# Patent

## Title
Aminoethylaromatic compounds suitable for treating disorders that respond to modulation of the dopamine D3 receptor

## Abstract

The present invention relates to aromatic compounds of the formula I




wherein Ar is phenyl or an aromatic 5- or 6-membered C-bound heteroaromatic radical, wherein Ar may carry 1 radical Ra and wherein Ar may also carry 1 or 2 radicals Rb;

    X is N or CH;
    E is CR6R7 or NR3;
    R1 is C1-C4-alkyl, C3-C4-cycloalkyl, C3-C4-cycloalkylmethyl, C3-C4-alkenyl, fluorinated C1-C4-alkyl, fluorinated C3-C4-cycloalkyl, fluorinated C3-C4-cycloalkylmethyl, fluorinated C3-C4-alkenyl, formyl or C1-C3-alkylcarbonyl;
    R1a is H, C1-C4-alkyl, C3-C4-cycloalkyl, C3-C4-cycloalkylmethyl, C3-C4-alkenyl, fluorinated C1-C4-alkyl, fluorinated C3-C4-cycloalkyl, fluorinated C3-C4-cycloalkylmethyl, fluorinated C3-C4-alkenyl, or R1a and R2 together are (CH2)n with n being 2, 3 or 4, or R1a and R2a together are (CH2)n with n being 2, 3 or 4;
    R2 and R2a are are independently of each other H, C1-C4-alkyl or fluorinated C1-C4-alkyl or R2a and R2 together are (CH2)m with m being 1, 2, 3, 4 or 5;
    R3 is H or C1-C4-alkyl;
    R6, R7 independently of each other are selected from H, fluorine, C1-C4-alkyl and fluorinated C1-C4-alkyl or together form a moiety (CH2)p with p being 2, 3, 4 or 5;

and the physiologically tolerated acid addition salts thereof.



The invention also relates to the use of a compound of the formula I or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for the treatment of a medical disorder susceptible to treatment with a dopamine D3 receptor ligand.

## Background
BACKGROUND OF THE INVENTION
The present invention relates to novel aminoethylaromatic 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 al., The Dopamine D3 Receptor as a Target for Antipsychotics, in Novel Antipsychotic Drugs, H. Y. Meltzer, Ed. Raven Press, New York 1992, pages 135-144; M. Dooley et al., Drugs and Aging 1998, 12, 495-514, J. N. Joyce, Pharmacology and Therapeutics 2001, 90, pp. 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, 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 C1-C3-alkyl, 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 are not satisfactory. Consequently there is an ongoing need to provide new compounds, which either have an high affinity and an 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 invention is based on the object of providing compounds which act as highly selective dopamine D3 receptor ligands. This object is surprisingly achieved by means of aminoethylaromatic compounds of the formula I




wherein

    Ar is phenyl or an aromatic 5- or 6-membered C-bound heteroaromatic radical, wherein Ar may carry 1 radical Ra and wherein Ar may also carry 1 or 2 radicals Rb;
    Ra being selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, fluorinated C2-C6-alkenyl, C3-C6-cycloalkyl, C1-C6-alkoxy, fluorinated C1-C6-alkyl, fluorinated C3-C6-cycloalkyl, fluorinated C1-C6-alkoxy, C1-C6-hydroxyalkyl, C1-C6-alkoxy-C1-C4-alkyl, C1-C6-hydroxyalkoxy, C1-C6-alkoxy-C1-C4-alkoxy, COOH, NR4R5, CH2NR4R5, ONR4R5, NHC(O)NR4R5, C(O)NR4R5, SO2NR4R5, C1-C6-alkylcarbonyl, fluorinated C1-C6-alkylcarbonyloxy, fluorinated C1-C6-alkylcarbonyloxy, C1-C6-alkoxycarbonyl, C1-C6-alkylthio, fluorinated C1-C6-alkylthio, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, fluorinated C1-C6-alkylsulfinyl, fluorinated C1-C6-alkylsulfonyl, phenylsulfonyl, phenyl, phenoxy, benzyloxy and a 3- to 7-membered heterocyclic radical, wherein the five last mentioned radicals may carry 1, 2, 3 or 4 radicals selected from halogen, cyano, OH, oxo, CN, and the radicals Ra,
    Rb being, independently from each other, selected from halogen, cyano, nitro, OH, methyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy and trifluoromethoxy,
    
        the radical Ra and one radical Rb, if present and bound to two adjacent carbon atoms of phenyl, may form a 5- or 6-membered heterocyclic or carbocylic ring which is fused to the phenyl ring and which is unsubstituted or which may carry 1, 2 or 3 radicals selected from halogen, NO2, NH2, OH, CN, C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-alkoxy, fluorinated C1-C6-alkyl, fluorinated C3-C6-cycloalkyl, fluorinated C1-C6-alkoxy, C1-C6-hydroxyalkyl, C1-C4-alkoxy-C2-C4-alkyl, C1-C6-hydroxyalkoxy, C1-C4-alkoxy-C2-C4-alkoxy, C1-C6-alkylcarbonyl, C1-C6-alkylamino, di-C1-C6-alkylamino, C1-C6-alkylaminocarbonyl, di-C1-C6-alkylaminocarbonyl, fluorinated C1-C6-alkylcarbonyl, C1-C6-alkylcarbonylamino, fluorinated C1-C6-alkylcarbonylamino, C1-C6-alkylcarbonyloxy, fluorinated C1-C6-alkylcarbonyloxy, C1-C6-alkoxycarbonyl, C1-C6-alkylthio, fluorinated C1-C6-alkylthio, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, fluorinated C1-C6-alkylsulfinyl and fluorinated C1-C6-alkylsulfonyl,
    
    
    X is N or CH;
    E is CR6R7 or NR3;
    R1 is C1-C4-alkyl, C3-C4-cycloalkyl, C3-C4-cycloalkylmethyl, C3-C4-alkenyl, fluorinated C1-C4-alkyl, fluorinated C3-C4-cycloalkyl, fluorinated C3-C4-cycloalkylmethyl, fluorinated C3-C4-alkenyl, formyl or C1-C3-alkylcarbonyl;
    R1a is H, C1-C4-alkyl, C3-C4-cycloalkylmethyl, C3-C4-alkenyl, fluorinated C1-C4-alkyl, fluorinated C3-C4-cycloalkyl, fluorinated C3-C4-cycloalkylmethyl, fluorinated C3-C4-alkenyl, or R1a and R2 together are (CH2), with n being 2, 3 or 4, or R1a and R2a together are (CH2)n with n being 2, 3 or 4;
    R2 and R2a are independently of each other H, C1-C4-alkyl or fluorinated C1-C4-alkyl or R2a and R2 together are (CH2)m with m being 2, 3, 4 or 5;
    R3 is H or C1-C4-alkyl;
    R4, R5 independently of each other are selected from H, C1-C3-alkyl, C1-C3-alkoxy and fluorinated C1-C3-alkyl;
    R6, R7 independently of each other are selected from H, fluorine, C1-C4-alkyl and fluorinated C1-C4-alkyl or together form a moiety (CH2)p with p being 2, 3, 4 or 5;

provided that for R1 being C1-C4-alkyl, R2═R2a being H, E being NH, X being CH and Ar=substituted phenyl Ar carries at least one substituent Ra which is different from linear C1-C3-alkyl, OCH3, OCF3, CF3, SCH3 or NHC(O)CH3, and which is preferably selected from secondary C3-C6-alkyl, fluorinated C2-C6-alkyl, fluorinated C3-C6-cycloalkyl, fluorinated C2-C6-alkoxy, CHF2, CF2, OCHF2, OCF2, NR4R5, 1-aziridinyl, azetidin-1-yl, pyrrolidin-1-yl or piperidin-1-yl, wherein the last for mentioned radicals may be fluorinated or may carry 1 or 2 radicals selected from OH, oxo, C1-C2-alkyl, fluorinated C1-C2-alkyl or C1-C2-alkoxy, a phenyl group and an aromatic 5- or 6-membered C-bound heteroaromatic radical, comprising 1 nitrogen atom as ring member and 0, 1, 2 or 3 further heteroatoms, independently of each other, selected from O, S and N, wherein the last two mentioned radicals may carry 1, 2, 3 or 4 radicals selected from halogen, NO2, OH, CN, and the radicals Ra such as NH2, C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-alkoxy, fluorinated C1-C6-alkyl, fluorinated C3-C6-cycloalkyl, fluorinated C1-C6-alkoxy, C1-C6-hydroxyalkyl, C1-C4-alkoxy-C2-C4-alkyl, C1-C6-hydroxyalkoxy, C1-C4-alkoxy-C2-C4-alkoxy, C1-C6-alkylcarbonyl, C1-C6-alkylamino, di-C1-C6-alkylamino, C1-C6-alkylaminocarbonyl, di-C1-C6-alkylaminocarbonyl, fluorinated C1-C6-alkylcarbonyl, C1-C6-alkylcarbonylamino, fluorinated C1-C6-alkylcarbonylamino, C1-C6-alkylcarbonyloxy, fluorinated C1-C6-alkylcarbonyloxy, C1-C6-alkoxycarbonyl, C1-C6-alkylthio, fluorinated C1-C6-alkylthio, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, fluorinated C1-C6-alkylsulfinyl and fluorinated C1-C6-alkylsulfonyl;

and the physiologically tolerated acid addition salts of these compounds.



The present invention therefore relates to aminoethylaromatic compounds of the general formula I and to their physiologically tolerated acid addition salts.
The present invention also relates to a pharmaceutical composition which comprises at least one aminoethylaromatic compound of the formula I and/or at least one physiologically tolerated acid addition salt of 1, where appropriate together with physiologically acceptable carriers and/or auxiliary substances.
The present invention also relates to a method for treating disorders which respond to influencing by dopamine D3 receptor antagonists or dopamine D3 agonists, said method comprising administering an effective amount of at least one aminoethylaromatic compound of the formula I and/or at least one physiologically tolerated acid addition salt of I to a subject in need thereof.


DETAILED DESCRIPTION OF THE INVENTION
The diseases which respond to the influence of dopamine D3 receptor antagonists or agonists include, in particular, disorders and diseases of the central nervous system, in particular affective disturbances, neurotic disturbances, stress disturbances and somatoform disturbances and psychoses, especially schizophrenia and depression and, in addition, disturbances of kidney function, in particular kidney function disturbances which are caused by diabetes mellitus (see WO 00/67847).
According to the invention, at least one compound of the general formula I having the meanings mentioned at the outset is used for treating the above mentioned indications. Provided the compounds of the formula I of a given constitution may exist in different spatial arrangements, for example if they possess one or more centers of asymmetry, poly-substituted rings or double bonds, or as different tautomers, it is also possible to use enantiomeric mixtures, in particular racemates, diastereomeric mixtures and tautomeric mixtures, preferably, however, the respective essentially pure enantiomers, diastereomers and tautomers of the compounds of formula I and/or of their salts.
It is likewise possible to use physiologically tolerated salts of the compounds of the formula I, especially acid addition salts with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, C1-C4-alkylsulfonic acids; such as methanesulfonic acid, aromatic sulfonic acids, such as benzenesulfonic acid and toluenesulfonic acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid and benzoic acid. Other utilizable acids are described in Fortschritte-der Arzneimittelforschung [Advances in drug research], Volume 10, pages 224 ff., Birkhäuser Verlag, Base1 and Stuttgart, 1966.
The organic moieties mentioned in the above definitions of the variables are—like the term halogen—collective terms for individual listings of the individual group members. The prefix Cn—Cm indicates in each case the possible number of carbon atoms in the group.
The term halogen denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine or chlorine.
C1-C4 Alkyl (and likewise in C1-C4 hydroxyalkyl, C1-C6 alkoxy-C1-C4-alkyl, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, C1-C4 alkylcarbonyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl etc.) is a straight-chain or branched alkyl group having from 1 to 4 carbon atoms. Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl or tert-butyl.
C1-C6 Alkyl (and likewise in C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C4-alkyl, C1-C6 alkylcarbonyl, C1-C6 alkylcarbonylamino, C1-C6 alkylcarbonyloxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl etc.) is a straight-chain or branched alkyl group having from 1 to 6 carbon atoms. Examples include C1-C4 alkyl as mentioned above and also pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl;
Fluorinated C1-C6 alkyl (and likewise in fluorinated C1-C6 alkylcarbonyl, fluorinated C1-C6 alkylcarbonylamino, fluorinated C1-C6 alkylcarbonyloxy, fluorinated C1-C6 alkylthio, fluorinated C1-C6 alkylsulfinyl, fluorinated C1-C6 alkylsulfonyl etc.) is a straight-chain or branched alkyl group having from 1 to 6, in particular 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by a fluorine atoms such as in fluoromethyl, difluoromethyl, trifluoromethyl, (R)-1-fluoroethyl, (S)-1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (R)-1-fluoropropyl, (S)-1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 1,1-difluoropropyl, 2,2-difluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, (R)-2-fluoro-1-methylethyl, (S)-2-fluoro-1-methylethyl, (R)-2,2-difluoro-1-methylethyl, (S)-2,2-difluoro-1-methylethyl, (R)-1,2-difluoro-1-methylethyl, (S)-1,2-difluoro-1-methylethyl, (R)-2,2,2-trifluoro-1-methylethyl, (S)-2,2,2-trifluoro-1-methylethyl, 2-fluoro-1-(fluoromethyl)ethyl, 1-(difluoromethyl)-2,2-difluoroethyl, (R)-1-fluorobutyl, (S)-1-fluorobutyl, 2-fluorobutyl, 3-fluorobutyl, 4-fluorobutyl, 1,1-difluorobutyl, 2,2-difluorobutyl, 3,3-difluorobutyl, 4,4-difluorobutyl, 4,4,4-trifluorobutyl, etc.;
Branched C3-C6 alkyl is alkyl having 3 to 6 carbon atoms at least one being a secondary or tertiary carbon atom. Examples are isopropyl, tert.-butyl, 2-butyl, isobutyl, 2-pentyl, 2-hexyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl 1-methyl-1-ethylpropyl.
C1-C6 Alkoxy (and likewise in C1-C6 alkoxycarbonyl, C1-C6 alkoxy-C1-C4 alkyl, C1-C6 alkoxy-C1-C4 alkoxy and C1-C6 hydroxyalkoxy) is a straight-chain or branched alkyl group having from 1 to 6, in particular 1 to 4 carbon atoms, which is bound to the remainder of the molecule via an oxygen atom. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, iso-butoxy, tert.-butoxy pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1,1-dimethylbutyloxy, 1,2-dimethylbutyloxy, 1,3-dimethylbutyloxy, 2,2-dimethylbutyloxy, 2,3-dimethylbutyloxy, 3,3-dimethylbutyloxy, 1-ethylbutyloxy, 2-ethylbutyloxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy;
Fluorinated C1-C6 alkyoxy (and likewise in fluorinated C1-C6alkoxycarbonyl) is a straight-chain or branched alkoxy group having from 1 to 6, in particular 1 to 4 carbon atoms, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by a fluorine atoms such as in fluoromethoxy, difluoromethoxy, trifluoromethoxy, (R)-1-fluoroethoxy, (S)-1-fluoroethoxy, 2-fluoroethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, (R)-1-fluoropropoxy, (S)-1-fluoropropoxy, 2-fluoropropoxy, 3-fluoropropoxy, 1,1-difluoropropoxy, 2,2-difluoropropoxy, 3,3-difluoropropoxy, 3,3,3-trifluoropropoxy, (R)-2-fluoro-1-methylethoxy, (S)-2-fluoro-1-methylethoxy, (R)-2,2-difluoro-1-methylethoxy, (S)-2,2-difluoro-1-methylethoxy, (R)-1,2-difluoro-1-methylethoxy, (S)-1,2-difluoro-1-methylethoxy, (R)-2,2,2-trifluoro-1-methylethoxy, (S)-2,2,2-trifluoro-1-methylethoxy, 2-fluoro-1-(fluoromethyl)ethoxy, 1-(difluoromethyl)-2,2-difluoroethoxy, (R)-1-fluorobutoxy, (S)-1-fluorobutoxy, 2-fluorobutoxy, 3-fluorobutoxy, 4-fluorobutoxy, 1,1-difluorobutoxy, 2,2-difluorobutoxy, 3,3-difluorobutoxy, 4,4-difluorobutoxy, 4,4,4-trifluorobutoxy, etc.;
C3-C6 Cycloalkyl is a cycloaliphatic radical having from 3 to 6 C atoms, such as cyclopropyl, cyclobutyl and cyclopentyl. The cycloalkyl radical may be unsubstituted or may carry 1, 2, 3 or 4 C1-C4 alkyl radicals, preferably a methyl radical. One alkyl radical is preferably located in the 1-position of the cycloalkyl radical, such as in 1-methylcyclopropyl or 1-methylcyclobutyl.
Fluorinated C3-C6 cycloalkyl is a cycloaliphatic radical having from 3 to 6 C atoms, such as cyclopropyl, cyclobutyl and cyclopentyl, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by a fluorine atoms such as in 1-fluorocyclopropyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 1,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, pentafluorocyclopropyl, 1-fluorocyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl, 1,2-difluorocyclobutyl, 1,3-difluorocyclobutyl, 2,3-difluorocyclobutyl, 2,4-difluorocyclobutyl, or 1,2,2-trifluorocyclobutyl.
C3-C6 Cycloalkylmethyl is methyl which carries a cycloaliphatic radical having from 3 to 6 C atoms as mentioned above
Fluorinated C3-C6 cycloalkylmethyl is methyl which carries a cycloaliphatic radical having from 3 to 6 C atoms, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by a fluorine atoms.
C2-C6-Alkenyl is a singly unsaturated hydrocarbon radical having 2, 3, 4, 5 or 6 C-atoms, e.g. vinyl, allyl(2-propen-1-yl), 1-propen-1-yl, 2-propen-2-yl, methallyl(2-methylprop-2-en-1-yl) and the like. C3-C4-Alkenyl is, in particular, allyl, 1-methylprop-2-en-1-yl, 2-buten-1-yl, 3-buten-1-yl, methallyl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-methylbut-2-en-1-yl or 2-ethylprop-2-en-1-yl.
Fluorinated C2-C6-alkenyl is a singly unsaturated hydrocarbon radical having 2, 3, 4, 5 or 6 C-atoms, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by a fluorine atoms such as in 1-fluorovinyl, 2-fluorovinyl, 2,2-fluorovinyl, 3,3,3-fluoropropenyl, 1,1-difluoro-2-propenyl 1-fluoro-2-propenyl and the like.
C1-C6-hydroxyalkyl is an alkyl radical having from 1 to 6 carbon atoms as defined above, wherein one hydrogen atom is replaced by hydroxy. Examples comprise hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-methyl-1-hydroxyethyl and the like.
C1-C6 hydroxyalkoxy is an alkoxy radical having from 1 to 6, preferably from 2 to 4 carbon atoms as defined above, wherein one hydrogen atom is replaced by hydroxy. Examples comprise 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-methyl-2-hydroxyethyl and the like.
C1-C6 alkoxy-C1-C4-alkyl is an alkyl radical having from 1 to 4 carbon atoms as defined above, wherein one hydrogen atom is replaced by C1-C6 alkoxy. Examples comprise methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 3-methoxypropyl, 2-methoxypropyl, 1-methyl-1-methoxyethyl, ethoxymethyl, 2-ethoxyethyl, 1-ethoxyethyl, 3-ethoxypropyl, 2-ethoxypropyl, 1-methyl-1-ethoxyethyl and the like.
C1-C6 alkoxy-C1-C4-alkoxy is an alkoxy radical having from 1 to 4 carbon atoms as defined above, wherein one hydrogen atom is replaced by C1-C6 alkoxy. Examples comprise methoxymethoxy, 2-methoxyethoxy, 1-methoxyethoxy, 3-methoxypropoxy, 2-methoxypropoxy, 1-methyl-1-methoxyethoxy, ethoxymethoxy, 2-ethoxyethoxy, 1-ethoxyethoxy, 3-ethoxypropoxy, 2-ethoxypropoxy, 1-methyl-1-ethoxyethoxy and the like.
C1-C6 alkylcarbonyl is a radical of the formula R—C(O)—, wherein R is an alkyl radical having from 1 to 6 carbon atoms as defined above. Examples comprise acetyl, propionyl, n-butyryl, 2-methylpropionyl, pivaloyl and the like.
C1-C6 alkylcarbonylamino is a radical of the formula R—C(O)—NH—, wherein R is an alkyl radical having from 1 to 6 carbon atoms as defined above. Examples comprise acetamido, propionamido, n-butyramido, 2-methylpropionamido, 2,2-dimethylpropionamido and the like.
C1-C6 alkylcarbonyloxy is a radical of the formula R—C(O)—O—, wherein R is an alkyl radical having from 1 to 6 carbon atoms as defined above. Examples comprise acetyloxy, propionyloxy, n-butyryloxy, 2-methylpropionyloxy, 2,2-dimethylpropionyloxy and the like.
C1-C6 alkylthio is a radical of the formula R—S—, wherein R is an alkyl radical having from 1 to 6 carbon atoms as defined above. Examples comprise methylthio, ethylthio, propylthio, butylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, hexylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 1-methylpentylthio, 2-methylpentylthio, 3-methylpentylthio, 4-methylpentylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethylbutylthio, 2-ethylbutylthio, 1,1,2-trimethylpropylthio, 1,2,2-trimethylpropylthio, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl;
C1-C6 alkylsulfinyl is a radical of the formula R—S(O)—, wherein R is an alkyl radical having from 1 to 6 carbon atoms as defined above. Examples comprise methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, pentylsulfinyl, 1-methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl, 2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl, 1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl, 1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl, 4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl, 1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl;
C1-C6 alkylsulfonyl is a radical of the formula R—S(O)2—, wherein R is an alkyl radical having from 1 to 6 carbon atoms as defined above. Examples comprise methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl, 1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl, 1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl, 1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl;
fluorinated C1-C6 alkylcarbonyl is a radical of the formula R—C(O)—, wherein R is a fluorinated alkyl radical having from 1 to 6 carbon atoms as defined above. Examples comprise fluoroacetyl, difluoroacetyl, trifluoroacetyl, (R)-1-fluoroethylcarbonyl, (S)-1-fluoroethylcarbonyl, 2-fluoroethylcarbonyl, 1,1-difluoroethylcarbonyl, 2,2-difluoroethylcarbonyl, 2,2,2-trifluoroethylcarbonyl, (R)-1-fluoropropylcarbonyl, (S)-1-fluoropropylcarbonyl, 2-fluoropropylcarbonyl, 3-fluoropropylcarbonyl, 1,1-difluoropropylcarbonyl, 2,2-difluoropropylcarbonyl, 3,3-difluoropropylcarbonyl, 3,3,3-trifluoropropylcarbonyl, (R)-2-fluoro-1-methylethylcarbonyl, (S)-2-fluoro-1-methylethylcarbonyl, (R)-2,2-difluoro-1-methylethylcarbonyl, (S)-2,2-difluoro-1-methylethylcarbonyl, (R)-1,2-difluoro-1-methylethylcarbonyl, (S)-1,2-difluoro-1-methylethylcarbonyl, (R)-2,2,2-trifluoro-1-methylethylcarbonyl, (S)-2,2,2-trifluoro-1-methylethylcarbonyl, 2-fluoro-1-(fluoromethyl)ethylcarbonyl, 1-(difluoromethyl)-2,2-difluoroethylcarbonyl, (R)-1-fluorobutylcarbonyl, (S)-1-fluorobutylcarbonyl, 2-fluorobutylcarbonyl, 3-fluorobutylcarbonyl, 4-fluorobutylcarbonyl, 1,1-difluorobutylcarbonyl, 2,2-difluorobutylcarbonyl, 3,3-difluorobutylcarbonyl, 4,4-difluorobutylcarbonyl, 4,4,4-trifluorobutylcarbonyl, etc.;
fluorinated C1-C6 alkylcarbonylamino is a radical of the formula R—C(O)—NH—, wherein R is a fluorinated alkyl radical having from 1 to 6 carbon atoms as defined above. Examples comprise fluoroacetamido, difluoroacetamido, trifluoroacetamido, (R)-1-fluoroethylcarbonylamino, (S)-1-fluoroethylcarbonylamino, 2-fluoroethylcarbonylamino, 1,1-difluoroethylcarbonylamino, 2,2-difluoroethylcarbonylamino, 2,2,2-trifluoroethylcarbonylamino, (R)-1-fluoropropylcarbonylamino, (S)-1-fluoropropylcarbonylamino, 2-fluoropropylcarbonylamino, 3-fluoropropylcarbonylamino, 1,1-difluoropropylcarbonylamino, 2,2-difluoropropylcarbonylamino, 3,3-difluoropropylcarbonylamino, 3,3,3-trifluoropropylcarbonylamino, (R)-2-fluoro-1-methylethylcarbonylamino, (S)-2-fluoro-1-methylethylcarbonylamino, (R)-2,2-difluoro-1-methylethylcarbonylamino, (S)-2,2-difluoro-1-methylethylcarbonylamino, (R)-1,2-difluoro-1-methylethylcarbonylamino, (S)-1,2-difluoro-1-methylethylcarbonylamino, (R)-2,2,2-trifluoro-1-methylethylcarbonylamino, (S)-2,2,2-trifluoro-1-methylethylcarbonylamino, 2-fluoro-1-(fluoromethyl)ethylcarbonylamino, 1-(difluoromethyl)-2,2-difluoroethylcarbonylamino, (R)-1-fluorobutylcarbonylamino, (S)-1-fluorobutylcarbonylamino, 2-fluorobutylcarbonylamino, 3-fluorobutylcarbonylamino, 4-fluorobutylcarbonylamino, 1,1-difluorobutylcarbonylamino, 2,2-difluorobutylcarbonylamino, 3,3-difluorobutylcarbonylamino, 4,4-difluorobutylcarbonylamino, 4,4,4-trifluorobutylcarbonylamino, etc.,
fluorinated C1-C6 alkylcarbonyloxy is a radical of the formula R—C(O)—O—, wherein R is a fluorinated alkyl radical having from 1 to 6 carbon atoms as defined above fluoroacetyl, difluoroacetyl, trifluoroacetyl, (R)-1-fluoroethylcarbonyloxy, (S)-1-fluoroethylcarbonyloxy, 2-fluoroethylcarbonyloxy, 1,1-difluoroethylcarbonyloxy, 2,2-difluoroethylcarbonyloxy, 2,2,2-trifluoroethylcarbonyloxy, (R)-1-fluoropropylcarbonyloxy, (S)-1-fluoropropylcarbonyloxy, 2-fluoropropylcarbonyloxy, 3-fluoropropylcarbonyloxy, 1,1-difluoropropylcarbonyloxy, 2,2-difluoropropylcarbonyloxy, 3,3-difluoropropylcarbonyloxy, 3,3,3-trifluoropropylcarbonyloxy, (R)-2-fluoro-1-methylethylcarbonyloxy, (S)-2-fluoro-1-methylethylcarbonyloxy, (R)-2,2-difluoro-1-methylethylcarbonyloxy, (S)-2,2-difluoro-1-methylethylcarbonyloxy, (R)-1,2-difluoro-1-methylethylcarbonyloxy, (S)-1,2-difluoro-1-methylethylcarbonyloxy, (R)-2,2,2-trifluoro-1-methylethylcarbonyloxy, (S)-2,2,2-trifluoro-1-methylethylcarbonyloxy, 2-fluoro-1-(fluoromethyl)ethylcarbonyloxy, 1-(difluoromethyl)-2,2-difluoroethylcarbonyloxy, (R)-1-fluorobutylcarbonyloxy, (S)-1-fluorobutylcarbonyloxy, 2-fluorobutylcarbonyloxy, 3-fluorobutylcarbonyloxy, 4-fluorobutylcarbonyloxy, 1,1-difluorobutylcarbonyloxy, 2,2-difluorobutylcarbonyloxy, 3,3-difluorobutylcarbonyloxy, 4,4-difluorobutylcarbonyloxy, 4,4,4-trifluorobutylcarbonyloxy, etc.;
fluorinated C1-C6 alkylthio is a radical of the formula R—S—, wherein R is a fluorinated alkyl radical having from 1 to 6 carbon atoms as defined above. Examples comprise fluoromethylthio, difluoromethylthio, trifluoromethylthio, (R)-1-fluoroethylthio, (S)-1-fluoroethylthio, 2-fluoroethylthio, 1,1-difluoroethylthio, 2,2-difluoroethylthio, 2,2,2-trifluoroethylthio, (R)-1-fluoropropylthio, (S)-1-fluoropropylthio, 2-fluoropropylthio, 3-fluoropropylthio, 1,1-difluoropropylthio, 2,2-difluoropropylthio, 3,3-difluoropropylthio, 3,3,3-trifluoropropylthio, (R)-2-fluoro-1-methylethylthio, (S)-2-fluoro-1-methylethylthio, (R)-2,2-difluoro-1-methylethylthio, (S)-2,2-difluoro-1-methylethylthio, (R)-1,2-difluoro-1-methylethylthio, (S)-1,2-difluoro-1-methylethylthio, (R)-2,2,2-trifluoro-1-methylethylthio, (S)-2,2,2-trifluoro-1-methylethylthio, 2-fluoro-1-(fluoromethyl)ethylthio, 1-(difluoromethyl)-2,2-difluoroethylthio, (R)-1-fluorobutylthio, (S)-1-fluorobutylthio, 2-fluorobutylthio, 3-fluorobutylthio, 4-fluorobutylthio, 1,1-difluorobutylthio, 2,2-difluorobutylthio, 3,3-difluorobutylthio, 4,4-difluorobutylthio, 4,4,4-trifluorobutylthio, etc.;
fluorinated C1-C6 alkylsulfinyl is a radical of the formula R—S(O)—, wherein R is a fluorinated alkyl radical having from 1 to 6 carbon atoms as defined above. Examples comprise fluoromethylsulfonyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, (R)-1-fluoroethylsulfinyl, (S)-1-fluoroethylsulfinyl, 2-fluoroethylsulfinyl, 1,1-difluoroethylsulfinyl, 2,2-difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, (R)-1-fluoropropylsulfinyl, (S)-1-fluoropropylsulfinyl, 2-fluoropropylsulfinyl, 3-fluoropropylsulfinyl, 1,1-difluoropropylsulfinyl, 2,2-difluoropropylsulfinyl, 3,3-difluoropropylsulfinyl, 3,3,3-trifluoropropylsulfinyl, (R)-2-fluoro-1-methylethylsulfinyl, (S)-2-fluoro-1-methylethylsulfinyl, (R)-2,2-difluoro-1-methylethylsulfinyl, (S)-2,2-difluoro-1-methylethylsulfinyl, (R)-1,2-difluoro-1-methylethylsulfinyl, (S)-1,2-difluoro-1-methylethylsulfinyl, (R)-2,2,2-trifluoro-1-methylethylsulfinyl, (S)-2,2,2-trifluoro-1-methylethylsulfinyl, 2-fluoro-1-(fluoromethyl)ethylsulfinyl, 1-(difluoromethyl)-2,2-difluoroethylsulfinyl, (R)-1-fluorobutylsulfinyl, (S)-1-fluorobutylsulfinyl, 2-fluorobutylsulfinyl, 3-fluorobutylsulfinyl, 4-fluorobutylsulfinyl, 1,1-difluorobutylsulfinyl, 2,2-difluorobutylsulfinyl, 3,3-difluorobutylsulfinyl, 4,4-difluorobutylsulfinyl, 4,4,4-trifluorobutylsulfinyl, etc.;
fluorinated C1-C6 alkylsulfonyl is a radical of the formula R—S(O)2—, wherein R is a fluorinated alkyl radical having from 1 to 6 carbon atoms as defined above. Examples comprise fluoromethylsulfonyl, difluoromethylsulfinyl, trifluoromethylsulfonyl, (R)-1-fluoromethylsulfonyl, (S)-1-fluoromethylsulfonyl, 2-fluoromethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, (R)-1-fluoropropylsulfonyl, (S)-1-fluoropropylsulfonyl, 2-fluoropropylsulfonyl, 3-fluoropropylsulfonyl, 1,1-difluoropropylsulfonyl, 2,2-difluoropropylsulfonyl, 3,3-difluoropropylsulfonyl, 3,3,3-trifluoropropylsulfonyl, (R)-2-fluoro-1-methylethylsulfonyl, (S)-2-fluoro-1-methylethylsulfonyl, (R)-2,2-difluoro-1-methylethylsulfonyl, (S)-2,2-difluoro-1-methylethylsulfonyl, (R)-1,2-difluoro-1-methylethylsulfonyl, (S)-1,2-difluoro-1-methylethylsulfonyl, (R)-2,2,2-trifluoro-1-methylethylsulfonyl, (S)-2,2,2-trifluoro-1-methylethylsulfonyl, 2-fluoro-1-(fluoromethyl)ethylsulfonyl, 1-(difluoromethyl)-2,2-difluoroethylsulfonyl, (R)-1-fluorobutylsulfonyl, (S)-1-fluorobutylsulfonyl, 2-fluorobutylsulfonyl, 3-fluorobutylsulfonyl, 4-fluorobutylsulfonyl, 1,1-difluorobutylsulfonyl, 2,2-difluorobutylsulfonyl, 3,3-difluorobutylsulfonyl, 4,4-difluorobutylsulfonyl, 4,4,4-trifluorobutylsulfonyl, etc.
3- to 7-membered heterocyclic radicals comprise saturated heterocyclic radicals, which generally have 3-, 4-, 5-, 6- or 7 ring forming atoms (ring members), unsaturated non-aromatic heterocyclic radicals, which generally have 5-, 6- or 7 ring forming atoms, and heteroaromatic radicals, which generally have 5-, 6- or 7 ring forming atoms. The heterocyclic radicals may be bound via a carbon atom (C-bound) or an nitrogen atom (N-bound). Preferred heterocyclic radicals comprise 1 nitrogen atom as ring member atom and optionally 1, 2 or 3 further heteroatoms as ring members, which are selected, independently of each other from O, S and N. Likewise preferred heterocyclic radicals comprise 1 heteroatom as ring member, which is selected from O, S and N, and optionally 1, 2 or 3 further nitrogen atoms as ring members.
Examples of 3- to 7-membered, saturated heterocyclic radicals comprise 1- or 2-aziridinyl, 1-, 2-, 3-azetidinyl, 1-, 2-, or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 1-, 2- or 3-morpholinyl, 1-, 2- or 3-thiomorpholinyl, 1-, 2- or 3-piperazinyl, 1-, 2- or 4-oxazolidinyl, 1-, 3- or 4-isoxazolidinyl, 2-oxiranyl, 2- or 3-oxetanyl, 2- or 3-oxylanyl, 2-, 3- or 4-oxylanyl, 1,3-dioxolan-2- or 4-yl and the like, which may be unsubstituted or which may carry 1, 2 or 3 of the aforementioned radicals Ra and/or Rb.
Unsaturated non-aromatic heterocyclic radicals, are heterocyclic radicals which generally have 5-, 6- or 7 ring forming atoms and which have 1 or 2 doublebonds that do not form an aromatic p-electron system. Examples are 2,3-dihydropyrrolyl, 3,4-dihydropyrrolyl, 2,3-dihydrofuranyl, 3,4-dihydrofuranyl, 2,3-dihydrothiophenyl, 3,4-dihydrothiophenyl, 1,2-dihydropyridinyl, 2,3-Dihydropyridiynl, 3,4-dihydropyridinyl, 1,2,3,4-tetrahydropyridinyl, 2,3,4,5-tetrahydropyridinyl, and the like.
5- or 6-membered heteroaromatic radicals are heteroaromatic cyclic radicals, wherein the cyclic radical has 5 or 6 atoms which form the ring (ring members) and wherein generally 1, 2, 3 or 4 ring member atoms are selected from O, S and N, the other ring member atoms being carbon atoms. The heteroaromatic radicals may be bound via a carbon atom (C-bound) or an nitrogen atom (N-bound). Preferred heteroaromatic radicals comprise 1 nitrogen atom as ring member atom and optionally 1, 2 or 3 further heteroatoms as ring members, which are selected, independently of each other from O, S and N. Likewise preferred heteroaromatic radicals comprise 1 heteroatom as ring member, which is selected from O, S and N, and optionally 1, 2 or 3 further nitrogen atoms as ring members. Examples of 5- or 6-membered heteroaromatic radicals comprise 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, pyrazinyl, 3- or 4-pyridazinyl, 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2- or 4-imidazolyl, 1-, 3- or 4-pyrazolyl, 1- or 3-[1,2,4]-triazolyl, 1- or 4-[1,2,3]-triazolyl, 1-, 2- or 5-tetrazolyl, 2-, 3- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 3- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-[1,2,3]-oxadiazolyl, [1,2,5]-oxadiazolyl (=furazanyl), 3- or 5-[1,2,4]-oxadiazolyl, [1,3,4]-oxadiazolyl, 4- or 5-[1,2,3]-thiadiazolyl, [1,2,5]-thiadiazolyl, 3- or 5-[1,2,4]-thiadiazolyl or [1,3,4]-thiadiazolyl, which may be unsubstituted or which may carry 1, 2 or 3 of the aforementioned radicals Ra and/or Rb.
A skilled person will appreciate that the radical -E-SO2—Ar may be bound to any of the carbon atoms of the phenyl part of the bicyclic moiety in formula I, thereby substituting a hydrogen atom. Preferably the radical -E-SO2—Ar is not bound to a carbon atom, which is not adjacent to a bridgehead carbon atom of the bicyclic moiety.
Preferably, Ar is phenyl or an aromatic 5- or 6-membered C-bound heteroaromatic radical, comprising 1 nitrogen atom as ring member and 0, 1, 2 or 3 further heteroatoms, independently of each other, selected from O, S and N, as ring members which may be unsubstituted or which may carry 1, 2 or 3 of the aforementioned radicals Ra and/or Rb. Amongst these heteroaromatic radicals those are preferred, which comprise 1, 2 or 3 nitrogen atoms and no further heteroatom as ring members, or 1 or 2 nitrogen atoms and 1 atom, selected from O and S, as ring members. However, thienyl and furyl are likewise preferred. Particularly preferred radicals Ar are 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or 5-thiazolyl, 1,2,4-triazol-3-yl, 1,2,3-triazol-4-yl, 1,3,4-thiadiazol-2-yl, in particular 2-thienyl, 2-pyrimidinyl, 5-pyrimidinyl, 2-pyridinyl and more particularly phenyl which may be unsubstituted or which may carry 1, 2 or 3 of the aforementioned radicals Ra and/or Rb.
Preferably the aromatic radical Ar carries one radical Ra and optionally one or two further radicals Rb as mentioned above, Rb being particularly selected from methyl, fluorinated methyl, halogen, more preferably from fluorine or chlorine.
The aforementioned 5-membered heteroaromatic radicals Ar preferably one radical Ra in the 3-position (related to the position of the SO2-radical) and optionally one or two further radicals Rb, which are preferably selected from halogen, in particular fluorine or chlorine.
Phenyl and the aforementioned 6-membered heteroaromatic radicals Ar preferably carry one radical Ra in the 4-position (related to the position of the SO2-radical) and optionally one or two further radicals Rb, which are preferably selected from halogen, in particular fluorine or chlorine.
In a very preferred embodiment of the invention Ar is phenyl that carries a radical Ra in the 4-position of the phenyl ring and optionally 1 or 2 further radicals Rb, which are preferably selected from halogen, in particular from fluorine or chlorine.
In another preferred embodiment of the invention Ar is 2-pyrimidinyl that carries a radical Ra in the 5-position of the pyrimidine ring and optionally 1 or 2 further radicals Rb, which are preferably selected from halogen, in particular from fluorine or chlorine.
In a further preferred embodiment of the invention Ar is 5-pyrimidinyl that carries a radical Ra in the 2-position of the pyrimidine ring and optionally 1 or 2 further radicals Rb, which are preferably selected from halogen, in particular from fluorine or chlorine.
In a further preferred embodiment of the invention Ar is 2-thienyl that carries a radical Ra in the 3-position of the thiophen ring and optionally 1 or 2 further radicals Rb, which are preferably selected from halogen, in particular from fluorine or chlorine.
In a preferred embodiment Ar carries 1 radical Ra which is selected from the group consisting of C2-C6-alkyl, C3-C6-cycloalkyl, C1-C6-alkoxy, fluorinated C1-C6-alkyl, fluorinated C3-C6-cycloalkyl, fluorinated C1-C6-alkoxy, NR4R5, 1-aziridinyl, azetidin-1-yl, pyrrolidin-1-yl or piperidin-1-yl, wherein the last four mentioned radicals may be fluorinated, a phenyl group and an aromatic 5- or 6-membered C-bound heteroaromatic radical, comprising 1 nitrogen atom as ring member and 0, 1, 2 or 3 further heteroatoms, independently of each other, selected from O, S and N, wherein the last two mentioned radicals may carry 1, 2, 3 or 4 radicals selected from halogen and the radicals Ra; and wherein Ar may carry 1 or 2 further radicals Rb, which are independently from each other selected from halogen, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy. In this embodiment R4, R5 are, independently of each other, preferably selected from H, C1-C2-alkyl and fluorinated C1-C2-alkyl. Preferably one of the radicals R4 or R5 is different from hydrogen. One of the radicals R4 or R5 may also be C1-C2-alkoxy.
In a very preferred embodiment, the radical Ar preferably carries one radical Ra, which has the formula Ra′




wherein

    Y is N, CH or CF,
    Ra1 and Ra2 are independently of each other selected from C1-C2-alkyl, C1-C2-alkoxy, fluorinated C1-C2-alkyl, provided for Y being CH or CF one of the radicals Ra1 or Ra2 may also be hydrogen or fluorine, or
    Ra1 and Ra2 together form a radical (CH2)m wherein 1 or 2 of the hydrogen atoms may be replaced by fluorine, hydroxy, oxo, C1-C2-alkyl or C1-C2-alkoxy, wherein one CH2 moiety may be replaced by O, S, S═O, SO2 or N—Rc, Rc being hydrogen or C1-C2-alkyl and wherein m is 2, 3, 4, 5 or 6;


In particular

    Ra1 or Ra2 may also be hydrogen or fluorine Ra1 and Ra2 are independently of each other selected from C1-C2-alkyl, fluorinated C1-C2-alkyl, in particular fluoromethyl, difluoromethyl or trifluoromethyl, provided for Y being CH or CF one of the radicals Ra1 or Ra2 may also be hydrogen or fluorine, or
    Ra1 and Ra2 form a radical (CH2)k wherein 1 or 2 of the hydrogen atoms may be replaced by fluorine and wherein k is 2, 3 or 4, in particular CH2—CH2, CHF—CH2 CF2—CH2, CH2—CH2—CH2, CHF—CH2—CH2, CF2—CH2—CH2, CH2—CHF—CH2, CH2—CF2—CH2.


