receptor antagonist, wherein the amounts of each of the active compounds (i.e., the compound of formula I and the histamine-3 (H₃) receptor antagonist) are such that the combination is effective in treating or preventing such condition.

A "unit dosage form" as used herein is any form that contains a unit dose of the compound of formula I. A unit dosage form may be, for example, in the form of a tablet or a capsule. The unit dosage form may also be in liquid form, such as a solution or a suspension. The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g.. intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation. For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner.

The active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

The active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.

A proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above (e.g., schizophrenia) is 0.1 to 200 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day. Aerosol formulations for treatment of the conditions referred to above (e.g., schizophrenia) in the average adult human are preferably arranged so that each metered dose or "puff of aerosol contains 20 Dg to 1000 Dg of the compound of the invention. The overall daily dose with an aerosol will be within the range 100 Dg to 100 mg. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.

In connection with the use of an active compound of this invention with a 5-HT re- uptake inhibitor, preferably sertraline, for the treatment of subjects possessing any of the above conditions, it is to be noted that these compounds may be administered either alone or in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages. More particularly, the active combination can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspension, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, such oral pharmaceutical formulations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes. In general, the compounds of formula I are present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage and a 5-HT reuptake inhibitor, preferably sertraline, is present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.

A proposed daily dose of an active compound of this invention in the combination formulation (a formulation containing an active compound of this invention and a 5-HT reuptake inhibitor) for oral, parenteral, rectal or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the active ingredient of formula I per unit dose which could be administered, for example, 1 to 4 times per day.

A proposed daily dose of a 5-HT reuptake inhibitor, preferably sertraline, in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.1 mg to about 2000 mg, preferably from about 1 mg to about 200 mg of the 5-HT reuptake inhibitor per unit dose which could be administered, for example, 1 to 4 times per day.

A preferred dose ratio of sertraline to an active compound of this invention in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.00005 to about 20,000, preferably from about 0.25 to about 2,000. Aerosol combination formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff' of aerosol contains from about 0.01 Dg to about 100 mg of the active compound of this invention, preferably from about 1 Dg to about 10 mg of such compound. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.

Aerosol formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff of aerosol contains from about 0.01 mg to about 2000 mg of a 5-HT re-uptake inhibitor, preferably sertraline, preferably from about 1 mg to about 200 mg of sertraline. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.

As previously indicated, a 5-HT re-uptake inhibitor, preferably sertraline, in combination with compounds of formula I are readily adapted to therapeutic use as antipsychotic agents. In general, these antipsychotic compositions containing a 5-HT re- uptake inhibitor, preferably sertraline, and a compound of formula I are normally administered in dosages ranging from about 0.01 mg to about 100 mg per kg of body weight per day of a 5-HT re-uptake inhibitor, preferably sertraline, preferably from about 0.1 mg. to about 10 mg per kg of body weight per day of sertraline; with from about 0.001 mg. to about 100 mg per kg of body weight per day of a compound of formula I, preferably from about 0.01 mg to about 10 mg per kg of body weight 'per day of a compound of formula I, although variations will necessarily occur depending upon the conditions of the subject being treated and the particular route of administration chosen.

The present invention also relates to novel intermediates used in the preparation and manufacture of the compounds of formula I of the present invention, and to the preparation and processes used therein.

Detailed Description of the Invention Compounds of formulae (I) may be prepared according to reaction scheme 1 :

Scheme 1

Reaction Step 1 : Morpholine lactol formation. Compounds of formula (V) may be prepared through reaction of an alpha-halogen substituted acetophenone of formula (Vl) with an aminoethanol of formula (X) in the presence of a non-nucleophilic amine base, preferably triethylamine or diisopropylethyl amine, in a suitably non-reactive solvent such as methylene chloride, 1 ,2-dichloroethane, acetonitrile or dimethylformamide at temperatures ranging from 1O⁰C to 11O⁰C, where 2O⁰C to 8O⁰C is preferred.

Reaction Step 2: Dehydroxylation of Morpholine lactol.

Compounds of formula (IV) may be formed from compounds of formula (V) by reaction with a hydride source, preferably triethylsilane in the presence of a Lewis acidic reagent such as trimethylsilyltriflate or more preferably with an acidic reagent such as trifluoroacetic acid in methylene chloride or 1 ,2-dichloroethane at temperatures ranging from

O⁰C to 8O⁰C, where 40° to 8O⁰C is preferred.

Reaction Step 3: Reduction of nitro to amine.

Compounds of formula (III) may be prepared from compounds of formula (IV) by reduction with hydrogen gas at about 45 psi in the presence of a catalyst such as palladium hydroxide or preferably 5-10 wt % palladium on activated carbon, where the preferred solvent is ethyl alcohol.

Reaction Step 4: Sulfonamide formation.

Sulfonamide compounds of formula (I) may formed by treatment of compounds of formula (III) with an optionally substituted benzenesulfonyl chloride in the presence of a non- nucleophilic amine base, such as triethylamine or diisopropylethyl amine, in a suitably non- reactive solvent such as methylene chloride or tetrahydrofuran at temperatures ranging from 1O⁰C to 11O⁰C, or more preferably in pyridine with no added base at temperatures ranging from O⁰C to 100⁰C, where 2O⁰C to 6O⁰C is preferred.

Reaction Steps 5 and 6: Bis-sulfonamide formation and hydrolysis.

Alternatively, a compound of formula (I) may be prepared from a compound of formula (III) by treatment with two or more equivalents of an optionally substituted benzenesulfonyl chloride in the presence of a non-nucleophilic amine base, such as triethylamine or diisopropylethyl amine, in a suitably non-reactive solvent such as methylene chloride or tetrahydrofuran at temperatures ranging from 1O⁰C to 110⁰C as shown in Step 5 to form bis-sulfonylated compound of formula (II). This may then be hydrolyzed as shown in Step 6 to form compound of formula (I) by reaction with an alkali hydroxide such as sodium hydroxide or an alkoxide such as sodium ethoxide in an aqueous alcohol solution at temperatures ranging from 1O⁰C to 120⁰C, where 5O⁰C to 100⁰C is preferred.

Compounds of formula (III) can also be made from compounds of formula (V) as shown in reaction scheme 2.

Scheme 2

Reaction step 7: Reduction of lactol and nitro to form amino diol.

Compounds of formula (VII) may be formed by reduction of compounds of formula (V) with lithium aluminum hydride in appropriately non-reactive solvent such as tetrahydrofuran at refluxing temperatures or more preferably by hydrogenation with about 45 psi hydrogen and 5-10 wt% palladium on carbon in alcohols such as methanol or ethanol at temperatures ranging from 2O⁰C to 8O⁰C, where ambient temperature is preferred.

Reaction step 8: Morpholine ring closure.

Diol compounds of formula (VII) can be ring-closed to morpholine compounds of formula (III) using a number of methods. For example treating a dichloromethane solution of (VII) with excess concentrated sulfuric acid at room temperature will effect cyclization. Alternatively, the ring closure may be effected using Mitsunobu-type conditions employing the using of 1.1 equivalents of a dialkyl azodicarboxylate reagent, such as diispropyl azodicarboxylate (DIAD), and 1.1 equivalents of triphenylphosphine in an inert solvent such as tetrahydrofuran. A further alternative is to use a sulfonylating agent, such as p- toluenesulfonylimidazole (1 equivalent) in the presence of strong base such as sodium hydride in an inert solvent such as tetrahydrofuran, as described in Organic Letters 2004, 6(6). 1045-1047.

Non-commercially available alpha bromoketones of formula (Vl) may be prepared as described in Scheme 3.

Scheme 3

(VIII) (IX) (Vl)

Reaction step 9: Acid chloride formation.

Acid chlorides of formula (IX) may be prepared from optionally substituted nitrobenzoic acids by reaction with chlorinating reagents such as oxalyl chloride or preferably thionyl chloride, preferably with a catalytic amount of dimethylformamide at temperatures ranging from ambient to 12O⁰C, where reflux is preferred.

Reaction step 10: Conversion of acid chloride to alpha bromoketone. Compounds of formula (Vl) may be formed in a two step, one pot procedure by first treating compounds of formula (IX) in a mixture of acetonitrile/tetrahydrofuran with diazomethane in methylene chloride, or preferably trimethylsilyldiazomethane in hexane solution at -2O⁰C to 2O⁰C to form a diazoacetophenone intermediate which is then converted to compounds of formula (Vl) by treatment with an aqueous solution of hydrobromic acid.

Derivatization of the morpholine nitrogen in compounds of formula (I) may also accomplished as detailed in scheme 4. Scheme 4

Reaction step 11: Nitro reduction and amine deprotection.

Compounds of formula (IV), where PG is benzyl or 4-methoxybenzyl may be converted into compounds of formula (Xl) by hydrogenation with about 45 psi hydrogen and 5-10 wt% palladium on carbon in alcohols such methanol or ethanol at temperatures ranging from 2O⁰C to 8O⁰C where ambient temperature is preferred or by transfer hydrogenation with ammonium formate and 5-10 wt% palladium on carbon in alcohols such methanol or ethanol at temperatures ranging from 2O⁰C to 8O⁰C.

Reaction step 12: Protection of morpholine amine.

Compounds of formula (XII) may be obtained by treatment of compounds of formula (Xl) with preferably a single equivalent of di-t-butyl dicarbonate in a biphasic mixture of an aqueous base such as sodium hydroxide and a non-reactive organic solvent such as methylene chloride at temperatures ranging form O⁰C to 8O⁰C, where ambient temperature is preferred. Reaction step 13: Sulfonylation.

Sulfonamide compounds of formula (XIII) may formed by treatment of compounds of formula (XII) with an optionally substituted benzenesulfonyl chloride in the presence of a non- nucleophilic amine base, such as triethylamine or diisopropylethyl amine, in a suitably non- reactive solvent such as methylene chloride or tetrahydrofuran at temperatures ranging from 1O⁰C to 11O⁰C or more preferably in pyridine with no added base at temperatures ranging from O⁰C to 100⁰C, where 2O⁰C to 6O⁰C is preferred. Reaction Step 14: Boc removal.

