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WO2013068785A1 - Indanone and indandione derivatives and heterocyclic analogs - Google Patents

Indanone and indandione derivatives and heterocyclic analogs Download PDF

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Publication number
WO2013068785A1
WO2013068785A1 PCT/IB2011/054998 IB2011054998W WO2013068785A1 WO 2013068785 A1 WO2013068785 A1 WO 2013068785A1 IB 2011054998 W IB2011054998 W IB 2011054998W WO 2013068785 A1 WO2013068785 A1 WO 2013068785A1
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WIPO (PCT)
Prior art keywords
indan
piperazin
benzyl
dione
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2011/054998
Other languages
French (fr)
Inventor
Heinz Fretz
John Gatfield
Markus Isler
Thierry Kimmerlin
Ralf Koberstein
Isabelle Lyothier
Lucile MONNIER
Julien Pothier
Anja Valdenaire
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Actelion Pharmaceuticals Ltd
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Actelion Pharmaceuticals Ltd
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Filing date
Publication date
Application filed by Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Priority to PCT/IB2011/054998 priority Critical patent/WO2013068785A1/en
Publication of WO2013068785A1 publication Critical patent/WO2013068785A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C07D295/116—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings with the doubly bound oxygen or sulfur atoms directly attached to a carbocyclic ring
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    • A61P25/00—Drugs for disorders of the nervous system
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Definitions

  • the present invention relates to novel indanone/indandione derivatives and heterocyclic analogs of Formula (I), and their use as pharmaceuticals.
  • the invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of Formula (I), and especially their use as neuropeptide S receptor antagonists.
  • a further aspect of the invention relates to novel compounds of Formula (II) and to salts thereof that serve as intermediates to prepare compounds of Formula (I).
  • NPS Neuropeptide S
  • NPS receptor G- protein-coupled receptor
  • NPS was found to stimulate wakefulness and locomotion in mice and rats while suppressing all sleep stages (Xu ei a/., Neuron 2004; 43: 487-97). Furthermore, NPSR -/- mice displayed reduced arousal in different paradigms (Duangdao ei a/., Behav Brain Res. 2009; 205:1-9), suggesting a physiological role for this peptide as a central regulator of arousal potentially offering novel therapeutic approaches to insomnia and other sleep disorders as well as other disorders related to increased arousal. On the other hand, it was observed that NPS application suppresses food intake in rats (Beck ei a/., Biochem. Biophys. Res. Commun.
  • NPS receptors are found in the mammalian brain (Xu ei a/., Neuron 2004; 43: 487-97; Xu ei a/., J. Comp. Neurol. 2007; 500: 84-102) and may have numerous implications in psychiatric and neurological pathologies known from the literature. In addition, NPS receptors are also expressed in the periphery (Xu ef a/., Neuron 2004; 43: 487-97; Laitinen ef a/., Science 2004; 304: 300-4, D ' Amato ef a/., Gastroenterology 2007; 133: 808- 17; Sundman ef a/., Neurogastroenterol Motil.
  • the NPS receptor occurs in two major polymorphic forms differing at amino acid 107, human NPSR asparagine 107 (hNPSR-107N) and human isoleucine 107 (hNPSR-1071).
  • This single nucleotide polymorphism affects receptor sensitivity to NPS (Reinborg ef a/., J. Pharmacol. Exp. Ther. 2005; 315: 1338- 45) with hNPSR-1071 being the more sensitive receptor version.
  • gain of sensitivity in hNPSR-1071 is linked to later mean bed time (Gott Kunststoffef a/., BMC Med. Genet.
  • Bicyclic piperazine compounds were claimed to block NPS-induced proliferation of human colon carcinoma cells (WO2005/021555), were shown to block NPS-induced hyperlocomotion in mice (Okamura ef a/., J Pharmacol Exp Ther. 2008; 325: 893-901) and claimed to increase anxiety (open field tests) and to increase fear memory extinction time in mice (Jiingling ef a/., Neuron. 2008; 59: 298-310).
  • the present invention provides indanone/indandione derivatives, which are non-peptide antagonists of the human NPS receptor. These compounds are useful for the prevention or treatment of diseases which respond to the modulation of the NPS receptor such as sleep disorders; eating disorders; drinking disorders; stress-related syndromes; addiction; psychoactive substance use, abuse, seeking and reinstatement; dementias and cognitive dysfunctions; anxiety disorders; dysthymic disorders; chronic and acute allergic/inflammatory/immune disorders or diseases; all sorts of cancers; and pain.
  • diseases which respond to the modulation of the NPS receptor such as sleep disorders; eating disorders; drinking disorders; stress-related syndromes; addiction; psychoactive substance use, abuse, seeking and reinstatement; dementias and cognitive dysfunctions; anxiety disorders; dysthymic disorders; chronic and acute allergic/inflammatory/immune disorders or diseases; all sorts of cancers; and pain.
  • the present invention relates to com ounds of Formula (I)
  • Ar 1 represents a fused benzene or a fused pyridine ring
  • (R 1 ) n represents one or two optional substituents each independently selected from the group consisting of (Ci. 4)alkyl, (Ci-4)alkoxy, hydroxy, trifluoromethyl, (Ci)fluoroalkoxy, and halogen; wherein any R 1 is attached to a carbon atom of Ar 1 ;
  • L 1 re resents a group selected from the group consisting of:
  • Z represents -(CH2) m -, wherein m represents the integers 1 to 4, wherein optionally one CH2 group may be replaced by oxygen;
  • A represents aryl or heteroaryl, wherein said aryl or heteroaryl independently is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci.
  • A represents an unsubstituted partially aromatic bicyclic ring system, wherein A is attached to the rest of the molecule at the aromatic ring of said partially aromatic bicyclic ring system;
  • B represents aryl or heteroaryl, wherein said aryl or heteroaryl independently is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci.
  • B represents a partially aromatic bicyclic ring system; wherein said partially aromatic bicyclic ring system is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from (Ci-4)alkyl, (Ci- 4 )alkoxy, halogen and oxo;
  • the compounds of Formula (I) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms.
  • the compounds of Formula (I) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
  • indan-1 ,3-dione moiety may be in absolute (R)- or in absolute (S)-configuration; and both epimers, or mixtures thereof, are encompassed in the scope of the present invention.
  • the compounds of Formula (I) also contain a chiral quaternary carbon center in the particular case wherein Y represents CH2 (see embodiments 2) and 3) below).
  • Y represents CH2 (see embodiments 2) and 3) below).
  • the thus formed indan-1 -one moiety may be in absolute (R)- or in absolute (S)-configuration; and both epimers, or mixtures thereof, are encompassed in the scope of the present invention.
  • a fused benzene or a fused pyridine ring as used for "Ar 1 " means that such ring Ar 1 together with the cyclopentane moiety to which it is fused forms notably an indane (also named 2,3-dihydro-1 H-indene), or a 6,7-dihydro-5H-cyclopenta[b]pyridine or 6,7-dihydro-5H-cyclopenta[c]pyridine ring; wherein the respective cyclopentane moiety carries the prescribed oxo substituent(s); and wherein said rings may optionally be substituted at the aromatic ring with one or two optional substituents R 1 ; it being well understood that the nitrogen atom of a 6,7-dihydro-5H-cyclopenta[b]pyridine or 6,7-dihydro-5H- cyclopenta[c]pyridine ring will not carry such substituent R 1 .
  • (R 1 ) n representing one or two optional substituents
  • n represents the integer 0 (i.e. (R 1 ) n is absent), 1 (i.e. one R 1 is present), or 2 (i.e. two R 1 are present).
  • a substituent R 1 may be attached in ortho or meta position. In case a substituent R 1 is referred to as being in ortho-position, this means that said substituent is attached in position 4 or 7 of an indan-1 -one, respectively, indan-1 ,3-dione moiety.
  • a substituent R 1 is referred to as being in meta-position, this means that said substituent is attached in position 5 or 6 of an indan-1 -one, respectively, indan-1 ,3-dione moiety (Mutatis mutandis for the respective 6,7-dihydro-5H-cyclopenta[b]pyridine and 6,7-dihydro-5H-cyclopenta[c]pyridine derivatives).
  • halogen means fluorine, chlorine, or bromine, preferably fluorine or chlorine.
  • R 1 preferred is fluorine.
  • alkyl refers to a straight or branched saturated hydrocarbon chain containing one to four carbon atoms.
  • (C x . y )alkyl refers to an alkyl group as defined before containing x to y carbon atoms.
  • a (Ci-4)alkyl group contains from one to four carbon atoms.
  • Examples of (Ci-4)alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec- butyl and fe/t-butyl. Preferred are methyl and ethyl. Most preferred is methyl.
  • -(CH 2 ) m -, wherein m represents the integers 1 to 4, wherein optionally one CH 2 group may be replaced by oxygen refers to a bivalent radical derived from a straight chain (Ci- 4)alkyl group as defined before by removal of a further hydrogen atom from a carbon atom of the chain.
  • one CH2 group of the chain may be replaced by oxygen.
  • m preferably represents the integer 3 or 4, and said oxygen atom is separated from the nitrogen atom of the ring L 1 of the parent molecule by 2 carbon atoms.
  • Examples are methylene (-CH2-), ethylene (-CH2-CH2-), propane-1 ,3-diyl (trimethylene), butane-1 ,4-diyl (tetramethylene), ethylen-oxy (-CH2-CH2-O- * ), and ethylen-oxy-methylen (-CH2-CH2-O-CH2-*); wherein the asterisks signify the bond to which B is attached to.
  • Preferred are methylene, ethylene, trimethylene, tetramethylene, and ethylen-oxy, especially methylene.
  • alkoxy refers to an alkyl-O- group wherein the alkyl group is as defined before.
  • (C x . y )alkoxy (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms.
  • a (Ci-4)alkoxy group means a group of the formula (Ci- 4 )alkyl-0- in which the term "(Ci -4 )alkyl" has the previously given significance.
  • Examples of (Ci-4)alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy and ieri.-butoxy. Preferred is methoxy.
  • substituents of the substituent "A" most preferred are methoxy and ethoxy, especially methoxy.
  • (Ci-3)fluoroalkyl refers to an alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
  • (C x . y )fluoroalkyl (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms.
  • a (Ci-3)fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine.
  • (Ci-3)fluoroalkyl groups include trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, and difluoromethyl. Preferred are (Ci)fluoroalkyl groups such as trifluoromethyl or difluoromethyl.
  • (Ci-3)fluoroalkoxy refers to an alkoxy group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
  • (C x . y)fluoroalkoxy (x and y each being an integer) refers to a fluoroalkoxy group as defined before containing x to y carbon atoms.
  • a (Ci-3)fluoroalkoxy group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine.
  • (Ci-3)fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy and 2,2,2-trifluoroethoxy. Preferred are (C-i)fluoroalkoxy groups such as trifluoromethoxy and difluoromethoxy. Most preferred is trifluoromethoxy.
  • cycloalkyl refers to a saturated carbocyclic ring containing three to seven carbon atoms.
  • (C x - y )cycloalkyl refers to a cycloalkyl group as defined before containing x to y carbon atoms.
  • a (C3-7)cycloalkyl group contains from three to seven carbon atoms.
  • Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • cydopropyl Preferred are cydopropyl, cyclopentyl and cyclohexyl.
  • substituents of the substituent "A” most preferred is cydopropyl.
  • substituents of the substituent "B” most preferred are cydopropyl and especially cyclohexyl.
  • alkenyl refers to a straight or branched hydrocarbon chain containing two to four carbon atoms and one carbon-carbon double bond.
  • (C x - y )alkenyl refers to an alkenyl group as defined before containing x to y carbon atoms.
  • a (C2- 4 )alkenyl group contains from two to four carbon atoms.
  • Examples of (C2- 4 )alkenyl groups are 2-propen-1-yl (also referred to as “allyl”), 2-methyl-2-propen-1-yl, and 3-buten-1-yl, especially 2-propen-1-yl, and in addition to the above-mentioned groups ethenyl (also referred to as vinyl), which group is a particular example in case the term "alkenyl" is used alone.