In case Ra1 and Ra2 are different from each other, the radical of the aforementioned formula Ra′ may have either (R)- or (S)-configuration with regard to the Y-moiety.
Examples for preferred radicals Ra′ comprise isopropyl, (R)-1-fluoroethyl, (S)-1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (R)-1-fluoropropyl, (S)-1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 1,1-difluoropropyl, 2,2-difluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, (R)-2-fluoro-1-methylethyl, (S)-2-fluoro-1-methylethyl, (R)-2,2-difluoro-1-methylethyl, (S)-2,2-difluoro-1-methylethyl, (R)-1,2-difluoro-1-methylethyl, (S)-1,2-difluoro-1-methylethyl, (R)-2,2,2-trifluoro-1-methylethyl, (S)-2,2,2-trifluoro-1-methylethyl, 2-fluoro-1-(fluoromethyl)ethyl, 1-(difluoromethyl)-2,2-difluoroethyl cyclopropyl, cyclobutyl, 1-fluorocyclopropyl, and 2-fluorocyclopropyl
Also preferred are radicals Ra′ wherein one of Ra1 or Ra2 is C1-C2-alkoxy and the other other of Ra1 or Ra2 is selected from H, C1-C2-alkyl, in particular methyl, fluorinated C1-C2-alkyl, in particular fluoromethyl, difluoromethyl or trifluoromethyl. Examples comprise N-methoxy-N-methylamino, N-methoxyamino and N-ethoxyamino.
Preferred radicals of the formula Ra′ also comprise those wherein Y is nitrogen and wherein Ra1 and Ra2 form a radical (CH2)m wherein 1 or 2 of the hydrogen atoms may be replaced by fluorine, methyl, trifluoromethyl, methoxy or oxo and wherein m is 2, 3, 4 or 5. Examples comprise azetidin-1-yl, 2-methylazetidin-1-yl, (S)-2-methylazetidin-1-yl, (R)-2-methylazetidin-1-yl, 3-fluoroazetidin-1-yl, 3-methoxyazetidin-1-yl, 3-hydroxyazetidin-1-yl, pyrrolidin-1-yl, (S)-2-fluoropyrrolidin-1-yl, (R)-2-fluoropyrrolidin-1-yl, 3-fluoropyrrolidin-1-yl, (S)-3-fluoropyrrolidin-1-yl, (R)-3-fluoropyrrolidin-1-yl, 2,2-difluoropyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, (S)-2-methylpyrrolidin-1-yl, (R)-2-methylpyrrolidin-1-yl, 3-methylpyrrolidin-1-yl, (S)-3-methylpyrrolidin-1-yl, (R)-3-methylpyrrolidin-1-yl, 2,2-dimethylpyrrolidine-1-yl, 3,3-dimethylpyrrolidine-1-yl, 2-trifluoromethylpyrrolidin-1-yl, (S)-2-trifluoromethylpyrrolidin-1-yl, (R)-2-trifluoromethylpyrrolidin-1-yl, 3-trifluoromethylpyrrolidin-1-yl, (S)-3-trifluoromethylpyrrolidin-1-yl, (R)-3-trifluoromethylpyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, piperidin-1-yl, 2-methylpiperidin-1-yl, (S)-2-methylpiperidin-1-yl and (R)-2-methylpiperidin-1-yl.
Likewise preferred are radicals Ra′, wherein Ra1 and Ra2 together form a radical (CH2)m wherein 1 or 2 of the hydrogen atoms may be replaced by fluorine, hydroxy, oxo, C1-C2-alkyl or C1-C2-alkoxy, wherein one CH2 moiety is replaced by O, S, S═O, SO2 or N—Rc, Rc being hydrogen or C1-C2-alkyl and wherein m is 2, 3, 4, 5 or 6. Examples for preferred radicals of the formula Ra′ also comprise 4-morpholinyl, 4-thiomorpholinyl, 4-(1,1-dioxo)thiomorpholinyl, piperazin-1-yl, 4-methylpiperazin-1-yl, 2-oxo-oxazolidin-3-yl, pyrrolidin-2-yl, (S)-pyrrolidin-2-yl, (R)-pyrrolidin-2-yl, pyrrolidin-3-yl, (S)-pyrrolidin-3-yl, (R)-pyrrolidin-3-yl, 2-fluoropyrrolidin-1-yl, 1-methylpyrrolidin-2-yl, (S)-1-methylpyrrolidin-2-yl, (R)-1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, (S)-1-methylpyrrolidin-3-yl and (R)-1-methylpyrrolidin-3-yl.
Amongst the radicals of the formula Ra′ those are preferred which carry 1, 2, 3 or 4, in particular 1, 2 or 3 fluorine atoms.
In a further preferred embodiment Ar carries one radical Ra, which is selected from 5- or 6-membered heteroaromatic radicals having as ring members 1 heteroatom selected from O, S and N and which may further have 1, 2 or 3 nitrogen atoms as ring members, and wherein the 5- or 6-membered heteroaromatic radical may carry 1, 2 or 3 substituents selected from halogen, NO2, NH2, OH, CN, C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-alkoxy, fluorinated C1-C6-alkyl, fluorinated C3-C6-cycloalkyl, fluorinated C1-C6-alkoxy, C1-C6-hydroxyalkyl, C1-C4-alkoxy-C2-C4-alkyl, C1-C6-hydroxyalkoxy, C1-C4-alkoxy-C2-C4-alkoxy, C1-C6-alkylcarbonyl, C1-C6-alkylamino, di-C1-C6-alkylamino, C1-C6-alkylaminocarbonyl, di-C1-C6-alkylaminocarbonyl, fluorinated C1-C6-alkylcarbonyl, C1-C6-alkylcarbonylamino, fluorinated C1-C6-alkylcarbonylamino, C1-C6-alkylcarbonyloxy, fluorinated C1-C6-alkylcarbonyloxy, C1-C6-alkoxycarbonyl, C1-C6-alkylthio, fluorinated C1-C6-alkylthio, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, fluorinated C1-C6-alkylsulfinyl and fluorinated C1-C6-alkylsulfonyl. Amongst these radicals Ra, preference is given to radicals selected from 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, pyrazinyl, 3-, 4-pyridazinyl, 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2- or 4-imidazolyl, 1-, 3- or 4-pyrazolyl, 1- or 3-[1,2,4]-triazolyl, 1- or 4-[1,2,3]-triazolyl, 1-, 2- or 5-tetrazolyl, 2-, 3- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 3- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-[1,2,3]-oxadiazolyl, [1,2,5]-oxadiazolyl (=furazanyl), 3- or 5-[1,2,4]-oxadiazolyl, [1,3,4]-oxadiazolyl, 4- or 5-[1,2,3]-thiadiazolyl, [1,2,5]-thiadiazolyl, 3- or 5-[1,2,4]-thiadiazolyl or [1,3,4]-thiadiazolyl, in particular from 2- or 3-furanyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl and tetrazolyl, where the heteroaromatic radical may be unsubstituted or may carry 1 to 3 substituents as given above. Preferred substituents on heteroaromatic Ra are selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4-alkoxy.
In a further preferred embodiment Ar carries 1 radical Ra which selected from the group consisting of CHF2, CH2F, OCHF2 and OCH2F, with OCHF2 being preferred. In this embodiment Ar may also carry 1 or 2 further radicals Rb, which are independently from each other selected from halogen, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy. Preferably Ar carries no further radical Rb. In this embodiment Ar is preferably phenyl which carries 1 radical Ra which selected from the group consisting of CHF2, CH2F, OCHF2 and OCH2F, with OCHF2 being preferred. In this embodiment Ar is preferably phenyl, which carries Ra in the 4 position with respect to the SO2-group.
In another embodiment of the invention, Ar carries 1 radical Ra which selected from the group consisting of C2-C6-alkenyl, fluorinated C2-C6-alkenyl, C1-C6-hydroxyalkyl, C1-C6-alkoxy-C1-C4-alkyl, C1-C6-hydroxyalkoxy, C1-C6-alkoxy-C1-C4-alkoxy, COOH, CH2NR4R5, ONR4R5, NHC(O)NR4R5, C(O)NR4R5, SO2NR4R5, C1-C6-alkylcarbonyl, fluorinated C2-C6-alkylcarbonyl, C1-C6-alkylcarbonylamino, fluorinated C1-C6-alkylcarbonylamino, C1-C6-alkylcarbonyloxy, fluorinated C1-C6-alkylcarbonyloxy, C1-C6-alkoxycarbonyl, C1-C6-alkylthio, fluorinated C1-C6-alkylthio, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, fluorinated C1-C6-alkylsulfinyl, fluorinated C1-C6-alkylsulfonyl, phenylsulfonyl, phenoxy, benzyloxy and a 5- or 6-membered N-bound heteroaromatic radical, wherein the four last mentioned radicals may carry 1, 2, 3 or 4 radicals selected from halogen, NO2, NH2, OH, CN, C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-alkoxy, fluorinated C1-C6-alkyl, fluorinated C3-C6-cycloalkyl, fluorinated C1-C6-alkoxy, C1-C6-hydroxyalkyl, C1-C4-alkoxy-C2-C4-alkyl, C1-C6-hydroxyalkoxy, C1-C4-alkoxy-C2-C4-alkoxy, C1-C6-alkylcarbonyl, C1-C6-alkylamino, di-C1-C6-alkylamino, C1-C6-alkylaminocarbonyl, di-C1-C6-alkylaminocarbonyl, fluorinated C1-C6-alkylcarbonyl, C1-C6-alkylcarbonylamino, fluorinated, C1-C6-alkylcarbonylamino, C1-C6-alkylcarbonyloxy, fluorinated C1-C6-alkylcarbonyloxy, C1-C6-alkoxycarbonyl, C1-C6-alkylthio, fluorinated C1-C6-alkylthio, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, fluorinated C1-C6-alkylsulfinyl and fluorinated C1-C6-alkylsulfonyl.
In another embodiment of the invention, Ar is phenyl, which carries 1 radical Ra and at least one radical Rb and wherein Ra and one radical Rb are bound to two adjacent carbon atoms of phenyl and form a 5- or 6-membered heterocyclic or carbocylic ring which is fused to the phenyl ring and which is unsubstituted or which may carry 1, 2 or 3 radicals as given above. Examples of a phenyl ring fused to a saturated or unsaturated 5- or 6-membered carbocyclic or heterocyclic ring comprise indenyl, indanyl, naphthyl, tetralin, benzofuranyl, 2,3-dihydrobenzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxathiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzoxazinyl, dihydrobenzoxazinyl, chinolinyl, isochinolinyl, tetrahydroisochinolinyl, chromenyl, chromanyl and the like, which may be unsubstituted or which may carry 1, 2 or 3 of the aforementioned radicals. Preferred substituents for the saturated or unsaturated 5- or 6-membered carbocyclic or heterocyclic ring fused to the phenyl ring are selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4-alkoxy.
The radical R1 is preferably C2-C4-alkyl, C3-C4-cycloalkyl, C3-C4-cycloalkylmethyl, C3-C4-alkenyl, fluorinated C1-C4-alkyl, fluorinated C3-C4-cycloalkyl, fluorinated C3-C4-cycloalkylmethyl, fluorinated C3-C4-alkenyl, formyl or C1-C3-alkylcarbonyl, in particular C2-C4-alkyl, C3-C4-alkenyl, fluorinated C2-C4-alkyl, fluorinated C3-C4-alkenyl, more preferably n-propyl, fluorinated C2-C3-alkyl or 1-propen-3-yl, in particular n-propyl.
A first preferred embodiment of the invention relates to compounds, wherein R1a is hydrogen. In these compounds R1 has the meanings given above. In particular R1 is n-propyl. In this embodiment R2a is preferably hydrogen while R2 is preferably hydrogen, methyl or fluorinated methyl. In particular, both R2a and R2 are hydrogen or one of the radicals R2a and R2 is hydrogen while the other is methyl.
In a second preferred embodiment, R1a is different from hydrogen and preferably C2-C4-alkyl, C3-C4-alkenyl, fluorinated C2-C4-alkyl, fluorinated C3-C4-alkenyl, more preferably n-propyl, fluorinated C2-C3-alkyl or 1-propen-3-yl, in particular n-propyl In these compounds R1 has the meanings given above. In particular R1 is n-propyl. In this embodiment R2a is preferably hydrogen while R2 is preferably hydrogen, methyl or fluorinated methyl. In particular both R2a and R2 are hydrogen or, one of the radicals R2a and R2 is hydrogen while the other is methyl.
In a third preferred embodiment, R2a and R1a together are (CH2)n with n being 3 or 4. R2 is preferably hydrogen. In these compounds R1 has the meanings given above. In particular R1 is n-propyl, 1-propen-3-yl.
One preferred embodiment of the invention, relates to compounds of the formula I, wherein X is CH. Another embodiment of the invention, relates to compounds of the formula I, wherein X is N.
Preferably the moiety E is N—R3, wherein R3 is as defined above. R3 is in particular H or methyl and most preferred H. If E is a moiety CR6R7, preferably one and in particular both of the radicals R6 and R7 are hydrogen.
Preferred embodiments of the invention are compounds of the following formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ik, Im, In, Io, Ip, Iq, Ir, Is, It, Iu and Iv and to the physiologically tolerated acid addition salts thereof. With regard to the carbon atom carrying the NR1-group, compounds of the formulae Ic, Id, Ii, Ik, Io, Ip, Iu and Iv may exist as R-enantiomers or S-enantiomers as well as mixtures of the enantiomers such as racemic mixtures. The preferred embodiments include the R- and S-enantiomers of Ic, Id, Ii, Ik, Io, Ip, Iu and Iv and the mixtures of the enantiomers.
In the compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ik, Im, In, Io, Ip, Iq, Ir, Is, It, Iu and Iv R1, Ar and R1a are as defined above with particular preference given to those compounds wherein R1, Ar and R1a have one of the preferred meanings.










Examples of preferred compounds of the general formula I are given in the following tables A-1, A-2, A-3, A-4, A5, A-6, A-7, A-8, A-9, A-10, A-11, A-12, A-13, A-14, A-15, A-16, A-17, A-18, A-19 and A-20.
Table A-1: Compounds of the formula Ia, wherein R1a is H and Ar and R1 have the meaning given in one of the rows 61 to 1704 of table A.
Table A-2: Compounds of the formula Ib, wherein R1a is H and Ar and R1 have the meaning given in one row of table A.
Table A-3: Compounds of the formula Ic, including the pure S-isomers, the pure R-isomers and the racemic mixtures, wherein R1a is H and Ar and R1 have the meaning given in one row of table A.
Table A-4: Compounds of the formula Id, including the pure S-isomers, the pure R-isomers and the racemic mixtures, wherein R1a is H and Ar and R1 have the meaning given in one row of table A.
Table A-5: Compounds of the formula Ie, wherein R1a is H and Ar and R1 have the meaning given in one row of table A.
Table A-6: Compounds of the formula If, wherein R1a is H and Ar and R1 have the meaning given in one row of table A.
Table A-7: Compounds of the formula Ig, wherein R1a is H and Ar and R1 have the meaning given in one row of table A.
Table A-8: Compounds of the formula Ih, wherein R1a is H and Ar and R1 have the meaning given in one row of table A.
Table A-9: Compounds of the formula Ii, including the pure S-isomers, the pure R-isomers and the racemic mixtures, wherein Ar and R1 have the meaning given in one row of table A.
Table A-10: Compounds of the formula Ik, including the pure S-isomers, the pure R-isomers and the racemic mixtures, wherein Ar and R1 have the meaning given in one row of table A.
Table A-11: Compounds of the formula Im, wherein R1a is H and Ar and R1 have the meaning given in one of the rows of table A.
Table A-12: Compounds of the formula In, wherein R1a is H and Ar and R1 have the meaning given in one row of table A.
Table A-13: Compounds of the formula Io, including the pure S-isomers, the pure R-isomers and the racemic mixtures, wherein R1a is H and Ar and R1 have the meaning given in one row of table A.
Table A-14: Compounds of the formula Ip, including the pure S-isomers, the pure R-isomers and the racemic mixtures, wherein R1a is H and Ar and R1 have the meaning given in one row of table A.
Table A-15: Compounds of the formula Iq, wherein R1a is H and Ar and R1 have the meaning given in one row of table A.
Table A-16: Compounds of the formula Ir, wherein R1a is H and Ar and R1 have the meaning given in one row of table A.
Table A-17: Compounds of the formula Is, wherein R1a is H and Ar and R1 have the meaning given in one row of table A.
Table A-18: Compounds of the formula It, wherein R1a is H and Ar and R1 have the meaning given in one row of table A.
Table A-19: Compounds of the formula Iu, including the pure S-isomers, the pure R-isomers and the racemic mixtures, wherein Ar and R1 have the meaning given in one row of table A.
Table A-20: Compounds of the formula Iv, including the pure S-isomers, the pure R-isomers and the racemic mixtures, wherein Ar and R1 have the meaning given in one row of table A.