De-protection of the morpholine nitrogen of compound (XIII) to afford a compound of formula (XIV) may be accomplished by reaction with a suitably strong acid such as trifluoroacetic acid, hydrobromic acid or hydrochloric acid in a non-reactive solvent such as tetrahydrofuran, methanol or ethanol, or with no added solvent, at temperatures ranging from

-10⁰C to 12O⁰C where ambient temperature generally preferred.

Reaction Step 15: Alkylation of morpholine nitrogen. Compounds of formula (I) may be prepared from compounds of formula (XIV) by reductive amination with optionally substituted aldehydes in the presence of a metal hydride reducing agent such as sodium cyanoborohydride or preferably sodium triacetoxyborohydride in suitably non-reactive solvent such as methylene chloride, 1 ,2-dichloroethane or tetrahydrofuran with the optional addition of acetic acid at temperatures ranging from O⁰C to 100⁰C, where ambient temperature is preferred.

Intermediates of formula (VII) may also be prepared as shown in Scheme 5.

Reaction step 16: Aniline protection.

Compounds of formula (XVI), wherein, for example, PGN is the 2,5-dimethylpyrrole system [as described in J. Chem. Soc. Perkin Trans. 1. 1984, 2801-2807, and as illustrated by the compound of formula (XVIa)], may be prepared through reaction of an aniline of formula (XV) with 1-2 equivalents of 2,5-hexanedione in toluene at reflux with azeotropic removal of water and an acid catalyst, such as para-toluenesulfonic acid.

Reaction step 17: Addition to morpholinone.

Compounds of formula (XVII) may be prepared by reaction of an organometallic reagent generated from a halogenated aniline compound of formula (XVI), with a morpholinone compound of formula (XIX). Suitable organometallic aniline derivatives include

Grignard (organomagnesium) or organolithium reagents, which may be prepared from the corresponding bromide (or iodide) by halogen-metal exchange. Typical conditions comprise addition of isopropylmagnesium chloride (or butyllithium) to the bromide (XVI) in an anhydrous ethereal solvent such as tetrahydrofuran at room temperature (may require heating in certain cases when isopropylmagnesium chloride is used as the metallating agent) or below (e.g. -78 °C when butyllithium is used) to perform the halogen metal exchange reaction, followed by addition of the morpholinone (XIX) at 0 ⁰C or lower.

Reaction step 18: Conversion of lactol to diol.

Compounds of formula (XVIII) may be formed by reduction of compounds of formula (XVIII) with sodium borohydride in appropriately non-reactive solvent such as tetrahydrofuran at refluxing temperatures or at temperatures ranging from O⁰C to 8O⁰C, where O⁰C to ambient temperature is preferred.

Reaction step 19: Removal of aniline protecting group.

Compounds of formula (VII) may be prepared from compounds of formula (XVIII) by de-protection reaction with one to five equivalents of hydroxylamine hydrochloride in ethanol, preferably at reflux.

Intermediate compounds of formula (X) may be prepared according to reaction scheme 6.

Scheme 6

(XX") (XXI) (^χ)

Reaction Step 20: Amide formation.

Compounds of the formula (XXI) may be prepared by reacting an amino acid ester of the formula (XXII) with acid chlorides (R = (Ci-Ce)alkyl) in the presence of a suitable base such as N-methylmorpholine, triethylamine or diisopropylethylamine in a non-reactive solvent such as tetrahydrofuran or preferably methylene chloride at temperatures ranging from -1O⁰C to 8O⁰C where 10-40⁰C is preferred. Examples of compounds of formula (XXI) are also commercially available.

Reaction step 21 : Amide and ester reduction. Compounds of formula (X) may be prepared by reacting compounds of formula (XXI) with metal hydride reagents such as borane-THF complex or lithium aluminum hydride in suitably non-reactive solvents such as diethyl ether or tetrahydrofuran at temperatures ranging from O⁰C to reflux, where reflux is preferred, followed by suitable quenching procedures with a strong acid (e.g. 5N HCI) in the case of borane, or water or sodium sulfate decahydrate in the case of lithium aluminum hydride. Examples of compounds of formula (X) are also commercially available.

Morpholinone compounds of formula (XIX) may be prepared as shown in Scheme 7.

Scheme 7

Reaction step 22: Aminoethyl alcohol conversion to morpholinone.

Morpholinone compounds of formula (XIX) may be prepared by the reaction of an amino alcohol of formula (X) with an α-halo ester compound such as methyl bromoacetate (XXIII) in the presence of a non-nucleophilic base such as triethylamine or N- methylmorpholine in suitable solvent such as toluene, tetrahydrofuran or methylene chloride, generally at temperatures ranging from ambient temperature to reflux, where reflux is preferred.

The compounds of formula I of the present invention are surprisingly highly selective dopamine D₃ receptor ligands which, because of their low affinity for other receptors such as dopamine D₁ and D₄ and, in particular, dopamine D₂, adrenergic D₁ and D₂, muscarinic, histaminic and opiate, give rise to fewer side effects than do the classical antagonists which are dopamine D₂ selective antagonists. Compounds of the current invention can also be partial D₃ agonists or partial D₃ antagonists.

Disorders or diseases of the central nervous system (CNS) are understood as meaning disorders which affect the spinal chord and, in particular, the brain. Within the meaning of the invention, the term "disorder" denotes disturbances and / or anomalies which are as a rule regarded as being pathological conditions or functions and which can manifest themselves in the form of particular signs, symptoms and / or malfunctions. While the treatment according to the invention can be directed toward individual disorders, i.e. anomalies or pathological conditions, it is also possible for several anomalies, which may be causatively linked to each other, to be combined into patterns, i.e., syndromes, which can be treated in accordance with the invention.

The disorders which can be treated in accordance to the invention are, in particular, psychiatric and neurological disturbances. These disturbances include, in particular, organic disturbances, including symptomatic disturbances, such as psychoses of the acute exogenous reaction type or attendant psychoses or organic or exogenous cause, e.g., in association with metabolic disturbances, infections and endocrinopathologies; endogenous psychoses, such as schizophrenia and schizotype and delusional disturbances; affective disturbances, such as depressions, mania and / or manic-depressive ^conditions; and also mixed forms of the above described disturbances; neurotic and somatoform disturbances and disturbances in association with stress; dissociative disturbances, e.g., loss of consciousness, clouding of consciousness, double consciousness and personality disturbances; disturbances in attention and waking and / or sleeping behavior, such as behavioral disturbances and emotional disturbances whose onset lies in childhood and youth, e.g., hyperactivity in children, intellectual deficits, in particular attention disturbances (attention deficit disorders), memory disturbances and cognitive disturbances, e.g., impaired learning and memory (impaired cognitive function), dementia, narcolepsy and sleep disturbances, e.g., restless leg syndrome; developmental disturbances; anxiety states, delirium, sex-life disturbances, e.g., impotence in men; eating disturbances, e.g., anorexia or bulimia, addiction and other unspecified disturbances.

The disorders which can be treated in accordance with the invention also include Parkinson's disease and epilepsy, and, in particular, the affective disturbances connected thereto.

The addiction diseases include psychic disorders and behavioral disturbances which are caused by the abuse of psychotropic substances, such as pharmaceuticals or narcotics and also other addiction diseases, such as addiction to gaming (impulse control disorders not elsewhere classified). Examples of addictive substances are opioids (e.g., morphine, heroin and codeine), cocaine; nicotine; alcohol; substances which interact with GABA chloride channel complex; sedatives; hypnotics and tranquilizers, for example, benzodiazepines; LSD; cannabinoids; psychomotor stimulants, such as 3,4-methylenedioxy-N-methylamphetamine (i.e., ecstasy); amphetamine and amphetamine-like substances such as methylphenidate and other stimulants including caffeine. Addictive substances of particular consideration are opioids, cocaine, amphetamine or amphetamine-like substances, nicotine and alcohol.

With regard to the treatment of addiction diseases, particular preference is given to those compounds according to the invention of formula I which themselves do not possess any psychotropic effect. This can also be observed in a test using rats which, after having been administered compounds which can be used in accordance with the invention, reduce their self-administration of psychotropic substance, for example, cocaine.

According to another aspect of the present invention, the compounds according to the invention may be suitable for treating disorders whose cause can at least be partially attributed to an anomalous activity of dopamine D₃ receptors.

According to another aspect of the present invention, the treatment is directed, in particular, toward those disorders which can be influenced by the binding of preferably exogenously administered binding ligands to dopamine D₃ receptors.

The diseases which can be treated with the compounds according to the invention are frequently characterized by progressive development, i.e., the above-described conditions change over the course of time; as a rule, the severity increases and conditions may possibly merge into each other, or other conditions may appear in addition to those which already exist.

The compounds according to the invention can be used to treat a large number of signs, symptoms and / or malfunctions which are connected with the disorders of the central nervous system and, in particular the abovementioned conditions. These signs, symptoms and / or malfunctions include, for example, a disturbed relationship to reality, lack of insight and ability to meet customary social norms or the demands made by life, changes in temperament, changes in individual drives, such as hunger, sleep, thirst, etc., and in mood, disturbances in the ability to observe and combine, changes in personality, in particular emotional lability, hallucinations, ego-disturbances, distractedness, ambivalence, autism, depersonalization and false perceptions, delusional ideas, chanting speech, lack of synkinesia, short-step gait, flexed posture of trunk and limbs, tremor, poverty of facial expression, monotonous speech, depressions, apathy, impeded spontaneity and decisiveness, impoverished association ability, anxiety, nervous agitation, stammering, social phobia, panic disturbances, withdrawal symptoms in association with dependency, maniform syndromes, states of excitation and confusion, dysphoria, dyskinetic syndromes and tic disorders, e.g. Huntington's chorea and Gilles-de-la-Tourette's syndrome, vertigo syndromes, e.g., peripheral positional, rotational and oscillatory vertigo, melancholia, hysteria, hypochondria and the like.

Within the meaning of the invention, a treatment also includes a preventative treatment (i.e., prophylaxis), in particular as relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and / or malfunctions. The treatment can be orientated symptomatically, for example as the suppression of symptoms. It can be effected over a short period, be oriented over a medium term or can be a long-term treatment, for example within the context of a maintenance therapy. Therefore the compounds according to the invention are preferentially suitable for treatment of diseases of the central nervous system, in particular for treating affective disorders; neurotic disturbances, stress disturbances and somatoform disturbances and psychoses and, in particular, for treating schizophrenia and depression. Because of their high selectivity with regard to the D₃ receptor, the compounds of formulae I according to the inventions are also suitable for treating disturbances of kidney function which are caused by diabetes mellitus (see WO 00/67847) and, especially, diabetic nephropathy.