  • R 2 and R 3 independently represent hydrogen or (Ci-3)alkyl
  • R 2 and R 3 independently represent hydrogen or (Ci-3)alkyl
  • R 4 and R 5 independently represent hydrogen or (Ci-3)alkyl
  • R 4 and R 5 independently represent hydrogen or (Ci-3)alkyl
  • a "and a 5- or 6-membered ring selected from pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, which ring, in case it is attached to A through a carbon atom or in case it is a piperazinyl ring, may in turn optionally be substituted at the vacant nitrogen atom with (Ci -4 )alkyl" are pyrrol id in- 1 -yl , piperidin-1-yl, 1-(Ci.
  • alkyl-pyrrolidin-2-yl groups such as especially 1 -methyl-pyrrolidin-2-yl, 4-(Ci-4)alkyl-piperazin-1-yl groups such as especially 4-methyl-piperazin-1-yl, and especially morpholin-4-yl.
  • aryl used alone or in combination, means phenyl or naphthyl.
  • aryl groups are unsubstituted or substituted as explicitly defined.
  • A representing "aryl” means phenyl (preferred) or naphthyl, which is independently unsubstituted, or mono-, di-, or tri-substituted (especially unsubstituted, or mono-, or di-substituted; notably unsubstituted or mono- substituted); wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci. 4)alkoxy;
  • substituents are selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (Ci.3)fluoroalkyl; (Ci. 3)fluoroalkoxy; halogen; (C3-6)cycloalkyl; and a 5- or 6-membered ring selected from pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, which ring, in case it is attached to A through a carbon atom or in case it is a piperazinyl ring, may in turn optionally be substituted at the vacant nitrogen atom with (C -4 )alkyl (especially substituents are selected from (Ci-4)alkyl, (Ci-4)alkoxy, (Ci.3)fluoroalkyl, halogen; (C ⁇ cycloalkyl; and morpholinyl; notably from methyl, ethyl, isopropyl, methoxy, fluoro,
  • the substituents are selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, and halogen (especially substituents are selected from (Ci- 4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, and halogen; notably from methyl, ethyl, isopropyl, methoxy, fluoro, chloro, bromo, and trifluoromethyl).
  • Naphthyl groups are preferably unsubstituted.
  • Examples of "A” representing "aryl” are phenyl, 1 -naphthyl, 2-naphthyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 3-ethylphenyl, 3- isopropylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4- chlorophenyl, 3-chlorophenyl, 4-bromophenyl, 3-bromophenyl, 3-trifluoromethylphenyl, 3-fluoro-5-methylphenyl, 3-fluoro-5-methoxyphenyl, 3-methoxy-5-methylphenyl, 3,5-difluorophenyl, 3-vinylphenyl, 3,5-dimethylphenyl, 3,5-diethylphenyl, 3,5-dimethoxyphenyl, 3-n-propoxyphenyl, 3-cyclopropylpheny
  • B representing "aryl” means phenyl (preferred) or naphthyl, which is independently unsubstituted, or mono-, di-, or tri-substituted; wherein the substituents are independently selected from the group consisting of (Ci.
  • the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci- 4)alkoxy; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; and -NR 4 R 5 , wherein R 4 and R 5 independently represent hydrogen or (Ci-3)alkyl (especially from (Ci-4)alkyl; (Ci-4)alkoxy; halogen; and -NR 4 R 5 ).
  • the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, halogen, cyano, (Ci -3)al koxy-(Ci -4 )al kyl , (Ci-3)alkoxy-(C2-4)alkoxy, nitro, hydroxy, (C2-4)alkenyloxy, unsubstituted 5- or 6-membered monocyclic heteroaryl (especially 5-membered heteroaryl, notably pyrazolyl or thiadiazolyl), and unsubstituted phenyl.
  • the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, (Ci- 3)fluoroalkoxy, and halogen (especially from (Ci-4)alkyl; (Ci-4)alkoxy; and halogen).
  • Naphthyl groups are preferably unsubstituted.
  • B representing "aryl” are phenyl, 1-naphthyl, 2-naphthyl, 4- methylphenyl, 3-methylphenyl, 2-methylphenyl, 2-ethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 4- isopropylphenyl, 2-isopropylphenyl, 2-n-propylphenyl, 4-fe/t-butylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2-hydroxyphenyl, 4-cyanophenyl, 3-cyanophenyl, 2-cyanophenyl, 4- chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 5-fluoro-2,4- dichlorophenyl, 4-fluorophenyl, 3-fluor
  • heteroaryl used alone or in combination, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing one to a maximum of three heteroatoms, each independently selected from oxygen, nitrogen and sulfur.
  • heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzo
  • the term means the above-mentioned groups.
  • the term means a 5- or 6-membered monocyclic aromatic ring containing one to a maximum of three (especially 1 or 2) heteroatoms, each independently selected from oxygen, nitrogen and sulfur.
  • heteroaryl groups as used for the substituent "A" are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, qui
  • isoxazolyl notably isoxazol-3-yl
  • thiophenyl notably thiophen-2-yl, and thiophen-3-yl
  • thiazolyl notably thiazol-4-yl
  • pyrazolyl notably 1 H-pyrazol-3-yl and 1H-pyrazol-4-yl
  • pyridyl notably pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl
  • pyrimidyl notably pyrimidin-4-yl
  • pyrazinyl notably pyrazin-2-yl
  • benzothiazolyl notably benzothiazol-2-yl
  • quinolinyl notably quinolin-4-yl
  • quinoxalinyl notably quinoxalin-2-yl
  • heteroaryl groups as used for the substituent "A" are unsubstituted, mono-, di-, or tri-substituted (preferred unsubstituted, mono-, or di-substituted), wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; (C3-6)cycloalkyl; (C2- 4 )alkenyl; phenyl; -NR 2 R 3 , wherein R 2 and R 3 independently represent hydrogen or (Ci-3)alkyl; and a 5- or 6- membered ring selected from pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, which ring, in case it is attached to A through a carbon atom or in case it is a piperazinyl ring, may in turn optionally be substitute
  • substituents are selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (C 1 -3)fl u o roa I ky I ; (Ci-3)fluoroalkoxy; halogen; (C3-6)cycloalkyl; and a 5- or 6- membered ring selected from pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, which ring, in case it is attached to A through a carbon atom or in case it is a piperazinyl ring, may in turn optionally be substituted at the vacant nitrogen atom with (Ci-4)alkyl (especially substituents are selected from (Ci-4)alkyl, (Ci-4)alkoxy, (Ci.
  • the substituents are selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci.3)fluoroalkyl, (Ci-3)fluoroalkoxy, and halogen (notably from (Ci-4)alkyl, (Ci-4)alkoxy, trifluoromethyl, and halogen; especially from (Ci-4)alkyl, (Ci-4)alkoxy and halogen).
  • A representing "heteroaryl” are 1 -methyl - 1 H-pyrazol -3-yl , 4-bromo-thiophen- 2-yl, thiophen-3-yl, 2 , 5-d i methyl-th iazol-4-y 1 , 5-methyl-isoxazol-3-yl, pyrazin-2-yl, 6-methyl-pyrazin-2-yl, pyrimidin-4-yl, 6-methyl-pyrimidin-4-yl, pyridin-2-yl, 6-chloro-pyridin-2-yl, 6-b ro mo-py rid in-2-yl , 4-methyl-pyridin- 2-yl, 6-ethyl-py rid i n-2-yl , 6-ethoxy- pyrid i n-2-yl , 4,6-dimethyl-pyridin-2-yl, pyridin-3-yl, 5-bromo-pyrid i n-3
  • the term means the above-mentioned groups.
  • the term means a 5- or 6-membered monocyclic aromatic ring containing one to a maximum of three heteroatoms, each independently selected from oxygen, nitrogen and sulfur.
  • heteroaryl groups as used for the substituent "B” are oxazolyl (notably oxazol-4-yl), isoxazolyl (notably isoxazol-3-yl), oxadiazolyl (notably [1 ,2,4]oxadiazol-3-yl), thiophenyl (notably thiophen-2-yl), thiazolyl (notably thiazol-4-yl), thiadiazolyl (notably [1 ,2,4]thiadiazol-5-yl, and [1 ,2,3]thiadiazol-4-yl), imidazolyl (notably imidazol-2-yl), pyridyl (notably pyridin-2-yl, pyridin-3-yl, and pyrid ine-4-yl), indolyl (notably indol-3-yl), benzothiophenyl (notably benzo[Jb]thiophen-2-yl), benzimidazolyl (notably oxazol
  • heteroaryl groups as used for the substituent "B” are unsubstituted, mono-, di-, or tri-substituted (preferred unsubstituted, mono-, or di-substituted, more preferred unsubstituted, or mono- substituted), wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci.
  • the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (Ci-3)fluoroalkyl; halogen; and -NR 4 R 5 , wherein R 4 and R 5 independently represent hydrogen or (Ci-3)alkyl (especially from (Ci-4)alkyl; (Ci-4)alkoxy; halogen; and -NR 4 R 5 ).
  • the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci- 4 )alkoxy, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, halogen, cyano, (Ci -3)al koxy-(Ci -4 )al kyl , (Ci-3)alkoxy-(C2-4)alkoxy, nitro, hydroxy, (C2- 4 )alkenyloxy, unsubstituted 5- or 6-membered monocyclic heteroaryl, and unsubstituted phenyl.
  • the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci -4 )alkoxy, (Ci-3)fluoroalkyl, halogen, and unsubstituted phenyl (especially from (Ci-4)alkyl, halogen, and unsubstituted phenyl; notably from (Ci -4 )alkyl, and halogen).
  • B representing "heteroaryl” are 5-phenyl- oxazol-4-yl, 5-methyl-isoxazol-3-yl, 5-ferf.-butyl-[1 ,2,4]oxadiazol-3-yl, [1 ,2,4]oxadiazol-3-yl, thiophen-2-yl, thiazol- 4-yl, 3-chloro-[1 ,2,4]thiadiazol-5-yl, 5-chloro-[1 ,2,3]thiadiazol-4-yl, imidazol-2-yl, pyridin-2-yl, pyridin-3-yl, 6- chloro-pyridin-3-yl, pyridine-4-yl, 1 H-indol-3-yl, 3-methyl-benzo[Jb]thiophen-2-yl, 1-methyl-1H-benzimidazol-2-yl, benzothiazol-2-yl, 1-methyl-1H-benzotriazol-5-
  • partially aromatic bicyclic ring system used alone or in combination, means a phenyl ring or a 5- or 6-membered monocyclic heteroaryl ring (preferably containing one to two heteroatoms) as defined before, wherein said ring is fused to a 5- or 6-membered saturated or partially unsaturated non-aromatic ring optionally containing up to two (i.e. 0, 1 , or 2) heteroatoms independently selected from the group consisting of oxygen and nitrogen (i.e. such partially aromatic bicyclic ring system is a 8-, 9-, or 10-membered bicyclic ring system).
  • a partially aromatic bicyclic ring system may be attached to the rest of the molecule either at the aromatic ring or at the saturated or partially unsaturated non-aromatic ring of said bicyclic ring system.
  • a partially aromatic bicyclic ring system is attached to the rest of the molecule at the aromatic ring of said bicyclic ring system.
  • the group of partially aromatic bicyclic ring systems comprises three sub-groups, notably "partially aromatic bicyclic heteroaryl ring systems", “carbocyclyl” groups, and “heterocyclyl” groups, as defined hereinafter.
  • the above-mentioned partially aromatic bicyclic ring systems are preferably unsubstituted, or may be mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen and oxo.
  • substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen and oxo.
  • a preferred sub-group of partially aromatic bicyclic ring systems are partially aromatic bicyclic heteroaryl ring systems as defined below.
  • a preferred sub- group of partially aromatic bicyclic ring systems are heterocyclyl groups as defined below.