TABLE A





No.
R1
Ar

















1.
methyl
4-(trifluoromethoxy)-phenyl


2.
methyl
3-(trifluoromethoxy)-phenyl


3.
methyl
4-cyanophenyl


4.
methyl
4-methylphenyl


5.
methyl
4-ethylphenyl


6.
methyl
4-propylphenyl


7.
methyl
4-methoxyphenyl


8.
methyl
4-fluorophenyl


9.
methyl
4-chlorophenyl


10.
methyl
4-bromophenyl


11.
methyl
3-(trifluoromethyl)phenyl


12.
methyl
4-(trifluoromethyl)phenyl


13.
methyl
2-(trifluoromethyl)phenyl


14.
methyl
3,4-difluorophenyl


15.
methyl
4-bromo-3-fluorophenyl


16.
methyl
4-bromo-2-fluorophenyl


17.
methyl
4-bromo-2,5-difluorophenyl


18.
methyl
2-fluoro-4-isopropylphenyl


19.
methyl
4-methylsulfanyl


20.
methyl
4-hydroxyphenyl


21.
ethyl
4-(trifluoromethoxy)-phenyl


22.
ethyl
3-(trifluoromethoxy)-phenyl


23.
ethyl
4-cyanophenyl


24.
ethyl
4-methylphenyl


25.
ethyl
4-ethylphenyl


26.
ethyl
4-propylphenyl


27.
ethyl
4-methoxyphenyl


28.
ethyl
4-fluorophenyl


29.
ethyl
4-chlorophenyl


30.
ethyl
4-bromophenyl


31.
ethyl
3-(trifluoromethyl)phenyl


32.
ethyl
4-(trifluoromethyl)phenyl


33.
ethyl
2-(trifluoromethyl)phenyl


34.
ethyl
3,4-difluorophenyl


35.
ethyl
4-bromo-3-fluorophenyl


36.
ethyl
4-bromo-2-fluorophenyl


37.
ethyl
4-bromo-2,5-difluorophenyl


38.
ethyl
2-fluoro-4-isopropylphenyl


39.
ethyl
4-methylsulfanyl


40.
ethyl
4-hydroxyphenyl


41.
propyl
4-(trifluoromethoxy)-phenyl


42.
propyl
3-(trifluoromethoxy)-phenyl


43.
propyl
4-cyanophenyl


44.
propyl
4-methylphenyl


45.
propyl
4-ethylphenyl


46.
propyl
4-propylphenyl


47.
propyl
4-methoxyphenyl


48.
propyl
4-fluorophenyl


49.
propyl
4-chlorophenyl


50.
propyl
4-bromophenyl


51.
propyl
3-(trifluoromethyl)phenyl


52.
propyl
4-(trifluoromethyl)phenyl


53.
propyl
2-(trifluoromethyl)phenyl


54.
propyl
3,4-difluorophenyl


55.
propyl
4-bromo-3-fluorophenyl


56.
propyl
4-bromo-2-fluorophenyl


57.
propyl
4-bromo-2,5-difluorophenyl


58.
propyl
2-fluoro-4-isopropylphenyl


59.
propyl
4-methylsulfanyl


60.
propyl
4-hydroxyphenyl


61.
propyl
4-isopropylphenyl


62.
propyl
4-sec-butylphenyl


63.
propyl
4-isobutylphenyl


64.
propyl
4-(1,1-dimethylpropyl)-phenyl


65.
propyl
4-vinylphenyl


66.
propyl
4-isopropenylphenyl


67.
propyl
4-(fluoromethyl)phenyl


68.
propyl
3-(fluoromethyl)phenyl


69.
propyl
2-(fluoromethyl)phenyl


70.
propyl
4-(difluoromethyl)phenyl


71.
propyl
3-(difluoromethyl)phenyl


72.
propyl
2-(difluoromethyl)phenyl


73.
propyl
4-(1-fluoroethyl)-phenyl


74.
propyl
4-((S)-1-fluoroethyl)-phenyl


75.
propyl
4-((R)-1-fluoroethyl)-phenyl


76.
propyl
4-(2-fluoroethyl)-phenyl


77.
propyl
4-(1,1-difluoroethyl)-phenyl


78.
propyl
4-(2,2-difluoroethyl)-phenyl


79.
propyl
4-(2,2,2-trifluoroethyl)-phenyl


80.
propyl
4-(3-fluoropropyl)-phenyl


81.
propyl
4-(2-fluoropropyl)-phenyl


82.
propyl
4-((S)-2-fluoropropyl)-phenyl


83.
propyl
4-((R)-2-fluoropropyl)-phenyl


84.
propyl
4-(3,3-difluoropropyl)-phenyl


85.
propyl
4-(3,3,3-trifluoropropyl)-phenyl


86.
propyl
4-(1-fluoro-1-methylethyl)-phenyl


87.
propyl
4-(2-fluoro-1-methylethyl)-phenyl


88.
propyl
4-((S)-2-fluoro-1-methylethyl)-phenyl


89.
propyl
4-((R)-2-fluoro-1-methylethyl)-phenyl


90.
propyl
4-(2,2-difluoro-1-methylethyl)-phenyl


91.
propyl
4-((S)-2,2-difluoro-1-methylethyl)-phenyl


92.
propyl
4-((R)-2,2-difluoro-1-methylethyl)-phenyl


93.
propyl
4-(2,2,2-trifluoro-1-methylethyl)-phenyl


94.
propyl
4-((S)-2,2,2-trifluoro-1-methylethyl)-phenyl


95.
propyl
4-((R)-2,2,2-trifluoro-1-methylethyl)-phenyl


96.
propyl
4-(2-fluoro-1-fluoromethylethyl)-phenyl


97.
propyl
4-(1-difluoromethyl-2,2-difluoroethyl)-phenyl


98.
propyl
4-(1,1-dimethyl-2-fluoroethyl)-phenyl


99.
propyl
4-ethoxyphenyl


100.
propyl
4-propoxyphenyl


101.
propyl
4-isopropoxyphenyl


102.
propyl
4-butoxyphenyl


103.
propyl
4-(fluoromethoxy)-phenyl


104.
propyl
4-(difluoromethoxy)-phenyl


105.
propyl
4-(2-fluoroethoxy)-phenyl


106.
propyl
4-(2,2-difluoroethoxy)-phenyl


107.
propyl
4-(2,2,2-trifluoroethoxy)-phenyl


108.
propyl
4-(1,1,2,2-tetrafluoroethoxy)-phenyl


109.
propyl
4-cyclopropylphenyl


110.
propyl
4-cyclobutylphenyl


111.
propyl
4-cyclopentylphenyl


112.
propyl
4-(2,2-difluorocyclopropyl)-phenyl


113.
propyl
2-fluoro-4-isopropylphenyl


114.
propyl
3-fluoro-4-isopropylphenyl


115.
propyl
4-(1-hydroxy-1-methylethyl)-phenyl


116.
propyl
4-(2-hydroxy-2-methylpropyl)-phenyl


117.
propyl
4-acetylphenyl


118.
propyl
4-carboxyphenyl


119.
propyl
4-(O-benzyl)-phenyl


120.
propyl
4-(2-methoxyethoxy)-phenyl


121.
propyl
4-(CH2—N(CH3)2)-phenyl


122.
propyl
4-(NH—CO—NH2)-phenyl


123.
propyl
4-(fluoromethylsulfanyl)-phenyl


124.
propyl
4-(difluoromethylsulfanyl)-phenyl


125.
propyl
4-(trifluoromethylsulfanyl)-phenyl


126.
propyl
4-(methylsulfonyl)-phenyl


127.
propyl
4-(N-methoxy-N-methyl-amino)-phenyl


128.
propyl
4-(methoxyamino)-phenyl


129.
propyl
4-(ethoxyamino)-phenyl


130.
propyl
4-(N-methylaminooxy)-phenyl


131.
propyl
4-(N,N-dimethylaminooxy)-phenyl


132.
propyl
4-(azetidin-1-yl)-phenyl


133.
propyl
4-(2-methylazetidin-1-yl)-phenyl


134.
propyl
4-((S)-2-methylazetidin-1-yl)-phenyl


135.
propyl
4-((R)-2-methylazetidin-1-yl)-phenyl


136.
propyl
4-(3-fluoroazetidin-1-yl)-phenyl


137.
propyl
4-(3-methoxyazetidin-1-yl)-phenyl


138.
propyl
4-(3-hydroxyazetidin-1-yl)-phenyl


139.
propyl
4-(pyrrolidin-1-yl)-phenyl


140.
propyl
4-(pyrrolidin-2-yl)-phenyl


141.
propyl
4-((S)-pyrrolidin-2-yl)-phenyl


142.
propyl
4-((R)-pyrrolidin-2-yl)-phenyl


143.
propyl
4-(pyrrolidin-3-yl)-phenyl


144.
propyl
4-((S)-pyrrolidin-3-yl)-phenyl


145.
propyl
4-((R)-pyrrolidin-3-yl)-phenyl


146.
propyl
4-(2-fluoropyrrolidin-1-yl)-phenyl


147.
propyl
4-((S)-2-fluoropyrrolidin-1-yl)-phenyl


148.
propyl
4-((R)-2-fluoropyrrolidin-1-yl)-phenyl


149.
propyl
4-(3-fluoropyrrolidin-1-yl)-phenyl


150.
propyl
4-((S)-3-fluoropyrrolidin-1-yl)-phenyl


151.
propyl
4-((R)-3-fluoropyrrolidin-1-yl)-phenyl


152.
propyl
4-(2,2-difluoropyrrolidin-1-yl)-phenyl


153.
propyl
4-(3,3-difluoropyrrolidin-1-yl)-phenyl


154.
propyl
4-(2-methylpyrrolidin-1-yl)-phenyl


155.
propyl
4-((S)-2-methylpyrrolidin-1-yl)-phenyl


156.
propyl
4-((R)-2-methylpyrrolidin-1-yl)-phenyl


157.
propyl
4-(3-methylpyrrolidin-1-yl)-phenyl


158.
propyl
4-((S)-3-methylpyrrolidin-1-yl)-phenyl


159.
propyl
4-((R)-3-methylpyrrolidin-1-yl)-phenyl


160.
propyl
4-(1-methylpyrrolidin-2-yl)-phenyl


161.
propyl
4-((S)-1-methylpyrrolidin-2-yl)-phenyl


162.
propyl
4-((R)-1-methylpyrrolidin-2-yl)-phenyl


163.
propyl
4-(1-methylpyrrolidin-3-yl)-phenyl


164.
propyl
4-((S)-1-methylpyrrolidin-3-yl)-phenyl


165.
propyl
4-((R)-1-methylpyrrolidin-3-yl)-phenyl


166.
propyl
4-(2,2-dimethylpyrrolidin-1-yl)-phenyl


167.
propyl
4-(3,3-dimethylpyrrolidin-1-yl)-phenyl


168.
propyl
4-(2-trifluoromethylpyrrolidin-1-yl)-phenyl


169.
propyl
4-((S)-2-trifluoromethylpyrrolidin-1-yl)-phenyl


170.
propyl
4-((R)-2-trifluoromethylpyrrolidin-1-yl)-phenyl


171.
propyl
4-(3-trifluoromethylpyrrolidin-1-yl)-phenyl


172.
propyl
4-((S)-3-trifluoromethylpyrrolidin-1-yl)-phenyl


173.
propyl
4-((R)-3-trifluoromethylpyrrolidin-1-yl)-phenyl


174.
propyl
4-(2-oxopyrrolidin-1-yl)-phenyl


175.
propyl
4-(2-oxo-oxazolidin-3-yl)-phenyl


176.
propyl
4-(piperidin-1-yl)-phenyl


177.
propyl
4-(2-methylpiperidin-1-yl)-phenyl


178.
propyl
4-((S)-2-methylpiperidin-1-yl)-phenyl


179.
propyl
4-((R)-2-methylpiperidin-1-yl)-phenyl


180.
propyl
4-(piperazin-1-yl)-phenyl


181.
propyl
4-(4-methylpiperazin-1-yl)-phenyl


182.
propyl
4-(morpholin-4-yl)-phenyl


183.
propyl
4-(thiomorpholin-4-yl)-phenyl


184.
propyl
4-(1-oxo-thiomorpholin-4-yl)-phenyl


185.
propyl
4-(1,1-dioxo-thiomorpholin-4-yl)-phenyl


186.
propyl
4-(pyrrol-1-yl)-phenyl


187.
propyl
4-(pyrrol-2-yl)-phenyl


188.
propyl
4-(pyrrol-3-yl)-phenyl


189.
propyl
4-(1-methylpyrrol-2-yl)-phenyl


190.
propyl
4-(1-methylpyrrol-3-yl)-phenyl


191.
propyl
4-(furan-2-yl)-phenyl


192.
propyl
4-(furan-3-yl)-phenyl


193.
propyl
4-(thiophen-2-yl)-phenyl


194.
propyl
4-(thiophen-3-yl)-phenyl


195.
propyl
4-(5-propylthien-2-yl)-phenyl


196.
propyl
4-(pyrazol-1-yl)-phenyl


197.
propyl
4-(pyrazol-3-yl)-phenyl


198.
propyl
4-(pyrazol-4-yl)-phenyl


199.
propyl
4-(1-methyl-1H-pyrazol-4-yl)-phenyl


200.
propyl
4-(1-ethyl-1H-pyrazol-4-yl)-phenyl


201.
propyl
4-(1-methyl-1H-pyrazol-5-yl)-phenyl


202.
propyl
4-(1H-imidazol-2-yl)-phenyl


203.
propyl
4-(imidazol-1-yl)-phenyl


204.
propyl
4-(1-methylimidazol-2-yl)-phenyl


205.
propyl
4-(oxazol-2-yl)-phenyl


206.
propyl
4-(oxazol-4-yl)-phenyl


207.
propyl
4-(oxazol-5-yl)-phenyl


208.
propyl
4-(isoxazol-3-yl)-phenyl


209.
propyl
4-(isoxazol-4-yl)-phenyl


210.
propyl
4-(isoxazol-5-yl)-phenyl


211.
propyl
4-([1,2,3]-triazol-1-yl)-phenyl


212.
propyl
4-([1,2,4]-triazol-1-yl)-phenyl


213.
propyl
4-([1,2,3]-triazol-2-yl)-phenyl


214.
propyl
4-(4H-[1,2,4]-triazol-3-yl)-phenyl


215.
propyl
4-([1,2,4]-triazol-4-yl)-phenyl


216.
propyl
4-(2H-[1,2,3]-triazol-4-yl)-phenyl


217.
propyl
4-(4-methyl-4H-[1,2,4]-triazol-3-yl)-phenyl


218.
propyl
4-(2-methyl-2H-[1,2,3]-triazol-4-yl)-phenyl


219.
propyl
4-([1,3,4]-oxadiazol-2-yl)-phenyl


220.
propyl
4-([1,2,4]-oxadiazol-3-yl)-phenyl


221.
propyl
4-([1,2,4]-oxadiazol-5-yl)-phenyl


222.
propyl
4-([1,2,3]-oxadiazol-4-yl)-phenyl


223.
propyl
4-([1,2,3]-oxadiazol-5-yl)-phenyl


224.
propyl
4-([1,2,3]-thiadiazol-4-yl)-phenyl


225.
propyl
4-(1H-tetrazol-5-yl)-phenyl


226.
propyl
4-(tetrazol-1-yl)-phenyl


227.
propyl
4-(2-methyl-2H-tetrazol-5-yl)-phenyl


228.
propyl
4-(1-methyl-1H-tetrazol-5-yl)-phenyl


229.
propyl
4-furazan-3-yl-phenyl


230.
propyl
4-(pyrid-2-yl)-phenyl


231.
propyl
4-(pyrid-3-yl)-phenyl


232.
propyl
4-(pyrid-4-yl)-phenyl


233.
propyl
4-(pyrimidin-2-yl)-phenyl


234.
propyl
4-(pyrimidin-4-yl)-phenyl


235.
propyl
4-(pyrimidin-5-yl)-phenyl


236.
propyl
5-isopropylthiophen-2-yl


237.
propyl
2-chlorothiophen-5-yl


238.
propyl
2,5-dichlorothiophen-4-yl


239.
propyl
2,3-dichlorothiophen-5-yl


240.
propyl
2-chloro-3-nitrothiophen-5-yl


241.
propyl
2-(phenylsulfonyl)-thiophen-5-yl


242.
propyl
2-(pyridin-2-yl)thiophen-5-yl


243.
propyl
2-(5-(trifluoromethyl)isoxazol-3-yl)-thiophen-5-yl


244.
propyl
2-(2-methylthiazol-4-yl)-thiophen-5-yl


245.
propyl
1-methyl-1H-imidazol-4-yl


246.
propyl
1,2-dimethyl-1H-imidazol-4-yl


247.
propyl
3,5-dimethylisoxazol-4-yl


248.
propyl
thiazol-2-yl


249.
propyl
4-methylthiazol-2-yl


250.
propyl
4-isopropylthiazol-2-yl


251.
propyl
4-trifluoromethylthiazol-2-yl


252.
propyl
5-methylthiazol-2-yl


253.
propyl
5-isopropylthiazol-2-yl


254.
propyl
5-trifluoromethylthiazol-2-yl


255.
propyl
2,4-dimethylthiazol-5-yl


256.
propyl
2-acetamido-4-methylthiazol-5-yl


257.
propyl
4H-[1,2,4]triazol-3-yl


258.
propyl
5-methyl-4H-[1,2,4]triazol-3-yl


259.
propyl
4-methyl-4H-[1,2,4]triazol-3-yl


260.
propyl
5-isopropyl-4H-[1,2,4]triazol-3-yl


261.
propyl
5-trifluoromethyl-4H-[1,2,4]triazol-3-yl


262.
propyl
4,5-dimethyl-4H-[1,2,4]triazol-3-yl


263.
propyl
5-isopropyl-4-methyl-4H-[1,2,4]triazol-3-yl


264.
propyl
5-trifluoromethyl-4-methyl-4H-[1,2,4]triazol-3-yl


265.
propyl
[1,3,4]thiadiazol-2-yl


266.
propyl
5-methyl-[1,3,4]thiadiazol-2-yl


267.
propyl
5-isopropyl-[1,3,4]thiadiazol-2-yl


268.
propyl
5-trifluoromethyl-[1,3,4]thiadiazol-2-yl


269.
propyl
3-bromo-2-chloropyrid-5-yl


270.
propyl
2-(4-morpholino)-pyrid-5-yl


271.
propyl
2-phenoxypyrid-5-yl


272.
propyl
(2-isopropyl)-pyrimidin-5-yl


273.
propyl
(5-isopropyl)-pyrimidin-2-yl


274.
propyl
8-quinolyl


275.
propyl
5-isoquinolyl


276.
propyl
2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-




yl


277.
propyl
5-chloro-3-methylbenzothiophen-2-yl


278.
propyl
3,4-dihydro-4-methyl-2H-benzo[b][1,4]oxazinyl


279.
propyl
benzothiazol-6-yl


280.
propyl
benzo[2,1,3]oxadiazol-4-yl


281.
propyl
5-chlorobenzo[2,1,3]oxadiazol-4-yl


282.
propyl
7-chlorobenzo[2,1,3]oxadiazol-4-yl


283.
propyl
benzo[2,1,3]thiadiazol-4-yl


284.
ethyl
4-isopropylphenyl


285.
ethyl
4-sec-butylphenyl


286.
ethyl
4-isobutylphenyl


287.
ethyl
4-(1,1-dimethylpropyl)-phenyl


288.
ethyl
4-vinylphenyl


289.
ethyl
4-isopropenylphenyl


290.
ethyl
4-(fluoromethyl)phenyl


291.
ethyl
3-(fluoromethyl)phenyl


292.
ethyl
2-(fluoromethyl)phenyl


293.
ethyl
4-(difluoromethyl)phenyl


294.
ethyl
3-(difluoromethyl)phenyl


295.
ethyl
2-(difluoromethyl)phenyl


296.
ethyl
4-(trifluoromethyl)phenyl


297.
ethyl
3-(trifluoromethyl)phenyl


298.
ethyl
2-(trifluoromethyl)phenyl


299.
ethyl
4-(1-fluoroethyl)-phenyl


300.
ethyl
4-((S)-1-fluoroethyl)-phenyl


301.
ethyl
4-((R)-1-fluoroethyl)-phenyl


302.
ethyl
4-(2-fluoroethyl)-phenyl


303.
ethyl
4-(1,1-difluoroethyl)-phenyl


304.
ethyl
4-(2,2-difluoroethyl)-phenyl


305.
ethyl
4-(2,2,2-trifluoroethyl)-phenyl


306.
ethyl
4-(3-fluoropropyl)-phenyl


307.
ethyl
4-(2-fluoropropyl)-phenyl


308.
ethyl
4-((S)-2-fluoropropyl)-phenyl


309.
ethyl
4-((R)-2-fluoropropyl)-phenyl


310.
ethyl
4-(3,3-difluoropropyl)-phenyl


311.
ethyl
4-(3,3,3-trifluoropropyl)-phenyl


312.
ethyl
4-(1-fluoro-1-methylethyl)-phenyl


313.
ethyl
4-(2-fluoro-1-methylethyl)-phenyl


314.
ethyl
4-((S)-2-fluoro-1-methylethyl)-phenyl


315.
ethyl
4-((R)-2-fluoro-1-methylethyl)-phenyl


316.
ethyl
4-(2,2-difluoro-1-methylethyl)-phenyl


317.
ethyl
4-((S)-2,2-difluoro-1-methylethyl)-phenyl


318.
ethyl
4-((R)-2,2-difluoro-1-methylethyl)-phenyl


319.
ethyl
4-(2,2,2-trifluoro-1-methylethyl)-phenyl


320.
ethyl
4-((S)-2,2,2-trifluoro-1-methylethyl)-phenyl


321.
ethyl
4-((R)-2,2,2-trifluoro-1-methylethyl)-phenyl


322.
ethyl
4-(2-fluoro-1-fluoromethylethyl)-phenyl


323.
ethyl
4-(1-difluoromethyl-2,2-difluoroethyl)-phenyl


324.
ethyl
4-(1,1-dimethyl-2-fluoroethyl)-phenyl


325.
ethyl
4-ethoxyphenyl


326.
ethyl
4-propoxyphenyl


327.
ethyl
4-isopropoxyphenyl


328.
ethyl
4-butoxyphenyl


329.
ethyl
4-(fluoromethoxy)-phenyl


330.
ethyl
4-(difluoromethoxy)-phenyl


331.
ethyl
4-(2-fluoroethoxy)-phenyl


332.
ethyl
4-(2,2-difluoroethoxy)-phenyl


333.
ethyl
4-(2,2,2-trifluoroethoxy)-phenyl


334.
ethyl
4-(1,1,2,2-tetrafluoroethoxy)-phenyl


335.
ethyl
4-cyclopropylphenyl


336.
ethyl
4-cyclobutylphenyl


337.
ethyl
4-cyclopentylphenyl


338.
ethyl
4-(2,2-difluorocyclopropyl)-phenyl


339.
ethyl
3,4-difluorophenyl


340.
ethyl
2-fluoro-4-isopropylphenyl


341.
ethyl
3-fluoro-4-isopropylphenyl


342.
ethyl
4-(1-hydroxy-1-methylethyl)-phenyl


343.
ethyl
4-(2-hydroxy-2-methylpropyl)-phenyl


344.
ethyl
4-acetylphenyl


345.
ethyl
4-carboxyphenyl


346.
ethyl
4-(O-benzyl)-phenyl


347.
ethyl
4-(2-methoxyethoxy)-phenyl


348.
ethyl
4-(CH2—N(CH3)2)-phenyl


349.
ethyl
4-(NH—CO—NH2)-phenyl


350.
ethyl
4-(fluoromethylsulfanyl)-phenyl


351.
ethyl
4-(difluoromethylsulfanyl)-phenyl


352.
ethyl
4-(trifluoromethylsulfanyl)-phenyl


353.
ethyl
4-(methylsulfonyl)-phenyl


354.
ethyl
4-(N-methoxy-N-methyl-amino)-phenyl


355.
ethyl
4-(methoxyamino)-phenyl


356.
ethyl
4-(ethoxyamino)-phenyl


357.
ethyl
4-(N-methylaminooxy)-phenyl


358.
ethyl
4-(N,N-dimethylaminooxy)-phenyl


359.
ethyl
4-(azetidin-1-yl)-phenyl


360.
ethyl
4-(2-methylazetidin-1-yl)-phenyl


361.
ethyl
4-((S)-2-methylazetidin-1-yl)-phenyl


362.
ethyl
4-((R)-2-methylazetidin-1-yl)-phenyl


363.
ethyl
4-(3-fluoroazetidin-1-yl)-phenyl


364.
ethyl
4-(3-methoxyazetidin-1-yl)-phenyl


365.
ethyl
4-(3-hydroxyazetidin-1-yl)-phenyl


366.
ethyl
4-(pyrrolidin-1-yl)-phenyl


367.
ethyl
4-(pyrrolidin-2-yl)-phenyl


368.
ethyl
4-((S)-pyrrolidin-2-yl)-phenyl


369.
ethyl
4-((R)-pyrrolidin-2-yl)-phenyl


370.
ethyl
4-(pyrrolidin-3-yl)-phenyl


371.
ethyl
4-((S)-pyrrolidin-3-yl)-phenyl


372.
ethyl
4-((R)-pyrrolidin-3-yl)-phenyl


373.
ethyl
4-(2-fluoropyrrolidin-1-yl)-phenyl


374.
ethyl
4-((S)-2-fluoropyrrolidin-1-yl)-phenyl


375.
ethyl
4-((R)-2-fluoropyrrolidin-1-yl)-phenyl


376.
ethyl
4-(3-fluoropyrrolidin-1-yl)-phenyl


377.
ethyl
4-((S)-3-fluoropyrrolidin-1-yl)-phenyl


378.
ethyl
4-((R)-3-fluoropyrrolidin-1-yl)-phenyl


379.
ethyl
4-(2,2-difluoropyrrolidin-1-yl)-phenyl


380.
ethyl
4-(3,3-difluoropyrrolidin-1-yl)-phenyl


381.
ethyl
4-(2-methylpyrrolidin-1-yl)-phenyl


382.
ethyl
4-((S)-2-methylpyrrolidin-1-yl)-phenyl


383.
ethyl
4-((R)-2-methylpyrrolidin-1-yl)-phenyl


384.
ethyl
4-(3-methylpyrrolidin-1-yl)-phenyl


385.
ethyl
4-((S)-3-methylpyrrolidin-1-yl)-phenyl


386.
ethyl
4-((R)-3-methylpyrrolidin-1-yl)-phenyl


387.
ethyl
4-(1-methylpyrrolidin-2-yl)-phenyl


388.
ethyl
4-((S)-1-methylpyrrolidin-2-yl)-phenyl


389.
ethyl
4-((R)-1-methylpyrrolidin-2-yl)-phenyl


390.
ethyl
4-(1-methylpyrrolidin-3-yl)-phenyl


391.
ethyl
4-((S)-1-methylpyrrolidin-3-yl)-phenyl


392.
ethyl
4-((R)-1-methylpyrrolidin-3-yl)-phenyl


393.
ethyl
4-(2,2-dimethylpyrrolidin-1-yl)-phenyl


394.
ethyl
4-(3,3-dimethylpyrrolidin-1-yl)-phenyl


395.
ethyl
4-(2-trifluoromethylpyrrolidin-1-yl)-phenyl


396.
ethyl
4-((S)-2-trifluoromethylpyrrolidin-1-yl)-phenyl


397.
ethyl
4-((R)-2-trifluoromethylpyrrolidin-1-yl)-phenyl


398.
ethyl
4-(3-trifluoromethylpyrrolidin-1-yl)-phenyl


399.
ethyl
4-((S)-3-trifluoromethylpyrrolidin-1-yl)-phenyl


400.
ethyl
4-((R)-3-trifluoromethylpyrrolidin-1-yl)-phenyl


401.
ethyl
4-(2-oxopyrrolidin-1-yl)-phenyl


402.
ethyl
4-(2-oxo-oxazolidin-3-yl)-phenyl


403.
ethyl
4-(piperidin-1-yl)-phenyl


404.
ethyl
4-(2-methylpiperidin-1-yl)-phenyl


405.
ethyl
4-((S)-2-methylpiperidin-1-yl)-phenyl


406.
ethyl
4-((R)-2-methylpiperidin-1-yl)-phenyl


407.
ethyl
4-(piperazin-1-yl)-phenyl


408.
ethyl
4-(4-methylpiperazin-1-yl)-phenyl


409.
ethyl
4-(morpholin-4-yl)-phenyl


410.
ethyl
4-(thiomorpholin-4-yl)-phenyl


411.
ethyl
4-(1-oxo-thiomorpholin-4-yl)-phenyl


412.
ethyl
4-(1,1-dioxo-thiomorpholin-4-yl)-phenyl


413.
ethyl
4-(pyrrol-1-yl)-phenyl


414.
ethyl
4-(pyrrol-2-yl)-phenyl


415.
ethyl
4-(pyrrol-3-yl)-phenyl


416.
ethyl
4-(1-methylpyrrol-2-yl)-phenyl


417.
ethyl
4-(1-methylpyrrol-3-yl)-phenyl


418.
ethyl
4-(furan-2-yl)-phenyl


419.
ethyl
4-(furan-3-yl)-phenyl


420.
ethyl
4-(thiophen-2-yl)-phenyl


421.
ethyl
4-(thiophen-3-yl)-phenyl


422.
ethyl
4-(5-propylthien-2-yl)-phenyl


423.
ethyl
4-(pyrazol-1-yl)-phenyl


424.
ethyl
4-(pyrazol-3-yl)-phenyl


425.
ethyl
4-(pyrazol-4-yl)-phenyl


426.
ethyl
4-(1-methyl-1H-pyrazol-4-yl)-phenyl


427.
ethyl
4-(1-ethyl-1H-pyrazol-4-yl)-phenyl


428.
ethyl
4-(1-methyl-1H-pyrazol-5-yl)-phenyl


429.
ethyl
4-(1H-imidazol-2-yl)-phenyl


430.
ethyl
4-(imidazol-1-yl)-phenyl


431.
ethyl
4-(1-methylimidazol-2-yl)-phenyl


432.
ethyl
4-(oxazol-2-yl)-phenyl


433.
ethyl
4-(oxazol-4-yl)-phenyl


434.
ethyl
4-(oxazol-5-yl)-phenyl


435.
ethyl
4-(isoxazol-3-yl)-phenyl


436.
ethyl
4-(isoxazol-4-yl)-phenyl


437.
ethyl
4-(isoxazol-5-yl)-phenyl


438.
ethyl
4-([1,2,3]-triazol-1-yl)-phenyl


439.
ethyl
4-([1,2,4]-triazol-1-yl)-phenyl


440.
ethyl
4-([1,2,3]-triazol-2-yl)-phenyl


441.
ethyl
4-(4H-[1,2,4]-triazol-3-yl)-phenyl


442.
ethyl
4-([1,2,4]-triazol-4-yl)-phenyl


443.
ethyl
4-(2H-[1,2,3]-triazol-4-yl)-phenyl


444.
ethyl
4-(4-methyl-4H-[1,2,4]-triazol-3-yl)-phenyl


445.
ethyl
4-(2-methyl-2H-[1,2,3]-triazol-4-yl)-phenyl


446.
ethyl
4-([1,3,4]-oxadiazol-2-yl)-phenyl


447.
ethyl
4-([1,2,4]-oxadiazol-3-yl)-phenyl


448.
ethyl
4-([1,2,4]-oxadiazol-5-yl)-phenyl


449.
ethyl
4-([1,2,3]-oxadiazol-4-yl)-phenyl


450.
ethyl
4-([1,2,3]-oxadiazol-5-yl)-phenyl


451.
ethyl
4-([1,2,3]-thiadiazol-4-yl)-phenyl


452.
ethyl
4-(1H-tetrazol-5-yl)-phenyl


453.
ethyl
4-(tetrazol-1-yl)-phenyl


454.
ethyl
4-(2-methyl-2H-tetrazol-5-yl)-phenyl


455.
ethyl
4-(1-methyl-1H-tetrazol-5-yl)-phenyl


456.
ethyl
4-furazan-3-yl-phenyl


457.
ethyl
4-(pyrid-2-yl)-phenyl


458.
ethyl
4-(pyrid-3-yl)-phenyl


459.
ethyl
4-(pyrid-4-yl)-phenyl


460.
ethyl
4-(pyrimidin-2-yl)-phenyl


461.
ethyl
4-(pyrimidin-4-yl)-phenyl


462.
ethyl
4-(pyrimidin-5-yl)-phenyl


463.
ethyl
5-isopropylthiophen-2-yl


464.
ethyl
2-chlorothiophen-5-yl


465.
ethyl
2,5-dichlorothiophen-4-yl


466.
ethyl
2,3-dichlorothiophen-5-yl


467.
ethyl
2-chloro-3-nitrothiophen-5-yl


468.
ethyl
2-(phenylsulfonyl)-thiophen-5-yl


469.
ethyl
2-(pyridin-2-yl)thiophen-5-yl


470.
ethyl
2-(5-(trifluoromethyl)isoxazol-3-yl)-thiophen-5-yl


471.
ethyl
2-(2-methylthiazol-4-yl)-thiophen-5-yl


472.
ethyl
1-methyl-1H-imidazol-4-yl


473.
ethyl
1,2-dimethyl-1H-imidazol-4-yl


474.
ethyl
3,5-dimethylisoxazol-4-yl


475.
ethyl
thiazol-2-yl


476.
ethyl
4-methylthiazol-2-yl


477.
ethyl
4-isopropylthiazol-2-yl


478.
ethyl
4-trifluoromethylthiazol-2-yl


479.
ethyl
5-methylthiazol-2-yl


480.
ethyl
5-isopropylthiazol-2-yl


481.
ethyl
5-trifluoromethylthiazol-2-yl


482.
ethyl
2,4-dimethylthiazol-5-yl


483.
ethyl
2-acetamido-4-methylthiazol-5-yl


484.
ethyl
4H-[1,2,4]triazol-3-yl


485.
ethyl
5-methyl-4H-[1,2,4]triazol-3-yl


486.
ethyl
4-methyl-4H-[1,2,4]triazol-3-yl


487.
ethyl
5-isopropyl-4H-[1,2,4]triazol-3-yl


488.
ethyl
5-trifluoromethyl-4H-[1,2,4]triazol-3-yl


489.
ethyl
4,5-dimethyl-4H-[1,2,4]triazol-3-yl


490.
ethyl
5-isopropyl-4-methyl-4H-[1,2,4]triazol-3-yl


491.
ethyl
5-trifluoromethyl-4-methyl-4H-[1,2,4]triazol-3-yl


492.
ethyl
[1,3,4]thiadiazol-2-yl


493.
ethyl
5-methyl-[1,3,4]thiadiazol-2-yl


494.
ethyl
5-isopropyl-[1,3,4]thiadiazol-2-yl


495.
ethyl
5-trifluoromethyl-[1,3,4]thiadiazol-2-yl


496.
ethyl
3-bromo-2-chloropyrid-5-yl


497.
ethyl
2-(4-morpholino)-pyrid-5-yl


498.
ethyl
2-phenoxypyrid-5-yl


499.
ethyl
(2-isopropyl)-pyrimidin-5-yl


500.
ethyl
(5-isopropyl)-pyrimidin-2-yl


501.
ethyl
8-quinolyl


502.
ethyl
5-isoquinolyl


503.
ethyl
2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-




yl


504.
ethyl
5-chloro-3-methylbenzothiophen-2-yl


505.
ethyl
3,4-dihydro-4-methyl-2H-benzo[b][1,4]oxazinyl


506.
ethyl
benzothiazol-6-yl


507.
ethyl
benzo[2,1,3]oxadiazol-4-yl


508.
ethyl
5-chlorobenzo[2,1,3]oxadiazol-4-yl


509.
ethyl
7-chlorobenzo[2,1,3]oxadiazol-4-yl


510.
ethyl
benzo[2,1,3]thiadiazol-4-yl


511.
methyl
4-isopropylphenyl


512.
methyl
4-sec-butylphenyl


513.
methyl
4-isobutylphenyl


514.
methyl
4-(1,1-dimethylpropyl)-phenyl


515.
methyl
4-vinylphenyl


516.
methyl
4-isopropenylphenyl


517.
methyl
4-(fluoromethyl)phenyl


518.
methyl
3-(fluoromethyl)phenyl


519.
methyl
2-(fluoromethyl)phenyl


520.
methyl
4-(difluoromethyl)phenyl


521.
methyl
3-(difluoromethyl)phenyl


522.
methyl
2-(difluoromethyl)phenyl


523.
methyl
4-(1-fluoroethyl)-phenyl


524.
methyl
4-((S)-1-fluoroethyl)-phenyl


525.
methyl
4-((R)-1-fluoroethyl)-phenyl


526.
methyl
4-(2-fluoroethyl)-phenyl


527.
methyl
4-(1,1-difluoroethyl)-phenyl


528.
methyl
4-(2,2-difluoroethyl)-phenyl


529.
methyl
4-(2,2,2-trifluoroethyl)-phenyl


530.
methyl
4-(3-fluoropropyl)-phenyl


531.
methyl
4-(2-fluoropropyl)-phenyl


532.
methyl
4-((S)-2-fluoropropyl)-phenyl


533.
methyl
4-((R)-2-fluoropropyl)-phenyl


534.
methyl
4-(3,3-difluoropropyl)-phenyl


535.
methyl
4-(3,3,3-trifluoropropyl)-phenyl


536.
methyl
4-(1-fluoro-1-methylethyl)-phenyl


537.
methyl
4-(2-fluoro-1-methylethyl)-phenyl


538.
methyl
4-((S)-2-fluoro-1-methylethyl)-phenyl


539.
methyl
4-((R)-2-fluoro-1-methylethyl)-phenyl


540.
methyl
4-(2,2-difluoro-1-methylethyl)-phenyl


541.
methyl
4-((S)-2,2-difluoro-1-methylethyl)-phenyl


542.
methyl
4-((R)-2,2-difluoro-1-methylethyl)-phenyl


543.
methyl
4-(2,2,2-trifluoro-1-methylethyl)-phenyl


544.
methyl
4-((S)-2,2,2-trifluoro-1-methylethyl)-phenyl


545.
methyl
4-((R)-2,2,2-trifluoro-1-methylethyl)-phenyl


546.
methyl
4-(2-fluoro-1-fluoromethylethyl)-phenyl


547.
methyl
4-(1-difluoromethyl-2,2-difluoroethyl)-phenyl


548.
methyl
4-(1,1-dimethyl-2-fluoroethyl)-phenyl


549.
methyl
4-ethoxyphenyl


550.
methyl
4-propoxyphenyl


551.
methyl
4-isopropoxyphenyl


552.
methyl
4-butoxyphenyl


553.
methyl
4-(fluoromethoxy)-phenyl


554.
methyl
4-(difluoromethoxy)-phenyl


555.
methyl
4-(2-fluoroethoxy)-phenyl


556.
methyl
4-(2,2-difluoroethoxy)-phenyl


557.
methyl
4-(2,2,2-trifluoroethoxy)-phenyl


558.
methyl
4-(1,1,2,2-tetrafluoroethoxy)-phenyl


559.
methyl
4-cyclopropylphenyl


560.
methyl
4-cyclobutylphenyl


561.
methyl
4-cyclopentylphenyl


562.
methyl
4-(2,2-difluorocyclopropyl)-phenyl


563.
methyl
3-fluoro-4-isopropylphenyl


564.
methyl
4-(1-hydroxy-1-methylethyl)-phenyl


565.
methyl
4-(2-hydroxy-2-methylpropyl)-phenyl


566.
methyl
4-acetylphenyl


567.
methyl
4-carboxyphenyl


568.
methyl
4-cyanophenyl


569.
methyl
4-hydroxyphenyl


570.
methyl
4-(O-benzyl)-phenyl


571.
methyl
4-(2-methoxyethoxy)-phenyl


572.
methyl
4-(CH2—N(CH3)2)-phenyl


573.
methyl
4-(NH—CO—NH2)-phenyl


574.
methyl
4-(methylsulfanyl)-phenyl


575.
methyl
4-(fluoromethylsulfanyl)-phenyl


576.
methyl
4-(difluoromethylsulfanyl)-phenyl


577.
methyl
4-(trifluoromethylsulfanyl)-phenyl


578.
methyl
4-(methylsulfonyl)-phenyl


579.
methyl
4-(N-methoxy-N-methyl-amino)-phenyl


580.
methyl
4-(methoxyamino)-phenyl


581.
methyl
4-(ethoxyamino)-phenyl


582.
methyl
4-(N-methylaminooxy)-phenyl


583.
methyl
4-(N,N-dimethylaminooxy)-phenyl


584.
methyl
4-(azetidin-1-yl)-phenyl


585.
methyl
4-(2-methylazetidin-1-yl)-phenyl


586.
methyl
4-((S)-2-methylazetidin-1-yl)-phenyl


587.
methyl
4-((R)-2-methylazetidin-1-yl)-phenyl


588.
methyl
4-(3-fluoroazetidin-1-yl)-phenyl


589.
methyl
4-(3-methoxyazetidin-1-yl)-phenyl


590.
methyl
4-(3-hydroxyazetidin-1-yl)-phenyl


591.
methyl
4-(pyrrolidin-1-yl)-phenyl


592.
methyl
4-(pyrrolidin-2-yl)-phenyl


593.
methyl
4-((S)-pyrrolidin-2-yl)-phenyl


594.
methyl
4-((R)-pyrrolidin-2-yl)-phenyl


595.
methyl
4-(pyrrolidin-3-yl)-phenyl


596.
methyl
4-((S)-pyrrolidin-3-yl)-phenyl


597.
methyl
4-((R)-pyrrolidin-3-yl)-phenyl


598.
methyl
4-(2-fluoropyrrolidin-1-yl)-phenyl


599.
methyl
4-((S)-2-fluoropyrrolidin-1-yl)-phenyl


600.
methyl
4-((R)-2-fluoropyrrolidin-1-yl)-phenyl


601.
methyl
4-(3-fluoropyrrolidin-1-yl)-phenyl


602.
methyl
4-((S)-3-fluoropyrrolidin-1-yl)-phenyl


603.
methyl
4-((R)-3-fluoropyrrolidin-1-yl)-phenyl


604.
methyl
4-(2,2-difluoropyrrolidin-1-yl)-phenyl


605.
methyl
4-(3,3-difluoropyrrolidin-1-yl)-phenyl


606.
methyl
4-(2-methylpyrrolidin-1-yl)-phenyl


607.
methyl
4-((S)-2-methylpyrrolidin-1-yl)-phenyl


608.
methyl
4-((R)-2-methylpyrrolidin-1-yl)-phenyl


609.
methyl
4-(3-methylpyrrolidin-1-yl)-phenyl


610.
methyl
4-((S)-3-methylpyrrolidin-1-yl)-phenyl


611.
methyl
4-((R)-3-methylpyrrolidin-1-yl)-phenyl


612.
methyl
4-(1-methylpyrrolidin-2-yl)-phenyl


613.
methyl
4-((S)-1-methylpyrrolidin-2-yl)-phenyl


614.
methyl
4-((R)-1-methylpyrrolidin-2-yl)-phenyl


615.
methyl
4-(1-methylpyrrolidin-3-yl)-phenyl


616.
methyl
4-((S)-1-methylpyrrolidin-3-yl)-phenyl


617.
methyl
4-((R)-1-methylpyrrolidin-3-yl)-phenyl


618.
methyl
4-(2,2-dimethylpyrrolidin-1-yl)-phenyl


619.
methyl
4-(3,3-dimethylpyrrolidin-1-yl)-phenyl


620.
methyl
4-(2-trifluoromethylpyrrolidin-1-yl)-phenyl


621.
methyl
4-((S)-2-trifluoromethylpyrrolidin-1-yl)-phenyl


622.
methyl
4-((R)-2-trifluoromethylpyrrolidin-1-yl)-phenyl


623.
methyl
4-(3-trifluoromethylpyrrolidin-1-yl)-phenyl


624.
methyl
4-((S)-3-trifluoromethylpyrrolidin-1-yl)-phenyl


625.
methyl
4-((R)-3-trifluoromethylpyrrolidin-1-yl)-phenyl


626.
methyl
4-(2-oxopyrrolidin-1-yl)-phenyl


627.
methyl
4-(2-oxo-oxazolidin-3-yl)-phenyl


628.
methyl