Within the context of the treatment, the use according to the invention of the described compounds involves a method. In this method, an effective quantity of one or more compounds, as a rule formulated in accordance with pharmaceutical and veterinary practice, is administered to the individual to be treated, preferably a mammal, in particular a human being, productive animal or domestic animal. Whether such a treatment is indicated, and in which it is to take place, depends on the individual case and is subject to medical assessment (diagnosis) which takes into consideration signs, symptoms and / or malfunctions which are present, the risks of developing particular signs, symptoms and / or malfunctions, and other factors.

The invention also relates to the production of pharmaceutical compositions for treating an individual, preferably a mammal and particularly a human being, production animal or domestic animal. Thus they are customarily administered in the form of pharmaceutical compositions which comprise a pharmaceutically acceptable excipient together with at least one compound according to the invention and, where appropriate, other active compounds. These compositions can, for example, be administered orally, rectally, transdermal^, subcutaneously, intravenously, intramuscularly or intranasally.

Examples of suitable pharmaceutical formulations are solid medicinal forms, such as powders, granules, tablets, in particular film tablets, lozenges, sachets, cachets, sugar-coated tablets, capsules, such as hard gelatin capsules and soft gelatin capsules, suppositories, semisolid medicinal forms such as ointments, creams, hydrogels, pastes or plasters, and liquid medicinal forms such as solutions, emulsions, suspensions, lotions, injection preparations and infusion preparations, eye drops and eardrops. Implanted release devices can also be used for administering compositions according to the invention.

When producing the compositions, the compounds according to the invention are optionally mixed or diluted with one or more excipients. Excipients can be solid, semisolid or liquid materials which serve as vehicles, carriers or medium for the active compound.

Such excipients are known to those who practice the art. In addition, the formulations comprise pharmaceutically acceptable carriers or customary auxiliary substances, such as wetting agents, preservatives, emulsifying and suspending agents, antioxidants, anti-irritants, chelating agents, coating auxiliaries, emulsion stabilizers, film formers, gel formers, taste corrigents among others. In general, the compounds of formula I are present in such dosage forms at concentration levels ranging from about 0.5% to about 95% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage. The compounds of formula I of this invention may exist in different and distinct polymorphic forms, i.e., different crystalline forms.

A proposed dose of the active compounds of the invention for oral, parenteral or buccal administrations to an average adult human being for the treatment of the conditions referred to above is in the range of about 0.1 to about 200 mg of the active compound per unit dose which could be administered, for example, one to four times per day. The following Examples illustrate the preparation of the compounds of the present invention. Melting points are uncorrected. Nuclear magnetic resonance (NMR) data are reported in parts per million (ppm, D) referenced to the deuterium lock signal from the solvent used (e.g., deuteriochloroform, unless otherwise specified). Specific rotations were measured at room temperature (20-25 ⁰C) using the sodium D line (589 nM). Commercial solvents and reagents were used without further purification and reactions were run under a nitrogen atmosphere at standard pressure. Thin layer chromatography (tic) was performed using Kieselgel 60 F 254 plates eluting with the indicated mobile phase solvent and visualized with a 254 nm UV lamp or stained with either an aqueous KMnO₄ solution or an ethanolic solution of 12-molybdophosphoric acid. Flash chromatography was performed using wither pre- packed Biotage^® or ISCO^® columns in the indicated sizes. Nuclear magnetic resonance (NMR) spectra were acquired on a Unity 400 or 500 spectrometer at 400 MHz or 500 MHz for ¹H, and at 100 MHZ or 125 MHz for ¹³C, respectively. Chemical shifts for ¹³C NMR spectra are reported in parts per million (ppm) downfield relative to the centerline of the triplet of CDCI₃ at 77.0 ppm In the examples and descriptions that follow, the abbreviations used are intended to have the indicated, general meanings: bm: broad multiplet (NMR) bs: broad singlet (NMR) calcd.: calculated d: doublet (NMR) dd: doublet of doublets (NMR) d.e. diatomaceous earth, filter agent

DMA: dimethylacetamide

DMF: dimethylformamide DMSO: dimethylsulfoxide

EtOAc: ethyl acetate J: coupling constant (NMR) LAH: lithium aluminum hydride

LRMS: low resolution mass spectrometry m: multiplet (NMR) min: minute(s) m/z: mass to charge ratio (Mass spectrometry) obsd: observed

Rf: retention factor (chromatography)

Rt: retention time (chromatography) rt: room temperature (generally 25 ⁰C) s: singlet (NMR); second(s) t: triplet (NMR)

THF: tetrahydrofuran tic: thin layer chromatography

Examples Example 1

4-lsopropyl-N-(4-(octahvdropyridor2.1-ciπ .4loxazin-3-yl)phenyl)benzenesulfonamide.

2-Bromo-4'-nitroacetophenone (5.Og, 20.5 mmol) and 3-piperidinemethanol (7.7g, 41.0 mmol) in ether (100 mL) were stirred for 16h at room temperature. The mixture was then filtered to remove 3-piperidinemethanol hydrochloride salt and the filtrate was concentrated to afford 5.38g of a waxy red-brown solid. Silica gel chromatography using 50% EtOAc/heptane for elution yielded 4.17g (73%) of 3-(4-nitrophenyl)-octahydropyrido[2,1-c][1 ,4]oxazin-3-ol as a yellow solid: NMR (CDCI₃) δ 8.19 (d, J = 9.1 Hz, 2H), 7.79 (d, J = 8.7Hz, 2H), 4.93 (br s, 1H), 3.79-3.67 (m, 2H), 2.72 (br d, J = 11.2 Hz,1H), 2.66 (d, J = 11.2 Hz, 1 H), 2.30 (d, J = 11.2 Hz, 1 H), 2.23-2.16 (m, 1H), 2.09 (dt, J = 11.4, 3.3 Hz, 1 H), 1.80 (br d, J = 12.9 Hz, 1 H), 1.68-1.51 (m, 3H), 1.36-1.13 (m, 2H); ¹³C NMR (CDCI₃) δ 148.6, 148.1, 127.3, 123.5, 94.8, 65.8, 65.2, 60.7, 55.2, 27.3, 25.6, 23.8.

A partially dissolved mixture of 3-(4-nitrophenyl)-octahydropyrido[2,1-c][1 ,4]oxazin-3- ol (4.0O g, 14.37 mmol) in 150 ml. 1N aq. H₂SO₄ and 20% palladium hydroxide-on-carbon (230 mg) was hydrogenated at 20 psi for 18 h. The mixture was filtered through diatomaceous earth and made basic with 1 N aq. NaOH. Methylene chloride (250 mL) was added and the mixture was stirred overnight. The organics were separated and the aqueous was re- extracted with -200 mL CH₂CI₂. The combined organics were dried (MgSO₄) and concentrated to yield 1-(4-aminophenyl)-2-(2-(hydroxymethyl)piperidin-1-yl)ethanol as a sticky yellow foam (2.87g) .A mixture of this material and 48% aq. HBr(20 mL) was refluxed for 3.5h, concentrated, and the residue was dissolved in 1N NaOH and extracted twice with EtOAc. The extracts were washed with brine, dried (MgSO₄) and concentrated to a thick dirty yellow gum (2.63g). NMR (CDCI₃) shows a -2:1 mixture of isomers. The major isomer was isolated by flash chromatography using 1-2% MeOH/CH₂CH₂ affording 0.59 g of 4- octahydropyrido[2,1-c][1 ,4]oxazin-3-yl)benzenamine as a waxy yellow solid: LRMS m/z Calcd for C₁₄H₂₀N₂O, 232.3, found, 233.2 (M+H) APCI; NMR (CDCI₃) δ 7.12 (d, J = 8.3 Hz, 2H), 6.62 (d, J = 8.7 Hz, 2H), 4.54 (br d, J = 9.1 Hz, 1 H), 3.81 (dd, J = 11.3, 2.9Hz, 1 H),3.62 (br s, 2H), 3.42 (t, J = 10.8 Hz, 1 H), 2.79-2.75 (m, 2H), 2.21 (t, J = 11.0 Hz, 1H), 2.10-2.02 (m, 2H), 1.89 ( br d, J = 12.9 Hz, 1H), 1.70-1.55 (m, 2H), 1.48 (br dd, J = 12.4, 2.5 Hz, 1H), 1.37-1.23 (m 1 H), 1.21-1.09 (m, 1 H); ¹³C NMR (CDCI₃) δ 146.3, 130.5, 127.6, 115.1 , 78.6, 72.5, 62.1 , 61.2, 55.7, 27.3, 25.6, 24.1.

4-lsopropylbenzenesulfonyl chloride (0.10Og, 0.46 mmol) in 2 mL acetonitrile was added to a stirring, solution of 4-octahydropyrido[2,1-c][1 ,4]oxazin-3-yl)benzenamine (0.100g,

0.43 mmol) and diisopropylethyl amine (0.15 mL, 0.86 mmol) in 8 mL acetonitrile. This mixture was stirred at room temperature for 20 h, water was added and this was extracted into 50 mL EtOAc, dried (MgSO4) and concentrated to give a colorless oil (0.19g).LC/MS shows a trace starting material, mainly desired product and a minor amount of disulfonylated material. Purification by flash chromatography eluting with 50%-75% EtOAc/heptane yielded

117 mg of the title compound as a colorless oil which slowly solidified to a waxy white solid. HCI salt: NMR (MeOH-Cl₄) δ 7.66 (d, J = 7.9 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 7.9 Hz, 2H), 4.80 (d, J = 10.4 Hz, 1H), 4.10-4.04 (m, 1H), 3.73 (t, J = 11.8 Hz, 1 H), 3.66-3.30 (m, 3H), 3.09-3.00 (m, 2H), 2.91 (hept, J = 5.1 Hz, 1H), 1.98-1.80 (m, 5H), 1.70-1.53 (m, 2H), 1.19 (d, J = 7.1 Hz, 6H); ¹³C NMR (CDCI₃) δ 154.5, 138.6, 137.3, 132.9, 128.7, 127.2, 127.1 , 127.0, 120.4, 75.4, 68.7, 62.2, 57.5, 54.4, 34.1 , 24.4, 22.9, 22.8, 21.5.