  • One subgroup of "partially aromatic bicyclic ring systems" as defined before are “partially aromatic bicyclic heteroaryl ring systems”.
  • partially aromatic bicyclic heteroaryl ring system means a 5- or 6- membered monocyclic heteroaryl ring (preferably containing one to two heteroatoms) as defined before, which is fused to a 5- or 6-membered saturated or partially unsaturated non-aromatic ring optionally containing up to two heteroatoms independently selected from the group consisting of oxygen and nitrogen.
  • said heteroatoms in case one of said heteroatoms is a nitrogen atom, said nitrogen atom may be a bridgehead atom and thus be part of both the monocyclic heteroaryl ring and the 5- or 6-membered saturated ring, wherein the latter ring in this case may contain one further heteroatom selected from the group consisting of oxygen and nitrogen.
  • said fused 5- or 6-membered saturated or partially unsaturated non-aromatic ring is a carbocyclic ring.
  • Partially aromatic bicyclic heteroaryl ring systems are preferably attached to the rest of the molecule at the monocyclic heteroaryl ring of said group.
  • a partially aromatic bicyclic heteroaryl ring system is attached to the rest of the molecule at the aromatic ring of said bicyclic ring system.
  • Examples of such a “partially aromatic bicyclic heteroaryl ring system” are 5,6,7, 8-tetrahydro-quinolinyl, 5,6,7,8- tetrahydro-isoquinolinyl, 5,6,7, 8-tetrahydro-quinazolinyl, and 5,6,7,8-tetrahydro-quinoxalinyl.
  • substituent "A” a preferred example is 5,6,7, 8-tetrahydro-quinolinyl.
  • the above-mentioned partially aromatic bicyclic heteroaryl ring systems are preferably unsubstituted, or may be mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, halogen and oxo.
  • Another subgroup of "partially aromatic bicyclic ring systems" as defined before are carbocyclyl groups.
  • carbocyclyl used alone or in combination, means a phenyl ring fused to a 5- or 6-membered saturated or partially unsaturated non-aromatic carbocyclic ring. Preferably, said 5- or 6-membered fused carbocyclic ring is saturated.
  • a carbocyclyl group is attached to the rest of the molecule at the aromatic ring of said carbocyclyl group. Examples of such "carbocyclyl” groups are tetrahydronaphthalyl and indanyl.
  • carbocyclyl groups are preferably unsubstituted, or may be mono-, or di- substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci. 4)alkoxy, halogen and oxo.
  • substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci. 4)alkoxy, halogen and oxo.
  • a particular example of such carbocyclyl groups as used for the substituent "A" is indan-5-yl.
  • Another sub-group of "partially aromatic bicyclic ring systems" as defined before are heterocyclyl groups.
  • heterocyclyl used alone or in combination, means a phenyl ring fused to a 5- or 6-membered saturated or partially unsaturated non-aromatic ring containing up to two heteroatoms independently selected from the group consisting of oxygen (preferred) and nitrogen. Heterocyclyl groups are preferably attached to the rest of the molecule at the phenyl ring of said group. For the substituent "A”, a heterocyclyl group is attached to the rest of the molecule at the phenyl ring of said group.
  • heterocyclyl groups examples include 2,3-dihydro- benzofuranyl, 4H-benzo[1 ,3]dioxinyl, benzo[1 ,3]dioxolyl (especially benzo[1 ,3]dioxol-5-yl), 2,3-dihydro- benzo[1 ,4]dioxinyl, 2H-chromenyl, and chromanyl.
  • substituent "A” particular examples are 2,3-dihydro- benzo[1 ,4]dioxinyl.
  • substituent "B” particular examples are chromanyl, 3,4-dihydro-2H- benzo[1 ,4]oxazinyl, and (notably) benzo[1 ,3]dioxolyl.
  • the above-mentioned heterocyclyl groups are preferably unsubstituted, or may be mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, halogen and oxo.
  • Benzo[1 ,3]dioxolyl-groups are preferably unsubstituted, or may be mono-substituted in position 6 with chloro.
  • Chromanyl groups are preferably unsubstituted or di-substituted with methyl.
  • 3,4-Dihydro-2H-benzo[1 ,4]oxazinyl groups are preferably substituted with oxo at position 3 and may optionally be further substituted with methyl at the nitrogen atom.
  • a particular example of such heterocyclyl groups as used for the substituent "A" is 2,3-dihydro-benzo[1 ,4]dioxin-6-yl.
  • heterocyclyl groups as used for the substituent "B”are benzo[1 ,3]dioxol-5-yl, and 6- chloro-benzo[1 ,3]dioxol-5-yl, chroman-2-yl, 2,2-dimethyl-chroman-6-yl, and 3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl.
  • cyano refers to a group -CN.
  • (Ci-3)al koxy-(Ci- 4 )al kyl refers to a (Ci-3)alkyl-0-(Ci -4 )alkyl group wherein the alkyl groups are as defined before.
  • An example of a (Ci-3)alkoxy-(Ci -4 )alkyl group is 2-methoxy-ethyl.
  • (Ci-3)alkoxy-(C2-4)alkoxy refers to a (Ci-3)al kyl-0-(C2- 4 )al kyl-O- group wherein the alkyl groups are as defined before.
  • An example of a (Ci -3)al koxy-(C2- 4 )al kyl group is 2-methoxy-ethoxy.
  • nitro refers to a group -NO2.
  • (C2- 4 )alkenyloxy refers to a (C2- 4 )alkenyl-0- group wherein the alkenyl group is as defined before.
  • An example of a (C2-4)alkenyloxy group is allyloxy.
  • a further embodiment of the invention relates to compounds of Formula (I) according to embodiment 1), which are also compounds of Formula
  • W represents N or CH (preferably CH) (it being well understood that in case W represents N, W does not carry an optional substituent R 1 ).
  • Y preferably represents
  • a further embodiment of the invention relates to compounds of Formula (I) according to embodiment 2), wherein, in case Y represents CH 2 , the quaternary carbon atom of the thus formed indan-1-one moiety has the absolute configuration depicted in Formula (IEI) below:
  • Another embodiment relates to compounds of Formula (I) according to embodiment 2), wherein, in case Y represents CH2, the quaternary carbon atom of the thus formed indan-1 -one moiety has the absolute configuration depicted in Formula ( ) below:
  • Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1 ) to 4),
  • Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1 ) to 5), wherein L 1 represents
  • Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1 ) to 6), wherein X represents CH.
  • Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1 ) to 6), wherein X represents N.
  • Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1 ) to 8), wherein Y represents CH2.
  • Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 10), wherein Z represents a group selected from the group consisting of methylene (-CH2-), ethylene (-CH2-CH2-), propane-1 ,3-diyl (trimethylene), butane-1 ,4-diyl (tetramethylene), ethylen-oxy (-CH2-CH2-O- * ), and ethylen-oxy- methylen (-CH2-CH2-O-CH2-*); wherein the asterisks signify the bond to which B is attached to.
  • Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 11), wherein Z represents methylene (-CH2-).
  • FIG. 13 Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 12), wherein (R 1 ) n represents one (preferred) or two optional substituents (i.e. n represents the integer 0, 1 , or 2; preferably 0 or 1) each independently selected from the group consisting of (Ci )alkyl, (Ci-4)alkoxy, hydroxy, trifluoromethyl, and (especially) halogen (notably from (Ci-4)alkyl, (Ci-4)alkoxy, and (especially) halogen).
  • R 1 n represents one (preferred) or two optional substituents (i.e. n represents the integer 0, 1 , or 2; preferably 0 or 1) each independently selected from the group consisting of (Ci )alkyl, (Ci-4)alkoxy, hydroxy, trifluoromethyl, and (especially) halogen (notably from (Ci-4)alkyl, (Ci-4)alkoxy, and (especially) halogen).
  • Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 13), wherein (R 1 ) n represents one (preferred) or two substituents each independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, hydroxy, trifluoromethyl, and (especially) halogen (notably from (Ci-4)alkyl, (Ci-4)alkoxy, and (especially) halogen).
  • Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 13), wherein (R 1 ) n represents one optional substituent in ortho-position (notably of the indan-1 ,3-dione / indan-1-one moiety of the compounds of Formula (I)), wherein said R 1 is selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, hydroxy, and (especially) halogen (notably from (Ci-4)alkyl, (Ci-4)alkoxy, and (especially) halogen).
  • R 1 represents one optional substituent in meta-position (notably of the indan-1 ,3-dione / indan-1 -one moiety of the compounds of Formula (I)), wherein said R 1 is selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, trifluoromethyl, and (especially) halogen (notably from (Ci-4)alkyl, (Ci-4)alkoxy, and (especially) halogen).
  • Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 13), wherein (R 1 ) n is absent (i.e. n represents the integer 0).
  • A represents aryl, wherein said aryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; (C3-6)cycloalkyl; and a 5- or 6-membered ring selected from pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, which ring, in case it is attached to A through a carbon atom or in case it is a piperazinyl ring, may in turn optionally be substituted at the vacant nitrogen atom with (Ci-4)alkyl(notably from (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluor
  • A represents an unsubstituted partially aromatic bicyclic ring system, wherein A is attached to the rest of the molecule at the aromatic ring of said partially aromatic bicyclic ring system.
  • A represents aryl, wherein said aryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; (C3-6)cycloalkyl; and a 5- or 6-membered ring selected from pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, which ring, in case it is attached to A through a carbon atom or in case it is a piperazinyl ring, may in turn optionally be substituted at the vacant nitrogen atom with (Ci-4)alkyl(notably from (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluor
  • A represents heteroaryl, wherein said heteroaryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, halogen; (C3-6)cycloalkyl; and morpholinyl (notably from (Ci-4)alkyl, (Ci-4)alkoxy, trifluoromethyl and halogen; especially from (Ci-4)alkyl, (Ci-4)alkoxy, and halogen).
  • substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, halogen; (C3-6)cycloalkyl; and morpholinyl (notably from (Ci-4)alkyl, (Ci-4)alkoxy, trifluoromethyl and halogen; especially from
  • A represents aryl, wherein said aryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; (C3-6)cycloalkyl; and a 5- or 6-membered ring selected from pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, which ring, in case it is attached to A through a carbon atom or in case it is a piperazinyl ring, may in turn optionally be substituted at the vacant nitrogen atom with (Ci-4)alkyl(notably from (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluor
  • A represents heteroaryl, wherein said heteroaryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci. 3)fluoroalkyl, halogen; (C ⁇ cycloalkyl; and morpholinyl (notably from (Ci-4)alkyl, (Ci-4)alkoxy, trifluoromethyl and halogen; especially from (Ci-4)alkyl, (Ci-4)alkoxy, and halogen).
  • A represents heteroaryl, wherein said heteroaryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci. 3)fluoroalkyl, halogen; (C ⁇ cycloalkyl;
  • Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 18), wherein A represents an unsubstituted partially aromatic bicyclic ring system, wherein A is attached to the rest of the molecule at the aromatic ring of said partially aromatic bicyclic ring system.
  • Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 22), wherein B represents aryl, wherein said aryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; and -NR 4 R 5 , wherein R 4 and R 5 independently represent hydrogen or (Ci-3)alkyl (in another embodiment, from (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, halogen, cyano, (Ci- 3 )al koxy-(Ci -4 )al kyl , (Ci-3)alkoxy-(C2-4)alkoxy, nitro, hydroxy,
  • B represents heteroaryl, wherein said heteroaryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; halogen; and - NR 4 R 5 , wherein R 4 and R 5 independently represent hydrogen or (Ci-3)al kyl (in another embodiment, from (Ci-
  • B represents a partially aromatic bicyclic ring system; wherein said partially aromatic bicyclic ring system is unsubstituted, or may be mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, halogen and oxo (notably unsubstituted (preferred), or mono-substituted, wherein the substituent is halogen); or
  • B represents (C3-7)cycloalkyl (especially cyclopropyl or cyclohexyl).
  • Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 23), wherein B represents aryl, wherein said aryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci- 4 )alkoxy; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; and -NR 4 R 5 , wherein R 4 and R 5 independently represent hydrogen or (Ci-3)alkyl (in another embodiment, from (Ci-4)alkyl, (Ci -4 )alkoxy, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, halogen, cyano, (Ci- 3)al koxy-(Ci -4 )al kyl , (Ci-3)alkoxy-(C2-4)alkoxy, nitro,
  • Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 23), wherein B represents heteroaryl, wherein said heteroaryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl; (Ci -4 )alkoxy; halogen; and -NR 4 R 5 , wherein R 4 and R 5 independently represent hydrogen or (Ci-3)al kyl (in another embodiment, from (C -4 )alkyl, (Ci -4 )alkoxy, (Ci-3)fluoroalkyl, halogen, and unsubstituted phenyl; especially from (Ci -4 )alkyl, halogen, and unsubstituted phenyl).
  • B represents heteroaryl, wherein said heteroaryl is unsubstituted, or mono-, di-, or tri-substituted, wherein
  • Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 23), wherein B represents a partially aromatic bicyclic ring system (especially heterocyclyl); wherein said partially aromatic bicyclic ring system is unsubstituted, or may be mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, halogen and oxo (notably unsubstituted (preferred), or mono-substituted, wherein the substituent is halogen).
  • B represents a partially aromatic bicyclic ring system (especially heterocyclyl); wherein said partially aromatic bicyclic ring system is unsubstituted, or may be mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, halogen and oxo (notably unsubstituted (preferred), or mono-substituted, wherein the substituent is
  • Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 23), wherein B represents (C3-7)cycloalkyl (especially cyclopropyl or cyclohexyl).
  • Another embodiment relates to compounds of Formula (I) according to embodiment 2), wherein one or more (and notably all) of the following characteristics in any combination are present:
  • Z represents a group selected from the group consisting of methylene (-CH2-), ethylene (-CH2-CH2-), propane-1 ,3-diyl (trimethylene), butane-1 ,4-diyl (tetramethylene), and ethylen-oxy (-CH2-CH2-O- * ); wherein the asterisk signifies the bond to which B is attached to;
  • R 1 n represents one substituent in ortho-position of the indan-1 ,3-dione / indan-1-one moiety of the compounds of Formula (I), wherein said R 1 is selected from the group consisting of (Ci- 4)alkyl, (Ci-4)alkoxy, hydroxy, and (especially) halogen (notably from (Ci-4)alkyl, (Ci-4)alkoxy, and (especially) halogen); or
  • R 1 n represents one substituent in meta-position of the indan-1, 3-dione / indan-1 -one moiety of the compounds of Formula (I), wherein said R 1 is selected from the group consisting of (Ci- 4)alkyl, (Ci-4)alkoxy, trifluoromethyl, and (especially) halogen (notably from (Ci-4)alkyl, (Ci. 4)alkoxy, and (especially) halogen);
  • A represents aryl, wherein said aryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (Ci.
  • A represents heteroaryl, wherein said heteroaryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci.
  • B represents heterocyclyl; wherein said heterocyclyl is unsubstituted (preferred), or mono-, or di- substituted, wherein the substituents are independently selected from (Ci-4)alkyl, halogen and oxo; or B represents (C ⁇ cycloalkyl.
  • Another embodiment relates to compounds of Formula (I) according to embodiment 1), which are also compounds of Formula (lp)
  • X represents CH or N
  • Z represents -(CH2) m -, wherein m represents the integers 1 to 4 (especially 1), wherein optionally one CH2 group may be replaced by oxygen;
  • (R 1 ) n represents one or two optional substituents each independently selected from the group consisting of (Ci- 4)alkyl, (Ci-4)alkoxy, hydroxy, trifluoromethyl, (Ci)fluoroalkoxy, and halogen (notably from (Ci-4)alkyl, (Ci-4)alkoxy, and (especially) halogen);
  • A represents aryl or heteroaryl, wherein said aryl or heteroaryl independently is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci- 4)alkoxy, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, and halogen; or
  • A represents an unsubstituted partially aromatic bicyclic ring system, wherein A is attached to the rest of the molecule at the aromatic ring of said partially aromatic bicyclic ring system;
  • B represents aryl or heteroaryl, wherein said aryl or heteroaryl independently is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci- 4)alkoxy, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, halogen, cyano, (Ci -3)al koxy-(Ci -4 )al kyl , (Ci-3)alkoxy-(C2-4)alkoxy, nitro, hydroxy, (C2-4)alkenyloxy, unsubstituted 5- or 6-membered monocyclic heteroaryl, and unsubstituted phenyl; or B represents a partially aromatic bicyclic ring system; wherein said partially aromatic bicyclic ring system is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected
  • Another embodiment relates to compounds of Formula (Ip) according to embodiment 29), wherein one or more (and notably all) of the following characteristics in any combination are present:
  • Z represents a group selected from the group consisting of methylene (-CH 2 -), ethylene (-CH2-CH2-), propane-1 ,3-diyl (trimethylene), butane-1 ,4-diyl (tetramethylene), and ethylen-oxy (-CH2-CH2-O- * ); wherein the asterisk signifies the bond to which B is attached to;
  • (R 1 ) n is absent; or (R 1 ) n represents one substituent in ortho-position of the indan-1,3-dione / indan-1- one moiety of the compounds of Formula (I), wherein said R 1 is selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, hydroxy, and (especially) halogen (notably from (Ci-4)alkyl, (Ci-4)alkoxy, and (especially) halogen); or (R 1 ) n represents one substituent in meta-position of the indan-1 ,3-dione / indan-1-one moiety of the compounds of Formula (I), wherein said R 1 is selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, trifluoromethyl, and (especially) halogen (notably from (Ci-4)alkyl, (Ci-4)alkoxy, and (especially) halogen);
  • A represents aryl, wherein said aryl is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, and halogen; or
  • A represents heteroaryl, wherein said heteroaryl is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, and halogen; or
  • A represents an unsubstituted partially aromatic bicyclic heteroaryl ring system, wherein A is attached to the rest of the molecule at the aromatic ring of said partially aromatic bicyclic heteroaryl ring system;
  • B represents aryl, wherein said aryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, halogen, cyano, (Ci-3)alkoxy-(Ci-4)alkyl, (Ci-3)alkoxy-(C2-4)alkoxy, nitro, hydroxy, (C2-4)alkenyloxy, unsubstituted 5- or 6- membered monocyclic heteroaryl, and unsubstituted phenyl; or
  • B represents heteroaryl, wherein said heteroaryl is unsubstituted, or mono-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, halogen, and unsubstituted phenyl; or B represents heterocyclyl; wherein said heterocyclyl is unsubstituted (preferred), or mono-substituted, wherein the substituent is halogen; or
  • B represents (C3-7)cycloalkyl.
  • Examples of compounds of Formula (I) according to embodiment 1) are selected from the group consisting of:
  • a further aspect of the invention relates to compounds of Formula (II) or salts thereof,
  • any reference to a compound of Formula (I) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.
  • the term "pharmaceutically acceptable salts” refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.
  • the present invention also includes isotopically, especially 2 H (deuterium) labelled compounds of formula (I) which compounds are identical to the compound of formula (I) wherein one or more atoms have been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopically labelled, especially 2 H (deuterium) labelled compounds of formula (I) and salts thereof are within the scope of the present invention.
  • the compounds of formula (I) are not isotopically labelled, or labelled with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled. Isotopically labelled compounds of formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
  • the compounds of the present invention have useful, in particular pharmacologically useful, properties. They bind to the NPS receptor and thus modulate the effects of endogenous NPS.
  • the compounds of Formula (I) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral or parenteral administration.
  • the present invention further also relates to pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of Formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • the compounds according to Formula (I) according to embodiment 1) including the compound 2-(4-Benzyl- piperazin-1-yl)-2-phenyl-indan-1 ,3-dione are suitable for the prevention and/or treatment of diseases or disorders which respond to the modulation of the NPS receptor.
  • diseases or disorders are further described in the following:
  • the compounds according to Formula (I) are particularly suitable for the prevention or treatment selected from the group consisting of dysthymic disorders including major depression and cyclothymia, affective neurosis, all types of manic depressive disorders, delirium, psychotic disorders, schizophrenia, catatonic schizophrenia, delusional paranoia, adjustment disorders and all clusters of personality disorders; schizoaffective disorders; anxiety disorders including generalized anxiety, obsessive compulsive disorder, posttraumatic stress disorder, panic attacks, all types of phobic anxiety and avoidance; separation anxiety; all types of stress-related syndromes including hyperactivation of the hypothalamo-pituitary axis, irritable bowel syndrome, insomnia, hypertension, infertitly, depression, anxiety; all types of psychoactive substance use, abuse, seeking and reinstatement; all types of psychological or physical addictions, dissociative disorders including multiple personality syndromes and psychogenic amnesias; sexual and reproductive dysfunction; psychosexual dysfunction and addiction; tolerance to narcotics or withdrawal from narcotics
  • compounds of Formula (I) are particularly suitable for the prevention or treatment of diseases or disorders selected from the group consisting of sleep disorders; eating disorders; drinking disorders; stress-related syndromes; addiction; psychoactive substance use, abuse, seeking and reinstatement; dementias and cognitive dysfunctions; anxiety disorders; dysthymic disorders; chronic and acute allergic/inflammatory/immune disorders or diseases; all sorts of cancers; and pain.
  • diseases or disorders selected from the group consisting of sleep disorders; eating disorders; drinking disorders; stress-related syndromes; addiction; psychoactive substance use, abuse, seeking and reinstatement; dementias and cognitive dysfunctions; anxiety disorders; dysthymic disorders; chronic and acute allergic/inflammatory/immune disorders or diseases; all sorts of cancers; and pain.
  • compounds of Formula (I) are particularly suitable for the prevention or treatment of diseases or disorders selected from the group consisting of sleep disorders; eating disorders; drinking disorders; stress-related syndromes; addiction; psychoactive substance use, abuse, seeking and reinstatement; dementias and cognitive dysfunctions; anxiety disorders; and dysthymic disorders.
  • Eating disorders may be defined as comprising metabolic dysfunction; dysregulated appetite control; compulsive obesities; emeto-bulimia or anorexia nervosa; reduced appetite in the elderly; and reduced appetite due to another disease such as cancer.
  • Eating disorders or pathologically modified food intake may result from disturbed appetite (attraction or aversion for food); altered energy balance (intake vs. expenditure); disturbed perception of food quality (high fat or carbohydrates, high payability); disturbed food availability (unrestricted diet or deprivation), disrupted water balance, or from another disease such as cancer.
  • Drinking disorders may be defined as comprising polydipsias in psychiatric disorders and all other types of excessive fluid intake as well as reduced fluid intake in the elderly.
  • Sleep disorders may be defined as comprising all types of parasomnias, insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift-work syndrome, delayed or advanced sleep phase syndrome or insomnias related to psychiatric disorders.
  • Insomnias also comprise sleep disorders associated with aging; intermittent treatment of chronic insomnia; situational transient insomnia (new environment, noise) or short-term insomnia due to stress; grief; pain or illness.
  • Insomnia also comprise stress-related syndromes that comprise post-traumatic stress disorders; as well as other types and subtypes of anxiety disorders that comprise generalized anxiety, obsessive compulsive disorder, panic attacks, all types of phobic anxiety and avoidance, and separation anxiety.
  • stress-related syndromes may especially be defined as comprising hyperactivation of the hypothalamo-pituitary axis, irritable bowel syndrome, hypertension, infertitly; and, stress related syndromes may also be associated with / comprise insomnia, depression or anxiety.
  • Psychoactive substance use, abuse, seeking and reinstatement may be defined as comprising all types of psychological or physical addictions and their related tolerance and dependence components.