4-(piperidin-1-yl)-phenyl


629.
methyl
4-(2-methylpiperidin-1-yl)-phenyl


630.
methyl
4-((S)-2-methylpiperidin-1-yl)-phenyl


631.
methyl
4-((R)-2-methylpiperidin-1-yl)-phenyl


632.
methyl
4-(piperazin-1-yl)-phenyl


633.
methyl
4-(4-methylpiperazin-1-yl)-phenyl


634.
methyl
4-(morpholin-4-yl)-phenyl


635.
methyl
4-(thiomorpholin-4-yl)-phenyl


636.
methyl
4-(1-oxo-thiomorpholin-4-yl)-phenyl


637.
methyl
4-(1,1-dioxo-thiomorpholin-4-yl)-phenyl


638.
methyl
4-(pyrrol-1-yl)-phenyl


639.
methyl
4-(pyrrol-2-yl)-phenyl


640.
methyl
4-(pyrrol-3-yl)-phenyl


641.
methyl
4-(1-methylpyrrol-2-yl)-phenyl


642.
methyl
4-(1-methylpyrrol-3-yl)-phenyl


643.
methyl
4-(furan-2-yl)-phenyl


644.
methyl
4-(furan-3-yl)-phenyl


645.
methyl
4-(thiophen-2-yl)-phenyl


646.
methyl
4-(thiophen-3-yl)-phenyl


647.
methyl
4-(5-propylthien-2-yl)-phenyl


648.
methyl
4-(pyrazol-1-yl)-phenyl


649.
methyl
4-(pyrazol-3-yl)-phenyl


650.
methyl
4-(pyrazol-4-yl)-phenyl


651.
methyl
4-(1-methyl-1H-pyrazol-4-yl)-phenyl


652.
methyl
4-(1-ethyl-1H-pyrazol-4-yl)-phenyl


653.
methyl
4-(1-methyl-1H-pyrazol-5-yl)-phenyl


654.
methyl
4-(1H-imidazol-2-yl)-phenyl


655.
methyl
4-(imidazol-1-yl)-phenyl


656.
methyl
4-(1-methylimidazol-2-yl)-phenyl


657.
methyl
4-(oxazol-2-yl)-phenyl


658.
methyl
4-(oxazol-4-yl)-phenyl


659.
methyl
4-(oxazol-5-yl)-phenyl


660.
methyl
4-(isoxazol-3-yl)-phenyl


661.
methyl
4-(isoxazol-4-yl)-phenyl


662.
methyl
4-(isoxazol-5-yl)-phenyl


663.
methyl
4-([1,2,3]-triazol-1-yl)-phenyl


664.
methyl
4-([1,2,4]-triazol-1-yl)-phenyl


665.
methyl
4-([1,2,3]-triazol-2-yl)-phenyl


666.
methyl
4-(4H-[1,2,4]-triazol-3-yl)-phenyl


667.
methyl
4-([1,2,4]-triazol-4-yl)-phenyl


668.
methyl
4-(2H-[1,2,3]-triazol-4-yl)-phenyl


669.
methyl
4-(4-methyl-4H-[1,2,4]-triazol-3-yl)-phenyl


670.
methyl
4-(2-methyl-2H-[1,2,3]-triazol-4-yl)-phenyl


671.
methyl
4-([1,3,4]-oxadiazol-2-yl)-phenyl


672.
methyl
4-([1,2,4]-oxadiazol-3-yl)-phenyl


673.
methyl
4-([1,2,4]-oxadiazol-5-yl)-phenyl


674.
methyl
4-([1,2,3]-oxadiazol-4-yl)-phenyl


675.
methyl
4-([1,2,3]-oxadiazol-5-yl)-phenyl


676.
methyl
4-([1,2,3]-thiadiazol-4-yl)-phenyl


677.
methyl
4-(1H-tetrazol-5-yl)-phenyl


678.
methyl
4-(tetrazol-1-yl)-phenyl


679.
methyl
4-(2-methyl-2H-tetrazol-5-yl)-phenyl


680.
methyl
4-(1-methyl-1H-tetrazol-5-yl)-phenyl


681.
methyl
4-furazan-3-yl-phenyl


682.
methyl
4-(pyrid-2-yl)-phenyl


683.
methyl
4-(pyrid-3-yl)-phenyl


684.
methyl
4-(pyrid-4-yl)-phenyl


685.
methyl
4-(pyrimidin-2-yl)-phenyl


686.
methyl
4-(pyrimidin-4-yl)-phenyl


687.
methyl
4-(pyrimidin-5-yl)-phenyl


688.
methyl
5-isopropylthiophen-2-yl


689.
methyl
2-chlorothiophen-5-yl


690.
methyl
2,5-dichlorothiophen-4-yl


691.
methyl
2,3-dichlorothiophen-5-yl


692.
methyl
2-chloro-3-nitrothiophen-5-yl


693.
methyl
2-(phenylsulfonyl)-thiophen-5-yl


694.
methyl
2-(pyridin-2-yl)thiophen-5-yl


695.
methyl
2-(5-(trifluoromethyl)isoxazol-3-yl)-thiophen-5-yl


696.
methyl
2-(2-methylthiazol-4-yl)-thiophen-5-yl


697.
methyl
1-methyl-1H-imidazol-4-yl


698.
methyl
1,2-dimethyl-1H-imidazol-4-yl


699.
methyl
3,5-dimethylisoxazol-4-yl


700.
methyl
thiazol-2-yl


701.
methyl
4-methylthiazol-2-yl


702.
methyl
4-isopropylthiazol-2-yl


703.
methyl
4-trifluoromethylthiazol-2-yl


704.
methyl
5-methylthiazol-2-yl


705.
methyl
5-isopropylthiazol-2-yl


706.
methyl
5-trifluoromethylthiazol-2-yl


707.
methyl
2,4-dimethylthiazol-5-yl


708.
methyl
2-acetamido-4-methylthiazol-5-yl


709.
methyl
4H-[1,2,4]triazol-3-yl


710.
methyl
5-methyl-4H-[1,2,4]triazol-3-yl


711.
methyl
4-methyl-4H-[1,2,4]triazol-3-yl


712.
methyl
5-isopropyl-4H-[1,2,4]triazol-3-yl


713.
methyl
5-trifluoromethyl-4H-[1,2,4]triazol-3-yl


714.
methyl
4,5-dimethyl-4H-[1,2,4]triazol-3-yl


715.
methyl
5-isopropyl-4-methyl-4H-[1,2,4]triazol-3-yl


716.
methyl
5-trifluoromethyl-4-methyl-4H-[1,2,4]triazol-3-yl


717.
methyl
[1,3,4]thiadiazol-2-yl


718.
methyl
5-methyl-[1,3,4]thiadiazol-2-yl


719.
methyl
5-isopropyl-[1,3,4]thiadiazol-2-yl


720.
methyl
5-trifluoromethyl-[1,3,4]thiadiazol-2-yl


721.
methyl
3-bromo-2-chloropyrid-5-yl


722.
methyl
2-(4-morpholino)-pyrid-5-yl


723.
methyl
2-phenoxypyrid-5-yl


724.
methyl
(2-isopropyl)-pyrimidin-5-yl


725.
methyl
(5-isopropyl)-pyrimidin-2-yl


726.
methyl
8-quinolyl


727.
methyl
5-isoquinolyl


728.
methyl
2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-




yl


729.
methyl
5-chloro-3-methylbenzothiophen-2-yl


730.
methyl
3,4-dihydro-4-methyl-2H-benzo[b][1,4]oxazinyl


731.
methyl
benzothiazol-6-yl


732.
methyl
benzo[2,1,3]oxadiazol-4-yl


733.
methyl
5-chlorobenzo[2,1,3]oxadiazol-4-yl


734.
methyl
7-chlorobenzo[2,1,3]oxadiazol-4-yl


735.
methyl
benzo[2,1,3]thiadiazol-4-yl


736.
3-fluoropropyl
4-methylphenyl


737.
3-fluoropropyl
4-ethylphenyl


738.
3-fluoropropyl
4-propylphenyl


739.
3-fluoropropyl
4-isopropylphenyl


740.
3-fluoropropyl
4-sec-butylphenyl


741.
3-fluoropropyl
4-isobutylphenyl


742.
3-fluoropropyl
4-(1,1-dimethylpropyl)-phenyl


743.
3-fluoropropyl
4-vinylphenyl


744.
3-fluoropropyl
4-isopropenylphenyl


745.
3-fluoropropyl
4-fluorophenyl


746.
3-fluoropropyl
4-chlorophenyl


747.
3-fluoropropyl
4-bromophenyl


748.
3-fluoropropyl
4-(fluoromethyl)phenyl


749.
3-fluoropropyl
3-(fluoromethyl)phenyl


750.
3-fluoropropyl
2-(fluoromethyl)phenyl


751.
3-fluoropropyl
4-(difluoromethyl)phenyl


752.
3-fluoropropyl
3-(difluoromethyl)phenyl


753.
3-fluoropropyl
2-(difluoromethyl)phenyl


754.
3-fluoropropyl
4-(trifluoromethyl)phenyl


755.
3-fluoropropyl
3-(trifluoromethyl)phenyl


756.
3-fluoropropyl
2-(trifluoromethyl)phenyl


757.
3-fluoropropyl
4-(1-fluoroethyl)-phenyl


758.
3-fluoropropyl
4-((S)-1-fluoroethyl)-phenyl


759.
3-fluoropropyl
4-((R)-1-fluoroethyl)-phenyl


760.
3-fluoropropyl
4-(2-fluoroethyl)-phenyl


761.
3-fluoropropyl
4-(1,1-difluoroethyl)-phenyl


762.
3-fluoropropyl
4-(2,2-difluoroethyl)-phenyl


763.
3-fluoropropyl
4-(2,2,2-trifluoroethyl)-phenyl


764.
3-fluoropropyl
4-(3-fluoropropyl)-phenyl


765.
3-fluoropropyl
4-(2-fluoropropyl)-phenyl


766.
3-fluoropropyl
4-((S)-2-fluoropropyl)-phenyl


767.
3-fluoropropyl
4-((R)-2-fluoropropyl)-phenyl


768.
3-fluoropropyl
4-(3,3-difluoropropyl)-phenyl


769.
3-fluoropropyl
4-(3,3,3-trifluoropropyl)-phenyl


770.
3-fluoropropyl
4-(1-fluoro-1-methylethyl)-phenyl


771.
3-fluoropropyl
4-(2-fluoro-1-methylethyl)-phenyl


772.
3-fluoropropyl
4-((S)-2-fluoro-1-methylethyl)-phenyl


773.
3-fluoropropyl
4-((R)-2-fluoro-1-methylethyl)-phenyl


774.
3-fluoropropyl
4-(2,2-difluoro-1-methylethyl)-phenyl


775.
3-fluoropropyl
4-((S)-2,2-difluoro-1-methylethyl)-phenyl


776.
3-fluoropropyl
4-((R)-2,2-difluoro-1-methylethyl)-phenyl


777.
3-fluoropropyl
4-(2,2,2-trifluoro-1-methylethyl)-phenyl


778.
3-fluoropropyl
4-((S)-2,2,2-trifluoro-1-methylethyl)-phenyl


779.
3-fluoropropyl
4-((R)-2,2,2-trifluoro-1-methylethyl)-phenyl


780.
3-fluoropropyl
4-(2-fluoro-1-fluoromethylethyl)-phenyl


781.
3-fluoropropyl
4-(1-difluoromethyl-2,2-difluoroethyl)-phenyl


782.
3-fluoropropyl
4-(1,1-dimethyl-2-fluoroethyl)-phenyl


783.
3-fluoropropyl
4-methoxyphenyl


784.
3-fluoropropyl
4-ethoxyphenyl


785.
3-fluoropropyl
4-propoxyphenyl


786.
3-fluoropropyl
4-isopropoxyphenyl


787.
3-fluoropropyl
4-butoxyphenyl


788.
3-fluoropropyl
4-(fluoromethoxy)-phenyl


789.
3-fluoropropyl
4-(difluoromethoxy)-phenyl


790.
3-fluoropropyl
4-(trifluoromethoxy)-phenyl


791.
3-fluoropropyl
3-(trifluoromethoxy)-phenyl


792.
3-fluoropropyl
4-(2-fluoroethoxy)-phenyl


793.
3-fluoropropyl
4-(2,2-difluoroethoxy)-phenyl


794.
3-fluoropropyl
4-(2,2,2-trifluoroethoxy)-phenyl


795.
3-fluoropropyl
4-(1,1,2,2-tetrafluoroethoxy)-phenyl


796.
3-fluoropropyl
4-cyclopropylphenyl


797.
3-fluoropropyl
4-cyclobutylphenyl


798.
3-fluoropropyl
4-cyclopentylphenyl


799.
3-fluoropropyl
4-(2,2-difluorocyclopropyl)-phenyl


800.
3-fluoropropyl
3,4-difluorophenyl


801.
3-fluoropropyl
4-bromo-3-fluorophenyl


802.
3-fluoropropyl
4-bromo-2-fluorophenyl


803.
3-fluoropropyl
4-bromo-2,5-difluorophenyl


804.
3-fluoropropyl
2-fluoro-4-isopropylphenyl


805.
3-fluoropropyl
3-fluoro-4-isopropylphenyl


806.
3-fluoropropyl
4-(1-hydroxy-1-methylethyl)-phenyl


807.
3-fluoropropyl
4-(2-hydroxy-2-methylpropyl)-phenyl


808.
3-fluoropropyl
4-acetylphenyl


809.
3-fluoropropyl
4-carboxyphenyl


810.
3-fluoropropyl
4-cyanophenyl


811.
3-fluoropropyl
4-hydroxyphenyl


812.
3-fluoropropyl
4-(O-benzyl)-phenyl


813.
3-fluoropropyl
4-(2-methoxyethoxy)-phenyl


814.
3-fluoropropyl
4-(CH2—N(CH3)2)-phenyl


815.
3-fluoropropyl
4-(NH—CO—NH2)-phenyl


816.
3-fluoropropyl
4-(methylsulfanyl)-phenyl


817.
3-fluoropropyl
4-(fluoromethylsulfanyl)-phenyl


818.
3-fluoropropyl
4-(difluoromethylsulfanyl)-phenyl


819.
3-fluoropropyl
4-(trifluoromethylsulfanyl)-phenyl


820.
3-fluoropropyl
4-(methylsulfonyl)-phenyl


821.
3-fluoropropyl
4-(N-methoxy-N-methyl-amino)-phenyl


822.
3-fluoropropyl
4-(methoxyamino)-phenyl


823.
3-fluoropropyl
4-(ethoxyamino)-phenyl


824.
3-fluoropropyl
4-(N-methylaminooxy)-phenyl


825.
3-fluoropropyl
4-(N,N-dimethylaminooxy)-phenyl


826.
3-fluoropropyl
4-(azetidin-1-yl)-phenyl


827.
3-fluoropropyl
4-(2-methylazetidin-1-yl)-phenyl


828.
3-fluoropropyl
4-((S)-2-methylazetidin-1-yl)-phenyl


829.
3-fluoropropyl
4-((R)-2-methylazetidin-1-yl)-phenyl


830.
3-fluoropropyl
4-(3-fluoroazetidin-1-yl)-phenyl


831.
3-fluoropropyl
4-(3-methoxyazetidin-1-yl)-phenyl


832.
3-fluoropropyl
4-(3-hydroxyazetidin-1-yl)-phenyl


833.
3-fluoropropyl
4-(pyrrolidin-1-yl)-phenyl


834.
3-fluoropropyl
4-(pyrrolidin-2-yl)-phenyl


835.
3-fluoropropyl
4-((S)-pyrrolidin-2-yl)-phenyl


836.
3-fluoropropyl
4-((R)-pyrrolidin-2-yl)-phenyl


837.
3-fluoropropyl
4-(pyrrolidin-3-yl)-phenyl


838.
3-fluoropropyl
4-((S)-pyrrolidin-3-yl)-phenyl


839.
3-fluoropropyl
4-((R)-pyrrolidin-3-yl)-phenyl


840.
3-fluoropropyl
4-(2-fluoropyrrolidin-1-yl)-phenyl


841.
3-fluoropropyl
4-((S)-2-fluoropyrrolidin-1-yl)-phenyl


842.
3-fluoropropyl
4-((R)-2-fluoropyrrolidin-1-yl)-phenyl


843.
3-fluoropropyl
4-(3-fluoropyrrolidin-1-yl)-phenyl


844.
3-fluoropropyl
4-((S)-3-fluoropyrrolidin-1-yl)-phenyl


845.
3-fluoropropyl
4-((R)-3-fluoropyrrolidin-1-yl)-phenyl


846.
3-fluoropropyl
4-(2,2-difluoropyrrolidin-1-yl)-phenyl


847.
3-fluoropropyl
4-(3,3-difluoropyrrolidin-1-yl)-phenyl


848.
3-fluoropropyl
4-(2-methylpyrrolidin-1-yl)-phenyl


849.
3-fluoropropyl
4-((S)-2-methylpyrrolidin-1-yl)-phenyl


850.
3-fluoropropyl
4-((R)-2-methylpyrrolidin-1-yl)-phenyl


851.
3-fluoropropyl
4-(3-methylpyrrolidin-1-yl)-phenyl


852.
3-fluoropropyl
4-((S)-3-methylpyrrolidin-1-yl)-phenyl


853.
3-fluoropropyl
4-((R)-3-methylpyrrolidin-1-yl)-phenyl


854.
3-fluoropropyl
4-(1-methylpyrrolidin-2-yl)-phenyl


855.
3-fluoropropyl
4-((S)-1-methylpyrrolidin-2-yl)-phenyl


856.
3-fluoropropyl
4-((R)-1-methylpyrrolidin-2-yl)-phenyl


857.
3-fluoropropyl
4-(1-methylpyrrolidin-3-yl)-phenyl


858.
3-fluoropropyl
4-((S)-1-methylpyrrolidin-3-yl)-phenyl


859.
3-fluoropropyl
4-((R)-1-methylpyrrolidin-3-yl)-phenyl


860.
3-fluoropropyl
4-(2,2-dimethylpyrrolidin-1-yl)-phenyl


861.
3-fluoropropyl
4-(3,3-dimethylpyrrolidin-1-yl)-phenyl


862.
3-fluoropropyl
4-(2-trifluoromethylpyrrolidin-1-yl)-phenyl


863.
3-fluoropropyl
4-((S)-2-trifluoromethylpyrrolidin-1-yl)-phenyl


864.
3-fluoropropyl
4-((R)-2-trifluoromethylpyrrolidin-1-yl)-phenyl


865.
3-fluoropropyl
4-(3-trifluoromethylpyrrolidin-1-yl)-phenyl


866.
3-fluoropropyl
4-((S)-3-trifluoromethylpyrrolidin-1-yl)-phenyl


867.
3-fluoropropyl
4-((R)-3-trifluoromethylpyrrolidin-1-yl)-phenyl


868.
3-fluoropropyl
4-(2-oxopyrrolidin-1-yl)-phenyl


869.
3-fluoropropyl
4-(2-oxo-oxazolidin-3-yl)-phenyl


870.
3-fluoropropyl
4-(piperidin-1-yl)-phenyl


871.
3-fluoropropyl
4-(2-methylpiperidin-1-yl)-phenyl


872.
3-fluoropropyl
4-((S)-2-methylpiperidin-1-yl)-phenyl


873.
3-fluoropropyl
4-((R)-2-methylpiperidin-1-yl)-phenyl


874.
3-fluoropropyl
4-(piperazin-1-yl)-phenyl


875.
3-fluoropropyl
4-(4-methylpiperazin-1-yl)-phenyl


876.
3-fluoropropyl
4-(morpholin-4-yl)-phenyl


877.
3-fluoropropyl
4-(thiomorpholin-4-yl)-phenyl


878.
3-fluoropropyl
4-(1-oxo-thiomorpholin-4-yl)-phenyl


879.
3-fluoropropyl
4-(1,1-dioxo-thiomorpholin-4-yl)-phenyl


880.
3-fluoropropyl
4-(pyrrol-1-yl)-phenyl


881.
3-fluoropropyl
4-(pyrrol-2-yl)-phenyl


882.
3-fluoropropyl
4-(pyrrol-3-yl)-phenyl


883.
3-fluoropropyl
4-(1-methylpyrrol-2-yl)-phenyl


884.
3-fluoropropyl
4-(1-methylpyrrol-3-yl)-phenyl


885.
3-fluoropropyl
4-(furan-2-yl)-phenyl


886.
3-fluoropropyl
4-(furan-3-yl)-phenyl


887.
3-fluoropropyl
4-(thiophen-2-yl)-phenyl


888.
3-fluoropropyl
4-(thiophen-3-yl)-phenyl


889.
3-fluoropropyl
4-(5-propylthien-2-yl)-phenyl


890.
3-fluoropropyl
4-(pyrazol-1-yl)-phenyl


891.
3-fluoropropyl
4-(pyrazol-3-yl)-phenyl


892.
3-fluoropropyl
4-(pyrazol-4-yl)-phenyl


893.
3-fluoropropyl
4-(1-methyl-1H-pyrazol-4-yl)-phenyl


894.
3-fluoropropyl
4-(1-ethyl-1H-pyrazol-4-yl)-phenyl


895.
3-fluoropropyl
4-(1-methyl-1H-pyrazol-5-yl)-phenyl


896.
3-fluoropropyl
4-(1H-imidazol-2-yl)-phenyl


897.
3-fluoropropyl
4-(imidazol-1-yl)-phenyl


898.
3-fluoropropyl
4-(1-methylimidazol-2-yl)-phenyl


899.
3-fluoropropyl
4-(oxazol-2-yl)-phenyl


900.
3-fluoropropyl
4-(oxazol-4-yl)-phenyl


901.
3-fluoropropyl
4-(oxazol-5-yl)-phenyl


902.
3-fluoropropyl
4-(isoxazol-3-yl)-phenyl


903.
3-fluoropropyl
4-(isoxazol-4-yl)-phenyl


904.
3-fluoropropyl
4-(isoxazol-5-yl)-phenyl


905.
3-fluoropropyl
4-([1,2,3]-triazol-1-yl)-phenyl


906.
3-fluoropropyl
4-([1,2,4]-triazol-1-yl)-phenyl


907.
3-fluoropropyl
4-([1,2,3]-triazol-2-yl)-phenyl


908.
3-fluoropropyl
4-(4H-[1,2,4]-triazol-3-yl)-phenyl


909.
3-fluoropropyl
4-([1,2,4]-triazol-4-yl)-phenyl


910.
3-fluoropropyl
4-(2H-[1,2,3]-triazol-4-yl)-phenyl


911.
3-fluoropropyl
4-(4-methyl-4H-[1,2,4]-triazol-3-yl)-phenyl


912.
3-fluoropropyl
4-(2-methyl-2H-[1,2,3]-triazol-4-yl)-phenyl


913.
3-fluoropropyl
4-([1,3,4]-oxadiazol-2-yl)-phenyl


914.
3-fluoropropyl
4-([1,2,4]-oxadiazol-3-yl)-phenyl


915.
3-fluoropropyl
4-([1,2,4]-oxadiazol-5-yl)-phenyl


916.
3-fluoropropyl
4-([1,2,3]-oxadiazol-4-yl)-phenyl


917.
3-fluoropropyl
4-([1,2,3]-oxadiazol-5-yl)-phenyl


918.
3-fluoropropyl
4-([1,2,3]-thiadiazol-4-yl)-phenyl


919.
3-fluoropropyl
4-(1H-tetrazol-5-yl)-phenyl


920.
3-fluoropropyl
4-(tetrazol-1-yl)-phenyl


921.
3-fluoropropyl
4-(2-methyl-2H-tetrazol-5-yl)-phenyl


922.
3-fluoropropyl
4-(1-methyl-1H-tetrazol-5-yl)-phenyl


923.
3-fluoropropyl
4-furazan-3-yl-phenyl


924.
3-fluoropropyl
4-(pyrid-2-yl)-phenyl


925.
3-fluoropropyl
4-(pyrid-3-yl)-phenyl


926.
3-fluoropropyl
4-(pyrid-4-yl)-phenyl


927.
3-fluoropropyl
4-(pyrimidin-2-yl)-phenyl


928.
3-fluoropropyl
4-(pyrimidin-4-yl)-phenyl


929.
3-fluoropropyl
4-(pyrimidin-5-yl)-phenyl


930.
3-fluoropropyl
5-isopropylthiophen-2-yl


931.
3-fluoropropyl
2-chlorothiophen-5-yl


932.
3-fluoropropyl
2,5-dichlorothiophen-4-yl


933.
3-fluoropropyl
2,3-dichlorothiophen-5-yl


934.
3-fluoropropyl
2-chloro-3-nitrothiophen-5-yl


935.
3-fluoropropyl
2-(phenylsulfonyl)-thiophen-5-yl


936.
3-fluoropropyl
2-(pyridin-2-yl)thiophen-5-yl


937.
3-fluoropropyl
2-(5-(trifluoromethyl)isoxazol-3-yl)-thiophen-5-yl


938.
3-fluoropropyl
2-(2-methylthiazol-4-yl)-thiophen-5-yl


939.
3-fluoropropyl
1-methyl-1H-imidazol-4-yl


940.
3-fluoropropyl
1,2-dimethyl-1H-imidazol-4-yl


941.
3-fluoropropyl
3,5-dimethylisoxazol-4-yl


942.
3-fluoropropyl
thiazol-2-yl


943.
3-fluoropropyl
4-methylthiazol-2-yl


944.
3-fluoropropyl
4-isopropylthiazol-2-yl


945.
3-fluoropropyl
4-trifluoromethylthiazol-2-yl


946.
3-fluoropropyl
5-methylthiazol-2-yl


947.
3-fluoropropyl
5-isopropylthiazol-2-yl


948.
3-fluoropropyl
5-trifluoromethylthiazol-2-yl


949.
3-fluoropropyl
2,4-dimethylthiazol-5-yl


950.
3-fluoropropyl
2-acetamido-4-methylthiazol-5-yl


951.
3-fluoropropyl
4H-[1,2,4]triazol-3-yl


952.
3-fluoropropyl
5-methyl-4H-[1,2,4]triazol-3-yl


953.
3-fluoropropyl
4-methyl-4H-[1,2,4]triazol-3-yl


954.
3-fluoropropyl
5-isopropyl-4H-[1,2,4]triazol-3-yl


955.
3-fluoropropyl
5-trifluoromethyl-4H-[1,2,4]triazol-3-yl


956.
3-fluoropropyl
4,5-dimethyl-4H-[1,2,4]triazol-3-yl


957.
3-fluoropropyl
5-isopropyl-4-methyl-4H-[1,2,4]triazol-3-yl


958.
3-fluoropropyl
5-trifluoromethyl-4-methyl-4H-[1,2,4]triazol-3-yl


959.
3-fluoropropyl
[1,3,4]thiadiazol-2-yl


960.
3-fluoropropyl
5-methyl-[1,3,4]thiadiazol-2-yl


961.
3-fluoropropyl
5-isopropyl-[1,3,4]thiadiazol-2-yl


962.
3-fluoropropyl
5-trifluoromethyl-[1,3,4]thiadiazol-2-yl


963.
3-fluoropropyl
3-bromo-2-chloropyrid-5-yl


964.
3-fluoropropyl
2-(4-morpholino)-pyrid-5-yl


965.
3-fluoropropyl
2-phenoxypyrid-5-yl


966.
3-fluoropropyl
(2-isopropyl)-pyrimidin-5-yl


967.
3-fluoropropyl
(5-isopropyl)-pyrimidin-2-yl


968.
3-fluoropropyl
8-quinolyl


969.
3-fluoropropyl
5-isoquinolyl


970.
3-fluoropropyl
2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl


971.
3-fluoropropyl
5-chloro-3-methylbenzothiophen-2-yl


972.
3-fluoropropyl
3,4-dihydro-4-methyl-2H-benzo[b][1,4]oxazinyl


973.
3-fluoropropyl
benzothiazol-6-yl


974.
3-fluoropropyl
benzo[2,1,3]oxadiazol-4-yl


975.
3-fluoropropyl
5-chlorobenzo[2,1,3]oxadiazol-4-yl


976.
3-fluoropropyl
7-chlorobenzo[2,1,3]oxadiazol-4-yl


977.
3-fluoropropyl
benzo[2,1,3]thiadiazol-4-yl


978.
2-fluoroethyl
4-methylphenyl


979.
2-fluoroethyl
4-ethylphenyl


980.
2-fluoroethyl
4-propylphenyl


981.
2-fluoroethyl
4-isopropylphenyl


982.
2-fluoroethyl
4-sec-butylphenyl


983.
2-fluoroethyl
4-isobutylphenyl


984.
2-fluoroethyl
4-(1,1-dimethylpropyl)-phenyl


985.
2-fluoroethyl
4-vinylphenyl


986.
2-fluoroethyl
4-isopropenylphenyl


987.
2-fluoroethyl
4-fluorophenyl


988.
2-fluoroethyl
4-chlorophenyl


989.
2-fluoroethyl
4-bromophenyl


990.
2-fluoroethyl
4-(fluoromethyl)phenyl


991.
2-fluoroethyl
3-(fluoromethyl)phenyl


992.
2-fluoroethyl
2-(fluoromethyl)phenyl


993.
2-fluoroethyl
4-(difluoromethyl)phenyl


994.
2-fluoroethyl
3-(difluoromethyl)phenyl


995.
2-fluoroethyl
2-(difluoromethyl)phenyl


996.
2-fluoroethyl
4-(trifluoromethyl)phenyl


997.
2-fluoroethyl
3-(trifluoromethyl)phenyl


998.
2-fluoroethyl
2-(trifluoromethyl)phenyl


999.
2-fluoroethyl
4-(1-fluoroethyl)-phenyl


1000.
2-fluoroethyl
4-((S)-1-fluoroethyl)-phenyl


1001.
2-fluoroethyl
4-((R)-1-fluoroethyl)-phenyl


1002.
2-fluoroethyl
4-(2-fluoroethyl)-phenyl


1003.
2-fluoroethyl
4-(1,1-difluoroethyl)-phenyl


1004.
2-fluoroethyl
4-(2,2-difluoroethyl)-phenyl


1005.
2-fluoroethyl
4-(2,2,2-trifluoroethyl)-phenyl


1006.
2-fluoroethyl
4-(3-fluoropropyl)-phenyl


1007.
2-fluoroethyl
4-(2-fluoropropyl)-phenyl


1008.
2-fluoroethyl
4-((S)-2-fluoropropyl)-phenyl


1009.
2-fluoroethyl
4-((R)-2-fluoropropyl)-phenyl


1010.
2-fluoroethyl
4-(3,3-difluoropropyl)-phenyl


1011.
2-fluoroethyl
4-(3,3,3-trifluoropropyl)-phenyl


1012.
2-fluoroethyl
4-(1-fluoro-1-methylethyl)-phenyl


1013.
2-fluoroethyl
4-(2-fluoro-1-methylethyl)-phenyl


1014.
2-fluoroethyl
4-((S)-2-fluoro-1-methylethyl)-phenyl


1015.
2-fluoroethyl
4-((R)-2-fluoro-1-methylethyl)-phenyl


1016.
2-fluoroethyl
4-(2,2-difluoro-1-methylethyl)-phenyl


1017.
2-fluoroethyl
4-((S)-2,2-difluoro-1-methylethyl)-phenyl


1018.
2-fluoroethyl
4-((R)-2,2-difluoro-1-methylethyl)-phenyl


1019.
2-fluoroethyl
4-(2,2,2-trifluoro-1-methylethyl)-phenyl


1020.
2-fluoroethyl
4-((S)-2,2,2-trifluoro-1-methylethyl)-phenyl


1021.
2-fluoroethyl
4-((R)-2,2,2-trifluoro-1-methylethyl)-phenyl


1022.
2-fluoroethyl
4-(2-fluoro-1-fluoromethylethyl)-phenyl


1023.
2-fluoroethyl
4-(1-difluoromethyl-2,2-difluoroethyl)-phenyl


1024.
2-fluoroethyl
4-(1,1-dimethyl-2-fluoroethyl)-phenyl


1025.
2-fluoroethyl
4-methoxyphenyl


1026.
2-fluoroethyl
4-ethoxyphenyl


1027.
2-fluoroethyl
4-propoxyphenyl


1028.
2-fluoroethyl
4-isopropoxyphenyl


1029.
2-fluoroethyl
4-butoxyphenyl


1030.
2-fluoroethyl
4-(fluoromethoxy)-phenyl


1031.
2-fluoroethyl
4-(difluoromethoxy)-phenyl


1032.
2-fluoroethyl
4-(trifluoromethoxy)-phenyl


1033.
2-fluoroethyl
3-(trifluoromethoxy)-phenyl


1034.
2-fluoroethyl
4-(2-fluoroethoxy)-phenyl


1035.
2-fluoroethyl
4-(2,2-difluoroethoxy)-phenyl


1036.
2-fluoroethyl
4-(2,2,2-trifluoroethoxy)-phenyl


1037.
2-fluoroethyl
4-(1,1,2,2-tetrafluoroethoxy)-phenyl


1038.
2-fluoroethyl
4-cyclopropylphenyl


1039.
2-fluoroethyl
4-cyclobutylphenyl


1040.
2-fluoroethyl
4-cyclopentylphenyl


1041.
2-fluoroethyl
4-(2,2-difluorocyclopropyl)-phenyl


1042.
2-fluoroethyl
3,4-difluorophenyl


1043.
2-fluoroethyl
4-bromo-3-fluorophenyl


1044.
2-fluoroethyl
4-bromo-2-fluorophenyl


1045.
2-fluoroethyl
4-bromo-2,5-difluorophenyl


1046.
2-fluoroethyl
2-fluoro-4-isopropylphenyl


1047.
2-fluoroethyl
3-fluoro-4-isopropylphenyl


1048.
2-fluoroethyl
4-(1-hydroxy-1-methylethyl)-phenyl


1049.
2-fluoroethyl
4-(2-hydroxy-2-methylpropyl)-phenyl


1050.
2-fluoroethyl
4-acetylphenyl


1051.
2-fluoroethyl
4-carboxyphenyl


1052.
2-fluoroethyl
4-cyanophenyl


1053.
2-fluoroethyl
4-hydroxyphenyl


1054.
2-fluoroethyl
4-(O-benzyl)-phenyl


1055.
2-fluoroethyl
4-(2-methoxyethoxy)-phenyl


1056.
2-fluoroethyl
4-(CH2—N(CH3)2)-phenyl


1057.
2-fluoroethyl
4-(NH—CO—NH2)-phenyl


1058.
2-fluoroethyl
4-(methylsulfanyl)-phenyl


1059.
2-fluoroethyl
4-(fluoromethylsulfanyl)-phenyl


1060.
2-fluoroethyl
4-(difluoromethylsulfanyl)-phenyl


1061.
2-fluoroethyl
4-(trifluoromethylsulfanyl)-phenyl


1062.
2-fluoroethyl
4-(methylsulfonyl)-phenyl


1063.
2-fluoroethyl
4-(N-methoxy-N-methyl-amino)-phenyl


1064.
2-fluoroethyl
4-(methoxyamino)-phenyl


1065.
2-fluoroethyl
4-(ethoxyamino)-phenyl


1066.
2-fluoroethyl
4-(N-methylaminooxy)-phenyl


1067.
2-fluoroethyl
4-(N,N-dimethylaminooxy)-phenyl


1068.
2-fluoroethyl
4-(azetidin-1-yl)-phenyl


1069.
2-fluoroethyl
4-(2-methylazetidin-1-yl)-phenyl


1070.
2-fluoroethyl
4-((S)-2-methylazetidin-1-yl)-phenyl


1071.
2-fluoroethyl
4-((R)-2-methylazetidin-1-yl)-phenyl


1072.
2-fluoroethyl
4-(3-fluoroazetidin-1-yl)-phenyl


1073.
2-fluoroethyl
4-(3-methoxyazetidin-1-yl)-phenyl


1074.
2-fluoroethyl
4-(3-hydroxyazetidin-1-yl)-phenyl


1075.
2-fluoroethyl
4-(pyrrolidin-1-yl)-phenyl


1076.
2-fluoroethyl
4-(pyrrolidin-2-yl)-phenyl


1077.
2-fluoroethyl
4-((S)-pyrrolidin-2-yl)-phenyl


1078.
2-fluoroethyl
4-((R)-pyrrolidin-2-yl)-phenyl


1079.
2-fluoroethyl
4-(pyrrolidin-3-yl)-phenyl


1080.
2-fluoroethyl
4-((S)-pyrrolidin-3-yl)-phenyl


1081.
2-fluoroethyl
4-((R)-pyrrolidin-3-yl)-phenyl


1082.
2-fluoroethyl
4-(2-fluoropyrrolidin-1-yl)-phenyl


1083.
2-fluoroethyl
4-((S)-2-fluoropyrrolidin-1-yl)-phenyl


1084.
2-fluoroethyl
4-((R)-2-fluoropyrrolidin-1-yl)-phenyl


1085.
2-fluoroethyl
4-(3-fluoropyrrolidin-1-yl)-phenyl


1086.
2-fluoroethyl
4-((S)-3-fluoropyrrolidin-1-yl)-phenyl


1087.
2-fluoroethyl
4-((R)-3-fluoropyrrolidin-1-yl)-phenyl


1088.
2-fluoroethyl
4-(2,2-difluoropyrrolidin-1-yl)-phenyl


1089.
2-fluoroethyl
4-(3,3-difluoropyrrolidin-1-yl)-phenyl


1090.
2-fluoroethyl
4-(2-methylpyrrolidin-1-yl)-phenyl


1091.
2-fluoroethyl
4-((S)-2-methylpyrrolidin-1-yl)-phenyl


1092.
2-fluoroethyl
4-((R)-2-methylpyrrolidin-1-yl)-phenyl


1093.
2-fluoroethyl
4-(3-methylpyrrolidin-1-yl)-phenyl


1094.
2-fluoroethyl
4-((S)-3-methylpyrrolidin-1-yl)-phenyl


1095.
2-fluoroethyl
4-((R)-3-methylpyrrolidin-1-yl)-phenyl


1096.
2-fluoroethyl
4-(1-methylpyrrolidin-2-yl)-phenyl


1097.
2-fluoroethyl
4-((S)-1-methylpyrrolidin-2-yl)-phenyl


1098.
2-fluoroethyl
4-((R)-1-methylpyrrolidin-2-yl)-phenyl


1099.
2-fluoroethyl
4-(1-methylpyrrolidin-3-yl)-phenyl


1100.
2-fluoroethyl
4-((S)-1-methylpyrrolidin-3-yl)-phenyl


1101.
2-fluoroethyl
4-((R)-1-methylpyrrolidin-3-yl)-phenyl


1102.
2-fluoroethyl
4-(2,2-dimethylpyrrolidin-1-yl)-phenyl


1103.
2-fluoroethyl
4-(3,3-dimethylpyrrolidin-1-yl)-phenyl


1104.
2-fluoroethyl
4-(2-trifluoromethylpyrrolidin-1-yl)-phenyl


1105.
2-fluoroethyl
4-((S)-2-trifluoromethylpyrrolidin-1-yl)-phenyl


1106.
2-fluoroethyl
4-((R)-2-trifluoromethylpyrrolidin-1-yl)-phenyl


1107.
2-fluoroethyl
4-(3-trifluoromethylpyrrolidin-1-yl)-phenyl


1108.
2-fluoroethyl
4-((S)-3-trifluoromethylpyrrolidin-1-yl)-phenyl


1109.
2-fluoroethyl
4-((R)-3-trifluoromethylpyrrolidin-1-yl)-phenyl


1110.
2-fluoroethyl
4-(2-oxopyrrolidin-1-yl)-phenyl


1111.
2-fluoroethyl
4-(2-oxo-oxazolidin-3-yl)-phenyl


1112.
2-fluoroethyl
4-(piperidin-1-yl)-phenyl


1113.
2-fluoroethyl
4-(2-methylpiperidin-1-yl)-phenyl


1114.
2-fluoroethyl
4-((S)-2-methylpiperidin-1-yl)-phenyl


1115.
2-fluoroethyl
4-((R)-2-methylpiperidin-1-yl)-phenyl


1116.
2-fluoroethyl
4-(piperazin-1-yl)-phenyl


1117.
2-fluoroethyl
4-(4-methylpiperazin-1-yl)-phenyl


1118.
2-fluoroethyl
4-(morpholin-4-yl)-phenyl


1119.
2-fluoroethyl
4-(thiomorpholin-4-yl)-phenyl


1120.
2-fluoroethyl
4-(1-oxo-thiomorpholin-4-yl)-phenyl


1121.
2-fluoroethyl
4-(1,1-dioxo-thiomorpholin-4-yl)-phenyl


1122.
2-fluoroethyl
4-(pyrrol-1-yl)-phenyl


1123.
2-fluoroethyl
4-(pyrrol-2-yl)-phenyl


1124.
2-fluoroethyl
4-(pyrrol-3-yl)-phenyl


1125.
2-fluoroethyl
4-(1-methylpyrrol-2-yl)-phenyl


1126.
2-fluoroethyl
4-(1-methylpyrrol-3-yl)-phenyl


1127.
2-fluoroethyl
4-(furan-2-yl)-phenyl


1128.
2-fluoroethyl
4-(furan-3-yl)-phenyl


1129.
2-fluoroethyl
4-(thiophen-2-yl)-phenyl


1130.
2-fluoroethyl
4-(thiophen-3-yl)-phenyl


1131.
2-fluoroethyl
4-(5-propylthien-2-yl)-phenyl


1132.
2-fluoroethyl
4-(pyrazol-1-yl)-phenyl


1133.
2-fluoroethyl
4-(pyrazol-3-yl)-phenyl


1134.
2-fluoroethyl
4-(pyrazol-4-yl)-phenyl


1135.
2-fluoroethyl
4-(1-methyl-1H-pyrazol-4-yl)-phenyl


1136.
2-fluoroethyl
4-(1-ethyl-1H-pyrazol-4-yl)-phenyl


1137.
2-fluoroethyl
4-(1-methyl-1H-pyrazol-5-yl)-phenyl


1138.
2-fluoroethyl
4-(1H-imidazol-2-yl)-phenyl


1139.
2-fluoroethyl
4-(imidazol-1-yl)-phenyl


1140.
2-fluoroethyl
4-(1-methylimidazol-2-yl)-phenyl


1141.
2-fluoroethyl
4-(oxazol-2-yl)-phenyl


1142.
2-fluoroethyl
4-(oxazol-4-yl)-phenyl


1143.
2-fluoroethyl
4-(oxazol-5-yl)-phenyl


1144.
2-fluoroethyl
4-(isoxazol-3-yl)-phenyl


1145.
2-fluoroethyl
4-(isoxazol-4-yl)-phenyl


1146.
2-fluoroethyl
4-(isoxazol-5-yl)-phenyl


1147.
2-fluoroethyl
4-([1,2,3]-triazol-1-yl)-phenyl


1148.
2-fluoroethyl
4-([1,2,4]-triazol-1-yl)-phenyl


1149.
2-fluoroethyl
4-([1,2,3]-triazol-2-yl)-phenyl


1150.
2-fluoroethyl
4-(4H-[1,2,4]-triazol-3-yl)-phenyl


1151.
2-fluoroethyl
4-([1,2,4]-triazol-4-yl)-phenyl


1152.
2-fluoroethyl
4-(2H-[1,2,3]-triazol-4-yl)-phenyl


1153.
2-fluoroethyl
4-(4-methyl-4H-[1,2,4]-triazol-3-yl)-phenyl


1154.
2-fluoroethyl
4-(2-methyl-2H-[1,2,3]-triazol-4-yl)-phenyl


1155.
2-fluoroethyl
4-([1,3,4]-oxadiazol-2-yl)-phenyl


1156.
2-fluoroethyl
4-([1,2,4]-oxadiazol-3-yl)-phenyl


1157.
2-fluoroethyl
4-([1,2,4]-oxadiazol-5-yl)-phenyl


1158.
2-fluoroethyl
4-([1,2,3]-oxadiazol-4-yl)-phenyl


1159.
2-fluoroethyl
4-([1,2,3]-oxadiazol-5-yl)-phenyl


1160.
2-fluoroethyl
4-([1,2,3]-thiadiazol-4-yl)-phenyl


1161.
2-fluoroethyl
4-(1H-tetrazol-5-yl)-phenyl


1162.
2-fluoroethyl
4-(tetrazol-1-yl)-phenyl


1163.
2-fluoroethyl
4-(2-methyl-2H-tetrazol-5-yl)-phenyl


1164.
2-fluoroethyl
4-(1-methyl-1H-tetrazol-5-yl)-phenyl


1165.
2-fluoroethyl
4-furazan-3-yl-phenyl


1166.
2-fluoroethyl
4-(pyrid-2-yl)-phenyl


1167.
2-fluoroethyl
4-(pyrid-3-yl)-phenyl


1168.
2-fluoroethyl
4-(pyrid-4-yl)-phenyl