Example 2 N-(4-(4-ethylmorpholin-2-yltohenyl)-4-isopropylbenzenesulfonamide.

2-Bromo-4'-nitroacetophenone (5.Og, 20.5 mmol), (2-hydroxyethyl)ethyl amine (2.0 mL, 20.5 mmol) and diisopropylethylamine (3.6 mL, 21.0 mmol) in CH₂CI₂ (100 mL) were stirred at room temperature for 2.5 h to afford 4-ethyl-2-(4-nitro-phenyl)morpholin-2-ol. Triethylsilane (10.33 mL, 6.74 mmol) and trifluoroacetic acid (52.5 mL) were then added and the mixture was heated at 40 ⁰C for 6 days, then cooled and concentrated. Water and heptane were added and the heptane layer was decanted to remove silyl impurities. The aqueous was made basic with K₂CO₃ and extracted twice with EtOAc. The combined extracts were dried (MgSO₄) and concentrated to afford a dark red oil, which NMR (CDCI₃) showed to be a -2:1 mixture of 4-ethyl-2-(4-nitrophenyl)morpholine and 4-(4-ethylmorpholin-2- yl)benzenamine. Silica gel chromatography using EtOAc and 3-10% MeOH / EtOAc was used to purify these materials (yield - 3.42g) which were then used as a mixture in the next step.

Step 2:

The 2:1 mixture of 4-ethyl-2-(4-nitrophenyl)morpholine and 4-(4-ethylmorpholin-2- yl)benzenamine was combined with ammonium formate (6.4 g, 101.5 mmol), methanol (300 mL) and 10% palladium on carbon (275 mg) and stirred at room temperature for 19h. The mixture was filtered through diatomaceous earth and concentrated. The residue was partitioned between EtOAc and aq. K₂CO₃, the organics were dried (MgSO₄) and concentrated to yield 2.86 g of 4-(4-ethylmorpholin-2-yl)benzenamine as an orange oil which solidified to a waxy solid which scratched with a small amount of heptane: NMR (CDCI₃) δ 7.15 (d, J = 8.3 Hz, 2H), 6.44 (d, J = 8.7 Hz, 2H), 4.45 (dd, J = 10.4, 2.1 Hz, 1 H), 4.01 (ddd, J = 11.2, 1.7,1.7 Hz, 1H), 3.82 (dt, J = 11.6, 2.5 Hz, 1 H), 3.64 (br s, 2H), 2.90 (d, J = 11.6 Hz, 1 H), 2.81 (d, J = 11.2 Hz, 1 H), 2.44 (q, J = 7.2 Hz, 2H), 2.18 (dt, J = 11.4, 3.3 Hz, 1 H), 2.03 (t, J = 10.8 Hz, 1 H), 1.10 (t, J = 7.3 Hz, 3H); ¹³C NMR (CDCI₃) δ 146.4, 130.7, 127.7, 115.1 , 78.4, 67.3, 60.4, 52.9, 52.8, 12.0. Step 3:

4-lsopropylbenzenesulfonyl chloride (0.10 mL, 0.56 mmol) was added to a solution of 4-(4-ethylmorpholin-2-yl)benzenamine (0.109g, 0.528 mmol) and triethylamine (0.15 mL, 1.1 mmol) in CH₂CI₂ (10 mL) and stirred at room temperature overnight. Washed the reaction with sat NaHCO₃, dried (MgSO₄) and concentrated to a tan oil (287 mg). Purified by flash chromatography, eluting with 75% EtOAc/heptanes and EtOAc to afford the racemic title compound as a milky oil (106 mg.52%), which was converted to the HCI salt.

NMR(MeOH-d₄) δ 7.68 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.7 Hz, 2H), 4.66 (dd, J = 11.2, 2.1 Hz, 1 H), 4.24 (dd, J = 13.7, 3.1 Hz, 1 H), 3.94 (dt, J = 12.6, 2.1 Hz, 1 H), 3.59-3.52 (m, 2H), 3.25-3.11 (m, 2H), 3.01-2.91 (m, 2H), 1.25-1.21 (m, 9H).

LRMS m/z Calcd for C₂iH₂₈N₂O₃S, 388.2 , found, 389.0(M+H) (LCMS). The enantiomers were then separated by chiral preparative HPLC on a 10 cm x50 cm Chiralpak® AD column eluting at 475 ml/min with 3:1 heptane/EtOH + 0.2% diethylamine: Enantiomer #1 - retention time (Rt) 9.84 min; Enantiomer #2 - retention time (Rt) 12.26 min.

Example 3 N-(4-(4-ethylmorpholin-2-yl)phenyl)-4-isopropyl-N-methylbenzenesulfonamide.

60 % Sodium hydride (7.6 mg, 0.19 mmol) was added to a solution of N-(4-(4- ethylmorpholin-2-yl)phenyl)-4-isopropylbenzenesulfonamide (0.102 g, 0.263 mmol) in THF

(2mL). After stirring for 2 min, methyl iodide (0.018 mL, 0.29 mmol) was added and the mixture was stirred at room temperature. Additional portions of sodium hydride and methyl iodide were added at 19h, and after ~44h stirring time, water was added and the mixture was extracted into EtOAc. The extract was washed with brine, dried (MgSO₄) and concentrated to a red oil (73 mg). Purification by flash chromatography using EtOAc for elution yielded 20mg

(19%) of the title compound as a light orange oil: LRMS m/z Calcd for C₂₂H₃₀N₂O₃S, 402.2 , found, 403.0 (M+H) (APCI).

NMR (CDCI₃) δ 7.45 (d, J = 8.3 Hz, 2H), 7.32-7.25 (m, 4H), 7.08 (8.3 Hz, 2H), 4.59 (d, J = 8.7 Hz, 1 H), 4.07-4.03 (m, 1 H), 3.86 (dt, J = 11.4, 2.1 Hz, 1H), 3.14 (s, 3H), 3.09-2.91 (m, 2H), 2.86 (d, J = 11.2 Hz, 1 H), 2.48 (q, J = 7.2 Hz, 2H), 2.22 (dt, J = 11.6, 3.3 Hz, 1 H), 2.05-1.99 (m, 2H), 1.25 (d, J = 6.3 Hz, 6H), 1.12 (t, J = 7.3 Hz, 3H).

Example 4 N-(4-(4-ethylmorpholin-2-yl)-3-methoxyphenyl)-4-isopropylbenzenesulfonamide.

3-Methoxy-4-nitrobenzoic acid (4.Og, 20.2 mmol), thionyl chloride (20 ml_) and DMF (0.1 mL) were refluxed for 4h, cooled and concentrated, then slurried twice with heptane and re-concentrated to afford 3-methoxy-4-nitrobenzoyl chloride as a yellow solid.

NMR (CDCI₃) δ 7.87 (d, J = 8.3 Hz, 1 ), 7.82 (dd, J = 8.3, 1.8 Hz, 1H), 7.77 (d, J = 1.7 Hz, 1H), 4.04 (s, 3H).

(Trimethylsilyl)diazomethane solution (2N in ether, 4.64 mL, 9.28 mmol) was added to a stirring, room temperature solution of 3-methoxy-4-nitrobenzoyl chloride (2.Og, 9.0 mmol) in 50 ml of 1 :1 THF/acetonitrile. After 1h, 48% aq. HBr (2.1 mL) was added and the mixture was stirred for an additional 15 min. Water (20 mL) and solid K₂CO₃ were added carefully to make the mixture basic. The phases were separated and the organics dried (MgSO₄) and concentrated to yield 2.51 g (100%) of -85% pure 2-bromo-1-(3-methoxy-4- nitrophenyl)ethanone as a yellow-orange solid which was used without purification.

NMR (CDCI₃) δ 7.87 9d, J = 8.3 Hz, 1 H), 7.71 (d, J = 1.7 Hz, 1 H), 7.59 (dd, J = 8.3, 1.7 Hz, 1H), 4.43 9s, 2H), 4.02 (s, 3H).

4-(4-Ethylmorpholin-2-yl)-2-methoxybenzenamine was prepared from 2-bromo-1-(3- methoxy-4-nitrophenyl)ethanone following the general procedures described in steps 1 and 2 in Example 2: LRMS m/z Calcd for C₁₃H₂₀N₂O₂, 236.3 , found, 237.0 (M+H) (APCI).

NMR (CDCI₃) δ 8.82 (d, J = 1.7 Hz, 1 H), 6.76 (dd, J = 8.3, 1.9 Hz, 1 H), 6.66 (d, J = 7.9 Hz, 1H), 4.50 (br d, J = 9.1 Hz, 1H), 4.05-4.01 (m, 1 H), 3.93-3.60 ( 3H s @ 3.86 ppm and 2H br s @ 3.77 ppm overlapping a 1 H m, 6H total), 2.95 (br d, J = 11.2 Hz, 1 H), 2.85 (br d, J = 10.8 Hz, 1H), 2.56-2.38 (m, 2H), 2.32-2.17 (m, 1 H), 2.08 (br t, J = 11.4 Hz, 1 H), 1.13 (t, J = 7.1 Hz, 3H).

4-lsopropylbenzenesulfonyl chloride (0.086 ml_, 0.48 mmol) was added to a solution of 4-(4-ethylrnorpholin-2-yl)-2-methoxybenzenamine (0.103 g, 0.44 mmol) in pyridine (5 mL). After stirring for 6Oh, the mixture was concentrated and chromatographed , flushed first with EtOAc, then eluting 5%,-20% MeOH/EtOAc to yield a white semi-solid (212mg).NMR (CDCI₃) showed the title compound as a partial pyridine salt. This material was freebased with 1 N NaOH, extracted into EtOAc and washed with brine, dried and re-concentrated to yield clean title compound as a colorless oil (121 mg) which was converted to an HCI salt. LRMS m/z Calcd for C₂₂H₃₀N₂O₄S, 418.6, found, 419.4(M+H) (LCMS).