  • Dementias and cognitive dysfunctions may be defined as comprising deficits in all types of attention, learning and memory functions occurring transiently or chronically in the normal, healthy, young, adult or aging population, and also occurring transiently or chronically in psychiatric, neurologic, cardiovascular and immune disorders.
  • Anxiety disorders may be defined as comprising generalized anxiety, obsessive compulsive disorder, posttraumatic stress disorder, panic attacks, all types of phobic anxiety and avoidance, and separation anxiety.
  • Dysthymic disorders may be defined as comprising major depression and cyclothymia, affective neurosis, all types of manic depressive disorders, delirium, psychotic disorders, schizophrenia, catatonic schizophrenia, delusional paranoia, adjustment disorders and all clusters of personality disorders and schizoaffective disorders.
  • Pain may be defined as comprising migraine and headache; pain disorders; anaesthesia and analgesia; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; dental pain; pain related to infection e.g. by HIV; post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; osteoarthritis; conditions associated with visceral pain such as irritable bowel syndrome.
  • Chronic and acute allergic/inflammatory/immune disorders or diseases may be defined as comprising allergic asthma, rhinitis, allergic rhinitis, chronic obstructive pulmonary disease (COPD), dermatitis, inflammatory bowel disease, rheumatoid arthritis, allergic nephritis, conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, itching, inflammation, ischemia-reperfusion injury, cerebrovascular disorders, pleuritis, ulcerative colitis, eosinophil-related diseases comprising Churg- Strauss syndrome and sinusitis, and basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis, in humans and other mammals.
  • COPD chronic obstructive pulmonary disease
  • Cancers may be defined as comprising all sorts of cancers such as large intestine cancer, rectal cancer, breast cancer, lung cancer, non-small cell lung cancer, prostate cancer, esophagal cancer, stomach cancer, liver cancer, bile duct cancer, spleen cancer, kidney cancer, urinary bladder cancer, uterine cancer, ovarian cancer, cervical cancer, testicular cancer, thyroid cancer, pancreas cancer, brain tumor, blood tumor, basophil adenoma, prolactinoma, hyperprolactinemia, adenomas, endometrial cancer; and especially colon cancer.
  • cancers such as large intestine cancer, rectal cancer, breast cancer, lung cancer, non-small cell lung cancer, prostate cancer, esophagal cancer, stomach cancer, liver cancer, bile duct cancer, spleen cancer, kidney cancer, urinary bladder cancer, uterine cancer, ovarian cancer, cervical cancer, testicular cancer, thyroid cancer, pancreas cancer, brain tumor, blood tumor, basophil adenom
  • compounds of Formula (I) are particularly suitable for the prevention or treatment of sleep disorders.
  • the compounds of Formula (I) can be used for the preparation of a medicament and/or are particularly suitable for the prevention or treatment of sleep disorders selected from the group consisting of all types of parasomnias, insomnias, narcolepsy and other disorders of excessive sleepiness; sleep-related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift-work syndrome; delayed or advanced sleep phase syndrome; and insomnias related to psychiatric disorders.
  • compounds of Formula (I) are particularly suitable for the prevention or treatment of dementias and cognitive dysfunctions.
  • compounds of Formula (I) are particularly suitable for the prevention or treatment of eating disorders. ln another embodiment of the invention compounds of Formula (I) are particularly suitable for the prevention or treatment of psychoactive substance use, abuse, seeking and reinstatement.
  • compounds of Formula (I) are particularly suitable for the prevention or treatment of stress-related syndromes as well as other types and subtypes of anxiety disorders.
  • compounds of Formula (I) are particularly suitable for the prevention or treatment of dysthymic disorders.
  • compounds of Formula (I) are particularly suitable for the prevention or treatment of pain.
  • compounds of Formula (I) are particularly suitable for the prevention or treatment of chronic and acute allergic/inflammatory/immune disorders or diseases.
  • disorders or diseases are notably selected from the group consisting of allergic asthma, rhinitis, allergic rhinitis, COPD, dermatitis, inflammatory bowel disease, and rheumatoid arthritis.
  • compounds of Formula (I) are particularly suitable for the prevention or treatment of cancer.
  • a compound is mentioned as suitable for the prevention or treatment of a certain disease or disorder it is understood that such compound may be used for the preparation of a medicament for the prevention or treatment of said disease or disorder.
  • Another aspect of the invention concerns a method for the prevention or the treatment of a disease or disorder as mentioned above in a patient comprising the administration to said patient of a pharmaceutically active amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • any preferences indicated for the compounds of Formula (I) (whether for the compounds themselves, salts thereof, compositions containing the compounds or salts thereof, uses of the compounds or salts thereof, etc.) apply mutatis mutandis to compounds of formulae (IEI), and/or (h) and/or (IP) and/or (ICE) and vice versa.
  • the term "about” placed before a numerical value "X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X.
  • the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10 °C to Y plus 10 °C, and preferably to an interval extending from Y minus 5 °C to Y plus 5 °C.
  • room temperature r.t.
  • a further aspect of the invention is a process for the preparation of compounds of Formula (I).
  • Compounds according to Formula (I) of the present invention can be prepared from commercially available or well known starting materials according to the methods described in the experimental part, by analogous methods; or according to the general sequence of reactions outlined below, wherein Ar 1 , A, B, X, L 1 , Y, Z, and (R 1 ) n are as defined for Formula (I).
  • Other abbreviations used herein are explicitly defined, or are as defined in the experimental section.
  • the generic groups Ar 1 , A, B, X, L 1 , Y, Z, and (R 1 ) n might be incompatible with the assembly illustrated in the schemes below and so will require the use of protecting groups (PG).
  • protecting groups are well known in the art (see for example "Protective Groups in Organic Synthesis", T.W. Greene, P.G.M. Wuts, Wiley-lnterscience, 1999). For the purposes of this discussion, it will be assumed that such protecting groups as necessary are in place.
  • the compounds obtained may also be converted into salts, especially pharmaceutically acceptable salts thereof in a manner known per se.
  • Compounds of Formula (I) can be obtained by reacting a compound of Structure 1 , 2, 3, or 4, or a salt thereof, with a reagent of Structure 5, wherein Hal represents CI, Br or I; in the presence of a base such as NEt.3, DIPEA, K2CO3, CS2CO3, in the presence or absence of tetrabutylammonium iodide, in a solvent such as DMF or DCM in a temperature range from r.t. to about 80°C.
  • a base such as NEt.3, DIPEA, K2CO3, CS2CO3
  • a compound of Formula (I) can be obtained by reacting a compound of Structure 1 , 2, 3, or 4, or a salt thereof, with an aldehyde of Structure 6, wherein 71 represents -(CH 2 ) m -r, or -(CH 2 )i-2-0-; and a reducing agent such as NaBhU, NaBH(OAc)3, or NaBhhCN; in a solvent such as DCM, DCE, THF.
  • a base such as NEt.3, or DIPEA.
  • the corresponding compounds of Structure 5 and 6 are commercially available or synthesized from commercially available starting materials using well known methods.
  • compounds of Formula (I) can be obtained by reacting a compound of Structure 7, wherein Hal represents CI or Br, with a compound of Structure 8 or 9 in the presence of a base such as NEt.3, DIPEA, CS2CO3 or K2CO3 in a solvent such as dioxane, THF, DCM or DMF.
  • a base such as NEt.3, DIPEA, CS2CO3 or K2CO3
  • a solvent such as dioxane, THF, DCM or DMF.
  • a compound of Structure 8 or 9 can be silylated on the free amine, preferably trimethylsilylated, and coupled to a compound of Structure 7 in a solvent such as dioxane in the presence of a base, such as NEt or DIPEA, at r.t. up to reflux temperature, preferably around 60°C, to give compounds of Formula (I).
  • a solvent such as dioxane
  • a base such as NEt or DIPEA
  • a compound of Structure 1 can be obtained by methods described in the literature (U. Mikstais and A.Arens, Chemistry of Heterocyclic Compounds 1968, 811-813) e.g. a compound of Structure 7 is treated with piperazine hydrochloride in a solvent such as MeOH or is treated with a compound of Structure 10 or 11 , wherein PG represents an amino protective group such as Boc or Cbz, to give accordingly a compound of Structure 12 or 13, from which the PG can be removed applying known methods, to yield the corresponding compound of Structure 1 or 2.
  • a compound of Structure 10 or 11 can be silylated on the free amine, preferably trimethylsilylated, and coupled to a compound of Structure 7 in a solvent such as dioxane in the presence of a base, such as NEt or DIPEA, at r.t. up to reflux temperature, preferably around 60°C, to give compounds of Structure 12 and 13 respectively.
  • a solvent such as dioxane
  • a base such as NEt or DIPEA
  • a compound of Structure 12 is obtained by functional group modification on another compound of Structure 12 as in the particular cases of compounds of Structure 14 or 15 which can be obtained from compounds of Structure 16 in the known conditions of a Suzuki reaction.
  • Compounds of Structure 7 can be prepared by halogenating a compound of Structure 17 in the presence of a halogen donating reagent such as SO2CI2, POCI3, PEto, Efo, NBS or NCS, in a solvent such as Et.20, DCM, or AcOH.
  • a halogen donating reagent such as SO2CI2, POCI3, PEto, Efo, NBS or NCS
  • a solvent such as Et.20, DCM, or AcOH.
  • a compound of Structure 17 can be accessed using analogous methods starting with appropriately substituted acetic acid derivatives in a reaction with the respective phthalic acid anhydride in AC2O, or by treatment of indan-1 ,3-dione derivatives with azine N-oxides in the presence of AC2O, or in a reaction of diethyl phthalate with a methyl substituted heteroaryl derivative using NaH as condensing agent in a refluxing solvent such as DME in analogy to J. F. Wolfe ef a/., J. Org. Chem. 1974, 39, 2006.
  • a compound of Structure 17 can be accessed by reaction of appropriately substituted phthalide derivative of Structure 18 with a subtituted carboxaldehyde of Structure 19 following a procedure described in US2005/0059663 or by K. A. Menear ef a/., J. Med. Chem.
  • Compounds of Structure 18 and 19 are commercially available or can be obtained by methods well know in the art.
  • A represents pyridyl
  • compounds of Structure 19 can be obtained in a well know manner from the corresponding carboxylic acids whose syntheses are described for example in WO2009/024905.
  • Y represents CH2
  • a compound of Structure 17 can be prepared according to known protocols, either by cyclizing a compound of Structure 20 under Friedel-Crafts conditions (B. B. Datta and J. C. Bardhan, J. Chem. Soc.
  • a compound of Structure 1 wherein L 1 represents 4-piperidinyl, or of Structure 3 or 4 can be obtained from a compound of Structure 24, 25 or 26, respectively after cleavage of an amino protecting group PG, such as e.g. Boc, by applying known methods.
  • an amino protecting group PG such as e.g. Boc
  • a compound of Structure 27 can be obtained in a reaction of a compound of Structure 28 with a compound of Structure 29, wherein PG represents an amino protecting group such as Boc, in the presence of equimolar 2,6-dimethyl- l,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester and catalytic amount of DL -proline in a solvent such as DMSO (Ramachary, D.B; Kishor, M.; Reddy, G. B. Org. Biomol. Chem. 2006, 1641-1646).
  • DMSO solvent
  • a compound of Structure 1 wherein L 1 represents 4-piperidinyl, or of Structure 3 or 4 can be generated from a compound of Structure 30, 31 or 32, respectively, via hydrolysis of the imine and concomitant removal of the amino protecting group PG under well known conditions.
  • a compound of Structure 30, 31 or 32 can be obtained in an intramolecular cyclization reaction by means of ferf-BuLi from a compound of Structure 33, 34 or 35, respectively.
  • Such a compound of Structure 33, 34 or 35 can be prepared according to known procedures, e.g. by alkylating a compound of Structure 36, 37 or 38, respectively, with a compound of Structure 39 using a reagent such as NaH or LDA.
  • a compound of Structure 36, 37 or 38 can be obtained using the methods described in the experimental part below, by analogous methods, or by applying methods known to a person skilled in the art.