1169.
2-fluoroethyl
4-(pyrimidin-2-yl)-phenyl


1170.
2-fluoroethyl
4-(pyrimidin-4-yl)-phenyl


1171.
2-fluoroethyl
4-(pyrimidin-5-yl)-phenyl


1172.
2-fluoroethyl
5-isopropylthiophen-2-yl


1173.
2-fluoroethyl
2-chlorothiophen-5-yl


1174.
2-fluoroethyl
2,5-dichlorothiophen-4-yl


1175.
2-fluoroethyl
2,3-dichlorothiophen-5-yl


1176.
2-fluoroethyl
2-chloro-3-nitrothiophen-5-yl


1177.
2-fluoroethyl
2-(phenylsulfonyl)-thiophen-5-yl


1178.
2-fluoroethyl
2-(pyridin-2-yl)thiophen-5-yl


1179.
2-fluoroethyl
2-(5-(trifluoromethyl)isoxazol-3-yl)-thiophen-5-yl


1180.
2-fluoroethyl
2-(2-methylthiazol-4-yl)-thiophen-5-yl


1181.
2-fluoroethyl
1-methyl-1H-imidazol-4-yl


1182.
2-fluoroethyl
1,2-dimethyl-1H-imidazol-4-yl


1183.
2-fluoroethyl
3,5-dimethylisoxazol-4-yl


1184.
2-fluoroethyl
thiazol-2-yl


1185.
2-fluoroethyl
4-methylthiazol-2-yl


1186.
2-fluoroethyl
4-isopropylthiazol-2-yl


1187.
2-fluoroethyl
4-trifluoromethylthiazol-2-yl


1188.
2-fluoroethyl
5-methylthiazol-2-yl


1189.
2-fluoroethyl
5-isopropylthiazol-2-yl


1190.
2-fluoroethyl
5-trifluoromethylthiazol-2-yl


1191.
2-fluoroethyl
2,4-dimethylthiazol-5-yl


1192.
2-fluoroethyl
2-acetamido-4-methylthiazol-5-yl


1193.
2-fluoroethyl
4H-[1,2,4]triazol-3-yl


1194.
2-fluoroethyl
5-methyl-4H-[1,2,4]triazol-3-yl


1195.
2-fluoroethyl
4-methyl-4H-[1,2,4]triazol-3-yl


1196.
2-fluoroethyl
5-isopropyl-4H-[1,2,4]triazol-3-yl


1197.
2-fluoroethyl
5-trifluoromethyl-4H-[1,2,4]triazol-3-yl


1198.
2-fluoroethyl
4,5-dimethyl-4H-[1,2,4]triazol-3-yl


1199.
2-fluoroethyl
5-isopropyl-4-methyl-4H-[1,2,4]triazol-3-yl


1200.
2-fluoroethyl
5-trifluoromethyl-4-methyl-4H-[1,2,4]triazol-3-yl


1201.
2-fluoroethyl
[1,3,4]thiadiazol-2-yl


1202.
2-fluoroethyl
5-methyl-[1,3,4]thiadiazol-2-yl


1203.
2-fluoroethyl
5-isopropyl-[1,3,4]thiadiazol-2-yl


1204.
2-fluoroethyl
5-trifluoromethyl-[1,3,4]thiadiazol-2-yl


1205.
2-fluoroethyl
3-bromo-2-chloropyrid-5-yl


1206.
2-fluoroethyl
2-(4-morpholino)-pyrid-5-yl


1207.
2-fluoroethyl
2-phenoxypyrid-5-yl


1208.
2-fluoroethyl
(2-isopropyl)-pyrimidin-5-yl


1209.
2-fluoroethyl
(5-isopropyl)-pyrimidin-2-yl


1210.
2-fluoroethyl
8-quinolyl


1211.
2-fluoroethyl
5-isoquinolyl


1212.
2-fluoroethyl
2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl


1213.
2-fluoroethyl
5-chloro-3-methylbenzothiophen-2-yl


1214.
2-fluoroethyl
3,4-dihydro-4-methyl-2H-benzo[b][1,4]oxazinyl


1215.
2-fluoroethyl
benzothiazol-6-yl


1216.
2-fluoroethyl
benzo[2,1,3]oxadiazol-4-yl


1217.
2-fluoroethyl
5-chlorobenzo[2,1,3]oxadiazol-4-yl


1218.
2-fluoroethyl
7-chlorobenzo[2,1,3]oxadiazol-4-yl


1219.
2-fluoroethyl
benzo[2,1,3]thiadiazol-4-yl


1220.
cyclopropylmethyl
4-methylphenyl


1221.
cyclopropylmethyl
4-ethylphenyl


1222.
cyclopropylmethyl
4-propylphenyl


1223.
cyclopropylmethyl
4-isopropylphenyl


1224.
cyclopropylmethyl
4-sec-butylphenyl


1225.
cyclopropylmethyl
4-isobutylphenyl


1226.
cyclopropylmethyl
4-(1,1-dimethylpropyl)-phenyl


1227.
cyclopropylmethyl
4-vinylphenyl


1228.
cyclopropylmethyl
4-isopropenylphenyl


1229.
cyclopropylmethyl
4-fluorophenyl


1230.
cyclopropylmethyl
4-chlorophenyl


1231.
cyclopropylmethyl
4-bromophenyl


1232.
cyclopropylmethyl
4-(fluoromethyl)phenyl


1233.
cyclopropylmethyl
3-(fluoromethyl)phenyl


1234.
cyclopropylmethyl
2-(fluoromethyl)phenyl


1235.
cyclopropylmethyl
4-(difluoromethyl)phenyl


1236.
cyclopropylmethyl
3-(difluoromethyl)phenyl


1237.
cyclopropylmethyl
2-(difluoromethyl)phenyl


1238.
cyclopropylmethyl
4-(trifluoromethyl)phenyl


1239.
cyclopropylmethyl
3-(trifluoromethyl)phenyl


1240.
cyclopropylmethyl
2-(trifluoromethyl)phenyl


1241.
cyclopropylmethyl
4-(1-fluoroethyl)-phenyl


1242.
cyclopropylmethyl
4-((S)-1-fluoroethyl)-phenyl


1243.
cyclopropylmethyl
4-((R)-1-fluoroethyl)-phenyl


1244.
cyclopropylmethyl
4-(2-fluoroethyl)-phenyl


1245.
cyclopropylmethyl
4-(1,1-difluoroethyl)-phenyl


1246.
cyclopropylmethyl
4-(2,2-difluoroethyl)-phenyl


1247.
cyclopropylmethyl
4-(2,2,2-trifluoroethyl)-phenyl


1248.
cyclopropylmethyl
4-(3-fluoropropyl)-phenyl


1249.
cyclopropylmethyl
4-(2-fluoropropyl)-phenyl


1250.
cyclopropylmethyl
4-((S)-2-fluoropropyl)-phenyl


1251.
cyclopropylmethyl
4-((R)-2-fluoropropyl)-phenyl


1252.
cyclopropylmethyl
4-(3,3-difluoropropyl)-phenyl


1253.
cyclopropylmethyl
4-(3,3,3-trifluoropropyl)-phenyl


1254.
cyclopropylmethyl
4-(1-fluoro-1-methylethyl)-phenyl


1255.
cyclopropylmethyl
4-(2-fluoro-1-methylethyl)-phenyl


1256.
cyclopropylmethyl
4-((S)-2-fluoro-1-methylethyl)-phenyl


1257.
cyclopropylmethyl
4-((R)-2-fluoro-1-methylethyl)-phenyl


1258.
cyclopropylmethyl
4-(2,2-difluoro-1-methylethyl)-phenyl


1259.
cyclopropylmethyl
4-((S)-2,2-difluoro-1-methylethyl)-phenyl


1260.
cyclopropylmethyl
4-((R)-2,2-difluoro-1-methylethyl)-phenyl


1261.
cyclopropylmethyl
4-(2,2,2-trifluoro-1-methylethyl)-phenyl


1262.
cyclopropylmethyl
4-((S)-2,2,2-trifluoro-1-methylethyl)-phenyl


1263.
cyclopropylmethyl
4-((R)-2,2,2-trifluoro-1-methylethyl)-phenyl


1264.
cyclopropylmethyl
4-(2-fluoro-1-fluoromethylethyl)-phenyl


1265.
cyclopropylmethyl
4-(1-difluoromethyl-2,2-difluoroethyl)-phenyl


1266.
cyclopropylmethyl
4-(1,1-dimethyl-2-fluoroethyl)-phenyl


1267.
cyclopropylmethyl
4-methoxyphenyl


1268.
cyclopropylmethyl
4-ethoxyphenyl


1269.
cyclopropylmethyl
4-propoxyphenyl


1270.
cyclopropylmethyl
4-isopropoxyphenyl


1271.
cyclopropylmethyl
4-butoxyphenyl


1272.
cyclopropylmethyl
4-(fluoromethoxy)-phenyl


1273.
cyclopropylmethyl
4-(difluoromethoxy)-phenyl


1274.
cyclopropylmethyl
4-(trifluoromethoxy)-phenyl


1275.
cyclopropylmethyl
3-(trifluoromethoxy)-phenyl


1276.
cyclopropylmethyl
4-(2-fluoroethoxy)-phenyl


1277.
cyclopropylmethyl
4-(2,2-difluoroethoxy)-phenyl


1278.
cyclopropylmethyl
4-(2,2,2-trifluoroethoxy)-phenyl


1279.
cyclopropylmethyl
4-(1,1,2,2-tetrafluoroethoxy)-phenyl


1280.
cyclopropylmethyl
4-cyclopropylphenyl


1281.
cyclopropylmethyl
4-cyclobutylphenyl


1282.
cyclopropylmethyl
4-cyclopentylphenyl


1283.
cyclopropylmethyl
4-(2,2-difluorocyclopropyl)-phenyl


1284.
cyclopropylmethyl
3,4-difluorophenyl


1285.
cyclopropylmethyl
4-bromo-3-fluorophenyl


1286.
cyclopropylmethyl
4-bromo-2-fluorophenyl


1287.
cyclopropylmethyl
4-bromo-2,5-difluorophenyl


1288.
cyclopropylmethyl
2-fluoro-4-isopropylphenyl


1289.
cyclopropylmethyl
3-fluoro-4-isopropylphenyl


1290.
cyclopropylmethyl
4-(1-hydroxy-1-methylethyl)-phenyl


1291.
cyclopropylmethyl
4-(2-hydroxy-2-methylpropyl)-phenyl


1292.
cyclopropylmethyl
4-acetylphenyl


1293.
cyclopropylmethyl
4-carboxyphenyl


1294.
cyclopropylmethyl
4-cyanophenyl


1295.
cyclopropylmethyl
4-hydroxyphenyl


1296.
cyclopropylmethyl
4-(O-benzyl)-phenyl


1297.
cyclopropylmethyl
4-(2-methoxyethoxy)-phenyl


1298.
cyclopropylmethyl
4-(CH2—N(CH3)2)-phenyl


1299.
cyclopropylmethyl
4-(NH—CO—NH2)-phenyl


1300.
cyclopropylmethyl
4-(methylsulfanyl)-phenyl


1301.
cyclopropylmethyl
4-(fluoromethylsulfanyl)-phenyl


1302.
cyclopropylmethyl
4-(difluoromethylsulfanyl)-phenyl


1303.
cyclopropylmethyl
4-(trifluoromethylsulfanyl)-phenyl


1304.
cyclopropylmethyl
4-(methylsulfonyl)-phenyl


1305.
cyclopropylmethyl
4-(N-methoxy-N-methyl-amino)-phenyl


1306.
cyclopropylmethyl
4-(methoxyamino)-phenyl


1307.
cyclopropylmethyl
4-(ethoxyamino)-phenyl


1308.
cyclopropylmethyl
4-(N-methylaminooxy)-phenyl


1309.
cyclopropylmethyl
4-(N,N-dimethylaminooxy)-phenyl


1310.
cyclopropylmethyl
4-(azetidin-1-yl)-phenyl


1311.
cyclopropylmethyl
4-(2-methylazetidin-1-yl)-phenyl


1312.
cyclopropylmethyl
4-((S)-2-methylazetidin-1-yl)-phenyl


1313.
cyclopropylmethyl
4-((R)-2-methylazetidin-1-yl)-phenyl


1314.
cyclopropylmethyl
4-(3-fluoroazetidin-1-yl)-phenyl


1315.
cyclopropylmethyl
4-(3-methoxyazetidin-1-yl)-phenyl


1316.
cyclopropylmethyl
4-(3-hydroxyazetidin-1-yl)-phenyl


1317.
cyclopropylmethyl
4-(pyrrolidin-1-yl)-phenyl


1318.
cyclopropylmethyl
4-(pyrrolidin-2-yl)-phenyl


1319.
cyclopropylmethyl
4-((S)-pyrrolidin-2-yl)-phenyl


1320.
cyclopropylmethyl
4-((R)-pyrrolidin-2-yl)-phenyl


1321.
cyclopropylmethyl
4-(pyrrolidin-3-yl)-phenyl


1322.
cyclopropylmethyl
4-((S)-pyrrolidin-3-yl)-phenyl


1323.
cyclopropylmethyl
4-((R)-pyrrolidin-3-yl)-phenyl


1324.
cyclopropylmethyl
4-(2-fluoropyrrolidin-1-yl)-phenyl


1325.
cyclopropylmethyl
4-((S)-2-fluoropyrrolidin-1-yl)-phenyl


1326.
cyclopropylmethyl
4-((R)-2-fluoropyrrolidin-1-yl)-phenyl


1327.
cyclopropylmethyl
4-(3-fluoropyrrolidin-1-yl)-phenyl


1328.
cyclopropylmethyl
4-((S)-3-fluoropyrrolidin-1-yl)-phenyl


1329.
cyclopropylmethyl
4-((R)-3-fluoropyrrolidin-1-yl)-phenyl


1330.
cyclopropylmethyl
4-(2,2-difluoropyrrolidin-1-yl)-phenyl


1331.
cyclopropylmethyl
4-(3,3-difluoropyrrolidin-1-yl)-phenyl


1332.
cyclopropylmethyl
4-(2-methylpyrrolidin-1-yl)-phenyl


1333.
cyclopropylmethyl
4-((S)-2-methylpyrrolidin-1-yl)-phenyl


1334.
cyclopropylmethyl
4-((R)-2-methylpyrrolidin-1-yl)-phenyl


1335.
cyclopropylmethyl
4-(3-methylpyrrolidin-1-yl)-phenyl


1336.
cyclopropylmethyl
4-((S)-3-methylpyrrolidin-1-yl)-phenyl


1337.
cyclopropylmethyl
4-((R)-3-methylpyrrolidin-1-yl)-phenyl


1338.
cyclopropylmethyl
4-(1-methylpyrrolidin-2-yl)-phenyl


1339.
cyclopropylmethyl
4-((S)-1-methylpyrrolidin-2-yl)-phenyl


1340.
cyclopropylmethyl
4-((R)-1-methylpyrrolidin-2-yl)-phenyl


1341.
cyclopropylmethyl
4-(1-methylpyrrolidin-3-yl)-phenyl


1342.
cyclopropylmethyl
4-((S)-1-methylpyrrolidin-3-yl)-phenyl


1343.
cyclopropylmethyl
4-((R)-1-methylpyrrolidin-3-yl)-phenyl


1344.
cyclopropylmethyl
4-(2,2-dimethylpyrrolidin-1-yl)-phenyl


1345.
cyclopropylmethyl
4-(3,3-dimethylpyrrolidin-1-yl)-phenyl


1346.
cyclopropylmethyl
4-(2-trifluoromethylpyrrolidin-1-yl)-phenyl


1347.
cyclopropylmethyl
4-((S)-2-trifluoromethylpyrrolidin-1-yl)-phenyl


1348.
cyclopropylmethyl
4-((R)-2-trifluoromethylpyrrolidin-1-yl)-phenyl


1349.
cyclopropylmethyl
4-(3-trifluoromethylpyrrolidin-1-yl)-phenyl


1350.
cyclopropylmethyl
4-((S)-3-trifluoromethylpyrrolidin-1-yl)-phenyl


1351.
cyclopropylmethyl
4-((R)-3-trifluoromethylpyrrolidin-1-yl)-phenyl


1352.
cyclopropylmethyl
4-(2-oxopyrrolidin-1-yl)-phenyl


1353.
cyclopropylmethyl
4-(2-oxo-oxazolidin-3-yl)-phenyl


1354.
cyclopropylmethyl
4-(piperidin-1-yl)-phenyl


1355.
cyclopropylmethyl
4-(2-methylpiperidin-1-yl)-phenyl


1356.
cyclopropylmethyl
4-((S)-2-methylpiperidin-1-yl)-phenyl


1357.
cyclopropylmethyl
4-((R)-2-methylpiperidin-1-yl)-phenyl


1358.
cyclopropylmethyl
4-(piperazin-1-yl)-phenyl


1359.
cyclopropylmethyl
4-(4-methylpiperazin-1-yl)-phenyl


1360.
cyclopropylmethyl
4-(morpholin-4-yl)-phenyl


1361.
cyclopropylmethyl
4-(thiomorpholin-4-yl)-phenyl


1362.
cyclopropylmethyl
4-(1-oxo-thiomorpholin-4-yl)-phenyl


1363.
cyclopropylmethyl
4-(1,1-dioxo-thiomorpholin-4-yl)-phenyl


1364.
cyclopropylmethyl
4-(pyrrol-1-yl)-phenyl


1365.
cyclopropylmethyl
4-(pyrrol-2-yl)-phenyl


1366.
cyclopropylmethyl
4-(pyrrol-3-yl)-phenyl


1367.
cyclopropylmethyl
4-(1-methylpyrrol-2-yl)-phenyl


1368.
cyclopropylmethyl
4-(1-methylpyrrol-3-yl)-phenyl


1369.
cyclopropylmethyl
4-(furan-2-yl)-phenyl


1370.
cyclopropylmethyl
4-(furan-3-yl)-phenyl


1371.
cyclopropylmethyl
4-(thiophen-2-yl)-phenyl


1372.
cyclopropylmethyl
4-(thiophen-3-yl)-phenyl


1373.
cyclopropylmethyl
4-(5-propylthien-2-yl)-phenyl


1374.
cyclopropylmethyl
4-(pyrazol-1-yl)-phenyl


1375.
cyclopropylmethyl
4-(pyrazol-3-yl)-phenyl


1376.
cyclopropylmethyl
4-(pyrazol-4-yl)-phenyl


1377.
cyclopropylmethyl
4-(1-methyl-1H-pyrazol-4-yl)-phenyl


1378.
cyclopropylmethyl
4-(1-ethyl-1H-pyrazol-4-yl)-phenyl


1379.
cyclopropylmethyl
4-(1-methyl-1H-pyrazol-5-yl)-phenyl


1380.
cyclopropylmethyl
4-(1H-imidazol-2-yl)-phenyl


1381.
cyclopropylmethyl
4-(imidazol-1-yl)-phenyl


1382.
cyclopropylmethyl
4-(1-methylimidazol-2-yl)-phenyl


1383.
cyclopropylmethyl
4-(oxazol-2-yl)-phenyl


1384.
cyclopropylmethyl
4-(oxazol-4-yl)-phenyl


1385.
cyclopropylmethyl
4-(oxazol-5-yl)-phenyl


1386.
cyclopropylmethyl
4-(isoxazol-3-yl)-phenyl


1387.
cyclopropylmethyl
4-(isoxazol-4-yl)-phenyl


1388.
cyclopropylmethyl
4-(isoxazol-5-yl)-phenyl


1389.
cyclopropylmethyl
4-([1,2,3]-triazol-1-yl)-phenyl


1390.
cyclopropylmethyl
4-([1,2,4]-triazol-1-yl)-phenyl


1391.
cyclopropylmethyl
4-([1,2,3]-triazol-2-yl)-phenyl


1392.
cyclopropylmethyl
4-(4H-[1,2,4]-triazol-3-yl)-phenyl


1393.
cyclopropylmethyl
4-([1,2,4]-triazol-4-yl)-phenyl


1394.
cyclopropylmethyl
4-(2H-[1,2,3]-triazol-4-yl)-phenyl


1395.
cyclopropylmethyl
4-(4-methyl-4H-[1,2,4]-triazol-3-yl)-phenyl


1396.
cyclopropylmethyl
4-(2-methyl-2H-[1,2,3]-triazol-4-yl)-phenyl


1397.
cyclopropylmethyl
4-([1,3,4]-oxadiazol-2-yl)-phenyl


1398.
cyclopropylmethyl
4-([1,2,4]-oxadiazol-3-yl)-phenyl


1399.
cyclopropylmethyl
4-([1,2,4]-oxadiazol-5-yl)-phenyl


1400.
cyclopropylmethyl
4-([1,2,3]-oxadiazol-4-yl)-phenyl


1401.
cyclopropylmethyl
4-([1,2,3]-oxadiazol-5-yl)-phenyl


1402.
cyclopropylmethyl
4-([1,2,3]-thiadiazol-4-yl)-phenyl


1403.
cyclopropylmethyl
4-(1H-tetrazol-5-yl)-phenyl


1404.
cyclopropylmethyl
4-(tetrazol-1-yl)-phenyl


1405.
cyclopropylmethyl
4-(2-methyl-2H-tetrazol-5-yl)-phenyl


1406.
cyclopropylmethyl
4-(1-methyl-1H-tetrazol-5-yl)-phenyl


1407.
cyclopropylmethyl
4-furazan-3-yl-phenyl


1408.
cyclopropylmethyl
4-(pyrid-2-yl)-phenyl


1409.
cyclopropylmethyl
4-(pyrid-3-yl)-phenyl


1410.
cyclopropylmethyl
4-(pyrid-4-yl)-phenyl


1411.
cyclopropylmethyl
4-(pyrimidin-2-yl)-phenyl


1412.
cyclopropylmethyl
4-(pyrimidin-4-yl)-phenyl


1413.
cyclopropylmethyl
4-(pyrimidin-5-yl)-phenyl


1414.
cyclopropylmethyl
5-isopropylthiophen-2-yl


1415.
cyclopropylmethyl
2-chlorothiophen-5-yl


1416.
cyclopropylmethyl
2,5-dichlorothiophen-4-yl


1417.
cyclopropylmethyl
2,3-dichlorothiophen-5-yl


1418.
cyclopropylmethyl
2-chloro-3-nitrothiophen-5-yl


1419.
cyclopropylmethyl
2-(phenylsulfonyl)-thiophen-5-yl


1420.
cyclopropylmethyl
2-(pyridin-2-yl)thiophen-5-yl


1421.
cyclopropylmethyl
2-(5-(trifluoromethyl)isoxazol-3-yl)-thiophen-5-yl


1422.
cyclopropylmethyl
2-(2-methylthiazol-4-yl)-thiophen-5-yl


1423.
cyclopropylmethyl
1-methyl-1H-imidazol-4-yl


1424.
cyclopropylmethyl
1,2-dimethyl-1H-imidazol-4-yl


1425.
cyclopropylmethyl
3,5-dimethylisoxazol-4-yl


1426.
cyclopropylmethyl
thiazol-2-yl


1427.
cyclopropylmethyl
4-methylthiazol-2-yl


1428.
cyclopropylmethyl
4-isopropylthiazol-2-yl


1429.
cyclopropylmethyl
4-trifluoromethylthiazol-2-yl


1430.
cyclopropylmethyl
5-methylthiazol-2-yl


1431.
cyclopropylmethyl
5-isopropylthiazol-2-yl


1432.
cyclopropylmethyl
5-trifluoromethylthiazol-2-yl


1433.
cyclopropylmethyl
2,4-dimethylthiazol-5-yl


1434.
cyclopropylmethyl
2-acetamido-4-methylthiazol-5-yl


1435.
cyclopropylmethyl
4H-[1,2,4]triazol-3-yl


1436.
cyclopropylmethyl
5-methyl-4H-[1,2,4]triazol-3-yl


1437.
cyclopropylmethyl
4-methyl-4H-[1,2,4]triazol-3-yl


1438.
cyclopropylmethyl
5-isopropyl-4H-[1,2,4]triazol-3-yl


1439.
cyclopropylmethyl
5-trifluoromethyl-4H-[1,2,4]triazol-3-yl


1440.
cyclopropylmethyl
4,5-dimethyl-4H-[1,2,4]triazol-3-yl


1441.
cyclopropylmethyl
5-isopropyl-4-methyl-4H-[1,2,4]triazol-3-yl


1442.
cyclopropylmethyl
5-trifluoromethyl-4-methyl-4H-[1,2,4]triazol-3-yl


1443.
cyclopropylmethyl
[1,3,4]thiadiazol-2-yl


1444.
cyclopropylmethyl
5-methyl-[1,3,4]thiadiazol-2-yl


1445.
cyclopropylmethyl
5-isopropyl-[1,3,4]thiadiazol-2-yl


1446.
cyclopropylmethyl
5-trifluoromethyl-[1,3,4]thiadiazol-2-yl


1447.
cyclopropylmethyl
3-bromo-2-chloropyrid-5-yl


1448.
cyclopropylmethyl
2-(4-morpholino)-pyrid-5-yl


1449.
cyclopropylmethyl
2-phenoxypyrid-5-yl


1450.
cyclopropylmethyl
(2-isopropyl)-pyrimidin-5-yl


1451.
cyclopropylmethyl
(5-isopropyl)-pyrimidin-2-yl


1452.
cyclopropylmethyl
8-quinolyl


1453.
cyclopropylmethyl
5-isoquinolyl


1454.
cyclopropylmethyl
2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-




yl


1455.
cyclopropylmethyl
5-chloro-3-methylbenzothiophen-2-yl


1456.
cyclopropylmethyl
3,4-dihydro-4-methyl-2H-benzo[b][1,4]oxazinyl


1457.
cyclopropylmethyl
benzothiazol-6-yl


1458.
cyclopropylmethyl
benzo[2,1,3]oxadiazol-4-yl


1459.
cyclopropylmethyl
5-chlorobenzo[2,1,3]oxadiazol-4-yl


1460.
cyclopropylmethyl
7-chlorobenzo[2,1,3]oxadiazol-4-yl


1461.
cyclopropylmethyl
benzo[2,1,3]thiadiazol-4-yl


1462.
allyl
4-methylphenyl


1463.
allyl
4-ethylphenyl


1464.
allyl
4-propylphenyl


1465.
allyl
4-isopropylphenyl


1466.
allyl
4-sec-butylphenyl


1467.
allyl
4-isobutylphenyl


1468.
allyl
4-(1,1-dimethylpropyl)-phenyl


1469.
allyl
4-vinylphenyl


1470.
allyl
4-isopropenylphenyl


1471.
allyl
4-fluorophenyl


1472.
allyl
4-chlorophenyl


1473.
allyl
4-bromophenyl


1474.
allyl
4-(fluoromethyl)phenyl


1475.
allyl
3-(fluoromethyl)phenyl


1476.
allyl
2-(fluoromethyl)phenyl


1477.
allyl
4-(difluoromethyl)phenyl


1478.
allyl
3-(difluoromethyl)phenyl


1479.
allyl
2-(difluoromethyl)phenyl


1480.
allyl
4-(trifluoromethyl)phenyl


1481.
allyl
3-(trifluoromethyl)phenyl


1482.
allyl
2-(trifluoromethyl)phenyl


1483.
allyl
4-(1-fluoroethyl)-phenyl


1484.
allyl
4-((S)-1-fluoroethyl)-phenyl


1485.
allyl
4-((R)-1-fluoroethyl)-phenyl


1486.
allyl
4-(2-fluoroethyl)-phenyl


1487.
allyl
4-(1,1-difluoroethyl)-phenyl


1488.
allyl
4-(2,2-difluoroethyl)-phenyl


1489.
allyl
4-(2,2,2-trifluoroethyl)-phenyl


1490.
allyl
4-(3-fluoropropyl)-phenyl


1491.
allyl
4-(2-fluoropropyl)-phenyl


1492.
allyl
4-((S)-2-fluoropropyl)-phenyl


1493.
allyl
4-((R)-2-fluoropropyl)-phenyl


1494.
allyl
4-(3,3-difluoropropyl)-phenyl


1495.
allyl
4-(3,3,3-trifluoropropyl)-phenyl


1496.
allyl
4-(1-fluoro-1-methylethyl)-phenyl


1497.
allyl
4-(2-fluoro-1-methylethyl)-phenyl


1498.
allyl
4-((S)-2-fluoro-1-methylethyl)-phenyl


1499.
allyl
4-((R)-2-fluoro-1-methylethyl)-phenyl


1500.
allyl
4-(2,2-difluoro-1-methylethyl)-phenyl


1501.
allyl
4-((S)-2,2-difluoro-1-methylethyl)-phenyl


1502.
allyl
4-((R)-2,2-difluoro-1-methylethyl)-phenyl


1503.
allyl
4-(2,2,2-trifluoro-1-methylethyl)-phenyl


1504.
allyl
4-((S)-2,2,2-trifluoro-1-methylethyl)-phenyl


1505.
allyl
4-((R)-2,2,2-trifluoro-1-methylethyl)-phenyl


1506.
allyl
4-(2-fluoro-1-fluoromethylethyl)-phenyl


1507.
allyl
4-(1-difluoromethyl-2,2-difluoroethyl)-phenyl


1508.
allyl
4-(1,1-dimethyl-2-fluoroethyl)-phenyl


1509.
allyl
4-methoxyphenyl


1510.
allyl
4-ethoxyphenyl


1511.
allyl
4-propoxyphenyl


1512.
allyl
4-isopropoxyphenyl


1513.
allyl
4-butoxyphenyl


1514.
allyl
4-(fluoromethoxy)-phenyl


1515.
allyl
4-(difluoromethoxy)-phenyl


1516.
allyl
4-(trifluoromethoxy)-phenyl


1517.
allyl
3-(trifluoromethoxy)-phenyl


1518.
allyl
4-(2-fluoroethoxy)-phenyl


1519.
allyl
4-(2,2-difluoroethoxy)-phenyl


1520.
allyl
4-(2,2,2-trifluoroethoxy)-phenyl


1521.
allyl
4-(1,1,2,2-tetrafluoroethoxy)-phenyl


1522.
allyl
4-cyclopropylphenyl


1523.
allyl
4-cyclobutylphenyl


1524.
allyl
4-cyclopentylphenyl


1525.
allyl
4-(2,2-difluorocyclopropyl)-phenyl


1526.
allyl
3,4-difluorophenyl


1527.
allyl
4-bromo-3-fluorophenyl


1528.
allyl
4-bromo-2-fluorophenyl


1529.
allyl
4-bromo-2,5-difluorophenyl


1530.
allyl
2-fluoro-4-isopropylphenyl


1531.
allyl
3-fluoro-4-isopropylphenyl


1532.
allyl
4-(1-hydroxy-1-methylethyl)-phenyl


1533.
allyl
4-(2-hydroxy-2-methylpropyl)-phenyl


1534.
allyl
4-acetylphenyl


1535.
allyl
4-carboxyphenyl


1536.
allyl
4-cyanophenyl


1537.
allyl
4-hydroxyphenyl


1538.
allyl
4-(O-benzyl)-phenyl


1539.
allyl
4-(2-methoxyethoxy)-phenyl


1540.
allyl
4-(CH2—N(CH3)2)-phenyl


1541.
allyl
4-(NH—CO—NH2)-phenyl


1542.
allyl
4-(methylsulfanyl)-phenyl


1543.
allyl
4-(fluoromethylsulfanyl)-phenyl


1544.
allyl
4-(difluoromethylsulfanyl)-phenyl


1545.
allyl
4-(trifluoromethylsulfanyl)-phenyl


1546.
allyl
4-(methylsulfonyl)-phenyl


1547.
allyl
4-(N-methoxy-N-methyl-amino)-phenyl


1548.
allyl
4-(methoxyamino)-phenyl


1549.
allyl
4-(ethoxyamino)-phenyl


1550.
allyl
4-(N-methylaminooxy)-phenyl


1551.
allyl
4-(N,N-dimethylaminooxy)-phenyl


1552.
allyl
4-(azetidin-1-yl)-phenyl


1553.
allyl
4-(2-methylazetidin-1-yl)-phenyl


1554.
allyl
4-((S)-2-methylazetidin-1-yl)-phenyl


1555.
allyl
4-((R)-2-methylazetidin-1-yl)-phenyl


1556.
allyl
4-(3-fluoroazetidin-1-yl)-phenyl


1557.
allyl
4-(3-methoxyazetidin-1-yl)-phenyl


1558.
allyl
4-(3-hydroxyazetidin-1-yl)-phenyl


1559.
allyl
4-(pyrrolidin-1-yl)-phenyl


1560.
allyl
4-(pyrrolidin-2-yl)-phenyl


1561.
allyl
4-((S)-pyrrolidin-2-yl)-phenyl


1562.
allyl
4-((R)-pyrrolidin-2-yl)-phenyl


1563.
allyl
4-(pyrrolidin-3-yl)-phenyl


1564.
allyl
4-((S)-pyrrolidin-3-yl)-phenyl


1565.
allyl
4-((R)-pyrrolidin-3-yl)-phenyl


1566.
allyl
4-(2-fluoropyrrolidin-1-yl)-phenyl


1567.
allyl
4-((S)-2-fluoropyrrolidin-1-yl)-phenyl


1568.
allyl
4-((R)-2-fluoropyrrolidin-1-yl)-phenyl


1569.
allyl
4-(3-fluoropyrrolidin-1-yl)-phenyl


1570.
allyl
4-((S)-3-fluoropyrrolidin-1-yl)-phenyl


1571.
allyl
4-((R)-3-fluoropyrrolidin-1-yl)-phenyl


1572.
allyl
4-(2,2-difluoropyrrolidin-1-yl)-phenyl


1573.
allyl
4-(3,3-difluoropyrrolidin-1-yl)-phenyl


1574.
allyl
4-(2-methylpyrrolidin-1-yl)-phenyl


1575.
allyl
4-((S)-2-methylpyrrolidin-1-yl)-phenyl


1576.
allyl
4-((R)-2-methylpyrrolidin-1-yl)-phenyl


1577.
allyl
4-(3-methylpyrrolidin-1-yl)-phenyl


1578.
allyl
4-((S)-3-methylpyrrolidin-1-yl)-phenyl


1579.
allyl
4-((R)-3-methylpyrrolidin-1-yl)-phenyl


1580.
allyl
4-(1-methylpyrrolidin-2-yl)-phenyl


1581.
allyl
4-((S)-1-methylpyrrolidin-2-yl)-phenyl


1582.
allyl
4-((R)-1-methylpyrrolidin-2-yl)-phenyl


1583.
allyl
4-(1-methylpyrrolidin-3-yl)-phenyl


1584.
allyl
4-((S)-1-methylpyrrolidin-3-yl)-phenyl


1585.
allyl
4-((R)-1-methylpyrrolidin-3-yl)-phenyl


1586.
allyl
4-(2,2-dimethylpyrrolidin-1-yl)-phenyl


1587.
allyl
4-(3,3-dimethylpyrrolidin-1-yl)-phenyl


1588.
allyl
4-(2-trifluoromethylpyrrolidin-1-yl)-phenyl


1589.
allyl
4-((S)-2-trifluoromethylpyrrolidin-1-yl)-phenyl


1590.
allyl
4-((R)-2-trifluoromethylpyrrolidin-1-yl)-phenyl


1591.
allyl
4-(3-trifluoromethylpyrrolidin-1-yl)-phenyl


1592.
allyl
4-((S)-3-trifluoromethylpyrrolidin-1-yl)-phenyl


1593.
allyl
4-((R)-3-trifluoromethylpyrrolidin-1-yl)-phenyl


1594.
allyl
4-(2-oxopyrrolidin-1-yl)-phenyl


1595.
allyl
4-(2-oxo-oxazolidin-3-yl)-phenyl


1596.
allyl
4-(piperidin-1-yl)-phenyl


1597.
allyl
4-(2-methylpiperidin-1-yl)-phenyl


1598.
allyl
4-((S)-2-methylpiperidin-1-yl)-phenyl


1599.
allyl
4-((R)-2-methylpiperidin-1-yl)-phenyl


1600.
allyl
4-(piperazin-1-yl)-phenyl


1601.
allyl
4-(4-methylpiperazin-1-yl)-phenyl


1602.
allyl
4-(morpholin-4-yl)-phenyl


1603.
allyl
4-(thiomorpholin-4-yl)-phenyl


1604.
allyl
4-(1-oxo-thiomorpholin-4-yl)-phenyl


1605.
allyl
4-(1,1-dioxo-thiomorpholin-4-yl)-phenyl


1606.
allyl
4-(pyrrol-1-yl)-phenyl


1607.
allyl
4-(pyrrol-2-yl)-phenyl


1608.
allyl
4-(pyrrol-3-yl)-phenyl


1609.
allyl
4-(1-methylpyrrol-2-yl)-phenyl


1610.
allyl
4-(1-methylpyrrol-3-yl)-phenyl


1611.
allyl
4-(furan-2-yl)-phenyl


1612.
allyl
4-(furan-3-yl)-phenyl


1613.
allyl
4-(thiophen-2-yl)-phenyl


1614.
allyl
4-(thiophen-3-yl)-phenyl


1615.
allyl
4-(5-propylthien-2-yl)-phenyl


1616.
allyl
4-(pyrazol-1-yl)-phenyl


1617.
allyl
4-(pyrazol-3-yl)-phenyl


1618.
allyl
4-(pyrazol-4-yl)-phenyl


1619.
allyl
4-(1-methyl-1H-pyrazol-4-yl)-phenyl


1620.
allyl
4-(1-ethyl-1H-pyrazol-4-yl)-phenyl


1621.
allyl
4-(1-methyl-1H-pyrazol-5-yl)-phenyl


1622.
allyl
4-(1H-imidazol-2-yl)-phenyl


1623.
allyl
4-(imidazol-1-yl)-phenyl


1624.
allyl
4-(1-methylimidazol-2-yl)-phenyl


1625.
allyl
4-(oxazol-2-yl)-phenyl


1626.
allyl
4-(oxazol-4-yl)-phenyl


1627.
allyl
4-(oxazol-5-yl)-phenyl


1628.
allyl
4-(isoxazol-3-yl)-phenyl


1629.
allyl
4-(isoxazol-4-yl)-phenyl


1630.
allyl
4-(isoxazol-5-yl)-phenyl


1631.
allyl
4-([1,2,3]-triazol-1-yl)-phenyl


1632.
allyl
4-([1,2,4]-triazol-1-yl)-phenyl


1633.
allyl
4-([1,2,3]-triazol-2-yl)-phenyl


1634.
allyl
4-(4H-[1,2,4]-triazol-3-yl)-phenyl


1635.
allyl
4-([1,2,4]-triazol-4-yl)-phenyl


1636.
allyl
4-(2H-[1,2,3]-triazol-4-yl)-phenyl


1637.
allyl
4-(4-methyl-4H-[1,2,4]-triazol-3-yl)-phenyl


1638.
allyl
4-(2-methyl-2H-[1,2,3]-triazol-4-yl)-phenyl


1639.
allyl
4-([1,3,4]-oxadiazol-2-yl)-phenyl


1640.
allyl
4-([1,2,4]-oxadiazol-3-yl)-phenyl


1641.
allyl
4-([1,2,4]-oxadiazol-5-yl)-phenyl


1642.
allyl
4-([1,2,3]-oxadiazol-4-yl)-phenyl


1643.
allyl
4-([1,2,3]-oxadiazol-5-yl)-phenyl


1644.
allyl
4-([1,2,3]-thiadiazol-4-yl)-phenyl


1645.
allyl
4-(1H-tetrazol-5-yl)-phenyl


1646.
allyl
4-(tetrazol-1-yl)-phenyl


1647.
allyl
4-(2-methyl-2H-tetrazol-5-yl)-phenyl


1648.
allyl
4-(1-methyl-1H-tetrazol-5-yl)-phenyl


1649.
allyl
4-furazan-3-yl-phenyl


1650.
allyl
4-(pyrid-2-yl)-phenyl


1651.
allyl
4-(pyrid-3-yl)-phenyl


1652.
allyl
4-(pyrid-4-yl)-phenyl


1653.
allyl
4-(pyrimidin-2-yl)-phenyl


1654.
allyl
4-(pyrimidin-4-yl)-phenyl


1655.
allyl
4-(pyrimidin-5-yl)-phenyl


1656.
allyl
5-isopropylthiophen-2-yl


1657.
allyl
2-chlorothiophen-5-yl


1658.
allyl
2,5-dichlorothiophen-4-yl


1659.
allyl
2,3-dichlorothiophen-5-yl


1660.
allyl
2-chloro-3-nitrothiophen-5-yl


1661.
allyl
2-(phenylsulfonyl)-thiophen-5-yl


1662.
allyl
2-(pyridin-2-yl)thiophen-5-yl


1663.
allyl
2-(5-(trifluoromethyl)isoxazol-3-yl)-thiophen-5-yl


1664.
allyl
2-(2-methylthiazol-4-yl)-thiophen-5-yl


1665.
allyl
1-methyl-1H-imidazol-4-yl


1666.
allyl
1,2-dimethyl-1H-imidazol-4-yl


1667.
allyl
3,5-dimethylisoxazol-4-yl


1668.
allyl
thiazol-2-yl


1669.
allyl
4-methylthiazol-2-yl


1670.
allyl
4-isopropylthiazol-2-yl


1671.
allyl
4-trifluoromethylthiazol-2-yl


1672.
allyl
5-methylthiazol-2-yl


1673.
allyl
5-isopropylthiazol-2-yl


1674.
allyl
5-trifluoromethylthiazol-2-yl


1675.
allyl
2,4-dimethylthiazol-5-yl


1676.
allyl
2-acetamido-4-methylthiazol-5-yl


1677.
allyl
4H-[1,2,4]triazol-3-yl


1678.
allyl
5-methyl-4H-[1,2,4]triazol-3-yl


1679.
allyl
4-methyl-4H-[1,2,4]triazol-3-yl


1680.
allyl
5-isopropyl-4H-[1,2,4]triazol-3-yl


1681.
allyl
5-trifluoromethyl-4H-[1,2,4]triazol-3-yl


1682.
allyl
4,5-dimethyl-4H-[1,2,4]triazol-3-yl


1683.
allyl
5-isopropyl-4-methyl-4H-[1,2,4]triazol-3-yl


1684.
allyl
5-trifluoromethyl-4-methyl-4H-[1,2,4]triazol-3-yl


1685.
allyl
[1,3,4]thiadiazol-2-yl


1686.
allyl
5-methyl-[1,3,4]thiadiazol-2-yl


1687.
allyl
5-isopropyl-[1,3,4]thiadiazol-2-yl


1688.
allyl
5-trifluoromethyl-[1,3,4]thiadiazol-2-yl


1689.
allyl
3-bromo-2-chloropyrid-5-yl


1690.
allyl
2-(4-morpholino)-pyrid-5-yl


1691.
allyl
2-phenoxypyrid-5-yl


1692.
allyl
(2-isopropyl)-pyrimidin-5-yl


1693.
allyl
(5-isopropyl)-pyrimidin-2-yl


1694.
allyl
8-quinolyl


1695.
allyl
5-isoquinolyl


1696.
allyl
2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-




yl


1697.
allyl
5-chloro-3-methylbenzothiophen-2-yl


1698.
allyl
3,4-dihydro-4-methyl-2H-benzo[b][1,4]oxazinyl


1699.
allyl
benzothiazol-6-yl


1700.
allyl
benzo[2,1,3]oxadiazol-4-yl


1701.
allyl
5-chlorobenzo[2,1,3]oxadiazol-4-yl


1702.
allyl
7-chlorobenzo[2,1,3]oxadiazol-4-yl


1703.
allyl
benzo[2,1,3]thiadiazol-4-yl


1704.
allyl
6-chloroimidazo[2,1-b]thiazolyl









The compounds of the formula I where E is NH and R1a is hydrogen can be prepared by analogy to methods which are well known in the art, e.g. from the international patent applications cited in the introductory part. A preferred method for the preparation of compounds I is outlined in scheme 1:




In scheme 1, R1, R2, R2, X and Ar have the meanings as given above. PG is an amino-protecting group such as tert.-butoxycarbonyl. Suitable protecting groups are disclosed, for example, in P. Kocienski, Protecting Groups, Thieme-Verlag, Stuttgart 2000, Chapter 6.
In step a) the protected nitrophenethylamine II is reduced by conventional means into the corresponding amino compound III. The required reaction conditions correspond to the customary conditions for reducing aromatic nitro groups which have been described extensively in the literature (see, for example, J. March, Advanced Organic Chemistry, 3rd ed., J. Wiley & Sons, New-York, 1985, p. 1183 and the literature cited in this reference). The reduction is achieved, for example, by reacting the nitro compound VII with a metal such as iron, zinc or tin under acidic reaction conditions, i.e. using nascent hydrogen, or using a complex hydride such as lithium aluminum hydride or sodium borohydride, preferably in the presence of transition metal compounds of nickel or cobalt such as NiCl2(P(phenyl)3)2, or CoCl2, (see Ono et al. Chem. Ind. (London), 1983 p. 480), or using NaBH2S3 (see Lalancette et al. Can. J. Chem. 49, 1971, p. 2990), with it being possible to carry out these reductions, depending on the given reagent, in substance or in a solvent or diluent. Alternatively, the reduction of II to III can be carried out with hydrogen in the presence of a transition metal catalyst, e.g. using hydrogen in the presence of catalysts based on platinum, palladium, nickel, ruthenium or rhodium. The catalysts can contain the transition metal in elemental form or in the form of a complex compound, of a salt or of an oxide of the transition metal, with it being possible, for the purpose of modifying the activity, to use customary coligands, e.g. organic phosphine compounds, such as triphenylphosphine, tricyclohexylphosphine or tri-n-butylphosphines or phosphites. The catalyst is customarily employed in quantities of from 0.001 to 1 mol per mol of compound II, calculated as catalyst metal. In a preferred variant, the reduction is effected using tin(II) chloride in analogy with the methods described in Bioorganic and Medicinal Chemistry Letters, 2002, 12(15), pp. 1917-1919 and J. Med. Chem. 2002, 45(21), pp. 4679-4688. The reaction of II with tin(II) chloride is preferably carried out in an inert organic solvent, preferably an alcohol such as methanol, ethanol, isopropanol or butanol.
The thus obtained compound III is reacted with an arylchlorosulfonylchloride C1—SO2—Ar, preferably in the presence of a base, according to standard procedures in the art to obtain compound IV. The reaction depicted in scheme 1 step b) takes place under the reaction conditions which are customary for preparing arylsulfonamide compounds or arylsulfonic esters, respectively, and which are described, for example, in J. March, Advanced Organic Chemistry, 3rd edition, John Wiley & Sons, New York, 1985 p 444 and the literature cited therein, European J. Org. Chem. 2002 (13), pp. 2094-2108, Tetrahedron 2001, 57 (27) pp. 5885-5895, Bioorganic and Medicinal Chemistry Letters, 2000, 10(8), pp. 835-838 and Synthesis 2000 (1), pp. 103-108. The reaction customarily takes place in an inert solvent, for example in an ether, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether or tetrahydrofuran, a halohydrocarbon, such as dichloromethane, an aliphatic or cycloaliphatic hydrocarbon, such as pentane, hexane or cyclohexane, or an aromatic hydrocarbon, such as toluene, xylene, cumene and the like, or in a mixture of the abovementioned solvents. The reaction of III with C1—SO2—Ar is customarily carried out in the presence of an auxiliary base. Suitable bases are inorganic bases, such as sodium carbonate or potassium carbonate, or sodium hydrogencarbonate or potassium hydrogencarbonate, and organic bases, for example trialkylamines, such as triethylamine, or pyridine compounds, such as pyridine, lutidine and the like. The latter compounds can at the same time serve as solvents. The auxiliary base is customarily employed in at least equimolar quantities, based on the amine compound III.
The thus obtained compound can be alkylated or acylated in step c with a compound R1-L, wherein R1 has the meanings given above and L is a leaving group that can be replaced by the nucleophilic amino group. Leaving groups L comprise e.g. halogen, trifluoroacetate, arylsulfonyloxy such as tosylate, phenylsulfonyloxy, C1-C4-alkylsulfonyloxy, trifluoromethylsulfonyloxy, C1-C4-alkoxysulfonyloxy, etc. The reaction conditions which are required for the alkylation have been adequately disclosed, e.g. in Bioorganic and Medicinal Chemistry Lett. 2002, 12(7), pp. 2443-2446 and also 2002, 12(5), pp. 1917-1919.
In step d′) the protecting group PG is cleaved by conventional means (see e.g. P. Kocienski, Protecting Groups, Thieme-Verlag, Stuttgart 2000, Chapter 6) thereby obtaining a compound I, wherein R1a is hydrogen. This compound can be further reacted by alkylation or acylation with R1a-L, wherein L has the meanings given above and R1a is as defined above but different from hydrogen.
It is also possible to first cleave the protecting group in IV (step d), thereby obtaining the compound VI and then to introduce the radical R1 and optionally R1a (step e). The introduction of the radical R1 into compound VI can also be achieved, in the sense of a reductive amination, by reacting VI with a suitable ketone or aldehyde in the presence of a reducing agent, e.g. in the presence of a borohydride such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. The skilled person is familiar with the reaction conditions which are required for a reductive amination, e.g. from Bioorganic and Medicinal Chemistry Lett. 2002, 12(5), pp. 795-798 and 12(7) pp. 1269-1273. The introduction of the radical R1 into compound VI can also be achieved by reacting VI with a suitable acyl halide to obtain a compound of the formula I wherein R1 is C1-C3-alkylcarbonyl. The carbonyl group in these compounds can be reduced with diborane to obtain compounds of the general formula I, wherein R is C2-C4-alkyl. The carbonyl group can also be reacted with a fluorinating agent to obtain a compound I wherein R1 is 1,1-difluoroalkyl. Acylation and reduction can be achieved by standard methods, which are discussed in J. March, Advanced Organic Chemistry, 3rd ed. J. Wiley & Sons, New York 1985, p. 370 and 373 (acylation) and p. 1099 f. and in the literature cited in this publication (with regard to acylation, see also Synth. Commun. 1986, 16, p. 267, and with regard to reduction, see also J. Heterocycl. Chem. 1979, 16, p. 1525).
The starting materials of the formula II can be simply obtained from commercially available phenethylamines by selectively protecting the aliphatic amino group of these compounds according to standard methods (see e.g. P. Kocienski, Protecting Groups, loc. cit.).
A skilled person will also appreciate that the reactions of step b) and c) as well as steps b) and d) can be exchanged, e.g. by performing the reaction of step c) first and then the reaction of step b).
A skilled person will also appreciate that compounds of the formula I with E=N—R3, wherein R3 is different from hydrogen, can be obtained by selective alkylation of the sulfonamide group in the compounds of the formulae V, VI or I.
If R1 or R1a in compound I is (are) allyl the allyl group(s) can be cleaved to obtain a compound I′ or I′′ wherein R is hydrogen. The cleavage of the allyl group is achieved, for example, by reacting I [R1=allyl] with an allyl trapping agent, such as mercaptobenzoic acid or 1,3-dimethylbarbituric acid, in the presence of catalytic quantities of palladium (0) compounds or palladium compounds which are able to form a palladium(0) compound under reaction conditions, e.g. palladium dichloride, tetrakis(triphenylphosphine)palladium(0) or tris(dibenzylideneacetone)dipalladium(0), advantageously in combination with phosphine ligands, e.g. triarylphosphines, such as triphenylphosphine, trialkylphosphines, such as tributylphosphine, and cycloalkylphosphines, such as tricyclohexylphosphine, and especially with phosphine chelate ligands, such as 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl or 1,4-bis(diphenylphosphino)butane, using methods known from the literature (with regard to eliminating N-allyl in the presence of mercaptobenzoic acid, see WO 94/24088; with regard to eliminating in the presence of 1,3-dimethylbarbituric acid, see J. Am. Chem. Soc. 2001, 123 (28), pp. 6801-6808 and J. Org. Chem. 2002, 67(11) pp. 3718-3723). Alternatively, the cleavage of N-allyl can also be effected by reacting in the presence of rhodium compounds, such as tris(triphenylphosphine)chlororhodium(I), using methods known from the literature (see J. Chem. Soc., Perkin Transaction I Organic, and Bio-Organic Chemistry 1999 (21) pp. 3089-3104 and Tetrahedron Asymmetry 1997, 8(20), pp. 3387-3391). If R1 or R1a in compound I is (are) allyl the allyl group can be also converted into a n-propyl group by hydrogenation in the presence of Pd—C as a catalyst.
Compounds of the formula I, wherein R1a and R2 or R1a and R2a together are (CH2)n with n being 2, 3 or 4 can be prepared in a manner similar to the method outlined in scheme 1 starting from a compound of the formula VII, by the method outlined in scheme 2 (showing the sequence for R1a and R2 together are (CH2)n).




In scheme 2, R1, R2a, n and Ar have the meanings given above.
The reaction depicted in step a) in scheme 2 takes place under the reaction conditions which are customary for a nitration of an aromatic radical and which are described, for example, in J. March, Advanced Organic Chemistry, 3rd ed., John Wiley & Sons, New York 1985, pp 468-470 and the literature cited therein). In step b), the nitro group in VIII is reduced to the NH2 group according to the method of step b) in scheme 1. Step c) in scheme 2 corresponds to step b) in scheme 1, which can be performed in analogous manner. Thereby a compound of the general formula VIII is obtained.
The radical R in the thus obtained compounds VIII can be transformed into other radicals by the methods outlined in connection with scheme 1.
Compounds of the formula VII are known in the art or can be prepared according to standard procedures.
Compounds of the formula I, where R2a is H, X is N and E is NH can be also obtained by the synthetic approach outlined in scheme 3. In scheme 3, R2 and Ar have the meanings given above.




step a: K2CO3 in tetrahydrofuran
step b: p-toluene sulfonic acid, toluene
step c: reduction (see step a of scheme 1)
step d: reaction with Ar—SO2—Cl (see step b of scheme 1)
step e: reduction, e.g. by H2/Raney nickel, NH3 
The obtained compound VI can be further reacted as outlined in scheme 1 to obtain compound I.
The compounds of the formula I where E is CH2 as outlined in schemes 4a and 4b:








In schemes 4a and 4b, X, R1a, R2, R2a, and Ar have the meanings given above. R1′ is a radical R1 that is different from hydrogen, formyl or alkylcarbonyl. Hal is halogen, in particular bromine.
According to scheme 4a, the carboxyl group in compound X is transformed into the carboxamide group by standard methods, e.g. by successively reacting compound X with thionyl chloride and then with aqueous ammonia. The amide XI is then reacted in step b) with a mercapto compound HS—Ar in the presence of a base, such as sodium hydride or sodium alkoxide or with an alkali metal salt of HS—Ar, thereby yielding thioether compound. The thioether moiety is oxidized to a sulfone moiety, e.g. by oxone to obtain compound XII. Compound XII can be either reduced, e.g. by BH3-Dimethylsulfide, to obtain compound XIII with R2═R2a═H, or reacted with a suitable organometal compound or successively with a reducing agent and an organometal compound to obtain a compound XIII, where R2 and/or R2a is (are) different from hydrogen. Compound XIII can be further converted into compound I as outlined for scheme 1.
According to scheme 4b, compound X is reacted in step a) with a mercapto compound HS—Ar in the presence of a base, such as sodium hydride or sodium alkoxide or with an alkali metal salt of HS—Ar, thereby yielding thioether compound. The thioether moiety is oxidized to a sulfone moiety, e.g. by oxone to obtain compound XIV. Compound XIV is reacted in step b) with an amine R1′R1aNH in the presence of a dehydrating agent such as cyclohexylcarbodiimide (CDI). Compound XV can be either reduced, e.g. by BH3-dimethylsulfide, to obtain compound I′ with R2═R2a ═H, or reacted with a suitable organometal compound or successively with a reducing agent and an organometal compound to obtain a compound I′, where R2 and/or R2a is (are) different from hydrogen. Compound I′ can be further converted into other compounds I as outlined for scheme 1.
If not indicated otherwise, the above-described reactions are generally carried out in a solvent at temperatures between room temperature and the boiling temperature of the solvent employed. Alternatively, the activation energy which is required for the reaction can be introduced into the reaction mixture using microwaves, something which has proved to be of value, in particular, in the case of the reactions catalyzed by transition metals (with regard to reactions using microwaves, see Tetrahedron 2001, 57, p. 9199 ff. p. 9225 ff. and also, in a general manner, “Microwaves in Organic Synthesis”, Andre Loupy (Ed.), Wiley-VCH 2002.
The sulfonylchlorides C1—SO2—Ar are either commercially available or can be prepared according to standard synthetic methods. Sulfonylchlorides containing a fluorinated radical Ra may be prepared by different synthetic routes, e.g. by reacting suitable hydroxy or oxo precursor (e.g. a compound C1—SO2—Ar, carrying a hydroxy or oxo substituted radical) with fluorinating reagents like DAST (diethylaminosulfurtrifluoride), morpholine-DAST, deoxofluor (bis(2-methoxyethyl)aminosulfur trifluoride), Ishikawa's reagent (N,N-diethyl-(1,1,2,3,3,3-hexafluoropropyl)amine; Journal of Fluorine Chemistry, 1989, 43, 371-377). More conventionally, the hydroxy group of an aromatic compound which carries a hydroxy substituted radical but not a chlorosulfonyl group is transformed into a leaving group which is then replaced by a fluoride ion (J. Org. Chem., 1994, 59, 2898-22901; Tetrahedron Letters, 1998, 7305-6; J. Org. Chem., 1998, 63, 9587-9589, Synthesis, 1987, 920-21)). Sub-sequent direct chlorosulfonylation with chlorosulfonic acid (Heterocycles, 2001, 55, 9, 1789-1803; J. Org. Chem., 2000, 65, 1399-1406) or a two step process preparing first the sulfonic acid derivatives which are then transformed to the sulfonylchlorides with e.g. chlorosulfonic acid, phosphorus pentachloride (Eur. J. Med. Chem., 2002, 36, 809-828) and the like, yields the desired sulfonylchloride (Tetrahedron Letters, 1991, 33, 50 7787-7788)) Sulfonylchlorides may also be prepared by diazotation of suitable amine precursor Ar—NH2 with sodium nitrite under acidic conditions and reaction with sulfur dioxide in acetic acid (scheme (iii); J. Org. Chem., 1960, 25, 1824-26;); by oxidation of suitable heteroaryl-thiols HS—Ar or heteroaryl-benzyl-thioethers C6H5—CH2—S—Ar with chlorine (Synthesis, 1998, 36-38; J. Am. Chem. Soc., 1950, 74, 4890-92;) directly to the corresponding sulfonyl chlorides. The further are known in the art or may be prepared by standard methods. E.g. mercapto-pyrimidines or pyrimidinyl-benzylthioether precursors can e.g. be prepared according to literature (Chemische Berichte, 1960, 1208-11; Chemische Berichte, 1960, 95, 230-235; Collection Czechoslow. Chem. Comm., 1959, 24, 1667-1671; Austr. J. Chem., 1966, 19, 2321-30; Chemiker-Zeitung, 101, 6, 1977, 305-7; Tetrahedron, 2002, 58, 887-890; Synthesis, 1983, 641-645.
The aminocompounds of the formulae III or IX may also be prepared from the corresponding halogen compound XVI or XVII according to the method as described in scheme 5:




In scheme 5, R1, R2, R2a, n and X are as defined above. Hal is halogen, in particular bromine, and PG is a protecting group. The reaction can be performed by reacting XVI or XVII, respectively, with an alkalimetal salt of a bis(trialkylsilyl)amine such as lithium bis(trimethylsilyl)amide in the presence of a palladium catalyst and subsequent hydrolysis. An example for a suitable palladium catalyst is tris(dibenzylideneacetone)dipalladium(0), optionally in the presence of a tri(substituted)phosphine, e.g. a triarylphosphine such as triphenylphosphine or tritolylphosphine, tri(cyclo)alkylphosphine such as tris-n-butylphosphine, tris(tert.-butyl)phosphine or tris(cyclohexylphosphine), or PdCl2(dppf). The reaction of VIIa with the alkalimetal-bis(trialkylsilyl)amide can be performed by analogy to a Buchwald-Hartig coupling the alkalimetal-bis(trialkylsilyl)amide can be generated in-situ from the corresponding amine by a strong base such an alkalimetal alkoxide, e.g. potassium tert.-butylate or an alkalimetal hydride such as lithium hydride, sodium hydride and the like. Hydrolysis is simply achieved by aqueous work-up.
Compounds of the formulae XVI or XVII may also serve as a starting material in the synthetic route depicted in scheme 6.




In scheme 6, R1, R2, R2a, n, Ar and X are as defined above. Hal is halogen, in particular bromine, and PG is a protecting group. According to scheme 6, a compound of the formulae XVI or VXVII is reacted with an arylsulfonylamide Ar—SO2—NH2 or the lithium salt thereof in the presence of a palladium(0) compound such as tris(dibenzylideneacetone)-dipalladium(0) in the presence of a tri(substituted)phosphine, e.g. a triarylphosphine such as triphenylphosphine or tritolylphosphine, tri(cyclo)alkylphosphine such as tris-n-butylphosphine, tris(tert.-butyl)phosphine or tris(cyclohexylphosphine), preferably in the presence of a base such as sodium hydride according to the method described in J. Org. Chem., 68 (2993) pp 8274-8276, and outlined below.
A skilled person will readily appreciate that compounds of the formula I can also be obtained from structurally similar compounds by functional group interconversion. In particular N-bound radicals Ra can be introduced into compounds of the formula I by reacting the corresponding halogen compound, i.e. a compound of the formula I, which instead of Ra carries a halogen atom, in particular a bromine or iodine atom, with a primary or secondary amine in the presence of a base, preferably also in the presence of a palladium catalyst in terms of a Buchwald-Hartwig reaction.
In the following schemes 7 to 9 several routes are shown which are suitable to prepare benzenesulfonyl chlorides carrying a fluorinated propyl radical.




The 4-(1,1-difluoropropan-2-yl)benzene-1-sulfonyl chloride intermediate can be prepared from the commercially available 2-phenylpropanoic acid. In the first step a) the 2-phenylpropanic acid is converted to the alkyl ester by esterification with an alcohol (e.g. methanol or ethanol) under acid catalysis (e.g. HCl, SO2Cl2). The ester can be reduced to the corresponding 2-phenyl propanal by a reducing agent such as DIBAL (diisobutylaluminum hydride). The aldehyde is converted to the 1,1-difluoro-2-propyl derivative by reaction with a suitable fluorinating reagent like DAST (diethylaminosulfurtrifluoride), morpholine-DAST, deoxo-fluor (bis(2-methoxyethyl)aminosulfur trifluoride), Ishikawa's reagent (N,N-diethyl-(1,1,2,3,3,3-hexafluoropropyl)amine; Journal of Fluorine Chemistry, 1989, 43, 371-377) (step b). The thus obtained 1,1-difluoro-2-phenylpropane can be converted into 4-(1,1-difluoro-2-propyl)benzenesulfonyl chloride by either direct chlorosulfonylation with chlorosulfonic acid (Heterocycles, 2001, 55, 9, 1789-1803; J. Org. Chem., 2000, 65, 1399-1406) (step c) or by a two step process preparing first the sulfonic acid derivatives (step d) which are then transformed to the sulfonylchlorides (step e) by reaction with e.g. chlorosulfonic acid, phosphorous pentachloride (Eur. J. Med. Chem., 2002, 36, 809-828); through diazotisation of suitable amine precursors with sodium nitrite under acidic conditions and reaction with sulfur dioxide in acetic acid (J. Org. Chem., 1960, 25, 1824-26); oxidation of suitable heteroaryl-thiols or heteroaryl-benzyl-thioethers with chlorine (Synthesis, 1998, 36-38; J. Am. Chem. Soc., 1950, 74, 4890-92) directly to the corresponding sulfonyl chlorides.
The synthesis shown in scheme 7 can also be performed using (R)-2-phenylpropanic acid and (S)-2-phenylpropanic acid respectively to give the corresponding chiral 4-(1,1-difluoropropan-2-yl)benzene-1-sulfonyl chlorides.




4-(1,1,1-Trifluoropropan-2-yl)benzene-1-sulfonyl chloride intermediate can be prepared from the commercially available 2,2,2-trifluoro-1-phenylethanone by a synthetic route shown in scheme 6. The ketone can be converted to the 3,3,3-trifluoro-2-phenylpropene by a Wittig reaction with a suitable ylide such as methylene-triphenylphosphane (prepared by reaction of methyltriphenylphosphonium halide and a suitable base such as lithium diisopropylamide or potassium tert-butoxide) or according to a Horner-Emmons reaction by reacting the ketone with a suitable phosphonate such as diethyl methylphosphonate and a suitable suitable base such as lithium diisopropylamide or potassium tert-butoxide. The thus obtained 3,3,3-trifluoro-2-phenylpropene can then be reduced to the saturated alkane by catalytic hydrogenation (eg Pd—C) followed by conversion to the sulfonyl chloride by the methods described in scheme 5.
The synthesis of scheme 8 can also be performed using a chiral catalyst for the alkene hydrogenation to allow the preparation of the corresponding chiral 4-(1,1,1-triifluoropropan-2-yl)benzene-1-sulfonyl chlorides.