NMR(MeOH-d₄) δ 7.60 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.3 Hz, 1 H), 7.29 (d, J = 8.3 Hz, 2H), 6.93-6.91 (m, 2H), 4.70 (br d, J = 10.4 Hz, 1 H), 4.24 (br d, J = 12.9 Hz, 1H), 3.96 (br t, J = 12.3 Hz, 1H), 3.60-3.53 (3H s @ 3.55 ppm overlapping 2H m, 5H total), 3.29-3.10 (m, 3H), 3.03-2.90 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H), 1.21 (d, J = 7.1 Hz, 6H). Example 5

N-(4-(4-ethylmorpholin-2-yl)-2-methoxyphenyl)-4-isopropylbenzenesulfonarnide.

This material was prepared from 2-methoxy-4-nitrobenzoic acid following the general procedures described in Example 4.

HCI salt: LRMS m/z Calcd for C₂₂H₃₀N₂O₄S, 418.6, found, 419.0(M+H) (APCI). NMR(MeOH-d₄) δ 7.70 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 8.3 Hz, 1 H), 6.79 (d, J = 2.1 Hz, 1H), 6.71 (dd, J = 8.3, 2.1 Hz, 1 H), 4.97 (d, J = 9.5 Hz, 1 H), 4.25 (dd, J = 12.9, 3.5 Hz, 1H), 3.92 (t, J = 12.0 Hz, 1H), 3.78 (s, 3H), 3.57-3.52 (m, 2H), 3.25-3.09 (m, 3H), 2.94 (hept, 6.8 Hz, 1 H), 2.83 (br t, J = 11.6 Hz, 1 H), 1.34 (t, J = 7.3 Hz, 3H), 1.22 (d, J = 7.1 Hz, 6H).

Example 6

N-(4-(4-ethylmorpholin-2-yl)-2-fluorophenyl)-N-(4-isopropylphenyl)sulfonyl-4-iso- propylbenzenesulfonamide.

This material was prepared from 3-fluoro-4-nitrobenzoic acid following the general procedures described in Example 4 and using 2 eq. of sulfonyl chloride.

Free base: LRMS m/z Calcd for C₃₀H₃₇FN₂O₅S₂, 588.8, found, 406.9 (M+H) as mono sulfonamide (APCI).

NMR (CDCI₃) δ 787-7.82 (m, 4H), 7.38-7.35 (m, 4H), 7.18-7.10 (m, 2H), 7.08-7.03 (m, 1H), 4.58 (dd, J = 10.1 , 7.9 Hz, 1 H), 4.05-4.01 (m, 1H), 3.85-3.78 (m, 1 H), 3.05-2.95 (m, 3H), 2.85-2.78 (m, 1 H), 2.46 (dd, J = 7.1 , 14.5 Hz, 2H), 2.18 (ddd, J = 3.3, 3.3, 9.0 Hz, 1 H), 1.96 (ddd, J = 10.8, 10.8, 11.2 Hz, 1 H), 1.40-1.25 (m, 12H), 1.11 (t, J = 7.1 Hz, 3H). Example 7

N-(4-(4-ethylmorpholin-2-vπ-2-fluorophenyl)-4-isopropylbenzenesulfonamide.

To 104mg (0.177mmoles) of : N-(4-(4-ethylmorpholin-2-yl)-2-fluorophenyl)-N-(4- isopropylphenyl)sulfonyl-4-isopropylbenzenesulfonamide in 1.6ml of THF was added 35.3mg (0.883mmoles, 5eq.) of solid NaOH and the solution was heated to 9O⁰C. After 30 min, the reaction was cooled to room temperature and diluted withiOml H₂O and 30ml EtOAc. The layers were separated and the organics were dried over MgSO4, and concentrated under reduced pressure to a gummy material. This was redissolved into 5ml EtOAc and treated with 1eq. of 2N HCI / Et20 and after stirring the resulted slurry for 30min, the solids were collected by filtration and dried to recover 24mg of the title compound (33 % yield).

HCI salt: LRMS m/z Calcd for C_2IH₂₇FN₂O₃S, 406.5, found 407.0 (M+H), (APCI).

¹H NMR (CDCI₃) δ 7.66 (d, J = 9.7 Hz, 2H), 7..52 (t, J = 8.1 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 2H), 7.05-6.85 (m, 2H), 4.46 (dd, J = 2.1 , 2.1Hz, 1 H), 3.98 (dd, J = 2.1 , 2.1 Hz, 1 H), 3.76 (ddd, J = 11.6, 11.6, 2.1 Hz, 1 H), 2.90-2.83 (m, 2H), 2.79 (bd, 1 H), 2.41 (q, J = 5.0 Hz, 2H), 2.14 (dt, J = 6.2, 2.9 Hz, 1H), 1.89 (t, J = 10.8 Hz, 1 H), 1.28-1.17 (m, 6H), 1.05 (t, J = 11.2 Hz, 3H).

¹³C NMR (CDCI₃) 6171.3, 154.9, 153.5 (d, J _C-F = 245.0 Hz), 138.5 (d, J _C-F = 268.3 Hz), 127.5, 127.4, 124.3, 123.2, 122.6, 113.5 (d, J _C-F = 20.3 Hz), 67.2, 60.5, 60.1 , 52.7, 34.3, 23.7, 21.2, 14.4.

Example 8

N-(4-(4-ethylmorpholin-2-yl)-3-fluorophenyl)-4-isopropylbenzenesulfonamide.

This material was prepared from 2-fluoro-4-nitrobenzoic acid following the general procedures described in Example 4. LRMS m/z Calcd for C_2IH₂₇FN₂O₃S, 406.52, found 407.3 (M+H), (APCI).

¹H NMR (CDCI₃) δ 7.66 (d, J = 8.7 Hz, 2H), 7.30-7.20 (m, 3H), 6.90-6.80 (m, 2H), 4.74 (dd, J = 1.7, 2.1Hz, 1 H), 3.95 (dd, J = 2.1 , 2.1 Hz, 1 H), 3.78 (ddd, J = 11.6, 11.2, 2.5 Hz, 1 H), 2.94-2.76 (m, 3H), 2.46-2.36 (m, 2H), 2.14 (apt dt, J = 11.6, 5.5 Hz, 1 H), 1.90 (t, J = 10.8 Hz, 1 H), 1.28-1.17 (m, 6H), 1.05 (t, J = 11.2 Hz, 3H).

¹³C NMR (CDCI₃) 6161.1 , 158.6, 154.8, 138.1 (d, J _C-F = 10.5 Hz), 136.6, 127.5, 127.4, 123.8 (d, J _C-F = 14.3 Hz), 116.4, 107.8 (d, J _C-F = 25.6 Hz), 71.8, 67.3, 58.8, 52.6, 34.3, 23.8, 23.7, 11.7.

Example 9

N-(4-(4-ethylmorpholin-2-yl)-2-methylphenyl)-4-isopropylbenzenesulfonamide.

This material was prepared from 3-methyl-4-nitrobenzoic acid following the general procedures described in Example 4.

LRMS m/z Calcd for C₂₂H₃₀N₂O₃S, 402.56, found 403.3 (M+H), (APCI).

¹H NMR (CDCI₃) δ 7.66 (d, J = 8.5 Hz, 2H), 7.28-7.23 (m, 3H), 7.12-7.08 (m, 2H), 4.49 (dd, J = 1.7, 1.6 Hz, 1 H), 4.5-3.95 (m, 1 H), 3.82 (ddd, J = 11.6, 11.2, 2.5 Hz, 1H), 2.94- 2.78 (m, 3H), 2.50-2.42 (m, 2H), 2.24-2.15(m, 1 H), 2.02-1.96 (m, 1 H), 1.97 (s, 3H), 1.26-1.20 (m, 6H), 1.05 (t, J = 9.5 Hz, 3H).

¹³C NMR (CDCI₃) δ 154.7, 138.4, 134.2, 131.6, 129.2, 128.7, 127.5, 127.3, 125.0, 124.4, 67.3, 60.2, 52.8, 52.7, 34.5, 34.3, 23.8, 17.8, 11.8.

Example 10

N-(4-(4-ethylmorpholin-2-yl)-2-methyphenyl)-pyrrolidine-1-sulfonamide.

LRMS m/z Calcd for Ci₇H₂₇N₃O₃S, 353.48, found 354.0 (M+H), (APCI). ¹H NMR (CDCI₃) δ 7.35 (d, J = 8.3 Hz, 1 H), 7.14-7.08 (m, 2H), 6.68 (bs, 1 H), 4.46 (dd, J = 2.1 , 2.1 Hz, 1H), 4.03-3.96 (m, 1H), 3.78 (ddd, J = 11.6, 11.6, 2.5 Hz, 1H), 3.30-3.18 (m, 4H), 2.88 (bd, J = 11.5 Hz, 1 H), 2.78 (bd, J = 11.6 Hz, 1 H), 2.41 (q, J = 7.5 Hz, 2H), 2.25 (s, 3H), 2.21-2.12 (m 1H), 1.97 (apt t, J = 10.4 Hz, 1 H), 1.84-1.74 (m, 4H), 1.06 (t, J = 7.5 Hz, 3H).

¹³C NMR (CDCI₃) δ 137.2, 135.5, 129.3, 128.8, 125.0, 121.6, 77.8, 67.3, 60.3, 52.8, 52.7, 48.5, 25.9, 18.1 , 11.9.

Example 11

N-(4-(4-ethylmorpholin-2-yl)-3-methylphenyl) -4-isopropylbenzenesulfonamide.

This material was prepared from 2-methyl-4-nitrobenzoic acid following the general procedures described in Example 4.

LRMS m/z Calcd for C₂₂H₃₀N₂O₃S, 402.56, found 403.3 (M+H), (APCI).

¹H NMR (CD₃OD) δ 7.68 (d, J = 8.3 Hz, 2H), 7.37-7.26 (m, 3H), 7.04-6.99 (m, 1 H), 6.94 (bs, 1 H), 4.98-4.90 (m, 1H)₁ (dd, J = 11.3, 3.3 Hz, 1 H), 4.00 (bt, J = 12.0 Hz, 1 H), 3.62- 3.46 (m, 2H), 3.28-3.01 (m, 3H), 3.04-2.87 (m, 2H), 2.29 (s, 3H), 1.36 (t, J = 7.5 Hz, 3H), 1.26-1.16 (m, 6H).