  • a compound of Formula (I) can be obtained from a compound of Structure 40 under conditions analogous to those for converting compounds of Structure 30 to a compound of Structure 1.
  • Compounds of Structures 40 can be synthesized either by alkylating compounds of Structure 41 or by cyclizing compounds of Structure 42 using methods described herein before.
  • Compounds of Structure 41 can be obtained by anhydrous Boc cleavage, e.g. HCI in AcOEt at r.t., after cyclization of compounds of Structure 43 using methods described before for the compounds of Structure 33.
  • conditions of PG removal may lead directly to the corresponding compounds of Structure 1.
  • Compounds of Structure 42 are produced by PG removal on compounds of Structure 43 and subsequent alkylation under conditions analogous to those described for compounds of Structure 1.
  • Compounds of Structure 43 are produced by a Strecker synthesis involving the corresponding aldehyde under known conditions, followed by alkylation of the aminonitrile intermediate analogously to the alkylation of compounds of Structure 36.
  • the corresponding aldehydes are commercially available or synthesized from commercially available halides or carboxylic acid derivatives using well-known methods.
  • the enantiomers can be separated using methods known to one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Regis Whelk-01 (R,R) (10 ⁇ ) column, a Daicel ChiralCel OD-H (5-10 ⁇ ) column, or a Daicel ChiralPak IA (10 ⁇ ) or AD-H (5 ⁇ ) column.
  • a chiral stationary phase such as a Regis Whelk-01 (R,R) (10 ⁇ ) column, a Daicel ChiralCel OD-H (5-10 ⁇ ) column, or a Daicel ChiralPak IA (10 ⁇ ) or AD-H (5 ⁇ ) column.
  • Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH or /PrOH, in presence or absence of an amine such as NEt 3 , diethylamine) and eluent B (hexane), at a flow rate of 0.8 to 150 mL/min.
  • eluent A EtOH or /PrOH
  • amine such as NEt 3 , diethylamine
  • eluent B hexane
  • LC-12a,b,c,d Dionex HPG-3000 pump equipped with a Dionex Ultimate 3000 photodiode array detector, a Thermo MSQ MS mass detector and a PolymerLab ELS2100 ELSD Detector, using a Dionex TCC-3000 Column compartment, a CTC Pal HTS Sampler for LC and a Ascentis C18 (3 x 30 mm 2.7 ⁇ ) (Methods LC- 12a, 12b and 12c) or a Waters X-Bridge C18 (2,1 x 20mm 2,5 ⁇ ) (Method LC-12d)
  • LC-1 , LC-2 and LC-5 eluent A: MeCN, eluent B: 0.04% TFA in water; 5% to 95% MeCN over 1 min, flow rate 4.5 mL / min, fR given in min.
  • LC-4 eluent A: MeCN, eluent B: 13 mM NH3 in water; 5% to 95% MeCN over 45 s, flow rate 4.5 mL / min, fR given in min.
  • LC-11 eluent A: iPrOH with 0.1 % DEA, eluent B: hexane, isocratic (30%B) over 15 mn, flow rate 0.8 mL / min, t R given in min.
  • LC-12a eluent A: MeCN, eluent B: 5 mM HC02NH4 + 2% AcCN in water; 5% to 95% MeCN over 2.5 min, flow rate 3 mL / min, t R given in min.
  • LC-12b eluent A: MeCN, eluent B: 5 mM HC02NH4 + 2% AcCN in water; 5% to 95% MeCN over 1.4 min, flow rate 3 mL / min, t R given in min.
  • LC-12c eluent A: MeCN, eluent B: 5 mM HC02NH4 + 2% AcCN in water; 5% to 95% MeCN over 2 min, flow rate 3 mL / min, t R given in min.
  • LC-12d eluent A: MeCN + 0.04% HC02H, eluent B: water + 0.05% HC02H; 5% to 95% MeCN over 1.4 min, flow rate 3 mL / min, t R given in min.
  • LC-13 eluent A: iPrOH with 0.1 % DEA, eluent B: hexane, isocratic (80%B), flow rate 0.8 mL / min, t R given in min.
  • LC-14 eluent A: EtOH with 0.1 % DEA, eluent B: hexane, isocratic (80%B), flow rate 0.8 mL / min, t R given in min.
  • LC-15 eluent A: iPrOH with 0.1 % DEA, eluent B: hexane, isocratic (98%B), flow rate 0.8 mL / min, tR given
  • n.a. means: not applicable.
  • the experimental m/z is the one of the major experimentally observed bromine isotope peak that differs correspondingly from the molecular weight as known to the person skilled in the art.
  • NMR spectra are measured using 1 mm Microprobe® tubes and a PAXTI 1 mm probehead, the compounds are dissolved in non-deuterated DMSO. The spectra are then measured with double irradiation for suppression of the DMSO and H 2 0 peaks. In that case only a selection of representative NMR peaks of the compound is given.
  • LC-MS (A): Gilson 333/334 binary high pressure gradient pump system equipped with Dionex UVD340U DAD detector, Polymerlabs PL-ELS 1000 ELS detector, Finnigan AQA MS detector, Sedere Sedex V.F.S variable flow splitter, 2 x Dionex P680 isocratic make up pump and Gilson 215 autosampler and fraction collector.
  • LC-MS (B): Gilson 333/334 binary high pressure gradient pump system equipped with Dionex UVD340U DAD detector, Polymerlabs PL-ELS 1000 ELS detector, Finnigan AQA MS detector, Sedere Sedex V.F.S variable flow splitter, 2 x Dionex P680 isocratic make up pump and Gilson 215 autosampler and fraction collector.
  • LC-MS Waters HPLC apparatus equipped with Waters 600 controller, Waters 276 sample manager, Waters 996 Photodiode array detector, Waters SOF and Waters micromass ZQTM mass spectrometer.
  • LC-MS Preparative chiral separations are performed on a HPLC instrument equipped with Dionex P580 binary pump, photodiode array detector Dionex PDA-100. Column: Diacel ChiralPak AD-H (20 x 250 mm, 5 ⁇ ) or ChiralPak IA (20 x 250 mm, 10 ⁇ ). Conditions: eluent A: EtOH with 0.1 % DEA or iPrOH with 0.1 % DEA, eluent B hexane isocratic (%B) conditions, run time 30 min., flow rate 10 mL / min., detection at 210 nm. The compounds are dissolved in EtOH before loading.

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Abstract

The invention relates to indanone/indandione derivatives and heterocyclic analogs of Formula (I) wherein Ar1, A, B, L1, Y, Z, and (R1)n n are as described in the description; to pharmaceutically acceptable salts thereof, and to the use of such compounds as medicaments, especially as NPS receptor antagonists.

Description

Indanone and indandione derivatives and heterocyclic analogs
The present invention relates to novel indanone/indandione derivatives and heterocyclic analogs of Formula (I), and their use as pharmaceuticals. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of Formula (I), and especially their use as neuropeptide S receptor antagonists. A further aspect of the invention relates to novel compounds of Formula (II) and to salts thereof that serve as intermediates to prepare compounds of Formula (I).
Neuropeptide S (NPS) is a recently discovered neuropeptide whose sequence and possible physiological function was first described in 2004 (Xu ei a/., Neuron 2004; 43: 487-97). NPS is a 20 amino acid peptide produced in the brain stem by few discrete neurons (Xu ei a/., Neuron 2004; 43: 487-97) and binds to a G- protein-coupled receptor (NPS receptor = NPSR) thus inducing intracellular calcium fluxes and increases in intracellular cAMP levels (Xu ef a/., Neuron 2004; 43: 487-97, Reinscheid ef a/., J. Pharmacol. Exp. Ther. 2005; 315: 1338-45). NPS was found to stimulate wakefulness and locomotion in mice and rats while suppressing all sleep stages (Xu ei a/., Neuron 2004; 43: 487-97). Furthermore, NPSR -/- mice displayed reduced arousal in different paradigms (Duangdao ei a/., Behav Brain Res. 2009; 205:1-9), suggesting a physiological role for this peptide as a central regulator of arousal potentially offering novel therapeutic approaches to insomnia and other sleep disorders as well as other disorders related to increased arousal. On the other hand, it was observed that NPS application suppresses food intake in rats (Beck ei a/., Biochem. Biophys. Res. Commun. 2005; 332: 859- 65), activates the hypothalamo-pituitary-adrenal axis causing typical stress responses such as corticosterone release, hyperlocomotion, addiction re-instatement and reduction of intestinal motility (Smith ei a/., Endocrinology 2006; 147: 3510-8; Paneda ei a/., J Neurosci. 2009; 29:4155-61 ; Han ei a/., Peptides 2009; 30:1313-7.) in rats and mice, is anxiolytic in mice (Xu ei a/., Neuron. 2004;43: 487-97; Leonard ei a/., Psychopharmacology 2008; 197: 601-11), anti-depressant in susceptible rats (abstracts: Wegener ei a/. 2008; Slattery ei a/. 2008; Society for Neuroscience Annual Meeting), increases cocaine seeking behaviour and reinstatement of cocaine and ethanol addiction in rats (Paneda ei a/., J Neurosci. 2009; 29:4155-61 ; Cannella ei a/., Neuropsychopharmacology 2009; 34:2125-34) and decreases pain (Li ei a/., Regul Pept. 2009; 156:90-5) opening potential treatment approaches to sleep disorders, eating disorders, anxiety disorders, addiction, psychoactive substance use, abuse, seeking and reinstatement, stress-related syndromes and pain. It was also shown that intracerebroventricular (icv) application of NPS in mice increases both aversive memory consolidation as well as improves cognitive performance (abstract: Okamura ei a/. 2008; Society for Neuroscience Annual Meeting) while NPSR deficient mice display reduced aversive learning and memory consolidation (abstract: Duangdao ei a/. 2008; Society for Neuroscience Annual Meeting) potentially allowing novel therapies for dementias and cognitive dysfunctions.
NPS receptors are found in the mammalian brain (Xu ei a/., Neuron 2004; 43: 487-97; Xu ei a/., J. Comp. Neurol. 2007; 500: 84-102) and may have numerous implications in psychiatric and neurological pathologies known from the literature. In addition, NPS receptors are also expressed in the periphery (Xu ef a/., Neuron 2004; 43: 487-97; Laitinen ef a/., Science 2004; 304: 300-4, D'Amato ef a/., Gastroenterology 2007; 133: 808- 17; Sundman ef a/., Neurogastroenterol Motil. 2009; Jul 13 [Epub ahead of print].) and might play a role in chronic and acute allergic/inflammatory/immune disorders or diseases, e.g. asthma, celiac disease and inflammatory bowel disease (Laitinen ef a/., Science 2004; 304: 300-4, Pulkkinen ef a/., Hum Mol Genet. 2006; 15:1667-79. D'Amato ef a/., Gastroenterology 2007; 133: 808-17, Sundman ef a/., Neurogastroenterol Motil. 2009 Jul 13 [Epub ahead of print]) as well as all sorts of cancers (WO2005/021555).
In the human population, the NPS receptor occurs in two major polymorphic forms differing at amino acid 107, human NPSR asparagine107 (hNPSR-107N) and human isoleucine107 (hNPSR-1071). This single nucleotide polymorphism affects receptor sensitivity to NPS (Reinscheid ef a/., J. Pharmacol. Exp. Ther. 2005; 315: 1338- 45) with hNPSR-1071 being the more sensitive receptor version. In humans, gain of sensitivity in hNPSR-1071 is linked to later mean bed time (Gottlieb ef a/., BMC Med. Genet. 2007; 8: 59), an increased susceptibility to panic disorders in Japanese males (Okamura ef a/., Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 1444-8) and to an increased susceptibility to allergic disorders (Laitinen ef a/., Science 2004; 304: 300-4).
Bicyclic piperazine compounds were claimed to block NPS-induced proliferation of human colon carcinoma cells (WO2005/021555), were shown to block NPS-induced hyperlocomotion in mice (Okamura ef a/., J Pharmacol Exp Ther. 2008; 325: 893-901) and claimed to increase anxiety (open field tests) and to increase fear memory extinction time in mice (Jiingling ef a/., Neuron. 2008; 59: 298-310).