The 4-(1,1,1-trifluoropropan-2-yl)benzene-1-sulfonyl chloride can be also prepared from the commercially available 1-phenyl-ethanone by a four step procedure as shown in scheme 9. The ketone can be converted to the trifluoromethyl hydroxyl intermediate by reaction with trimethyl-trifluoromethyl-silane (Journal of Organic Chemistry, 2000, 65, 8848-8856; Journal of Fluorine Chemistry, 2003, 122, 243-246) which can then be converted to the trifluoromethyl bromide (Journal of the American Chemical Society, 1987, 109, 2435-4). Dehalogenation by catalytic hydrogenation (eg Pd—C) can then be followed by conversion to the sulfonyl chloride by the methods discussed above.
Examples of solvents which can be used are ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether or tetrahydrofuran, aprotic polar solvent, such as dimethylformamide, dimethyl sulfoxide, dimethoxyethane, and acetonitrile, aromatic hydrocarbons, such as toluene and xylene, ketones, such as acetone or methyl ethyl ketone, halohydrocarbons, such as dichloromethane, trichloromethane and dichloroethane, esters, such as ethyl acetate and methyl butyrate, carboxylic acids, such as acetic acid or propionic acid, and alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, 2-butanol and tert.-butanol.
If desired, it is possible for a base to be present in order to neutralize protons which are released in the reactions. Suitable bases include inorganic bases, such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, and, in addition, alkoxides, such as sodium methoxide or sodium ethoxide, alkali metal hydrides, such as sodium hydride, and also organometallic compounds, such as butyllithium compounds or alkylmagnesium compounds, or organic nitrogen bases, such as triethylamine or pyridine. The latter compounds can at the same time serve as solvents.
The crude product is isolated in a customary manner, for example by filtering, distilling off the solvent or extracting from the reaction mixture, etc. The resulting compounds can be purified in a customary manner, for example by means of recrystallizing from a solvent, by means of chromatography or by means of converting into an acid addition salt.
The acid addition salts are prepared in a customary manner by mixing the free base with a corresponding acid, where appropriate in 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 compounds according to the invention of the formula I are surprisingly highly selective dopamine D3 receptor ligands which, because of their low affinity for other receptors such as D1 receptors, D4 receptors, α1-adrenergic and/or α2-adrenergic receptors, muscarinergic receptors, histamine receptors, opiate receptors and, in particular, dopamine D2 receptors, give rise to fewer side-effects than do the classic neuroleptics, which are D2 receptor antagonists. A compound of the invention can be a dopamine D3 receptor agonist, including partial agonistic activity, or a dopamine D3 receptor antagonist, including partial antagonistic activity.
The high affinity of the compounds according to the invention for D3 receptors is reflected in very low in-vitro receptor binding constants (Ki(D3) values) of as a rule less than 50 nM (nmol/l), preferably of less than 10 nM and, in particular of less than 5 nM. The displacement of [125I]-iodosulpride can, for example, be used in receptor binding studies for determining binding affinities for D3 receptors.
The selectivity of the compounds according to the invention, i.e. the ratio Ki(D2)/Ki(D3) of the receptor binding constants, is as a rule at least 50, preferably at least 100, even better at least 150. The displacement of [3H]SCH23390, [125I] iodosulpride or [125I] spiperone can be used, for example, for carrying out receptor binding studies on D1, D2 and D4 receptors.
Because of their binding profile, the compounds can be used for treating diseases which respond to dopamine D3 receptor ligands (or which are susceptible to treatment with a dopamine D3 receptor ligand, respectively), i.e. they are effective for treating those medical disorders or diseases in which exerting an influence on (modulating) the dopamine D3 receptors leads to an improvement in the clinical picture or to the disease being cured. Examples of these diseases are disorders or diseases of the central nervous system.
Disorders or diseases of the central nervous system 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 with 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 of organic or exogenous cause, e.g., in association with metabolic disturbances, infections and endocrinopathogies; 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 also 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/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 legs syndrome; development disturbances; anxiety states, delirium; sexlife disturbances, e.g. impotence in men; eating disturbances, e.g. anorexia or bulimia; addiction; and other unspecified psychiatric 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 the GABA chloride channel complex, sedatives, hypnotics and tranquilizers, for example benzodiazepines; LSD; cannabinoids; psychomotor stimulants, such as 3,4-methylenedioxy-N-methylamphetamine (ecstasy); amphetamine and amphetamine-like substances such as methylphenidate and other stimulants including caffeine. Addictive substances which come particularly into 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 the 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 substances, for example cocaine.
According to another aspect of the present invention, the compounds according to the invention are suitable for treating disorders whose causes can at least partially be 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, within the sense of an expedient medicinal treatment, by the binding of preferably exogenously administered binding partners (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 liability, 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 preventive treatment (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 orientated over the 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 treating 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 I according to the invention are also suitable for treating disturbances of kidney function, in particular 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 form 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.
As a rule, the treatment is effected by means of single or repeated daily administration, where appropriate together, or alternating, with other active compounds or active compound-containing preparations such that a daily dose of preferably from about 0.1 to 1000 mg/kg of bodyweight, in the case of oral administration, or of from about 0.1 to 100 mg/kg of bodyweight, in the case of parenteral administration, is supplied to an individual to be treated.
The invention also relates to the production of pharmaceutical compositions for treating an individual, preferably a mammal, in particular a human being, productive animal or domestic animal. Thus, the ligands 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, transdermally, 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 or vaginal medicinal forms, semisolid medicinal forms, such as ointments, creams, hydrogels, pastes or plasters, and also liquid medicinal forms, such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, for example lotions, injection preparations and infusion preparations, and eyedrops and eardrops. Implanted release devices can also be used for administering inhibitors according to the invention. In addition, it is also possible to use liposomes or microspheres.
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.
Suitable excipients are listed in the specialist medicinal monographs. In addition, the formulations can comprise pharmaceutically acceptable carriers or customary auxiliary substances, such as glidants; wetting agents; emulsifying and suspending agents; preservatives; antioxidants; antiirritants; chelating agents; coating auxiliaries; emulsion stabilizers; film formers; gel formers; odor masking agents; taste corrigents; resin; hydrocolloids; solvents; solubilizers; neutralizing agents; diffusion accelerators; pigments; quaternary ammonium compounds; refatting and overfatting agents; raw materials for ointments, creams or oils; silicone derivatives; spreading auxiliaries; stabilizers; sterilants; suppository bases; tablet auxiliaries, such as binders, fillers, glidants, disintegrants or coatings; propellants; drying agents; opacifiers; thickeners; waxes; plasticizers and white mineral oils. A formulation in this regard is based on specialist knowledge as described, for example, in Fiedler, H. P., Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields], 4th edition, Aulendorf: ECV-Editio-Kantor-Verlag, 1996.
The following examples serve to explain the invention without limiting it.
The compounds were either characterized via proton-NMR in d6-dimethylsulfoxide or d-chloroform, if not stated otherwise, on a 400 MHz or 500 MHz NMR instrument (Bruker AVANCE), or by mass spectrometry, generally recorded via HPLC-MS in a fast gradient on C18-material (electrospray-ionisation (ESI) mode), or melting point.
The magnetic nuclear resonance spectral properties (NMR) refer to the chemical shifts (δ) expressed in parts per million (ppm). The relative area of the shifts in the 1H NMR spectrum corresponds to the number of hydrogen atoms for a particular functional type in the molecule. The nature of the shift, as regards multiplicity, is indicated as singlet (s), broad singlet (s. br.), doublet (d), broad doublet (d br.), triplet (t), broad triplet (t br.), quartet (q), quintet (quint.) and multiplet (m).
PREPARATION EXAMPLES
I. Preparation of Intermediates
a. Preparation of 2-Aminopropylphenylamines
a. 1 4-((S)-2-Amino-propyl)-phenylamine×HCl
A mixture of 4-nitrophenylacetone (5 g, 27.91 mmol), (S)-(−)-α-phenylethylamine (3.4 g, 28.06 mmol), and platin(IV) oxide (100 mg) in methanol (MeOH) (50 ml) was hydrogenated at atmospheric pressure for a period of 8 h. After filtration and evaporation of the solvent under reduced pressure 4-[(S)-2-((S)-1-phenyl-ethylamino)-propyl]-phenylamine was obtained as a yellow oil 6.7 g, 94%). Without further purification a solution of this oil in methanol (100 ml) together with ammonium formate (16.4 g, 260.1 mmol), and 10% palladium on charcoal (200 mg) were heated to reflux for 30 h. The mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4 and evaporated under reduced pressure. To a solution of the obtained residue in isopropanol HCl in isopropanol was added. The hydrochloride salt was collected and dried in a vacuum oven at 50° C. to give orange crystals (900 mg, 17%).
a.2 4-((R)-2-Amino-propyl)-phenylamine×HCl
Starting from 4-nitrophenylacetone (5 g, 27.91 mmol) and (R)-(−)-α-phenylethylamine (3.4 g, 28.06 mmol) following the same synthetic procedure as described for 4-((S)-2-amino-propyl)-phenylamine×HCl the product was obtained as a yellow powder (3 g, 57%).
b. Preparation of N-Substituted propionamides
b. 1 N-[1,1-Dimethyl-2-(4-nitro-phenyl)-ethyl]-propionamide
b. 1.1: N-(1,1-Dimethyl-2-phenyl-ethyl)-propionamide
To a solution of (2-methyl-propenyl)-benzene (2.6 g, 19.67 mmol) in propionitrile (20 g, 363 mmol) H2SO4 (39.33 mmol) was added at 10° C. The mixture was stirred at room temperature for 16 h. Then the mixture was poured into water and adjusted to an alkaline pH with NaOH. The aqueous layer was extracted three times with ethyl acetate, the organic layers combined, washed with water and brine, dried over MgSO4, filtered, and the solvent evaporated under reduced pressure to give the product as a yellow oil (1.6 g, 40%).
b.1.2: N-[1,1-Dimethyl-2-(4-nitro-phenyl)-ethyl]-propionamide
To H2SO4(20 ml) at 0-10° C. N-(1,1-dimethyl-2-phenyl-ethyl)-propionamide was slowly added. The mixture was stirred until a clear solution was obtained. Then KNO3 (750 mg, 7.42 mmol) was added in portions at 0-5° C. The mixture was stirred at room temperature for 16 h after which it was poured into ice water. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with NaOH, water and brine, dried over MgSO4, filtered, and the solvent evaporated under reduced pressure to give the product as a brown oil (1 g, 55%).
b.2 N-[1-(4-Nitro-benzyl)-cyclopropyl]-propionamide
b.2.1:1-Benzylcyclopropylamine
To a solution of phenylacetonitrile (3 g, 25.61 mmol) and tetraisopropylorthotitanate (8 ml, 27.15 mmol) in diethyl ether (Et2O)/tetrahydrofuran (THF) (1/1, 100 ml) ethyl-magnesiumbromide (49.33 mmol) was added at room temperature. The exothermic mixture was stirred for 1 h at room temperature. Then BF3×Et2O (49.34 mmol) was added and the mixture was stirred for 1 h. The mixture was poured into a cold aqueous solution of NaOH (10%) and diluted with ethyl acetate. The mixture was filtered, and the organic layer was washed with water and brine, dried over MgSO4, filtered, and the solvent evaporated under reduced pressure to give the product as a yellow oil (3.6 g, 96%).
MS (ESI) m/z: 148.15 [M+H]+
b.2.2: N-(1-Benzyl-cyclopropyl)-propionamide
To a solution of 1-benzylcyclopropylamine (3.6 g, 24.45 mmol) and triethylamine (4.9 g, 48.85 mmol) in dichloromethane (100 ml) propionyl chloride (2 g, 27.02 mmol) was added at 10° C. The mixture was stirred at room temperature for 16 h. The mixture was partitioned between water and dichloromethane. The organic layer was washed with water, dried over MgSO4 and the solvent evaporated under reduced pressure. The residue was triturated with diethylether, the precipitate filtered and dried in vacuo to give the product as a brown powder (2 g, 40%).
MS (ESI) m/z: 204.10 [M+H]+
b.2.3: N-[1-(4-Nitro-benzyl)-cyclopropyl]-propionamide
To H2SO4(20 ml) at 0-10° C. N-(1-benzyl-cyclopropyl)-propionamide (2 g, 9.84 mmol) was slowly added. The mixture was stirred until a clear solution was obtained. Then KNO3 (1 g, 9.89 mmol) was added in portions at 0-5° C. The mixture was stirred at room temperature for 16 h after which it was poured into ice water, and 50% NaOH was added. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and the solvent evaporated under reduced pressure. The residue was triturated with isopropylether and the precipitate filtered and dried in vacuo to give the product as a brown powder (900 mg, 37%).
MS (ESI) m/z: 249.25 [M+H]+
c. Preparation of [2-(aminophenyl)ethyl]-carbamicacid tert-butyl ester
c. 1 [2-(4-Amino-phenyl)-ethyl]-carbamicacid tert-butyl ester
c.1.1: [2-(4-Nitro-phenyl)-ethyl]-carbamicacid tert-butyl ester
To a solution of 2-(4-nitrophenyl)ethylamine (25.2 g, 124.31 mmol) in Tetrahydrofuran (THF) (100 ml) at 0° C. di-tert-butyl dicarbonate (38.5 g, 176.33 mmol) was added slowly. The mixture was stirred at room temperature for 16 h. After filtration the mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with citric acid (5%), dried over MgSO4, filtered and the solvent evaporated under reduced pressure to give the product as a yellow powder (18.8 g, 57%).
c.1.2: [2-(4-Amino-phenyl)-ethyl]-carbamicacid tert-butyl ester
To a solution of [2-(4-nitro-phenyl)-ethyl]-carbamicacid tert-butyl ester (18.7 g, 70.30 mmol) in ethanol (200 ml) a slurry of 10% palladium on charcoal (2 g) in water (10 ml) was added. At 80° C. ammonium formate (44.3 g, 703 mmol) in water (90 ml) was added slowly. After complete addition the mixture was stirred at 80° C. for 1 h. The mixture was allowed to come to room temperature, filtered and concentrated in vacuo. The residue was diluted with water and extracted twice with dichloromethane. The combined organic layers were washed with water, dried over MgSO4, filtered and the solvent evaporated under reduced pressure to give the product as a yellow oil (13.5 g, 81%).
c.2 Allyl-[2-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester
To a solution of [2-(4-amino-phenyl)-ethyl]-carbamicacid tert-butyl ester (2.32 g, 9.82 mmol) in N,N-dimethylformamide (DMF) (50 ml) 18-crown-6 (50 mg) was added. At 0° C. potassium tert-butylate (1.10 g, 9.82 mmol) was added and the mixture stirred for 30 min. After the addition of allylbromide (1.19 g, 9.82 mmol) the mixture was stirred at room temperature for 16 h. After concentration in vacuo the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with water, dried over MgSO4, filtered and the solvent evaporated under reduced pressure to give the product as a red oil (2.50 g, 92%).
c.3 [2-(3-Amino-phenyl)-ethyl]-carbamicacid tert-butyl ester
c.3.1:2-(3-Nitrophenyl)ethylamine
A solution of (3-nitro-phenyl)-acetonitrile (11.4 g, 70.4 mmol) in THF (100 ml) was heated to reflux and borane dimethylsulfide (2M in THF, 77.34 mmol) was added. The mixture was stirred for 2 h under reflux. After complete conversion the mixture was allowed to come to room temperature and a solution of HCl in ethanol (1M) was added. After stirring the mixture for 30 min it was concentrated under reduced pressure. The residue was triturated with diethylether, filtered, washed with diethylether and dried in vacuo to give the product as a yellow powder (13.1 g, 92%).
c.3.2: [2-(3-Amino-phenyl)-ethyl]-carbamicacid tert-butyl ester
The desired product was obtained as a brown oil following the synthetic procedure described for allyl-[2-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester starting from 2-(3-Nitrophenyl)ethylamine.
c.4 Allyl-[2-(3-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester
The desired product was obtained as an orange oil following the synthetic procedure described for Allyl-[2-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester starting from [2-(3-Amino-phenyl)-ethyl]-carbamicacid tert-butyl ester and allylbromide.
d. Preparation of 2-(4-Aminobenzyl)-1-propylpyrrolidine
d. 1.1:2-(4-Nitrobenzyl)-1-propylpyrrolidine
2-Benzyl-1-propylpyrrolidine (0.90 g, 3.75 mmol) was dissolved in nitromethane (10 mL) and added to a mixture of concentrated H2SO4 (3.7 mL), concentrated nitric acid (0.3 mL) and water (0.6 mL) cooled to 5° C. After stirring for 2 h, the reaction solution was poured into water, extracted with ethyl acetate and the organic phase separated and dried over MgSO4. The filtered solution was concentrated to give a brown oil (0.95 g, 100%).
MS (ESI) m/z: 249.3 [M+H]+
d.1.2:2-(4-Aminobenzyl)-1-propylpyrrolidine
The mixture of nitro compounds from d.1.1 (0.94 g, 3.79 mmol) was dissolved in methanol (60 mL) and tin chloride (4.30 g, 19.1 mmol) added. The solution was heated to reflux for 3 h, the solution was concentrated and the residue partitioned between ethyl acetate and NaOH (2M), and the organic phase separated and dried over MgSO4. The filtered solution was concentrated and the residue separated by preparative HPLC (10-90% methanol) to give the 2 amino isomers. The p-amino product was obtained as a yellow oil (0.30 g, 37%). The m-amino product was obtained as a yellow oil (38 mg, 5%).
MS (ESI) m/z: 219.4 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 6.85 (d, 2H), 6.43 (d, 1H), 3.08 (m, 1H), 2.75 (m, 1H), 2.45 (m, 1H), 2.18 (m, 3H), 1.62-1.35 (m, 6H), 0.82 (t, 3H).
13C-NMR (DMSO-d6): δ [ppm] 146.5 (s), 129.4 (d), 126.5 (s), 113.8 (d), 66.2 (d), 55.8 (t), 53.3 (t), 29.7 (t), 21.6 (t), 11.9 (q).
e. Preparation of sulfonyl chlorides
e. 1 4-((S)-2-Fluoro-1-methyl-ethyl)-benzenesulfonyl chloride
e.1.1 Toluene-4-sulfonic acid (S)-2-phenyl-propyl ester
To a solution of 20 g of (S)-(−)-2-phenyl-1-propanol in 240 ml of dichloromethane was added in portions 28 g of p-toluenesulfonyl chloride (146.8 mmol). After stirring for 18 h at room temperature, the organic phase was washed with 100 ml of water, dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield 43 g of the title compound.
1H-NMR (CDCl3, 400 MHz): δ [ppm] 7.65 (d, 2H), 7.15-7.3 (m, 5H), 7.1 (d, 2H), 4.0-4.1 (m, 2H), 3.1 (m, 1H), 2.4 (s, 3H), 1.3 (d, 3H).
e.1.2 ((S)-2-Fluoro-1-methyl-ethyl)-benzene
9.62 g of toluene-4-sulfonic acid (S)-2-phenyl-propyl ester (33.13 mmol) were dissolved in 80 ml of polyethylenglycol 400. 9.62 g of potassium fluoride (165.6 mmol) were added and the reaction mixture was stirred at 50° C. for 3 days and another 2 days at 55-70° C. The reaction was treated with 150 ml of saturated aqueous sodium chloride solution, extracted three times with diethyl ether, and the combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified via silica gel chromatography using cyclohexyane/ethyl acetate 15% as eluent. 2.85 g of the desired product were isolated, containing  ̃25% of the elimination side product.
1H-NMR (CDCl3, 400 MHz): δ [ppm] 7.2-7.4 (m, 5H), 4.3-4.6 (several m, 2H), 3.15 (m, 1H) 1.3 (m, 3H).
e.1.3 4-((S)-2-Fluoro-1-methyl-ethyl)-benzenesulfonyl chloride
3.5 g of ((S)-2-fluoro-1-methyl-ethyl)-benzene (25.32 mmol) were dissolved in 80 ml of dichloromethane. At 0-5° C., 11.81 g of chlorosulfonic acid (101.31 mmol), dissolved in 20 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 30 min at room temperature and 2 h at 30° C. The solvent was evaporated. 150 ml of diethyl ether were added to the residue, washed once with 150 ml of water, and the organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The crude product was purified via silica gel chromatography with n-heptane-dichloromethane (6:4) as eluent to give 1.5 g of the title compound.
1H-NMR (CDCl3, 400 MHz): δ [ppm] 8.0 (d, 2H), 7.5 (d, 2H), 4.5 (dd, 2H), 3.25 (m, 1H), 1.4 (d, 3H).
e.2 4-((R)-2-Fluoro-1-methyl-ethyl)-benzenesulfonyl chloride
e.2.1 Toluene-4-sulfonic acid (R)-2-phenyl-propyl ester
Following the procedure analogous to that used for the synthesis of toluene-4-sulfonic acid (S)-2-phenyl-propyl ester, but using (R)-2-phenyl-1-propanol, the title compound was prepared.
e.2.2 ((R)-2-Fluoro-1-methyl-ethyl)-benzene
The title compound was prepared as described above for the synthesis of ((S)-2-fluoro-1-methyl-ethyl)-benzene, but using toluene-4-sulfonic acid (R)-2-phenyl-propyl ester instead of toluene-4-sulfonic acid (S)-2-phenyl-propyl ester.
1H-NMR (CDCl3, 400 MHz): δ [ppm] 7.2-7.4 (m, 5H), 4.3-4.6 (several m, 2H), 3.15 (m, 1H). 1.3 (m, 3H).
e.2.3 4-((R)-2-Fluoro-1-methyl-ethyl)-benzenesulfonyl chloride
1.3 g of ((R)-2-fluoro-1-methyl-ethyl)-benzene (9.4 mmol) were dissolved in 50 ml of dichloromethane. At 0-5° C., 1.1 g of chlorosulfonic acid (9.4 mmol), dissolved in 10 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 20 min at 0-5° C. and then added to a solution of 2.15 g of phosphorous pentachloride dissolved in 40 ml of dichloromethane. The reaction mixture was stirred for 30 min at 0-5° C. and 1 h at room temperature. The solvent was evaporated, 100 ml of diethyl ether were added, the mixture was washed once with 150 ml of water, and the organic layer dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The crude product was purified via silica gel chromatography with n-heptane-dichloromethane (1:1) as eluent to give 0.261 g of the title compound.
1H-NMR (CDCl3, 400 MHz): δ [ppm] 8.0 (d, 2H), 7.5 (d, 2H), 4.5 (dd, 2H), 3.25 (m, 1H), 1.4 (d, 3H).
e.3 4-(2-Fluoro-1-methyl-ethyl)-benzenesulfonyl chloride
Following the procedures analogous to that used for the preparation of 4-((S)-2-fluoro-1-methyl-ethyl)-benzenesulfonyl chloride, but starting with 2-phenyl-1-propanol in step a.3.1, the title compound was prepared.
1H-NMR (CDCl3, 400 MHz): δ [ppm] 8.0 (d, 2H), 7.5 (d, 2H), 4.5 (dd, 2H), 3.25 (m, 1H), 1.4 (d, 3H).
e.4 4-(2-Fluoro-1-fluoromethyl-ethyl)-benzenesulfonyl chloride
e.4.1 (2-Fluoro-1-fluoromethyl-ethyl)-benzene
4 g of 3-phenylglutaric acid (19.21 mmol) were suspended in 350 ml of dichloromethane. At room temperature, 6.5 g of xenon difluoride (38.42 mmol) were added and the reaction mixture was stirred at room temperature for 18 h. The organic phase was washed once with 975 ml of 6% aqueous sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and the solvent evaporated. The remaining residue was distilled at a bath temperature of 123° C. at 21 mm to yield 0.78 g of the title compound that contained  ̃50% of 4-(2-Fluoro-1-methyl-ethyl)-benzene.
1H-NMR (CDCl3, 400 MHz): δ [ppm] 7.2-7.4 (m, 5H), 4.6-4.8 (dd, 4H), 3.3 (m, 1H).
e.4.2 4-(2-Fluoro-1-fluoromethyl-ethyl)-benzenesulfonyl chloride
Following the procedures analogous to that used for the preparation of 4-((S)-2-fluoro-1-methyl-ethyl)-benzenesulfonyl chloride, but using 5 equivalents of chlorosulfonic acid, 0.12 g of the title compound were obtained.
1H-NMR (CDCl3, 400 MHz): δ [ppm] 8.05 (d, 2H), 7.55 (d, 2H), 4.75 (dd, 4H), 3.4 (m, 1H).
e.5 4-(3,3,3-Trifluoropropyl)-benzenesulfonyl chloride
2.9 g were obtained from commercially available (3,3,3-trifluoropropyl)-benzene following the procedure used for the synthesis of 4-((S)-2-fluoro-1-methyl-ethyl)-benzenesulfonyl chloride described above.
1H-NMR (CDCl3, 400 MHz): δ [ppm] 8.0 (d, 2H), 7.45 (d, 2H), 3.0 (t, 2H), 2.45 (m, 2H).
e.6 4-(2,2,2-Trifluoroethyl)-benzenesulfonyl chloride
The product was obtained from commercially available (2,2,2-trifluoroethyl)-benzene following the procedure as described in J. Org. Chem., 1960, 25, 1824-26.
1H-NMR (CDCl3, 400 MHz): δ [ppm] 8.05 (d, 2H), 7.55 (d, 2H), 3.5 (q, 2H).
e.7 4-(3-Fluoropropyl)-benzenesulfonyl chloride
e.7.1 (3-Fluoropropyl)-benzene
15.6 g of diethylaminosulfurtrifluoride (DAST, 96.91 mmol) were dissolved in 18 ml of dichloromethane. At 0-5° C., 12 g of 3-phenyl-1-propanol (88.1 mmol) dissolved in 30 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 18 h, and, after addition of 30 ml of dichloromethane, poured onto 100 ml of ice water. The organic layer was separated, dried over magnesium sulfate, filtered, and the solvent evaporated. The crude product was purified by distillation at a bath temperature of 106° C. at 20 mm to yield 7.4 g of the title compound.
1H-NMR (CDCl3, 400 MHz): δ [ppm] 7.1-7.3 (m, 5H), 4.4 (dt, 2H), 2.7 (m, 2H). 2.0 (m, 2H).
e.7.2 4-(3-Fluoropropyl)-benzenesulfonyl chloride
4.1 g of (3-fluoro-propyl)-benzene (29.67 mmol) were dissolved in 40 ml of dichloromethane. At 0-5° C., 6.91 g of chlorosulfonic acid (59.34 mmol), dissolved in 10 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 45 min at 0-5° C. and then added to a solution of 6.8 g of phosphorous pentachloride (32.63 mmol) dissolved in 50 ml of dichloromethane. The reaction mixture was stirred for 1 h at 5-10° C. The solvent was evaporated, 150 ml of diethyl ether added, washed once with 150 ml of ice water, and the organic layer dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The crude product was purified via silica gel chromatography with n-heptane-dichloromethane (11:9) as eluent to give 5.5 g of the title compound.
1H-NMR (CDCl3, 400 MHz): δ [ppm] 7.95 (d, 2H), 7.45 (d, 2H), 4.5 (dt, 2H), 2.9 (t, 2H), 2.05 (m, 2H).
e.8 4-(2,2-Difluoro-cyclopropyl)-benzenesulfonyl chloride
2.07 g of were obtained from commercially available (2,2-difluorocyclopropyl)-benzene following the procedure used for the synthesis of (3-fluoropropyl)-benzenesulfonyl chloride with the exception that only 1.1 equivalents of phosphorous pentachloride were used.
1H-NMR (CDCl3, 400 MHz): δ [ppm] 8.0 (d, 2H), 7.45 (d, 2H), 2.85 (m, 1H), 2.0 (m, 1H), 1.75 (m, 1H).
e.9 3-Bromo-4-trifluoromethoxy-benzenesulfonyl chloride
2.0 g of 1-bromo-2-(trifluoro-methoxy)benzene (8.3 mmol) were dissolved in 30 ml of dichloromethane. At 0-5° C., 1.06 g of chlorosulfonic acid (9.13 mmol), dissolved in 3 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 30 min at room temperature. Additional 5.5 equivalents of chlorosulfonic in dichloromethane were added to drive the reaction to completion. Standard work-up was followed and silica gel chromatography with n-heptane-dichloromethane (6:4) as eluent gave 2.19 g of the title compound.
1H-NMR (CDCl3, 400 MHz): δ [ppm] 8.3 (d, 1H), 8.05 (dd, 1H), 7.5 (dd, 1H).
e.10 4-(2-Fluoroethyl)-benzenesulfonyl chloride
e.10.1 (2-Fluoroethyl)-benzene
6.8 g of the title compound were obtained from commercially available 2-phenyl-ethanol following the procedure used for the synthesis of (3-fluoropropyl)-benzene.
1H-NMR (CDCl3, 400 MHz): δ [ppm] 7.1-7.3 (m, 5H), 4.6 (m, 1H), 4.45 (m, 1H), 2.95 (m, 1H), 2.9 (m, 1H).
e. 10.2 4-(2-Fluoroethyl)-benzenesulfonyl chloride
3.55 g were obtained following the procedure used for the synthesis of 4-((R)-2-fluoro-1-methyl-ethyl)-benzenesulfonyl chloride.
1H-NMR (CDCl3, 400 MHz): δ [ppm] 8.0 (d, 2H), 7.5 (d, 2H), 4.7 (dt, 2H), 3.05-3.2 (dt, 2H).
e.11 5-Propylthiophene-2-sulfonyl chloride
Following the procedures analogous to that used for the preparation of (3-fluoro-propyl)-benzenesulfonyl chloride, but using only 1 equivalent of phosphorous pentachloride, the title compound was prepared.
1H-NMR (CDCl3, 400 MHz): δ [ppm] 7.7 (d, 1H), 6.85 (d, 1H), 2.9 (t, 2H), 1.75 (m, 2H), 1.0 (t, 3H).
e.12 4-(1-Methyl-1H-pyrazol-4-yl)-benzenesulfonyl chloride
e.12.1 1-Methyl-4-phenyl-1H-pyrazole
1 g of 2-phenylmalonaldehyde (6.75 mmol) were dissolved in 25 ml of ethanol. 0.36 ml of N-methyl-hydrazine (6.75 mmol) were added, the reaction mixture was stirred under reflux for 4 h, the solvent evaporated under reduced pressure to yield 1.09 g of the product.
ESI-MS: 159.1 [M+H]+
1H-NMR (CDCl3, 400 MHz): δ [ppm] 7.75 (s, 1H), 7.6 (s, 1H), 7.45 (d, 2H), 7.35 (t, 2H), 7.2 (t, 1H), 3.9 (s, 3H)
e. 12.2 4-(1-Methyl-1H-pyrazol-4-yl)-benzenesulfonyl chloride
0.5 g of 1-methyl-4-phenyl-1H-pyrazole (3.16 mmol) were dissolved in 20 ml of dichloromethane. At 0° C., 0.232 ml of chlorosulfonic acid were added and the reaction mixture was stirred for 1 h under ice cooling. Additional 0.7 ml of chlorosulfonic acid were added, the mixture was stirred at 0° C. for 30 minutes and then 90 minutes at 50° C. The two phases were separated and the lower layer put on ice, extracted twice with diethyl ether, dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield 0.496 g of the product.
1H-NMR (CDCl3, 400 MHz): δ [ppm] 8.0 (d, 2H), 7.85 (s, 1H), 7.75 (s, 1H), 7.65 (d, 2H), 4.0 (s, 3H).
e.13 4-(1,1,1-Trifluoropropan-2-yl)benzenesulfonyl chloride and 2-(1,1,1-trifluoropropan-2-yl)benzenesulfonyl chloride
Prepared on a 14 g scale following the procedure outlined in Scheme 7. 2-(1,1,1-Trifluoropropan-2-yl)benzenesulfonyl chloride is a by-product of the reaction.
4-(1,1,1-Trifluoropropan-2-yl)benzenesulfonyl chloride:
MS (ESI) m/z: 273.1 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 7.62 (d, 2H), 7.33 (d, 2H), 3.81 (m, 1H), 1.42 (d, 3H).
2-(1,1,1-Trifluoropropan-2-yl)benzenesulfonyl chloride:
MS (ESI) m/z: 273.1 [M+H]+
e. 14 4-(1,1-Difluoropropan-2-yl)benzenesulfonyl chloride and 2-(1,1-Difluoropropan-2-yl)benzene-1-sulfonyl chloride
Prepared on an 11 g scale following the procedure outlined in Scheme 6. 2-(1,1-Difluoropropan-2-yl)benzene-1-sulfonyl chloride is a by-product of the reaction.
4-(1,1-Difluoropropan-2-yl)benzenesulfonyl chloride:
MS (ESI) m/z: 255.0 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 8.03 (d, 2H), 7.55 (d, 2H), 5.88 (dt, 1H), 3.34 (m, 1H), 1.47 (d, 3H).
13C-NMR (DMSO-d6): δ [ppm] 146.43, 143.54, 129.77, 127.28, 117.06 (t), 43.76, 13.78.
2-(1,1-difluoropropan-2-yl)benzene-1-sulfonyl chloride:
Isolated by chromatography on 110 mg scale.
MS (ESI) m/z: 255.0 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 8.15 (d, 1H), 7.77 (t, 1H), 7.70 (d, 1H), 7.54 (t, 1H), 5.99 (dt, 1H), 4.43 (m, 1H), 1.51 (d, 3H).
13C-NMR (DMSO-d6): δ [ppm] 143.45, 138.63, 135.53, 130.93, 129.04, 128.17, 116.61 (t), 38.38, 13.68.
II. Preparation of Compounds I
Example 1
N-[4-((S)-2-Propylamino-propyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide
1.1 N—[(S)-2-(4-Amino-phenyl)-1-methyl-ethyl]-propionamide
To a solution of 4-((S)-2-amino-propyl)-phenylamine×HCl (1.24 g, 6.66 mmol) and triethylamine (1.4 g, 13.83 mmol) in dichloromethane (20 ml) propionyl chloride (620 mg, 6.66 mmol) was added at −5-0° C. The mixture was stirred at room temperature for 4 h. The mixture was partitioned between water and dichloromethane and to the organic layer was added HCl (1M). At pH=8 the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water, dried over MgSO4 and the solvent evaporated under reduced pressure to give the product as an orange oil (300 mg, 22%).
1.2 N—{(S)-1-Methyl-2-[4-(4-trifluoromethoxy-benzenesulfonylamino)-phenyl]-ethyl}-propionamide
To a solution of N—[(S)-2-(4-amino-phenyl)-1-methyl-ethyl]-propionamide (300 mg, 1.45 mmol) and triethylamine (300 mg, 2.96 mmol) in tetrahydrofuran (THF) (30 ml) 4-trifluoromethoxy-benzenesulfonyl chloride (380 mg, 1.45 mmol) was added at −5-0° C. The mixture was stirred at room temperature for 2 h. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with 5% citric acid, saturated aqueous NaHCO3, water, and brine, dried over MgSO4 and the solvent evaporated under reduced pressure to give the product as a brown oil (500 mg, 80%).
1.3 N-[4-((S)-2-Propylamino-propyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide
To a solution of N-{(S)-1-methyl-2-[4-(4-trifluoromethoxy-benzenesulfonylamino)-phenyl]-ethyl}-propionamide (500 mg, 1.16 mmol) in THF (20 ml) borane-dimethylsulfid complex (2M in THF, 2.63 mmol) was added at room temperature. The mixture was heated to reflux for 2 h. The mixture was allowed to come to room temperature and HCl (2M) was added. This mixture was stirred for 16 h at room temperature. After extracting the mixture three times with dichloromethane the combined organic layers were washed with saturated aqueous NaHCO3, water, and brine, dried over MgSO4 and the solvent evaporated under reduced pressure to give the product as a yellow oil. Column chromatography (CH2Cl2, 2%/methanol, 5%, 10%) gave the product as a yellow oil (300 mg, 62%).
MS (ESI) m/z: 417.15 [M+H]+
1H-NMR (CDCl3): δ [ppm] 7.80 (d, 2H), 7.20 (d, 2H), 7.06 (d, 2H), 7.00 (d, 2H), 2.90-3.00 (m, 1H), 2.80-2.90 (m, 1H), 2.65-2.75 (m, 1H), 2.52-2.60 (m, 2H), 1.45-1.60 (m, 2H), 1.05-1.10 (m, 3H), 0.85 (t, 3H).
Example 2
N-[4-((R)-2-Propylamino-propyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide
The desired product was obtained as a yellow powder following the same synthetic procedure as described for N-[4-((S)-2-propylamino-propyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide starting from 4-((R)-2-amino-propyl)-phenylamine×HCl.
MS (ESI) m/z: 417.15 [M+H]+
1H-NMR (CDCl3): δ [ppm] 7.80 (d, 2H), 7.20 (d, 2H), 7.06 (d, 2H), 7.00 (d, 2H), 2.90-3.00 (m, 1H), 2.80-2.90 (m, 1H), 2.65-2.75 (m, 1H), 2.52-2.60 (m, 2H), 1.45-1.60 (m, 2H), 1.05-1.10 (m, 3H), 0.85 (t, 3H).
Example 3
4-Isopropyl-N-[4-(2-propylamino-propyl)-phenyl]-benzenesulfonamide×HCl
Starting from racemic 4-(2-amino-propyl)-phenylamine and propionyl chloride the desired product was obtained as a yellow powder following the synthetic protocol of example 1 using 4-Isopropyl-benzenesulfonyl chloride.
MS (ESI) m/z: 375.25 [M+H]+
1H-NMR (CDCl3): δ [ppm] 7.69 (d, 2H), 7.25 (d, 2H), 7.06 (d, 2H), 7.00 (d, 2H), 2.88-2.98 (m, 1H), 2.78-2.87 (m, 1H), 2.42-2.70 (several m, 4H), 1.36-1.49 (m, 2H), 1.19-1.22 (m, 6H), 0.99-1.01 (m, 3H), 0.82 (t, 3H).
Example 4
N-[4-(2-Methyl-2-propylamino-propyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide
4.1 N-[2-(4-Amino-phenyl)-1,1-dimethyl-ethyl]-propionamide
A mixture of N-[1,1-dimethyl-2-(4-nitro-phenyl)-ethyl]-propionamide (1 g, 4 mmol) and 10% palladium on charcoal (100 mg) in methanol (50 ml) was hydrogenated at atmospheric pressure. After filtration the solvent was evaporated and the residue dissolved in ethyl acetate. The solution was dried over MgSO4, filtered, and the solvent evaporated under reduced pressure to give the product as a yellow oil (800 mg, 91%).
4.2 N-{1,1-Dimethyl-2-[4-(4-trifluoromethoxy-benzenesulfonylamino)-phenyl]-ethyl}-propionamide
To a solution of N-[2-(4-amino-phenyl)-1,1-dimethyl-ethyl]-propionamide (800 mg, 3.63 mmol) and triethylamine (800 mg, 7.91 mmol) in THF (30 ml) 4-Trifluoromethoxy-benzenesulfonyl chloride (950 mg, 3.63 mmol) was added at −5-0° C. The mixture was stirred at room temperature for 2 h. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with 5% citric acid, saturated aqueous NaHCO3, water, and brine, dried over MgSO4 and the solvent evaporated under reduced pressure. The residue was triturated with diethylether and the precipitate filtered and dried in vacuo to give the product as a brown powder (700 mg, 43%).
MS (ESI) m/z: 445.35 [M+H]+
4.3 N-[4-(2-Methyl-2-propylamino-propyl)-phenyl]-4-trifluoromethoxy-benzene-sulfonamide
To a solution of N-{1,1-dimethyl-2-[4-(4-trifluoromethoxy-benzenesulfonylamino)-phenyl]-ethyl}-propionamide (700 mg, 1.57 mmol) in THF (20 ml) borane-dimethylsulfid complex (2M in THF, 6.32 mmol) was added at room temperature. The mixture was heated to reflux for 2 h. The mixture was allowed to come to room temperature and HCl (2M) was added. This mixture was stirred for 16 h at room temperature. After extracting the mixture three times with dichloromethane the combined organic layers were washed with saturated aqueous NaHCO3, water, brine, dried over MgSO4, filtered, and the solvent evaporated under reduced pressure to give the product as a yellow oil. Column chromatography (CH2Cl2, 2%/methanol, 5%, 10%) gave the product as a yellow foam (500 mg, 74%).
MS (ESI) m/z: 431.35 [M+H]+
1H-NMR (CDCl3): δ [ppm] 7.82 (d, 2H), 7.21 (d, 2H), 7.03 (d, 2H), 6.99 (d, 2H), 2.78 (s, 2H), 2.64-2.70 (m, 2H), 1.55-1.65 (m, 2H), 1.08 (s, 6H), 0.91 (t, 3H).
Example 5
N-[4-((1-Propylamino-cyclopropyl)methyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide
Starting from N-[1-(4-nitro-benzyl)-cyclopropyl]-propionamide the desired product was obtained as a yellow oil following the synthetic protocol of example 4.
MS (ESI) m/z: 429.15 [M+H]+
1H-NMR (CDCl3): δ [ppm] 7.81 (d, 2H), 7.24 (d, 2H), 7.12 (d, 2H), 7.02 (d, 2H), 2.70 (s, 2H), 2.58-2.63 (m, 2H), 1.30-1.40 (m, 2H), 0.81 (t, 3H), 0.64 (m, 2H), 0.50 (m, 2H).
Example 6
4-Isopropyl-N-[4-(2-propylamino-ethyl)-phenyl]-benzenesulfonamide×HCl
Starting from commercially available 2-(4-aminophenyl)ethylamine and propionyl chloride the desired product was obtained as a colorless powder following the synthetic protocol of example 1 using 4-isopropyl-benzenesulfonyl chloride.
MS (ESI) m/z: 361.15 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 10.25 (s, 1H); 8.93 (bs, 2H), 7.7 (d, 2H), 7.41 (d, 2H), 7.04-7.15 (m, 4H), 3.47-3.65 (m, 2H), 2.77-3.10 (m, 5H), 1.58-1.69 (m, 2H), 1.18 (d, 6H), 0.90 (t, 3H).
Example 7
N-{4-[2-(Cyclopropylmethyl-amino)-ethyl]-phenyl}-4-isopropyl-benzenesulfonamide×HCl
Starting from commercially available 2-(4-aminophenyl)ethylamine and cyclopropanecarbonyl chloride the desired product was obtained as a colorless powder following the synthetic protocol of example 1 using 4-isopropyl-benzenesulfonyl chloride.
MS (ESI) m/z: 373.15 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 10.28 (s, 1H); 9.02 (bs, 2H), 7.70 (d, 2H), 7.41 (d, 2H), 7.04-7.15 (m, 4H), 2.75-3.10 (several m, 7H), 1.15-1.22 (m, 2H), 1.01-1.12 (m, 1H), 0.52-0.61 (m, 2H), 0.30-0.41 (m, 2H).
Example 8
N-[4-(2-Dipropylamino-ethyl)-phenyl]-4-isopropyl-benzenesulfonamide×HCl
8.1 {2-[4-(4-Isopropyl-benzenesulfonylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester
To a solution of [2-(4-amino-phenyl)-ethyl]-carbamicacid tert-butyl ester (10.75 g, 45.49 mmol) in pyridine (125 ml) at 0° C. 4-isopropyl-benzenesulfonyl chloride (10.45 g, 47.76 mmol) was added. The mixture was stirred at 0° C. for 1 h and 16 h at room temperature. After concentration in vacuo the residue was partitioned between dichloromethane and saturated aqueous NaHCO3. The organic layer was washed with water, dried over MgSO4, filtered and the solvent evaporated under reduced pressure to give the product as a brown oil (20.82 g, 50%).
8.2 N-[4-(2-Amino-ethyl)-phenyl]-4-isopropyl-benzenesulfonamide×HCl
To a solution of {2-[4-(4-isopropyl-benzenesulfonylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester (20.42 g, 48.79 mmol) in diethylether (200 ml) and THF (80 ml) at 0° C. HCl in diethylether (100 ml) was added slowly. The mixture was stirred at room temperature for 16 h. After concentration in vacuo the product was obtained as a yellow foam (17.3 g, 99.9%).
8.3 N-[4-(2-Dipropylamino-ethyl)-phenyl]-4-isopropyl-benzenesulfonamide×HCl
A solution of N-[4-(2-amino-ethyl)-phenyl]-4-isopropyl-benzenesulfonamide×HCl (740 mg, 2.09 mmol), 4 Å molecular sieves (750 mg) and cesium hydroxide (1.09 g, 6.27 mmol) in DMF was stirred at room temperature for 1 h before 1-bromo-propane (516 mg, 4.2 mmol) was added. The mixture was stirred at room temperature for 16 h. After concentrating the mixture in vacuo the residue was purified by column chromatography (toluene/THF/methanol, 4/1/1+2.5% triethylamine). The obtained yellow oil was dissolved in diethylether, and HCl in diethylether (1M) was added. The precipitate was collected and dried in vacuo to give the product as a colorless powder (210 mg, 23%).
MS (ESI) m/z: 403.25 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 10.30 (s, 1H), 7.69 (d, 2H), 7.4 (d, 2H), 7.17 (d, 2H), 7.06 (d, 2H), 3.12-3.22 (m, 2H), 2.87-3.08 (m, 7H), 1.61-1.75 (m, 4H), 1.19 (d, 6H), 0.88 (t, 6H).
Example 9
N-[4-(2-Dipropylamino-ethyl)-phenyl]-4-isopropyl-N-methyl-benzenesulfonamide×HCl
To a solution of N-[4-(2-dipropylamino-ethyl)-phenyl]-4-isopropyl-benzenesulfonamide×HCl (80 mg, 0.17 mmol) in N,N-dimethylformamide (DMF) (2.5 ml) 15-crown 5, and sodium hydride (10 mg, 0.36 mmol) were added, and the mixture was stirred at room temperature for 30 min. At 0° C. methyliodide (10 ml, 0.17 mmol) was added and the mixture was kept at 0° C. for 1 h. Then it was stirred for 16 h at room temperature. After concentration in vacuo the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with water, dried over MgSO4, filtered and the solvent evaporated under reduced pressure. The residue was dissolved in THF/diethyl ether and HCl in diethyl ether (1M) was added. The precipitate was collected and dried in vacuo to give the product as a yellow powder (50 mg, 59%).
MS (ESI) m/z: 417.25 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 9.76 (bs, 1H), 7.45 (s, 4H), 7.29 (d, 2H), 7.09 (d, 2H), 3.21-3.4 (m, 2H), 2.95-3.15 (m, 10H), 1.60-1.76 (m, 4H), 1.23 (d, 6H), 0.90 (t, 6H).
Example 10
4-Isopropyl-N-[6-(2-propylamino-ethyl)-pyridin-3-yl]-benzenesulfonamide×2HCl
10.1 (5-Nitro-pyridin-2-yl)-acetonitrile
To a solution of 5-nitro-2-chloropyridine (18 g, 113.5 mmol) in THF (100 ml) at room temperature K2CO3 (39.2 g, 283.8 mmol), cyanoacetic acid tert-butyl ester (24 g, 170.30 mmol) and 4 Å molecular sieves were added. The mixture was heated to reflux and stirred for 20 h. After concentrating the mixture under reduced pressure the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4, filtered and the solvent evaporated under reduced pressure. The obtained oil was dissolved in toluene (300 ml), toluene-4-sulfonic acid (2 g, 11.6 mmol) was added, and the mixture was heated to reflux for 2 h. The mixture then was stirred at room temperature for 16 h. After which the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over MgSO4, filtered, and the solvent evaporated under reduced pressure. Column chromatography (cyclohexane/dichloromethane, 4/1) gave the product as a colorless oil (10.3 g, 66%).
10.2 (5-Amino-pyridin-2-yl)-acetonitrile
To a mixture of (5-nitro-pyridin-2-yl)-acetonitrile (500 mg, 3.06 mmol) in concentrated aqueous HCl (3.1 ml) and ethanol (3.1 ml) at 0° C. SnCl2 (2.3 g, 10.11 mmol) was added. The mixture was allowed to come to room temperature and was stirred for 2 h. The mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3. The aqueous layer was extracted three times with ethyl acetate and the combined organic layers were washed with brine, dried over MgSO4, filtered, and the solvent evaporated under reduced pressure to give the product as a brown oil (300 mg, 74%).
MS (ESI) m/z: 134.05 [M+H]+
10.3 N-(6-Cyanomethyl-pyridin-3-yl)-4-isopropyl-benzenesulfonamide
To a solution of (5-amino-pyridin-2-yl)-acetonitrile (1 g, 7.5 mmol) in pyridine (10 ml) 4-Isopropyl-benzenesulfonyl chloride (1.64 g, 7.5 mmol) was added at −5-0° C. The mixture was stirred at 0° C. for 2 h and at room temperature for 16 h. The mixture was concentrated under reduced pressure, and the residue partitioned between ethyl acetate and saturated aqueous NaHCO3. The aqueous layer was extracted three times with ethyl acetate and the combined organic layers were washed with water, and brine, dried over MgSO4, filtered, and the solvent evaporated under reduced pressure to give the product as a brown oil which was purified by column chromatography using methyl-tert-butylether as an eluent to give a colorless oil (1.7 g, 72%).
MS (ESI) m/z: 316.10 [M+H]+
10.4 N-[6-(2-Amino-ethyl)-pyridin-3-yl]-4-isopropyl-benzenesulfonamide
A mixture of N-(6-cyanomethyl-pyridin-3-yl)-4-isopropyl-benzenesulfonamide (1.7 g, 5.4 mmol) aqueous ammonia (45 ml) and raney-nickel (2.7 mmol) in ethanol (50 ml) was hydrogenated at atmospheric pressure. After filtration the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 and the aqueous layer extracted five times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and the solvent evaporated under reduced pressure to give the product as a yellow powder after recrystallisation from methanol/ethyl acetate (1.3 g, 73%).
MS (ESI) m/z: 320.00 [M+H]+
10.5 N-{2-[5-(4-Isopropyl-benzenesulfonylamino)-pyridin-2-yl]-ethyl}-propionamide
To a solution of N-[6-(2-Amino-ethyl)-pyridin-3-yl]-4-isopropyl-benzenesulfonamide (50 mg, 0.16 mmol) in pyridine (3 ml) propionyl chloride (10 mg, 0.16 mmol) was added at −5-0° C. The mixture was stirred at 0° C. for 2 h and 3 h at room temperature. The mixture was partitioned between water and ethyl acetate and HCl (1M) was added. At pH=8 the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water, dried over MgSO4, filtered, and the solvent evaporated under reduced pressure to give the product as a yellow oil (40 mg, 68%).
MS (ESI) m/z: 376.15 [M+H]+
10.6 4-Isopropyl-N-[6-(2-propylamino-ethyl)-pyridin-3-yl]-benzenesulfonamide×2HCl
To a solution of N-{2-[5-(4-Isopropyl-benzenesulfonylamino)-pyridin-2-yl]-ethyl}-propionamide (40 mg, 0.11 mmol) in THF (3 ml) borane-dimethylsulfid complex (2M in THF, 1.49 mmol) was added at room temperature. The mixture was heated to reflux for 2 h. The mixture was allowed to come to room temperature and HCl (2M) was added. This mixture was stirred for 16 h at room temperature. After extracting the mixture three times with dichloromethane the combined organic layers were washed with saturated aqueous NaHCO3, water, and brine, dried over MgSO4 and the solvent evaporated under reduced pressure to give the product as a yellow oil which was dissolved in diethylether, and HCl in diethylether (1M) was added. The precipitate was collected and dried in vacuo to give the product as a colorless powder (6 mg, 15%).
MS (ESI) m/z: 362.15 [M+H]+
1H-NMR (MeOD): δ [ppm] 8.39 (s, 1H), 7.98 (bs, 1H), 7.62-7.80 (m, 3H), 7.35 (d, 2H), 3.18-3.40 (m, 4H), 2.82-3.00 (m, 3H), 1.58-1.75 (m, 2H), 1.28 (d, 6H), 0.95 (t, 3H).
Example 11
4-Isopropyl-N-[4-(1-propyl-pyrrolidin-2-ylmethyl)-phenyl]-benzenesulfonamide
2-(4-Aminobenzyl)-1-propylpyrrolidine (300 mg, 1.37 mmol) was dissolved in pyridine-dichloromethane (1:2, 9 mL) and cooled to 5° C. 4-Isopropylbenzenesulfonyl chloride (300 mg, 0.24 mmol) was added and the solution stirred at 5° C. for 18 h. The solution was evaporated, partitioned between ethyl acetate and water, and the organic phase separated and dried over MgSO4. The filtered solution was concentrated and separated by column chromatography (dichloromethane-2% methanol) to give an oil. The oil was dissolved in ethyl acetate and HCl (4M, dioxane) was added to give the product as a white solid (180 mg, 30%).
MS (ESI) m/z: 401.5 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 10.52 (s, 1H), 7.67 (d, 2H), 7.38 (d, 2H), 7.18 (d, 2H), 7.04 (d, 1H), 3.52 (m, 1H), 3.43 (m, 1H), 3.24 (m, 1H), 3.10-2.75 (m, 5H), 1.82 (m, 3H), 1.62 (m, 3H), 1.15 (d, 6H), 0.82 (t, 3H).
13C-NMR (DMSO-d6): δ [ppm] 153.5 (s), 137.2 (s), 136.5 (s), 132.6 (s), 129.7 (d), 127.1 (d), 126.7 (d) 119.9(d), 68.1 (d), 54.5 (t), 52.8 (t), 35.2 (t), 33.2 (d), 29.1 (t), 26.8 (t), 23.3 (q), 21.1 (t), 18.2 (t), 11.0 (q).
Example 12
Reference
4-Isopropyl-N-[3-(1-propyl-pyrrolidin-2-ylmethyl)-phenyl]-benzenesulfonamide
2-(3-Aminobenzyl)-1-propylpyrrolidine (30 mg, 0.14 mmol) was converted to the target sulfonamide by a procedure identical to that described in example 11. The product was obtained as a white solid (18 mg, 26%).
MS (ESI) m/z: 401.5 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 10.81 (s, 1H), 10.32 (s, 1H), 7.70 (d, 2H), 7.47 (d, 2H), 7.18 (m, 1H), 6.97 (m, 2H), 3.42 (m, 2H), 3.30 (m, 1H), 3.13 (m, 1H), 3.02 (m, 1H), 2.85 (m, 2H), 1.88 (m, 2H), 1.62 (m, 4H), 1.15 (d, 6H), 0.82 (t, 3H).
13C-NMR (DMSO-d6): δ [ppm] 153.6 (s), 138.1 (s), 136.9 (s), 129.4 (d), 127.1 (d), 126.9 (d), 124.5 (d) 120.2 (d), 118.4 (d), 67.8 (d), 54.2 (t), 52.6 (t), 35.7 (t), 33.2 (d), 28.9 (t), 26.8 (d), 23.3 (q), 20.9 (t), 18.2 (t), 11.0 (q).
Example 13
N-[4-(2-Allylamino-ethyl)-phenyl]-4-isopropyl-benzenesulfonamide×HCl
13.1 Allyl-{2-[4-(4-isopropyl-benzenesulfonylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester
To a solution of allyl-[2-(4-amino-phenyl)ethyl]-carbamic acid tert-butyl ester (1.86 g, 6.74 mmol) in pyridine (25 ml) at 0° C. was added 4-isopropyl-benzenesulfonyl chloride (1.47 g, 6.74 mmol) and the mixture was stirred at 0° C. for 1 h. After concentration in vacuo the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with water, dried over MgSO4, filtered and the solvent evaporated under reduced pressure. The residue was purified by column chromatography (n-heptane/ethyl acetate, 2/1) to give the product as a yellow resin (1.35 g, 43.6 mmol).
MS (ESI) m/z: 459.2 [M+H]+
13.2 N-[4-(2-Allylamino-ethyl)-phenyl]-4-isopropyl-benzenesulfonamide×HCl
To a solution of allyl-{2-[4-(4-isopropyl-benzenesulfonylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.35 g, 2.94 mmol) in diethylether (25 ml) was added HCl in diethylether (1M, 10 ml), and the mixture was stirred for 2 h at room temperature. After concentration in vacuo the obtained residue was triturated with diethylether, filtered, washed with diethylether, and dried in vacuo to give the product as a yellow powder (1.16 g, 99.8%).
MS (ESI) m/z: 359.15 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 10.29 (s, 1H), 9.15 (bs, 2H), 7.69 (d, 2H), 7.42 (d, 2H), 7.05-7.12 (m, 4H), 5.85-5.96 (m, 1H), 5.35-5.48 (m, 2H), 3.50-3.59 (m, 2H), 2.8-3.09 (m, 5H), 1.19 (d, 6H).
Example 14
N-[4-(2-Allylamino-ethyl)-phenyl]-4-isopropyl-N-methyl-benzenesulfonamide×HCl
14.1 Allyl-(2-{4-[(4-isopropyl-benzenesulfonyl)-methyl-amino]-phenyl}-ethyl)-carbamic acid tert-butyl ester
To a solution of allyl-{2-[4-(4-isopropyl-benzenesulfonylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester (200 mg, 0.44 mmol) in DMF (5 ml), 15-crown-5, and sodium hydride (20 mg, 0.48 mmol) were added, and the mixture was stirred at room temperature for 30 min. Methyliodide (60 mg, 0.44 mmol) was added and the mixture was stirred for 3 h at room temperature. After concentration in vacuo the residue was partitioned between dichloromethane and saturated aqueous NaHCO3. The organic layer was washed with water, dried over MgSO4, filtered and the solvent evaporated under reduced pressure to give the product as a yellow oil (200 mg, 97%).
MS (ESI) m/z: 417.1 [M+H]+
14.2 N-[4-(2-Allylamino-ethyl)-phenyl]-4-isopropyl-N-methyl-benzenesulfonamide×HCl
To a solution of allyl-(2-{4-[(4-isopropyl-benzenesulfonyl)-methyl-amino]-phenyl}-ethyl)-carbamic acid tert-butyl ester (180 mg, 0.39 mmol) in diethylether (10 ml) was added HCl in diethylether (1M, 10 ml), and the mixture was stirred for 3 h at room temperature. After concentration in vacuo the obtained residue was dissolved in THF and with addition of n-pentane a precipitate was formed which was collected, washed with n-pentane and dried in vacuo to give the product as a yellow powder (110 mg, 68%).
MS (ESI) m/z: 373.15 [M+H]+
1H-NMR (CDCl3): δ [ppm] 9.93 (bs, 1H), 7.49 (d, 2H), 7.30 (d, 2H), 7.19 (m, 2H), 7.05 (d, 2H), 6.02-6.18 (m, 1H), 5.45-5.54 (m, 2H), 3.58-3.69 (m, 2H), 3.05-3.30 (m, 7H), 2.90-3.03 (m, 1H), 1.28 (d, 6H).
Example 15
N-[4-(2-Allylamino-ethyl)-phenyl]-4-isopropyl-N-propyl-benzenesulfonamide×HCl
The desired product was obtained as a colorless powder following the synthetic procedure described for N-[4-(2-allylamino-ethyl)-phenyl]-4-isopropyl-N-methyl-benzenesulfonamide×HCl starting from Allyl-{2-[4-(4-isopropyl-benzenesulfonylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester and 1-bromo-propane.
MS (ESI) m/z: 401.25 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 9.19 (bs, 2H), 7.50 (d, 2H), 7.45 (d, 2H), 7.25 (d, 2H), 7.02 (d, 2H), 5.88-6.00 (m, 1H), 5.38-5.51 (m, 2H), 3.55-3.65 (m, 2H), 3.42-3.51 (m, 2H), 3.07-3.17 (m, 2H), 2.90-3.05 (m, 3H), 1.18-1.45 (m, 8H), 0.81 (t, 3H).
Example 16
N-[4-(2-Allylamino-ethyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide×HCl
The desired product was obtained as a yellow powder following the synthetic procedure described for N-[4-(2-allylamino-ethyl)-phenyl]-4-isopropyl benzenesulfonamide×HCl starting from allyl-[2-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester and 4-trifluoromethoxy-benzenesulfonyl chloride.
MS (ESI) m/z: 401.05 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 10.45 (bs, 1H), 9.01 (bs, 2H), 7.89 (d, 2H), 7.56 (d, 2H), 7.15 (d, 2H), 7.06 (d, 2H), 5.81-5.98 (m, 1H), 5.35-5.49 (m, 2H), 3.52-3.60 (m, 2H), 3.0-3.08 (m, 2H), 2.8-2.9 (m, 2H).
Example 17
N-[4-(2-Allylamino-ethyl)-phenyl]-N-methyl-4-trifluoromethoxy-benzenesulfonamide×HCl
The desired product was obtained as a yellow powder following the synthetic procedure described for N-[4-(2-allylamino-ethyl)-phenyl]-4-isopropyl-N-methyl-benzenesulfonamide×HCl starting from Allyl-{2-[4-(4-trifluoromethoxy-benzenesulfonylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester and methyliodide.
MS (ESI) m/z: 415.15 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 9.12 (bs, 2H), 7.68 (d, 2H), 7.49 (d, 2H), 7.25 (d, 2H), 7.09 (d, 2H), 5.86-5.98 (m, 1H), 5.38-5.52 (m, 2H), 3.55-3.65 (m, 2H), 3.05-3.19 (m, 5H), 2.90-3.00 (m, 2H).
Example 18
N-[4-(2-Allylamino-ethyl)-phenyl]-N-propyl-4-trifluoromethoxy-benzenesulfonamide×HCl
The desired product was obtained as a colorless powder following the synthetic procedure described for N-[4-(2-Allylamino-ethyl)-phenyl]-4-isopropyl-N-methyl-benzenesulfonamide×HCl starting from Allyl-{2-[4-(4-trifluoromethoxy-benzenesulfonylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester and 1-bromo-propane.
MS (ESI) m/z: 443.15 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 9.18 (bs, 2H), 7.70 (d, 2H), 7.59 (d, 2H), 7.26 (d, 2H), 7.05 (d, 2H), 5.87-6.00 (m, 1H), 5.38-5.50 (m, 2H), 3.48-3.65 (m, 4H), 3.08-3.18 (m, 2H), 2.92-3.01 (m, 2H), 1.26-1.35 (m, 2H), 0.82 (t, 3H).
Example 19
N-[4-(2-Diallylamino-ethyl)-phenyl]-4-isopropyl-benzenesulfonamide×HCl
19.1 {2-[4-(4-Isopropyl-benzenesulfonylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester
To a solution of [2-(4-amino-phenyl)-ethyl]-carbamicacid tert-butyl ester (10.75 g, 45.49 mmol) in pyridine (125 ml) at 0° C. 4-Isopropyl-benzenesulfonyl chloride (10.45 g, 47.76 mmol) was added. The mixture was stirred at 0° C. for 1 h and 16 h at room temperature. After concentration in vacuo the residue was partitioned between dichloromethane and saturated aqueous NaHCO3. The organic layer was washed with water, dried over MgSO4, filtered and the solvent evaporated under reduced pressure to give the product as a brown oil (20.82 g, 50%).
19.2 N-[4-(2-Amino-ethyl)-phenyl]-4-isopropyl-benzenesulfonamide×HCl
To a solution of {2-[4-(4-isopropyl-benzenesulfonylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester (20.42 g, 48.79 mmol) in diethylether (200 ml) and THF (80 ml) at 0° C. HCl in diethylether (100 ml) was added slowly. The mixture was stirred at room temperature for 16 h. After concentration in vacuo the product was obtained as a yellow foam (17.3 g, 99.9%)
19.3 N-[4-(2-Diallylamino-ethyl)-phenyl]-4-isopropyl-benzenesulfonamide×HCl
A solution of N-[4-(2-Amino-ethyl)-phenyl]-4-isopropyl-benzenesulfonamide×HCl (740 mg, 2.09 mmol), 4 Å molecular sieves (750 mg) and cesium hydroxide (1.09 g, 6.27 mmol) in DMF was stirred at room temperature for 1 h before allylbromide (508 mg, 4.2 mmol) was added. The mixture was stirred at room temperature for 16 h. After concentrating the mixture in vacuo the residue was purified by column chromatography (toluene/THF/methanol, 4/1/1+2.5% triethylamine). The obtained yellow oil was dissolved in diethylether, and HCl in diethylether (1M) was added. The precipitate was collected and dried in vacuo to give the product as a colorless powder (210 mg, 23%).
MS (ESI) m/z: 399.15 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 10.39 (s, 1H), 7.69 (d, 2H), 7.41 (d, 2H), 7.04-7.13 (m, 4H), 5.96-6.08 (m, 2H), 5.47-5.59 (m, 4H), 3.71-3.80 (m, 4H), 3.04-3.15 (m, 2H), 2.89-2.99 (m, 3H), 1.19 (d, 6H).
Example 20
N-[4-(2-Diallylamino-ethyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide×HCl
The desired product was obtained as a yellow foam following the synthetic procedure described for N-[4-(2-diallylamino-ethyl)-phenyl]-4-isopropyl-benzenesulfonamide×HCl starting from [2-(4-amino-phenyl)-ethyl]-carbamicacid tert-butyl ester and 4-trifluoromethoxy-benzenesulfonyl chloride.
MS (ESI) m/z: 441.15 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 10.93 (bs, 1H), 10.45 (s, 1H), 7.89 (d, 2H), 7.55 (d, 2H), 7.14 (d, 2H), 7.06 (d, 2H), 5.93-6.09 (m, 2H), 5.46-5.59 (m, 4H), 3.68-3.84 (m, 4H), 3.04-3.17 (m, 2H), 2.90-3.01 (m, 2H).
Example 21
Reference
N-[3-(2-Allylamino-ethyl)-phenyl]-4-isopropyl-benzenesulfonamide
The desired product was obtained as a pink powder following the synthetic procedure described for N-[4-(2-Allylamino-ethyl)-phenyl]-4-isopropyl-benzenesulfonamide×HCl starting from allyl-[2-(3-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester and 4-Isopropyl-benzenesulfonyl chloride.
MS (ESI) m/z: 359.15 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 10.30 (s, 1H), 9.09 (bs, 2H), 7.69 (d, 2H), 7.42 (d, 2H), 7.19 (t, 1H), 6.95-7.03 (m, 2H), 6.90 (d, 1H), 5.85-5.98 (m, 1H), 5.38-5.50 (m, 2H), 2.80-3.05 (several m, 5H), 1.19 (d, 6H).
Example 22
N-[3-(2-Allylamino-ethyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide
The desired product was obtained as a pink powder following the synthetic procedure described for N-[4-(2-allylamino-ethyl)-phenyl]-4-isopropyl-benzenesulfonamide×HCl starting from allyl-[2-(3-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester and 4-trifluoromethoxy-benzenesulfonyl chloride.
MS (ESI) m/z: 401.05 [M+H]+
1H-NMR (DMSO-d6): δ [ppm]10.48 (s, 1H), 9.05 (bs, 2H), 7.89 (d, 2H), q 7.55 (d, 2H) 7.20 (t, 1H), 6.91-7.03 (m, 3H), 5.85-5.98 (m, 1H), 5.38-5.50 (m, 2H), 3.52-3.62 (m, 2H), 2.95-3.05 (m, 2H), 2.82-2.90 (m, 2H).
Example 23
Diallyl-{2-[4-(4-isopropyl-benzenesulfonylmethyl)-phenyl]-ethyl}-amine×HCl
23.1 2-(4-Bromomethyl-phenyl)-acetamide
To a solution of (4-bromomethyl-phenyl)-acetic acid (9.23 g, 40.30 mmol) and N,N-dimethylformamide (0.5 ml, 6.47 mmol) in toluene (100 ml) thionyl chloride (3.1 ml, 42.31 mmol) was added. The mixture was heated at 80° C. for 1 h. At 0° C., this mixture was added to a solution of ammonia in water (25%, 200 ml). After stirring for 30 min the precipitate was collected, washed with water and pentane, and dried in a vacuum oven at 50° C. to give the product as white crystals (5.8 g, 63%).
23.2 2-[4-(4-Isopropyl-benzenesulfonylmethyl)-phenyl]-acetamide
To a solution of 4-(isopropyl)thiophenol (1.91 g, 12.54 mmol) in N,N-dimethylformamide (50 ml) sodium hydride (530 mg, 13.17 mmol) was added. The exothermic reaction was allowed to cool down to room temperature. At 15° C., a solution of 2-(4-bromomethyl-phenyl)-acetamide (2.86 g, 12.54 mmol) in N,N-dimethylformamide (25 ml) was added. After stirring the reaction mixture at room temperature for 16 h, the mixture was poured into ice-water. The precipitate was collected, washed with water and pentane, and dried in a vacuum oven at 50° C. to give the title compound as a white powder (3.46 g, 92%). This powder was used without further purification in the next step.
The powder obtained above was dissolved in methanol (100 ml). At 0-5° C. a solution of oxone (20.6 g, 33.5 mmol) in water (75 ml) was added. The mixture was stirred at 0° C. for 1 h and at room temperature for 16 h. On diluting the mixture with water a white solid was formed, which was collected, washed with water and pentane, and dried in a vacuum oven at 50° C. to give 2-[4-(4-isopropyl-benzenesulfonylmethyl)-phenyl]-acetamide as a white powder (3.39 g, 92%).
23.3 2-[4-(4-Isopropyl-benzenesulfonylmethyl)-phenyl]-ethylamine×HCl
A solution of 2-[4-(4-isopropyl-benzenesulfonylmethyl)-phenyl]-acetamide (1.37 g, 4.13 mmol) in tetrahydrofuran (30 ml) was refluxed and then a solution of borane-dimethylsulfid complex (2M in tetrahydrofuran, 10.33 mmol) was added. The mixture was refluxed for 2 h. The mixture was allowed to cool down to room temperature and adjusted to pH=1 with a solution of HCl in ethanol (2M). After stirring the mixture for 15 min the solvents were evaporated under reduce pressure. Diethyl ether was added to residue. A slurry of the resulting white powder in diethyl ether was stirred for 15 min. The remaining solid was collected, washed with diethyl ether, and dried in a vacuum oven to give white crystals of 2-[4-(4-isopropyl-benzenesulfonylmethyl)-phenyl]-ethylamine×HCl (1.36 g, 92.6%).
MS (ESI) m/z: 318.15 [M+H]+
 23.4 Diallyl-{2-[4-(4-isopropyl-benzenesulfonylmethyl)-phenyl]-ethyl}-amine×HCl
To a solution of 2-[4-(4-isopropyl-benzenesulfonylmethyl)-phenyl]-ethylamine×HCl (0.81 g, 2.27 mmol) in N,N-dimethylformamide (30 ml) cesium hydroxide (1.2 g, 6.9 mmol) was added. After the mixture was stirred for 1 h, allylbromide (0.83 g, 6.8 mmol) was added. The mixture was stirred for 16 h. The solvents were evaporated under reduced pressure and the residue was purified by column chromatography (toluene:tetrahydrofuran:methanol, 4:1:1, +2.5% triethylamine). A solution of HCl in isopropanol (1M) was added to the resulting oil. The precipitate was collected, washed with pentane, and dried in vacuo to give a white powder (0.5 g, 50%).
MS (ESI) m/z: 398.20 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 11.10 (bs, 1H), 7.68 (d, 2H), 7.49 (d, 2H), 7.29 (d, 2H), 7.15 (d, 2H), 5.95-6.12 (m, 2H), 5.47-5.65 (m, 4H), 4.61 (m, 2H), 3.68-3.88 (m, 4H), 2.92-3.25 (m, 3H), 1.22 (d, 6H).
Example 24
Diallyl-{2-[4-(4-trifluoromethoxy-benzenesulfonylmethyl)-phenyl]-ethyl}-amine×HCl
24.1 2-[4-(4-Trifluoromethoxy-benzenesulfonylmethyl)-phenyl]-acetamide
To a solution of 4-(trifluoromethoxy)thiophenol (2.86 g, 12.54 mmol) in N,N-dimethylformamide (50 ml) sodium hydride (530 mg, 13.17 mmol) was added. The exothermic reaction was allowed to cool down to room temperature. At 15° C. a solution of 2-(4-bromomethyl-phenyl)-acetamide (2.86 g, 12.54 mmol) in N,N-dimethylformamide (25 ml) was added. After stirring the reaction mixture at room temperature for 16 h the mixture was added to ice-water. The precipitate was collected, washed with water and pentane, and dried in a vacuum oven at 50° C. to give the product as a yellow powder (3.56 g, 83%).
The thus obtained powder, which was used without further purification, was dissolved in methanol (200 ml). At room temperature a solution of oxone (18.4 g, 29.9 mmol) in water (75 ml) was added. The mixture was stirred at room temperature for 16 h and additional 3 h at 50° C. Upon diluting the mixture with water a white solid was formed, which was collected, washed with water and pentane, and dried in a vacuum oven at 50° C. to give 2-[4-(4-trifluoromethoxy-benzenesulfonylmethyl)-phenyl]-acetamide as a white powder (2.66 g, 71%).
24.2 2-[4-(4-Trifluoromethoxy-benzenesulfonylmethyl)-phenyl]-ethylamine×HCl
A solution of 2-[4-(4-trifluoromethoxy-benzenesulfonylmethyl)-phenyl]-acetamide (1.36 g, 3.64 mmol) in tetrahydrofuran (30 ml) was refluxed and a solution of borane-dimethylsulfid complex (2M in tetrahydrofuran, 9.11 mmol) was added. The mixture was refluxed for 2 h. The mixture was allowed to come to room temperature and was adjusted to pH=1 using a solution of HCl in ethanol (2M). After stirring the mixture for 15 min the solvents were evaporated under reduced pressure. A slurry of the resulting white powder in diethyl ether was stirred for 15 min. The remaining solid was collected, washed with diethyl ether, and dried in a vacuum oven to give white crystals of 2-[4-(4-trifluoromethoxy-benzenesulfonylmethyl)-phenyl]-ethylamine×HCl (1.22 g, 84.7%).
MS (ESI) m/z: 360.05 [M+H]+
24.3 Diallyl-{2-[4-(4-trifluoromethoxy-benzenesulfonylmethyl)-phenyl]-ethyl}-amine×HCl
To a solution of 2-[4-(4-trifluoromethoxy-benzenesulfonylmethyl)-phenyl]-ethylamine×HCl (1.14 g, 2.89 mmol) in N,N-dimethylformamide (30 ml) cesium hydroxide (1.5 g, 8.7 mmol) was added. After the mixture was stirred for 1 h, allylbromide (1.05 g, 8.7 mmol) was added. The mixture was stirred for 16 h. The solvents were evaporated in vacuo and the residue was purified by column chromatography (toluene: tetrahydrofuran:methanol, 4:1:1, +2.5% triethylamine). To the resulting oil a solution of HCl in isopropanol (1M) was added. The precipitate was collected, washed with pentane and dried in vacuo to give a white powder (0.78 g, 56%)
MS (ESI) m/z: 440.15 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 11.40 (bs, 1H), 7.88 (d, 2H), 7.60 (d, 2H), 7.20 (d, 2H), 7.15 (d, 2H), 5.98-6.11 (m, 2H), 5.49-5.65 (m, 4H), 4.71 (m, 2H), 3.70-3.85 (m, 4H), 3.30-3.40 (m, 2H), 3.00-3.22 (m, 4H).
Example 25
Dipropyl-{2-[4-(4-isopropyl-benzenesulfonylmethyl)-phenyl]-ethyl}-amine×HCl
To a solution of diallyl-{2-[4-(4-isopropyl-benzenesulfonylmethyl)-phenyl]-ethyl}-amine×HCl (90 mg, 0.21 mmol) in ethanol (25 ml) a suspension of palladium on charcoal (10%, 100 mg) in ethanol was added. The mixture was hydrogenated at atmospheric pressure. After filtration and removal of the solvents in vacuo the resulting oil was triturated with diethyl ether. The precipitate was collected, washed with diethyl ether and dried in vacuo to give the product as a yellow foam (30 mg, 36.2%).
MS (ESI) m/z: 402.25 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 10.30 (bs, 1H), 7.67 (d, 2H), 7.49 (d, 2H), 7.25 (d, 2H), 7.15 (d, 2H), 4.61 (m, 2H), 3.15-3.29 (m, 2H), 2.92-3.15 (m, 7H), 1.6-1.8 (m, 4H), 1.23 (d, 6H), 0.92 (t, 6H).
Example 26
Dipropyl-{2-[4-(4-trifluoromethoxy-benzenesulfonylmethyl)-phenyl]-ethyl}-dipropyl-amine×HCl
To a solution of diallyl-{2-[4-(4-trifluoromethoxy-benzenesulfonylmethyl)-phenyl]-ethyl}-amine×HCl (160 mg, 0.34 mmol) in ethanol (25 ml) a suspension of palladium on charcoal (10%, 150 mg) in ethanol was added. The mixture was hydrogenated at atmospheric pressure. After filtration and removal of the solvents in vacuo the resulting oil was triturated with diethyl ether. The precipitate was collected, washed with diethyl ether and dried in vacuo to give the product as a colourless powder (120 mg, 70%).
MS (ESI) m/z: 444.15 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 10.30 (bs, 1H), 7.89 (d, 2H), 7.59 (d, 2H), 7.25 (d, 2H), 7.13 (d, 2H), 4.71 (m, 2H), 3.15-3.29 (m, 2H), 2.98-3.15 (m, 6H), 1.61-1.78 (m, 4H), 0.92 (t, 6H).
Example 27
Allyl-{2-[4-(4-isopropyl-benzenesulfonylmethyl)-phenyl]-ethyl}-amine×HCl
2-[4-(4-Isopropyl-benzenesulfonylmethyl)-phenyl]-ethylamine×HCl (0.81 g, 2.27 mmol) was dissolved in a solution of sodium hydroxide in methanol (1M, 2.27 mmol), the methanol was removed and N,N-dimethylformamide (20 ml) was added. To a solution of the resulting 2-[4-(4-isopropyl-benzenesulfonylmethyl)-phenyl]-ethylamine in N,N-dimethylformamide activated 4 Å molecular sieves (700 mg) and cesium hydroxide (40 mg, 0.228 mmol) were added. The mixture was stirred at room temperature for 1 h. After addition of allybromide (0.82 g, 6.81 mmol) the mixture was stirred at room temperature for 16 h. The solvents were evaporated in vacuo and the residue was purified by column chromatography (toluene:tetrahydrofuran:methanol, 4:1:1, +2.5% triethylamine). To the resulting oil a solution of HCl in isopropanol (1M) was added. The precipitate was collected, washed with pentane, and dried in vacuo to give a white powder (0.14 g, 15%).
MS (ESI) m/z: 358.15 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 9.01-9.20 (m, 1H), 7.68 (d, 2H), 7.49 (d, 2H), 7.19 (d, 2H), 7.12 (d, 2H), 5.85-5.99 (m, 1H), 5.39-5.52 (m, 2H), 4.60 (s, 2H), 3.55-3.65 (m, 2H), 2.90-3.15 (m, 5H), 1.22 (d, 6H).
Example 28
{2-[4-(4-Isopropyl-benzenesulfonylmethyl)-phenyl]-ethyl}-propyl-amine×HCl
28.1 [4-(4-Isopropyl-phenylsulfanylmethyl)-phenyl]-acetic acid
To a solution of 4-(isopropyl)thiophenol (10 g, 65.68 mmol) in N,N-dimethylformamide (200 ml) sodium hydride (3.15 g, 131.35 mmol) was added. The exothermic reaction was allowed to cool down to room temperature. At 15° C. a solution of (4-bromomethyl-phenyl)-acetic acid (15.04 g, 65.68 mmol) in N,N-dimethylformamide (100 ml) was added. After stirring the reaction mixture at room temperature for 16 h the mixture was concentrated, diluted with water, and adjusted to pH=2 by adding HCl (2N). The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and the solvent evaporated under reduced pressure to give the product as a yellow oil (19.5 g, 99%).
MS (ESI) m/z: 301.15 [M+H]+
28.2 [4-(4-Isopropyl-benzenesulfonylmethyl)-phenyl]-acetic acid
A solution of [4-(4-isopropyl-phenylsulfanylmethyl)-phenyl]-acetic acid (20.3 g, 67.57 mmol) in acetic acid (100 ml) was heated to 70° C. and hydrogen peroxide (24.5 g, 216.23 mmol) was added over a period of 10 min. The mixture was stirred at 70° C. for 2 h. The mixture was poured into ice-water and the precipitate was filtered, washed with diisopropyl ether and dried in vacuo to give the product as a colorless powder (19.9 g, 89%).
28.3 2-[4-(4-Isopropyl-benzenesulfonylmethyl)-phenyl]-N-propyl-acetamide
To a solution of [4-(4-isopropyl-benzenesulfonylmethyl)-phenyl]-acetic acid (1 g, 3.00 mmol) in pyridine (15 ml)/N,N-dimethylformamide (15 ml) N,N′-carbonyldiimidazole (0.54 g, 3.31 mmol) was added and the mixture heated to 50° C. for 1 h. At 0° C. propylamine was added. The mixture was stirred at room temperature for 16 h. Then, the mixture was poured into water. The precipitate was collected and dried in a vacuum oven at 70° C. to give the product as a yellow powder (0.89 g, 2.39 mmol).
MS (ESI) m/z: 374.15 [M+H]+
28.4 {2-[4-(4-Isopropyl-benzenesulfonylmethyl)-phenyl]-ethyl}-propyl-amine
To a solution of 2-[4-(4-isopropyl-benzenesulfonylmethyl)-phenyl]-N-propylacetamide (500 mg, 1.34 mmol) in tetrahydrofuran (30 ml) borane-tetrahydrofuran complex (2M in tetrahydrofuran, 6.70 mmol) was added at 0° C. The mixture was stirred at room temperature for 16 h after which a solution of HCl in ethanol (1M) was added and the mixture was stirred for 2 h. The mixture was concentrated in vacuo, diluted with water, and adjusted to pH=10 by adding aqueous NaOH. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (water/methanol/0.1% acetic acid) to give the product as a colorless powder (130 mg, 27%).
MS (ESI) m/z: 360.25 [M+H]+
1H-NMR (DMSO-d6): δ [ppm] 7.68 (d, 2H), 7.49 (d, 2H), 7.19 (d, 2H), 7.12 (d, 2H), 4.59 (m, 2H), 2.83-3.10 (m, 5H), 2.68-2.82 (m, 2H), 1.52-1.68 (m, 2H), 1.22 (d, 6H), 0.90 (t, 6H).
III. Examples of Galenic Administration Forms
A) Tablets
Tablets of the following composition are pressed on a tablet press in the customary manner:
40 mg of substance from Example 8
120 mg of corn starch
13.5 mg of gelatin
45 mg of lactose
2.25 mg of Aerosil® (chemically pure silicic acid in submicroscopically fine dispersion)
6.75 mg of potato starch (as a 6% paste)
B) Sugar-coated tablets
20 mg of substance from Example 8
60 mg of core composition
70 mg of saccharification composition
The core composition consists of 9 parts of corn starch, 3 parts of lactose and 1 part of 60:40 vinylpyrrolidone/vinyl acetate copolymer. The saccharification composition consists of 5 parts of cane sugar, 2 parts of corn starch, 2 parts of calcium carbonate and 1 part of talc. The sugar-coated tablets which had been prepared in this way are subsequently provided with a gastric juice-resistant coating.
IV. Biological Investigations