Example 12

N-(4-(4-ethylmorpholin-2-yl)-3-methylphenyl)-1.2-dimethyl-1 H-imidazole-4-sulfon- amide.

LRMS m/z Calcd for C₁₈H₂₆N₄O₃S, 378.49, found 379.0 (M+H), (APCI).

¹H NMR (CD₃OD) δ 7.55 (s, 1 H), 7.24 (d, J = 8.3 Hz, 1H), 6.99 (dd, J = 8.7, 2.5 Hz, 1 H), 6.94 (d, J = 2.1 Hz, 1 H), 4.69 (dd, J= 10.4, 1.7 Hz, 1H), 4.03 (dd, J = 11.6, 2.5 Hz, 1 H), 3.82 (ddd, J = 12.0, 12.0, 2.1 Hz, 1 H), 3.57 (s, 3H), 3.02-2.94 (m, 2H), 2.64-2.54 (m, 2H), 2.37 (ddd, J = 6.6, 8.7, 3.3 Hz, 1H), 2.31 (s, 3H), 2.27 (s, 3H), 2.14 (q, J = 10.5 Hz, 1H), 1.15 (t, J = 7.5 Hz, 3H).

Examples 13 and 14 N-(4-((2S. 5S-4-ethyl-5-methylmorpholin-2-yl)phenyl)-4-isopropylbenzenesulfonamide and

N-(4-((2R. 5S-4-ethyl-5-methylmorpholin-2-yl)phertvπ-4- isopropylbenzenesulfonamide.

(S)-2-(ethylamino)propan-1 -ol.

To 4g of (S)-2-aminopropan-1-ol (50mmoles) dissolved in 100ml of CH₂CI₂ was added acetaldehyde (2.58g, 58.6mmoles), followed by pre-dried powdered 4A molecular sieves (8g) and the resulted slurry was stirred at room temperature for 18hrs. It was then filtered through a pad of celite, the pad washed with CH₂CI₂, and solvent evaporated to give clear oil. This oil was dissolved in 25ml of ethanol and hydrogenated over PtO₂ (0.5g) at a pressure of 30 psi H₂ for 18hrs. The reaction was filtered through a pad of celite and the solvent was removed by evaporation to obtain 3.32g (60% yield) of the title compound as colorless oil.

LRMS m/z Calcd for C₅H₁₃NO, 103.17, found 103.9 (M+H), (APCI).

1 H NMR (CDCI₃) δ 3.53 (dd, J = 4.1 , 10.4 Hz, 1 H), 3.24 (dd, J = 7.5, 10.8 Hz, 1 H), 2.78-2.66 (m, 2H), 2.58-2.48 (m, 2H), 1.08 (t, J = 7.1 Hz, 3H), 1.01 (d, J = 6.2Hz, 3H).

13C NMR (CDCI₃) δ 65.7, 54.5, 41.5, 17.2, 15.7. Step 2: (5S)-4-ethyl-5-methyl-2-(4-nitrophenyl)morpholin-2-ol.

4.16g (32.2mmoles) of diisopropyl ethylamine was added to 7.85g (32.2mmoles) of 2- bromo-1-(4-nitrophenyl)ethanone in 150ml of CH₂CI₂, followed by the addition of 3.32g (32.2mmoles) of (S)-2-(ethylamino)propan-1-ol at room temperature. After 15 min stirring the reaction was concentrated down under high vacuum to obtain the title compound which was used as is for the next step.

Step 3:

(5S)-4-ethyl-5-methyl-2-(4-nitrophenyl)morpholine.

78.9 ml of trifluoroacetic acid (1020 mmoles) was added to (64 ml) 1 ,2-dichloroethane solution of (5S)-4-ethyl-5-methyl-2-(4-nitrophenyl)morpholin-2-ol (32 mmoles) and triethylsilane(20.4 ml, 128 mmoles) and the resulting mixture was heated to 70 ⁰C. After 18hrs, the reaction was cooled to rt and concentrated down to an oil. This was redissolved in to 300 ml of EtOAc and treated with 100 ml of saturated NaHCO₃. The layers were separated and the organics was dried over MgSO₄, filtered and concentrated down to recover an oil. Mono HCI salt was made by treating it with 16 ml of 2N HCI / Et₂O, which was freebased again to recover the title compound, which also contained some of the aniline by-product. This was submitted to the next step without further purification. Step 4: 4-((5S)-4-ethyl-5-methylmorpholin-2-yl)benzenamine.

Diastereomers separated

To 32 mmol of (5S)-4-ethyl-5-methyl-2-(4-nitrophenyl)morpholine in 100 ml of ethanol was added 1.6 g of 10% Pd / C (50% wet) and hydrogenated using 45psi H₂ for 2 hours. The catalyst was filtered through celite and the filtrate was concentrated down to obtain an oil. This was converted into mono HCI salt which was then free based using saturated NaHCO₃ and extracted using EtOAc. The crude material was chromatographed using a 40 g ISCO cartridge and 6 % MeOH / EtOAc to recover both the diastereomers of the title compound. 4-((2R,5S)-4-ethyl-5-methylmorpholin-2-yl)benzenamine (223mq).

LRMS m/z Calcd for C₁₂H₂₀N₂O, 220.1 , found 221.1 (M+H), (APCI). 1 H NMR (CDCI₃) δ 7.10 (d, J = 8.3 Hz, 2H), 6.60 (d, J = 8.3 Hz, 2H), 4.44 (dd, J = 2.9, 9.9 Hz, 1H), 3.90 (dd, J = 11.2, 2.1 Hz, 1H), 3.39 (t, J = 10.8 Hz, 1 H), 2.96-2.80 (m, 2H), 2.54-2.30 (m, 3H), 1.04-0.95 (m, 6H). 4-((2S.5S)-4-ethyl-5-methylmorpholin-2-yl)benzenamine (128mq).

LRMS m/z Calcd for Ci₂H₂₀N₂O, 220.1 , found 221.1 (M+H), (APCI). 1H NMR (CDCI₃) δ 7.10 (d, J = 8.3 Hz, 2H), 6.60 (d, J = 8.3 Hz, 2H), 4.44 (dd, J = 2.9, 9.9 Hz, 1 H), 3.90 (dd, J = 11.2, 2.1 Hz, 1H)₁ 3.76 (dd, J = 1.2, 10.8 Hz, 1H), 3.00-2.82 (m, 1 H), 2.60-2.40 (m, 4H), 1.06-0.98 (m, 6H). Step 5:

The disulfonamides were prepared using the same procedure as for example 6 and then hydrolyzed using the same procedure as for example 7 to yield the title compounds. N-(4-((2S, 5S-4-ethyl-5-methylmorpholin-2-vπ phenvD-4- isopropylbenzenesulfonamide.

LRMS m/z Calcd for C₂₂H₃₀N₂O₃S, 402.56, found 403.3 (M+H), (APCI).

¹H NMR (CDCI₃) δ 7.68 (d, J = 8.3 Hz, 2H), 7.24 (apt t, J = 8.3 Hz, 4H), 7.05 (d, J = 8.7 Hz, 2H), 4.55 (apt d, J = 8.7 Hz, 1 H), 3.96 (apt d, J = 10.4 Hz, 1 H), 3.82 (apt d, J = 10.8 Hz, 1 H), 3.10-3.05 (m, 1 H0, 2.98-2.84 (m, 1H), 2.70 (bd, J = 11.2 Hz, 1 H), 2.62-2.45 (m, 3H), 1.26-1.18 (m 6H), 1.16-1.08 (m, 6H).

¹³C NMR (CDCI₃) δ 154.6, 136.5, 131.1 , 127.6, 127.4, 127.3, 121.4, 112.5,72.5, 52.9, 50.7, 48.4, 34.3, 23.8, 15.2, 11.9, 7.9.

N-(4-((2R, 5S-4-ethyl-5-methylmorpholin-2-vh phenyl)-4- isopropylbenzenesulfonamide.

LRMS m/z Calcd for C₂₂H₃₀N₂O₃S, 402.56, found 403.3 (M+H), (APCI).

¹H NMR (CDCI₃) δ 7.68 (d, J = 8.3 Hz, 2H), 7.26-7.16 (m, 4H), 7.05 (d, J = 8.7 Hz, 2H), 4.53 (apt d, J = 10.4 Hz, 1H), 3.83 (dd, J = 11.6, 3.3 Hz, 1 H), 3.82 (t, J = 10.8 Hz, 1 H), 2.98-2.82 (m, 3H), 2.52-2.36 (m, 2H), 2.15 (t, J = 11.2 Hz, 1 H), 1.26-1.12 (m 6H), 1.06-0.94 (m, 6H).

¹³C NMR (CDCI₃) δ 154.6, 137.2, 136.8, 136.5, 127.6, 127.4, 121.4, 112.5, 73.2, 58.0, 54.6, 47.3, 34.3, 23.8, 15.2, 14.8, 10.0.

Examples 15-90

The following compounds were prepared using the following protocol:

A 0.2 M stock solution of sulfonyl chloride (50 DL) in anhydrous DMF was added to a

0.2 M solution of 4-(4-ethylmorpholin-2-yl)-benzenamine (50DL) in pyridine. The vessel was capped and heated at 5O⁰C for 16h, then the volatiles were removed under high vacuum.

DMSO (300 DL) was added and the vessel was agitate for -30 min to dissolve the products.

Additional DMSO was added to bring the volume to 1 mL. The sample was then purified by

HPLC:

Preparative Chromatography:

Column: 19 x 50 Waters X-Bridge C-18, 5um

Flow rate: 25 mL/min; Injection volume: 900 uL in DMSO (10-30 mg)

Solvents: A: Water; B: Acetonitrile; C: 1% aq. TFA; D: 1% aq. ammonium hydroxide

Gradients: Determined based on retention time in pre-purification analyses:

Pre-Purification Retention Time: Purification Method

0.4 -0.7 min Focused Gradient 1

0.7 - 1.0 min Focused Gradient 2

1.0 -1.4 min Focused Gradient 3

1.4 -1.8 min Focused Gradient 4

1.8 - 2.4 min Focused Gradient 5

2.4 -3.0 min Focused Gradient 6 Time (min) % A/B/C/D

Focused Gradient 1 : 0.0 90/5/5/0

2.0 85/10/5/0

4.0 5/90/5/0

Focused Gradient 2: 0.0 90/5/5/0

2.0 70/25/5/0

4.0 5/90/5/0

Focused Gradient 3: 0.0 85/10/5/0

2.0 55/40/5/0

4.0 5/90/5/0

Focused Gradient 4: 0.0 70/25/5/0

2.0 40/55/5/0

4.0 5/90/5/0

Focused Gradient 5: 0.0 55/40/5/0

2.0 25/70/5/0

4.0 5/90/5/0

Focused Gradient 6: 0.0 40/55/5/0

2.0 10/85/5/0

4.0 5/90/5/0

Detectors: DAD, MS: ES (+) mode.