Certain compounds were shown to block NPS-induced hyperlocomotion in mice (Melamed ef a/., 238th Meeting of the American Chemical Society 2009). The present invention provides indanone/indandione derivatives, which are non-peptide antagonists of the human NPS receptor. These compounds are useful for the prevention or treatment of diseases which respond to the modulation of the NPS receptor such as sleep disorders; eating disorders; drinking disorders; stress-related syndromes; addiction; psychoactive substance use, abuse, seeking and reinstatement; dementias and cognitive dysfunctions; anxiety disorders; dysthymic disorders; chronic and acute allergic/inflammatory/immune disorders or diseases; all sorts of cancers; and pain.
1) In a first embodiment, the present invention relates to com ounds of Formula (I)
Figure imgf000003_0001
Formula (I)
wherein
Ar1 represents a fused benzene or a fused pyridine ring; (R1)n represents one or two optional substituents each independently selected from the group consisting of (Ci. 4)alkyl, (Ci-4)alkoxy, hydroxy, trifluoromethyl, (Ci)fluoroalkoxy, and halogen; wherein any R1 is attached to a carbon atom of Ar1;
L1 re resents a group selected from the group consisting of:
Figure imgf000004_0001
wherein X represents CH or N; and the asterisks signify the bond to which the group Z is attached to;
Y represents CH2 or C=0;
Z represents -(CH2)m-, wherein m represents the integers 1 to 4, wherein optionally one CH2 group may be replaced by oxygen;
A represents aryl or heteroaryl, wherein said aryl or heteroaryl independently is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci. 4)alkoxy; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; (C3-6)cycloalkyl; (C2-4)alkenyl; phenyl; -NR2R3, wherein R2 and R3 independently represent hydrogen or (Ci-3)alkyl; and a 5- or 6-membered ring selected from pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, which ring, in case it is attached to A through a carbon atom or in case it is a piperazinyl ring, may in turn optionally be substituted at the vacant nitrogen atom with (Ci-4)alkyl; or
A represents an unsubstituted partially aromatic bicyclic ring system, wherein A is attached to the rest of the molecule at the aromatic ring of said partially aromatic bicyclic ring system;
B represents aryl or heteroaryl, wherein said aryl or heteroaryl independently is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci. 4)alkoxy; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; cyano; (Ci -3)al koxy-(Ci-4)al kyl ; (Ci-3)alkoxy-(C2-4)alkoxy; nitro; hydroxy; (C2-4)alkenyl; (C2-4)alkenyloxy; -NR4R5, wherein R4 and R5 independently represent hydrogen or (Ci-3)alkyl; unsubstituted 5- or 6-membered monocyclic heteroaryl; and unsubstituted phenyl; or
B represents a partially aromatic bicyclic ring system; wherein said partially aromatic bicyclic ring system is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from (Ci-4)alkyl, (Ci-4)alkoxy, halogen and oxo;
or B represents (C3-7)cycloalkyl;
with the exception of the following compound: 2-(4-Benzyl-piperazin-1-yl)-2-phenyl-indan-1 ,3-dione (CAS Registry No. 898480-02-9).
The compounds of Formula (I) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms. The compounds of Formula (I) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
The compounds of Formula (I) contain a chiral quaternary carbon center in the particular case wherein Y represents C=0 and one of the following characteristics are present:
· one R1 is present;
• two R1 are present and said two R1 are not the same;
• two R1 are present, and said two R1 are the same, and said two R1 are not both in ortho-position and are not both in meta position.
In such case it is well understood that the thus formed indan-1 ,3-dione moiety may be in absolute (R)- or in absolute (S)-configuration; and both epimers, or mixtures thereof, are encompassed in the scope of the present invention.
The compounds of Formula (I) also contain a chiral quaternary carbon center in the particular case wherein Y represents CH2 (see embodiments 2) and 3) below). In such case it is well understood that the thus formed indan-1 -one moiety may be in absolute (R)- or in absolute (S)-configuration; and both epimers, or mixtures thereof, are encompassed in the scope of the present invention.
For avoidance of any doubt, the term "a fused benzene or a fused pyridine ring" as used for "Ar1" means that such ring Ar1 together with the cyclopentane moiety to which it is fused forms notably an indane (also named 2,3-dihydro-1 H-indene), or a 6,7-dihydro-5H-cyclopenta[b]pyridine or 6,7-dihydro-5H-cyclopenta[c]pyridine ring; wherein the respective cyclopentane moiety carries the prescribed oxo substituent(s); and wherein said rings may optionally be substituted at the aromatic ring with one or two optional substituents R1; it being well understood that the nitrogen atom of a 6,7-dihydro-5H-cyclopenta[b]pyridine or 6,7-dihydro-5H- cyclopenta[c]pyridine ring will not carry such substituent R1.
For avoidance of any doubt, the term "(R1)n representing one or two optional substituents" means that n represents the integer 0 (i.e. (R1)n is absent), 1 (i.e. one R1 is present), or 2 (i.e. two R1 are present). A substituent R1 may be attached in ortho or meta position. In case a substituent R1 is referred to as being in ortho-position, this means that said substituent is attached in position 4 or 7 of an indan-1 -one, respectively, indan-1 ,3-dione moiety. Likewise, if a substituent R1 is referred to as being in meta-position, this means that said substituent is attached in position 5 or 6 of an indan-1 -one, respectively, indan-1 ,3-dione moiety (Mutatis mutandis for the respective 6,7-dihydro-5H-cyclopenta[b]pyridine and 6,7-dihydro-5H-cyclopenta[c]pyridine derivatives).
The term "halogen" means fluorine, chlorine, or bromine, preferably fluorine or chlorine. For the substituent R1 preferred is fluorine.
The term "alkyl", used alone or in combination, refers to a straight or branched saturated hydrocarbon chain containing one to four carbon atoms. The term "(Cx.y)alkyl" (x and y each being an integer), refers to an alkyl group as defined before containing x to y carbon atoms. For example a (Ci-4)alkyl group contains from one to four carbon atoms. Examples of (Ci-4)alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec- butyl and fe/t-butyl. Preferred are methyl and ethyl. Most preferred is methyl.
The term "-(CH2)m-, wherein m represents the integers 1 to 4, wherein optionally one CH2 group may be replaced by oxygen", as used for the group "Z" refers to a bivalent radical derived from a straight chain (Ci- 4)alkyl group as defined before by removal of a further hydrogen atom from a carbon atom of the chain. Optionally, one CH2 group of the chain may be replaced by oxygen. In such case, m preferably represents the integer 3 or 4, and said oxygen atom is separated from the nitrogen atom of the ring L1 of the parent molecule by 2 carbon atoms. Examples are methylene (-CH2-), ethylene (-CH2-CH2-), propane-1 ,3-diyl (trimethylene), butane-1 ,4-diyl (tetramethylene), ethylen-oxy (-CH2-CH2-O-*), and ethylen-oxy-methylen (-CH2-CH2-O-CH2-*); wherein the asterisks signify the bond to which B is attached to. Preferred are methylene, ethylene, trimethylene, tetramethylene, and ethylen-oxy, especially methylene.
The term "alkoxy", used alone or in combination, refers to an alkyl-O- group wherein the alkyl group is as defined before. The term "(Cx.y)alkoxy" (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms. For example a (Ci-4)alkoxy group means a group of the formula (Ci- 4)alkyl-0- in which the term "(Ci-4)alkyl" has the previously given significance. Examples of (Ci-4)alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy and ieri.-butoxy. Preferred is methoxy. For substituents of the substituent "A" most preferred are methoxy and ethoxy, especially methoxy.
The term "(Ci-3)fluoroalkyl" refers to an alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The term "(Cx. y)fluoroalkyl" (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms. For example a (Ci-3)fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine. Representative examples of (Ci-3)fluoroalkyl groups include trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, and difluoromethyl. Preferred are (Ci)fluoroalkyl groups such as trifluoromethyl or difluoromethyl.
The term "(Ci-3)fluoroalkoxy" refers to an alkoxy group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The term "(Cx. y)fluoroalkoxy" (x and y each being an integer) refers to a fluoroalkoxy group as defined before containing x to y carbon atoms. For example a (Ci-3)fluoroalkoxy group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine. Representative examples of (Ci-3)fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy and 2,2,2-trifluoroethoxy. Preferred are (C-i)fluoroalkoxy groups such as trifluoromethoxy and difluoromethoxy. Most preferred is trifluoromethoxy.
The term "cycloalkyl", used alone or in combination, refers to a saturated carbocyclic ring containing three to seven carbon atoms. The term "(Cx-y)cycloalkyl" (x and y each being an integer), refers to a cycloalkyl group as defined before containing x to y carbon atoms. For example a (C3-7)cycloalkyl group contains from three to seven carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Preferred are cydopropyl, cyclopentyl and cyclohexyl. For substituents of the substituent "A" most preferred is cydopropyl. For the substituent "B" most preferred are cydopropyl and especially cyclohexyl.
The term "alkenyl", used alone or in combination, refers to a straight or branched hydrocarbon chain containing two to four carbon atoms and one carbon-carbon double bond. The term "(Cx-y)alkenyl" (x and y each being an integer), refers to an alkenyl group as defined before containing x to y carbon atoms. For example a (C2- 4)alkenyl group contains from two to four carbon atoms. Examples of (C2-4)alkenyl groups are 2-propen-1-yl (also referred to as "allyl"), 2-methyl-2-propen-1-yl, and 3-buten-1-yl, especially 2-propen-1-yl, and in addition to the above-mentioned groups ethenyl (also referred to as vinyl), which group is a particular example in case the term "alkenyl" is used alone.
Particular examples of "-NR2R3, wherein R2 and R3 independently represent hydrogen or (Ci-3)alkyl" are dimethylamine, diethylamine, and especially methylamine and ethylamine.
Particular examples of "-NR4R5, wherein R4 and R5 independently represent hydrogen or (Ci-3)alkyl" are methylamine, ethylamine, diethylamine and especially dimethylamine.
Particular examples of a "and a 5- or 6-membered ring selected from pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, which ring, in case it is attached to A through a carbon atom or in case it is a piperazinyl ring, may in turn optionally be substituted at the vacant nitrogen atom with (Ci-4)alkyl" are pyrrol id in- 1 -yl , piperidin-1-yl, 1-(Ci. 4)alkyl-pyrrolidin-2-yl groups such as especially 1 -methyl-pyrrolidin-2-yl, 4-(Ci-4)alkyl-piperazin-1-yl groups such as especially 4-methyl-piperazin-1-yl, and especially morpholin-4-yl.
The term "aryl", used alone or in combination, means phenyl or naphthyl. The above-mentioned aryl groups are unsubstituted or substituted as explicitly defined.