    
    
        Receptor Binding Studies:
        The substance to be tested was either dissolved in methanol/Chremophor® (BASF-AG) or in dimethyl sulfoxide and then diluted with water to the desired concentration.
        Dopamine D3 Receptor:
        The assay mixture (0.250 ml) was composed of membranes derived from  ̃106 HEK-293 cells possessing stably expressed human dopamine D3 receptors, 0.1 nM [125I]-iodosulpride and incubation buffer (total binding) or, in addition, test substance (inhibition curve) or 1 μM spiperone (nonspecific binding). Each assay mixture was run in triplicate.
        The incubation buffer contained 50 mM tris, 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 2 mM MgCl2 and 0.1% bovine serum albumin, 10 μM quinolone and 0.1% ascorbic acid (prepared fresh daily). The buffer was adjusted to pH 7.4 with HCl.
        Dopamine D2L Receptor:
        The assay mixture (1 ml) was composed of membranes from  ̃106 HEK-293 cells possessing stably expressed human dopamine D2L receptors (long isoform) and 0.01 nM [125I] iodospiperone and incubation buffer (total binding) or, in addition, test substance (inhibition curve) or 1 μM haloperidol (nonspecific binding). Each assay mixture was run in triplicate.
        The incubation buffer contained 50 mM tris, 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 2 mM MgCl2 and 0.1% bovine serum albumin. The buffer was adjusted to pH 7.4 with HCl.
        Measurement and Analysis:
        After having been incubated at 25° C. for 60 minutes, the assay mixtures were filtered through a Whatman GF/B glass fiber filter under vacuum using a cell collecting device. The filters were transferred to scintillation viols using a filter transfer system. After 4 ml of Ultima Gold® (Packard) have been added, the samples were shaken for one hour and the radioactivity was then counted in a Beta-Counter (Packard, Tricarb 2000 or 2200CA). The cpm values were converted into dpm using a standard quench series and the program belonging to the instrument.
        The inhibition curves were analyzed by means of iterative nonlinear regression analysis using the Statistical Analysis System (SAS) which is similar to the “LIGAND” program described by Munson and Rodbard.
        The results of the receptro binding studies are expressed as receptor binding constants Ki(D2) and Ki(D3), respectively, as herein before described, and given in table 3.
        In these tests, the compounds according to the invention exhibit very good affinities for the D3 receptor (<10 nM, frequently <5 nM) and bind selectively to the D3 receptor.
        The results of the binding tests are given in table 3.
    
    













TABLE 3







Example
Ki(D3)* [nM]
Ki(D2)*/Ki(D3)*




















 1
43
41



 2
21
57



 3
2.8
33



 6
2.2
22



 7
18
23



 8
0.2
54



 9
2
40



10
42
53



11
0.58
16



13
1.7
74



14
27
40



15
22
22



16
31
79



17
34
75



18
37
24



19
2.7
42



20
64
65



21 ref.
22
62



23
8.4
59



25
0.5
175



26
3.9
170



28
4.8
130







*Receptor binding constants obtained according to the assays described herein before

## Claims

1. An aminoethylaromatic compound of the formula I



wherein
Ar is phenyl wherein Ar optionally carries 1 radical Ra wherein if Ar carries Ra, Ar optionally carries 1 or 2 radicals Rb;
Ra being selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, fluorinated C2-C6-alkenyl, C3-C6-cycloalkyl, C1-C6-alkoxy, fluorinated C1-C6-alkyl, fluorinated C3-C6-cycloalkyl, fluorinated C1-C6-alkoxy, C1-C6-hydroxyalkyl, C1-C6-alkoxy-C1-C4-alkyl, C1-C6-hydroxyalkoxy, C1-C6-alkoxy-C1-C4-alkoxy, COOH, NR4R5, CH2NR4R5, ONR4R5, NHC(O)NR41e, C(O)NR4R5, SO2NR4R5, C1-C6-alkylcarbonyl, fluorinated C1-C6-alkylcarbonyl, C1-C6-alkylcarbonylamino, fluorinated C1-C6-alkylcarbonylamino, C1-C6-alkylcarbonyloxy, fluorinated C1-C6-alkylcarbonyloxy, C1-C6-alkoxycarbonyl, C1-C6-alkylthio, fluorinated C1-C6-alkylthio, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, fluorinated C1-C6-alkylsulfinyl, fluorinated C1-C6-alkylsulfonyl, phenylsulfonyl, phenyl, phenoxy, benzyloxy and a 3- to 7-membered heterocyclic radical, wherein the five last mentioned radicals may carry 1, 2, 3 or 4 radicals selected from halogen, cyano, OH, oxo, CN, and the radicals Ra;
Rb being, independently from each other, selected from halogen, cyano, nitro, OH, methyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluormethoxy, difluoromethoxy and trifluoromethoxy;
X is CH;
E is CR6R7;
R1 is C1-C4-alkyl, C3-C4-cycloalkyl, C3-C4-cycloalkylmethyl, C3-C4-alkenyl, fluorinated C1-C4-alkyl, fluorinated C3-C4-cycloalkyl, fluorinated C3-C4-cycloalkylmethyl, fluorinated C3-C4-alkenyl, formyl or C1-C3-alkylcarbonyl;
R1a is H, C1-C4-alkyl, C3-C4-cycloalkyl, C3-C4-cycloalkylmethyl, C3-C4-alkenyl, fluorinated C3-C4-alkyl, fluorinated C3-C4-cycloalkyl, fluorinated C3-C4-cycloalkylmethyl, fluorinated C1-C4-alkenyl, or R1a and R2 together are (CH2)n with n being 2, 3 or 4, or R1a and R2 together are (CH2)n with n being 2, 3 or 4;
R2, R2a are independently of each other H, C1-C4-alkyl or fluorinated C1-C4-alkyl;
R4, R5 independently of each other are selected from H, C1-C3-alkyl, C1-C3-alkoxy and fluorinated C1-C3-alkyl;
R6, R7 independently of each other are selected from H, fluorine, C1-C4-alkyl and fluorinated C1-C4-alkyl or together form a moiety (CH2)p with p being 2, 3, 4 or 5;
and the physiologically tolerated acid addition salts of these compounds.

2. The compounds as claimed in claim 1, wherein Ar is phenyl wherein Ar carries one radical Ra which is selected from the group consisting of C2-C6-alkyl, C3-C6-cycloalkyl, C1-C6-alkoxy, fluorinated C1-C6-alkyl, fluorinated C3-C6-cycloalkyl, fluorinated C1-C6-alkoxy, NR4R5, 1-aziridinyl, azetidin-1-yl, pyrrolidin-1-yl or piperidin-1-yl, wherein the last four mentioned radicals may be fluorinated, a phenyl group and an aromatic 5- or 6-membered C-bound heteroaromatic radical, comprising 1 nitrogen atom as ring member and 0, 1, 2 or 3 further heteroatoms, independently of each other, selected from 0, S and N, wherein the last two mentioned radicals may carry 1, 2, 3 or 4 radicals selected from halogen and the radicals Ra; and wherein Ar may carry 1 or 2 further radicals Rb, which are independently from each other selected from halogen, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy; and wherein R4, R5, independently of each other are selected from H, C1-C3-alkyl and fluorinated C1-C3-alkyl.

3. The compounds as claimed in claim 1, wherein Ar carries one radical Ra of the formula Ra′



wherein
Y is N, CH or CF,
Ra1 and Ra2 are independently of each other selected from C1-C2-alkyl, C1-C2-alkoxy, fluorinated C1-C2-alkyl, provided for Y being CH or CF one of the radicals Ra1 or Ra2 may also be hydrogen or fluorine, or.

4. The compounds as claimed in claim 3, wherein the radical Ra′ is selected from isopropyl, (R)-1-fluoroethyl, (S)-1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (R)-1-fluoropropyl, (S)-1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 1,1-difluoropropyl, 2,2-difluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, (R)-2-fluoro-1-methylethyl, (S)-2-fluoro-1-methylethyl, (R)-2,2-difluoro-1-methylethyl, (S)-2,2-difluoro-1-methylethyl, (R)-1,2-difluoro-1-methylethyl, (S)-1,2-difluoro-1-methylethyl, (R)-2,2,2-trifluoro-1-methylethyl, (S)-2,2,2-trifluoro-1-methylethyl, 2-fluoro-1-(fluoromethyhethyl, 1-(difluoromethyl)-2,2-difluoroethyl, cyclopropyl, cyclobutyl, 1-fluorocyclopropyl, and 2-fluorocyclopropyl.

5. The compounds as claimed in claim 3, wherein the radical Ra′ is selected from 4-morpholinyl, 4-thiomorpholinyl, 4-(1,1-dioxo)thiomorpholinyl, piperazin-1-yl, 4-methylpiperazin-1-yl, azetidin-1-yl, 2-methylazetidin-1-yl, (S)-2-methylazetidin-1-yl, (R)-2-methylazetidin-1-yl, 3-fluoroazetidin-1-yl, 3-methoxyazetidin-1-yl, 3-hydroxyazetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, (S)-pyrrolidin-2-yl, (R)-pyrrolidin-2-yl, pyrrolidin-3-yl, (S)-pyrrolidin-3-yl, (R)-pyrrolidin-3-yl, 2-fluoropyrrolidin-1-yl, (S)-2-fluoropyrrolidin-1-yl, (R)-2-fluoropyrrolidin-1-yl, 3-fluoropyrrolidin-1-yl, (S)-3-fluoropyrrolidin-1-yl, (R)-3-fluoropyrrolidin-1-yl, 2,2-difluoropyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, (S)-2-methylpyrrolidin-1-yl, (R)-2-methylpyrrolidin-1-yl, 3-methylpyrrolidin-1-yl, (S)-3-methylpyrrolidin-1-yl, (R)-3-methylpyrrolidin-1-yl, 1-methylpyrrolidin-2-yl, (S)-1-methylpyrrolidin-2-yl, (R)-1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, (S)-1-methylpyrrolidin-3-yl, (R)-1-methylpyrrolidin-3-yl, 2,2-dimethylpyrrolidin-1-yl, 3,3-dimethylpyrrolidin-1-yl, 2-trifluoromethylpyrrolidin-1-yl, (S)-2-trifluoromethylpyrrolidin-1-yl, (R)-2-trifluoromethylpyrrolidin-1-yl, 3-trifluoromethylpyrrolidin-1-yl, (S)-3-trifluoromethylpyrrolidin-1-yl, (R)-3-trifluoromethylpyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxo-oxazolidin-3-yl, piperidin-1-yl, 2-methylpiperidin-1-yl, (S)-2-methylpiperidin-1-yl and (R)-2-methylpiperidin-1-yl.

6. The compounds as claimed in claim 3, wherein the radical Ra′ carries 1, 2, 3 or 4 fluorine atoms.

7. The compounds as claimed in claim 1, wherein Ar carries one radical Ra, which is selected from CHF2CH2F, OCHF2 and OCH2F.

8. The compounds as claimed in claim 1, wherein Ar carries one radical Ra, which is selected from 5- or 6-membered heteroaromatic radicals having as ring members 1 heteroatom selected from O, S and N and which may further have 1, 2 or 3 nitrogen atoms as ring members, and wherein the 5- or 6-membered heteroaromatic radical may carry 1, 2 or 3 substituents selected from halogen, NO2, NH2, OH, CN, C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-alkoxy, fluorinated C1-C6-alkyl, fluorinated C3-C6-cycloalkyl, fluorinated C1-C6-alkoxy, C1-C6-hydroxyalkyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C6-hydroxyalkoxy, C1-C4-alkoxy-C2-C4-alkoxy, C1-C6-alkylcarbonyl, C1-C6-alkylamino, di-C1-C6-alkylamino, C1-C6-alkylaminocarbonyl, di-C1-C6-alkylaminocarbonyl, fluorinated C1-C6-alkylcarbonyl, C1-C6-alkylcarbonylamino, fluorinated C1-C6-alkylcarbonylamino, C1-C6-alkylcarbonyloxy, fluorinated C1-C6-alkylcarbonyloxy, C1-C6-alkoxycarbonyl, C1-C6-alkylthio, fluorinated C1-C6-alkylthio, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, fluorinated C1-C6-alkylsulfinyl and fluorinated C1-C6-alkylsulfonyl.

9. The compounds as claimed in claim 8, wherein Ar carries one heteroaromatic radical Ra, which is selected from furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl and tetrazolyl, where the heteroaromatic radical may be unsubstituted or may carry 1 to 3 substituents selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4-alkoxy.

10. The compounds as claimed in claim 1, wherein Ar is phenyl.

11. The compounds as claimed in claim 1, wherein Ar is phenyl that carries a radical Ra in the 4-position of the phenyl ring.

12. The compound as claimed in claim 1, wherein X is CH.

13. The compound as claimed in claim 1, wherein R1 is n-propyl, fluorinated C2-C3-alkyl or 1-propen-3-yl.

14. The compound as claimed in claim 1, wherein R1a is hydrogen.

15. The compound as claimed in claim 1, wherein R2a is hydrogen.

16. The compound as claimed in claim 15, wherein both R2a and R2 are hydrogen.

17. The compound as claimed in claim 1, wherein one of the radicals R2a and R2 is hydrogen while the other is methyl.

18. The compound as claimed in claim 1, wherein R1a is n-propyl or 1-propen-3-yl.

19. A pharmaceutical composition comprising at least one compound of the formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1, optionally together with at least one physiologically acceptable carrier or auxiliary substance.