Fraction Collection: Triggered by selected ion recording 3 MS; one tube per injection

Post-Durification analysis:

Column: 4.6 x 30 mm Waters X-Bridge C8, 5um

Flow rate: 2.5 mL/min; Injection volume: 2uL in DMSO

Solvents: A: Water; B: Acetonitrile; C: 1% aq. TFA; D: 1 l% aq. ammonium hydroxide

Gradient: 4% B to 95% B over 3.0 minutes, C held at 1%.

Detectors: DAD, ELSD, TOF MS: ES (+) mode

Examples 91- 172

Step 1: Preparation of 3-(4-EthvlmorDholin-2-vl)benzenamine.

This material was prepared following the general procedures described in Example 2, substituting 2-bromo-3'-nitroacetophenone for 2-bromo-4'-nitroacetophenone: HCI salt , NMR (MeOH-d₄) δ 7.64-7.54 (m, 3H), 7.43-7.40 (m, 1H), 4.97 (dd, J = 10.8, 2.1 Hz, 1 H), 4.31 (dd, J = 13.3, 2.9 Hz, 1 H), 4.12-4.05 (m, 1H), 3.74 (app dt, J = 12.4, 2.1 Hz, 1 H), 3.61 (br d, 13.3 Hz₁ 1 H), 3.27-3.19 (m, partially obscured by MeOH signal, 3H), 3.07 (t, J = 11.8 Hz, 1 H), 1.41 (t, J = 7.3 Hz, 3H); LRMS m/z Calcd for Ci₂H₁₈N₂O, 206.1 , found 207.1 (M+H), (APCI). Step 2: Formation of sulfonamides.

The following compounds were prepared using the following protocol: A 0.2 M stock solution of the appropriate sulfonyl chloride (50 DL) in anhydrous DMF was added to a 0.2 M solution of 3-(4-ethylmorpholin-2-yl)benzenamine (50DL) in pyridine. The vessel was capped and heated at 5O⁰C for 16h, then the volatiles were removed under high vacuum. DMSO (300 DL) was added and the vessel was agitate for -30 min to dissolve the products. Additional DMSO was added to bring the volume to 1 mL. The sample was then purified by HPLC:

The in vitro affinity of the compounds of the present invention at the rat or human dopamine receptors can be measured using |n vitro inhibition assays that have been described in the literature and modified according to the following procedures. Cell Membrane Preparation

Chinese hamster ovary (CHO) cells, modified to express the human dopamine D₂ receptor and D₃ receptor (P. Sokoloff, et a!.. "Pharmacology of human D3 receptor expressed in a mammalian cell line: comparison with D2 receptor." Eur. J. Pharmacol. 1992. 225:331-337) were pelletized in 5 mM EDTA (pH 7.4, 4 ⁰C) by centrifugation (1000 rpm, 5 min). The supernatant was removed and the cells were suspended in 20 ml of Buffer A [Buffer A contains 50 mM Tris HCI (i.e., tris(hydroxymethyl]aminomethane hydrochloride), 120 mM NaCI, 5 mM KCI, 2 mM CaCI₂ and 5 mM MgCI₂ at pH 7.4, 25 ⁰C] and homogenized two times with a Polytron (setting 6, 20 sec). The homogenate was centrifuged at 18,000 rpm (4 ⁰C for 10 min) after each homogenation. The pellets were resuspended in a final volume of Buffer A so that the concentrations of membranes were 4.3 and 10.0 mg/ml for D₂ and D₃ respectively. Receptor Binding Assay:

A solution of 25 Dl of 0.4 nM [³H]-Spiperone (or [³H]-DPAT) and 25 Dlof test drug (or 10 uM butaclamol or vehicle) were placed in an open well of a 96-well microtiter plate (U-bottom wells, polypropylene). The reaction is started by the addition of 200 Dl of membranes and incubated at 37 ⁰C for 15 min. The reaction is stopped by rapid filtration through Unifilter-96 GF/B filter plates which had previously been soaked in 0.5% PEI (i.e., polyethylenimine) for 2 hr. The filter plates were washed six time with ice-cold buffer Solution B (50 mM Tris HCI, pH 7.4 @ 25 ⁰C) in a Brandel® automated harvester and dried overnight. Afterwards, 60 Dl of MicroScin® was pipetted into each well of the Unifilter® plate and counted in a TOPCOUNT® counter. Measurement and Analysis of Data:

Data were expressed as IC₅₀ ¹S (the concentration that inhibits 50% of the specific binding), or as an apparent K₁, where the Kj = IC₅₀/I + [L]/«_d, [L] being the ligand concentration and Ka is the affinity constant for [³H]-ligand determined in separate experiments. The high affinity of the compounds of formula I, according to the invention, is reflected in very low in vitro binding constants (Ki). The following are representative examples of the compounds of formula I.

Claims

1. A compound of formula I;

or a pharmaceutically acceptable salt thereof, wherein: R¹ is hydrogen or Ci-C₈-alkyl optionally substituted with 1 to 3 halogens;

R² is selected from the group consisting of hydrogen, d-C₆-alkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₃-C₆-cycloalkyl, d-C₆-alkoxy, fluorinated d-C₆-alkyl, fluorinated C₃- C₆-cycloalkyl, fluorinated d-Cβ-alkoxy, CrC₆-hydroxyalkyl, d-Cε-alkoxy-d-d-alkyl, d- C₆-hydroxyalkoxy, d-Ce-alkoxy-d-d-alkoxy, COOH, NR⁷R⁸, CH₂NR⁷R⁸, ONR⁷R⁸, NHC(O)NR⁷R⁸, C(O)NR⁷R⁸, SO₂NR⁷R⁸, d-C₆-alkylcarbonyl, fluorinated C₁-C₆- alkylcarbonyl, d-Cβ-alkylcarbonylamino, fluorinated d-Cβ-alkylcarbonyl- amino, C₁-C₆- alkylcarbonyloxy, fluorinated d-Cβ-alkylcarbonyloxy, CrCβ-alkoxycarbonyl, d-C₆-alkylthio, fluorinated Ci-C₆-alkylthio, Ci-C₆-alkylsulfιnyl, d-C₆-alkylsulfonyl, fluorinated C₁-C₆- alkylsulfinyl, fluorinated d-C₆-alkylsulfonyl, phenylsulfonyl, phenyl, phenoxy, benzyloxy, and a 3- to 7-membered heterocyclic ring, wherein said phenylsulfonyl, phenyl, phenoxy, benzyloxy, and heterocyclic ring may be optionally substituted with 1 to 4 substituents selected from halogen, cyano, OH, oxo, and cyano;

R³ is selected from hydrogen, halogen, cyano, nitro, OH, methyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy and trifluoromethoxy; or optionally, when R² and R³ are bound to two adjacent carbon atoms, R² and R³ together with the two carbons to which they are attached, form a 5- or 6-membered heterocyclic or carbocylic ring; wherein said ring is optionally substituted with 1 to 4 substituents selected from halogen, NO₂, NH₂, OH, cyano_, d-C₆-alkyl, C₃-C₆-cycloalkyl, Ci- C₆-alkoxy, fluorinated d-C₆-alkyl, fluorinated C₃-C₆-cycloalkyl, fluorinated C_rC₆-alkoxy, C₁- Ce-hydroxyalkyl, d-C₄-alkoxy-C₂-C₄-alkyl, d-C₆-hydroxyalkoxy, d-d-alkoxy-C₂-C₄-alkoxy, d-C₆-alkylcarbonyl, d-C₆-alkylamino, di- d-C₆-alkylamino, d-Cβ-alkylaminocarbonyl, di-Cr C₆-alkylaminocarbonyl, fluorinated d-C₆-alkylcarbonyl, CrCβ-alkylcarbonylamino, fluorinated Ci-Ce-alkylcarbonylamino, CrCβ-alkylcarbonyloxy, fluorinated d-C₆-alkylcarbonyloxy, C₁-C₆- alkoxycarbonyl, CrCβ-alkylthio, fluorinated d-C₆-alkylthio, CrCβ-alkylsulfinyl, C₁-C₆- alkylsulfonyl, fluorinated d-C₆-alkylsulfinyl, and fluorinated d-C₆-alkylsulfonyl;

R⁴ is hydrogen, Ci-C₈-alkyl, or a 5-6-membered aryl optionally substituted with 1 to 3 substituents selected from halo, -OCH₃, -OCF₃, -CF₃, and cyano; or R¹ and R⁴ may be combined to form a 5- to 7-member carbocyclic ring; R⁵ is hydrogen or d-Cβ-alkyl;

R⁶ is selected from hydrogen, halo, C<ι-C₈-alkyl, -OCH₃, -OCF₃, -CF₃, and cyano; and R⁷ and R⁸ are independently selected from H, C^Cs-alky!, C₁-C₃-BIkOXy and fluorinated CrC₃-alkyl.

2. A compound according to claim 1 wherein the sulfonamide is located para to the point of attachment of the heterocyclic ring in formula I.

3. A compound according to claim 1 wherein the sulfonamide is located meta to the point of attachment of the heterocyclic ring

4. A compound according to claim 2 wherein R⁴ is hydrogen.

5. A compound according to claim 2 wherein R⁴ is methyl.

6. A compound according to claim 1 wherein R¹ and R⁴ form a 6-membered ring.

7. A compound according to claim 1 wherein said compound is selected from the group consisting of:

N-(4-(4-ethylmorpholin-2-yl)phenyl)-4-isopropylbenzenesulfonamide;

N-(4-(4-ethylmorpholin-2-yl)phenyl)-4-isopropyl-N-methylbenzenesulfonamide;

N-(4-(4-ethylmorpholin-2-yl)-3-methoxyphenyl)-4-isopropylbenzenesulfonamide; N-(4-(4-ethylmorpholin-2-yl)-2-methoxyphenyl)-4-isopropylbenzenesulfonamide;

N-(4-(4-ethylmorpholin-2-yl)-2-fluorophenyl) -4-isopropylbenzenesulfonamide;

N-(4-(4-ethylmorpholin-2-yl)-3-fluorophenyl) -4-isopropylbenzenesulfonamide;

N-(4-(4-ethylmorpholin-2-yl)-2-methylphenyl) -4-isopropylbenzenesulfonamide; and

N-(4-(4-ethylmorpholin-2-yl)-3-methylphenyl) -4-isopropylbenzenesulfonamide.

8. A compound according to claim 1 wherein said compound is selected from the group consisting of:

N-(4-(4-Ethylmorpholin-2-yl)phenyl)-4-isopropylbenzenesulfonamide;

N-(4-(4-Ethylmorpholin-2-yl)-2-methoxyphenyl)-4-isopropylbenzenesulfonamide;

N-(4-(4-Ethylmorpholin-2-yl)-2-fluorophenyl)-4-isopropylbenzenesulfonamide;

N-(4-(4-Ethylmorpholin-2-yl)-3-fluorophenyl)-4-isopropylbenzenesulfonamide;

N-(4-(4-Ethylmorpholin-2-yl)-2-methylphenyl)-4-isopropylbenzenesulfonamide; N-(4-(4-Ethylmorpholin-2-yl)-2-methyphenyl)-pyrrolidine-1-sulfonamide;

N-(4-((2S,5S-4-Ethyl-5-methylmorpholin-2-yl)phenyl)-4- isopropylbenzenesulfonamide; N-(4-((2R,5S-4-Ethyl-5-methylmorpholin-2-yl)phenyl)-4- isopropylbenzenesulfonamide;

[4-(4-Ethylmorpholin-2-yl)-phenyl]-4-isopropyl-benzenesulfonamide; [4-(4-Ethylmorpholin-2-yl)-phenyl]-3-fluoro-4-methoxybenzenesulfonamide; 3-{4-[4-(4-Ethylmorpholin-2-yl)-phenylsulfamoyl]-phenyl}-propionic acid methyl ester; 2-Oxo-2H-chromene-6-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

C-(3,4-Dichloro-phenyl)-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-methanesulfonamide; N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-C-(4-trifluoromethyl-phenyl)-methanesulfon- amide;

4-Methyl-thiophene-2-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide; Benzo[b]thiophene-2-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

C-(3,5-Dichlorophenyl)-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-methanesulfonamide; C-(4-Chlorophenyl)-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-methanesulfonamide; N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-C-(3-trifluoromethyl-phenyl)-methanesulfon- amide; N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2,4-dimethoxy-benzenesulfonamide;

C-(3-Chlorophenyl)-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-methanesulfonamide; 2-Ethoxy-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-4-methylbenzenesulfonamide; S-Methylthiophene^-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide; 2,5-Dimethyl-thiophene-3-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide; 3-Methylthiophene-2-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

4-[4-(4-Ethylmorpholin-2-yl)-phenylsulfamoyl]-2,5-dimethyl-furan-3-carboxylic acid methyl ester;

4-Methyl-3,4-dihydro-2H-benzo[1 ,4]oxazine-7-sulfonic acid [4-(4-ethylmorpholin-2-yl)- phenyl]-amide; 5-Methyl-2-trifluoromethyl-furan-3-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]- amide;

5-[4-(4-Ethylmorpholin-2-yl)-phenylsulfamoyl]-2-methylfuran-3-carboxylic acid methyl ester;

Benzo[b]thiophene-3-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide; 6-Morpholin-4-ylpyridine-3-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-4-fluoro-2-methylbenzenesulfonamide; 1-[4-(4-Ethylmorpholin-2-yl)-phenylsulfamoyl]-piperidine-3-carboxylic acid ethyl ester; 5-Methyl-1 -phenyl-1 H-pyrazole-4-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]- amide;

2,4-Dimethylthiazole-5-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

5-Pyridin-2-ylthiophene-2-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide; 1-[4-(4-Ethylmorpholin-2-yl)-phenylsulfamoyl]-piperidine-4-carboxylic acid ethyl ester;

Piperidine-1 -sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

Benzothiazole-6-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2-methylbenzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2,5-dimethyl-benzenesulfonamide; 5-Bromo-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-2-methoxybenzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide;

S.S-Dimethyl-isoxazole^-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2,5-dimethoxy-benzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-5-fluoro-2-methylbenzenesulfonamide; 5-Chloro-1 ,3-dimethyl-1 H-pyrazole-4-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]- amide;

5-Chloro-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-2-methoxybenzenesulfonamide;

4-Bromo-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-2-methylbenzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-3,4-difluoro-benzenesulfonamide; 3-Chloro-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-4-methylbenzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-3-fluorobenzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2-trifluoromethoxy-benzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-benzenesulfonamide;

Naphthalene-2-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide; N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-4-methyl-benzenesulfonamide;

4-Chloro-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-benzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2,4-dimethyl-benzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-3-methylbenzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-4-fluorobenzenesulfonamide; 4-tert-Butyl-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-benzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2-methoxy-5-methylbenzenesulfonamide;

2-Bromo-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-benzenesulfonamide;

Naphthalene-1 -sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

3-Chloro-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-benzenesulfonamide; 3-Chloro-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-2-methylbenzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2,4-difluoro-benzenesulfonamide;

2-Chloro-N-[4-(4-ethyl-morpholin-2-yl)-phenyl]-4-fluorobenzenesulfonamide; N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-4-propyl-benzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2-fluorobenzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2-methoxy-4-methylbenzenesulfonamide;

4-Ethyl-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-benzenesulfonamide; Thiophene-2-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

3-Chloropropane-1 -sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-2,4,6-trimethyl-benzenesulfonamide;

4-Butoxy-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-benzenesulfonamide;

Benzo[1 ,2,5]oxadiazole-4-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide; (E)-2-Phenyl-ethenesulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-4-vinyl-benzenesulfonamide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-4-fluoro-3-trifluoronnethyl-benzenesulfonaπnide;

1 ,2-Dimethyl-i H-imidazole-4-sulfonic acid [4-(4-ethylmorpholin-2-yl)-phenyl]-amide;

N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-4-formyl-benzenesulfonamide; N-[4-(4-Ethylmorpholin-2-yl)-phenyl]-3-trifluoromethoxy-benzenesulfonamide; and

4-Acetyl-N-[4-(4-ethylmorpholin-2-yl)-phenyl]-benzenesulfonamide.

9. A pharmaceutical composition for treating a disorder or condition selected from organic disturbances, symptomatic disturbances, psychoses of the acute exogenous reaction type or attendant psychoses or organic or exogenous cause; endogenous psychoses, schizophrenia, schizotype and delusional disturbances; affective disturbances, depression, mania, manic-depressive conditions; mixed forms of the above described disturbances; neurotic and somatoform disturbances and disturbances in association with stress; dissociative disturbances, loss of consciousness, clouding of consciousness, double consciousness and personality disturbances; disturbances in attention and waking and sleeping behavior, behavioral disturbances and emotional disturbances whose onset lies in childhood and youth, hyperactivity in children, intellectual deficits, in particular attention disturbances (attention deficit disorders), memory disturbances and cognitive disturbances, impaired learning and memory (impaired cognitive function), dementia, narcolepsy and sleep disturbances, restless leg syndrome; developmental disturbances; anxiety states, delirium, sex-life disturbances, impotence in men; eating disturbances, anorexia or bulimia, addiction and other unspecified disturbances, psychic disorders and behavioral disturbances which are caused by the abuse of psychotropic substances, pharmaceuticals or narcotics, addiction to gaming (impulse control disorders not elsewhere classified); addictions associated with opioids, morphine, heroin, codeine, cocaine; nicotine; alcohol; substances which interact with GABA chloride channel complex; sedatives; hypnotics and tranquilizers, benzodiazepines; LSD; cannabinoids; psychomotor stimulants, 3,4-methylenedioxy-N-methylamphetamine; amphetamine and amphetamine-like substances, methylphenidate, and caffeine; Parkinson's disease and epilepsy, and, the affective disturbances connected thereto in a mammal, comprising an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating such disorder or condition and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition for treating a disorder or condition that can be treated by inhibiting dopamine neurotransmission in a mammal, preferably a human, comprising an amount of a compound of the formula I₁ or a pharmaceutically acceptable salt thereof, effective in treating such disorder or condition and a pharmaceutically acceptable carrier.

11. A method for treating a disorder or condition selected from organic disturbances, symptomatic disturbances, psychoses of the acute exogenous reaction type or attendant psychoses or organic or exogenous cause; endogenous psychoses, schizophrenia, schizotype and delusional disturbances; affective disturbances, depression, mania, manic- depressive conditions; mixed forms of the above described disturbances; neurotic and somatoform disturbances and disturbances in association with stress; dissociative disturbances, loss of consciousness, clouding of consciousness, double consciousness and personality disturbances; disturbances in attention and waking and sleeping behavior, behavioral disturbances and emotional disturbances whose onset lies in childhood and youth, hyperactivity in children, intellectual deficits, in particular attention disturbances (attention deficit disorders), memory disturbances and cognitive disturbances, impaired learning and memory (impaired cognitive function), dementia, narcolepsy and sleep disturbances, restless leg syndrome; developmental disturbances; anxiety states, delirium, sex-life disturbances, impotence in men; eating disturbances, anorexia or bulimia, addiction and other unspecified disturbances, psychic disorders and behavioral disturbances which are caused by the abuse of psychotropic substances, pharmaceuticals or narcotics, addiction to gaming (impulse control disorders not elsewhere classified); addictions associated with opioids, morphine, heroin, codeine, cocaine; nicotine; alcohol; substances which interact with GABA chloride channel complex; sedatives; hypnotics and tranquilizers, benzodiazepines; LSD; cannabinoids; psychomotor stimulants, 3,4-methylenedioxy-N-methylamphetamine; amphetamine and amphetamine-like substances, methylphenidate, and caffeine; Parkinson's disease and epilepsy, and, the affective disturbances connected thereto in a mammal, 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.