"A" representing "aryl" means phenyl (preferred) or naphthyl, which is independently unsubstituted, or mono-, di-, or tri-substituted (especially unsubstituted, or mono-, or di-substituted; notably unsubstituted or mono- substituted); wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci. 4)alkoxy;
(Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; (C^cycloalkyl; (C2-4)alkenyl; phenyl; -NR2R3, wherein R2 and R3 independently represent hydrogen or (Ci-3)alkyl; and a 5- or 6-membered ring selected from pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, which ring, in case it is attached to A through a carbon atom or in case it is a piperazinyl ring, may in turn optionally be substituted at the vacant nitrogen atom with (Ci-4)alkyl. In a sub- embodiment, substituents are selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (Ci.3)fluoroalkyl; (Ci. 3)fluoroalkoxy; halogen; (C3-6)cycloalkyl; and a 5- or 6-membered ring selected from pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, which ring, in case it is attached to A through a carbon atom or in case it is a piperazinyl ring, may in turn optionally be substituted at the vacant nitrogen atom with (C -4)alkyl (especially substituents are selected from (Ci-4)alkyl, (Ci-4)alkoxy, (Ci.3)fluoroalkyl, halogen; (C^cycloalkyl; and morpholinyl; notably from methyl, ethyl, isopropyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, cydopropyl, and morpholinyl). In another embodiment, the substituents are selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, and halogen (especially substituents are selected from (Ci- 4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, and halogen; notably from methyl, ethyl, isopropyl, methoxy, fluoro, chloro, bromo, and trifluoromethyl). Naphthyl groups are preferably unsubstituted. Examples of "A" representing "aryl" are phenyl, 1 -naphthyl, 2-naphthyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 3-ethylphenyl, 3- isopropylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4- chlorophenyl, 3-chlorophenyl, 4-bromophenyl, 3-bromophenyl, 3-trifluoromethylphenyl, 3-fluoro-5-methylphenyl, 3-fluoro-5-methoxyphenyl, 3-methoxy-5-methylphenyl, 3,5-difluorophenyl, 3-vinylphenyl, 3,5-dimethylphenyl, 3,5-diethylphenyl, 3,5-dimethoxyphenyl, 3-n-propoxyphenyl, 3-cyclopropylphenyl, 3-difluoromethylphenyl, 3- trifluoromethoxyphenyl, 3-(morpholin-4-yl)-phenyl, 3-(4-methyl-piperazin-1-yl)-phenyl, 3-(piperidin-1-yl)-phenyl, and 3-(pyrrolidin-1-yl)-phenyl.
"B" representing "aryl" means phenyl (preferred) or naphthyl, which is independently unsubstituted, or mono-, di-, or tri-substituted; wherein the substituents are independently selected from the group consisting of (Ci. 4)alkyl; (Ci-4)alkoxy; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; cyano; (Ci-3)alkoxy-(Ci-4)alkyl; (Ci-3)alkoxy-(C2- 4)alkoxy; nitro; hydroxy; (C2-4)alkenyl; (C2-4)alkenyloxy; -NR4R5, wherein R4 and R5 independently represent hydrogen or (Ci-3)alkyl; unsubstituted 5- or 6-membered monocyclic heteroaryl; and unsubstituted phenyl. In a sub-embodiment, the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci- 4)alkoxy; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; and -NR4R5, wherein R4 and R5 independently represent hydrogen or (Ci-3)alkyl (especially from (Ci-4)alkyl; (Ci-4)alkoxy; halogen; and -NR4R5). In another particular embodiment, the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, halogen, cyano, (Ci -3)al koxy-(Ci-4)al kyl , (Ci-3)alkoxy-(C2-4)alkoxy, nitro, hydroxy, (C2-4)alkenyloxy, unsubstituted 5- or 6-membered monocyclic heteroaryl (especially 5-membered heteroaryl, notably pyrazolyl or thiadiazolyl), and unsubstituted phenyl. In a sub-embodiment, the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, (Ci- 3)fluoroalkoxy, and halogen (especially from (Ci-4)alkyl; (Ci-4)alkoxy; and halogen). Naphthyl groups are preferably unsubstituted. Examples of "B" representing "aryl" are phenyl, 1-naphthyl, 2-naphthyl, 4- methylphenyl, 3-methylphenyl, 2-methylphenyl, 2-ethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 4- isopropylphenyl, 2-isopropylphenyl, 2-n-propylphenyl, 4-fe/t-butylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2-hydroxyphenyl, 4-cyanophenyl, 3-cyanophenyl, 2-cyanophenyl, 4- chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 5-fluoro-2,4- dichlorophenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 3,4-difluorophenyl, 2,3-difluorophenyl, 2,4- difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3-chloro-2,6-difluorophenyl, 2-chloro-3,6-difluorophenyl, 3- chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-6-fluorophenyl, 2-chloro-6-fluoro-5-methylphenyl, 2- chloro-6-fluoro-3-methylphenyl, 3-fluoro-2-methylphenyl, 3-fluoro-4-methylphenyl, 3-fluoro-6-methylphenyl, 2- fluoro-4-methylphenyl, 2,3-difluoro-4-methylphenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 3-fluoro-4- methoxyphenyl, 2-fluoro-6-methoxyphenyl, 4-bromophenyl, 2-bromo-5-methoxyphenyl, 4- difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 2-difluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 4- trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 2-chloro-3-trifluoromethyl phenyl, 2- chloro-5-trifluoromethylphenyl, 3-chloro-6-trifluoromethylphenyl, 3-fluoro-2-trifluoromethylphenyl, 2-fluoro-5- trifluoromethylphenyl, 2-fluoro-6-trifluoromethylphenyl, 2-methyl-3-trifluoromethylphenyl, 4-methyl-3- trifluoromethylphenyl, 4-methoxy-3-trifluoromethylphenyl, 2-(2-methoxyethyl)-phenyl, 3-(2-methoxyethoxy)- phenyl, 2-allyloxyphenyl, 2-nitrophenyl, 4-(pyrrazol-1-yl)-phenyl, 4-([1 ,2,3,]thiadiazol-4-yl)-phenyl, 4-biphenyl, 2- biphenyl, 5-fluoro-2-methylphenyl, 2-bromo-5-fluorophenyl, 5-fluoro-2-vinylphenyl, 2-ethyl-5-fluorophenyl, 5- fluoro-2-methoxyphenyl, 5-bromo-2-methoxyphenyl, 5-isopropyl-2-methoxyphenyl, 2,5-dimethoxyphenyl, and 4- dimethylamino-2-methoxyphenyl.
The term "heteroaryl", used alone or in combination, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing one to a maximum of three heteroatoms, each independently selected from oxygen, nitrogen and sulfur. Examples of such heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo[1 ,5-a]pyridyl, pyrazolo[1 ,5-a]pyrimidyl, imidazo[1 ,2-a]pyridyl and imidazo[2,1-Jb]thiazolyl. The above- mentioned heteroaryl groups are unsubstituted or substituted as explicitly defined.
In case "A" represents "heteroaryl", the term means the above-mentioned groups. Preferably, the term means a 5- or 6-membered monocyclic aromatic ring containing one to a maximum of three (especially 1 or 2) heteroatoms, each independently selected from oxygen, nitrogen and sulfur. Preferred examples of such heteroaryl groups as used for the substituent "A" are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, and phthalazinyl. In a sub-embodiment, preferred examples are isoxazolyl (notably isoxazol-3-yl), thiophenyl (notably thiophen-2-yl, and thiophen-3-yl), thiazolyl (notably thiazol-4-yl), pyrazolyl (notably 1 H-pyrazol-3-yl and 1H-pyrazol-4-yl), pyridyl (notably pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidyl (notably pyrimidin-4-yl), pyrazinyl (notably pyrazin-2-yl), benzothiazolyl (notably benzothiazol-2-yl), quinolinyl (notably quinolin-4-yl), and quinoxalinyl (notably quinoxalin-2-yl). The above- mentioned heteroaryl groups as used for the substituent "A" are unsubstituted, mono-, di-, or tri-substituted (preferred unsubstituted, mono-, or di-substituted), wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; (C3-6)cycloalkyl; (C2- 4)alkenyl; phenyl; -NR2R3, wherein R2 and R3 independently represent hydrogen or (Ci-3)alkyl; and a 5- or 6- membered ring selected from pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, which ring, in case it is attached to A through a carbon atom or in case it is a piperazinyl ring, may in turn optionally be substituted at the vacant nitrogen atom with (Ci-4)alkyl. In a sub-embodiment, substituents are selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (C 1 -3)fl u o roa I ky I ; (Ci-3)fluoroalkoxy; halogen; (C3-6)cycloalkyl; and a 5- or 6- membered ring selected from pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, which ring, in case it is attached to A through a carbon atom or in case it is a piperazinyl ring, may in turn optionally be substituted at the vacant nitrogen atom with (Ci-4)alkyl (especially substituents are selected from (Ci-4)alkyl, (Ci-4)alkoxy, (Ci. 3)fluoroalkyl, halogen; (C3-6)cycloalkyl; and morpholinyl; notably from methyl, ethyl, isopropyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, cyclopropyl, and morpholinyl). In another embodiment, the substituents are selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci.3)fluoroalkyl, (Ci-3)fluoroalkoxy, and halogen (notably from (Ci-4)alkyl, (Ci-4)alkoxy, trifluoromethyl, and halogen; especially from (Ci-4)alkyl, (Ci-4)alkoxy and halogen). Particular examples of "A" representing "heteroaryl" are 1 -methyl - 1 H-pyrazol -3-yl , 4-bromo-thiophen- 2-yl, thiophen-3-yl, 2 , 5-d i methyl-th iazol-4-y 1 , 5-methyl-isoxazol-3-yl, pyrazin-2-yl, 6-methyl-pyrazin-2-yl, pyrimidin-4-yl, 6-methyl-pyrimidin-4-yl, pyridin-2-yl, 6-chloro-pyridin-2-yl, 6-b ro mo-py rid in-2-yl , 4-methyl-pyridin- 2-yl, 6-ethyl-py rid i n-2-yl , 6-ethoxy- pyrid i n-2-yl , 4,6-dimethyl-pyridin-2-yl, pyridin-3-yl, 5-bromo-pyrid i n-3-yl , 5- methoxy-pyridin-3-yl, pyridin-4-yl, 2-methyl-pyridin-4-yl, 3-methyl-pyridin-4-yl, 2,6-dimethyl-pyridin-4-yl, be nzoth iazol-2-yl , quinoxalin-2-yl, 3- met hyl-q u i noxal i n-2-y I , quinolin-4-yl, 1-methyl-1 H-pyrazol-4-yl, 1 ,3,5- trimethyl-1 H-pyrazol-4-yl, 2 , 5-d i methyl-oxazol -4-yl , 5-fluoro-pyridin-3-yl,. 5-methyl-pyridin-3-yl, 5-methyl-pyridin- 2-yl, 6- met hy I- pyrid i n-2-y 1 , 6-methyl-pyridin-3-yl, 6-methylamino-pyridin-2-yl, 6-ethylamino-pyrid i n-2-yl , 6- dimethylamino-pyridin-2-yl, 2-chloro-6-methyl-py rid in-4-yl , 2-ethyl-6-methyl-pyridin-4-yl, 2-isopropyl-6-methyl- pyridin-4-yl, 5-ethyl-pyridin-2-yl, 2,6-dimethyl-pyridin-4-yl, 2,6-diethyl-pyridin-4-yl, 5-trifluoromethyl-pyridin-3-yl, 2-(pyrrolidin-1-yl)-pyridin-4-yl, 5-(1 -methyl-pyrrol id in-2-yl)-pyrid i n-3-yl , 2-ethoxy-py ri mid i n-4-y 1 , 2-dimethylamino- pyrimidin-4-yl, 1-methyl-1 H-indazol-3-yl, quinolin-2-yl, and 1-phenyl-1 H-pyrazol-4-yl.
In case "B" represents "heteroaryl", the term means the above-mentioned groups. Preferably, the term means a 5- or 6-membered monocyclic aromatic ring containing one to a maximum of three heteroatoms, each independently selected from oxygen, nitrogen and sulfur. Preferred examples of such heteroaryl groups as used for the substituent "B" are oxazolyl (notably oxazol-4-yl), isoxazolyl (notably isoxazol-3-yl), oxadiazolyl (notably [1 ,2,4]oxadiazol-3-yl), thiophenyl (notably thiophen-2-yl), thiazolyl (notably thiazol-4-yl), thiadiazolyl (notably [1 ,2,4]thiadiazol-5-yl, and [1 ,2,3]thiadiazol-4-yl), imidazolyl (notably imidazol-2-yl), pyridyl (notably pyridin-2-yl, pyridin-3-yl, and pyrid ine-4-yl), indolyl (notably indol-3-yl), benzothiophenyl (notably benzo[Jb]thiophen-2-yl), benzimidazolyl (notably benzimidazol-2-yl), benzothiazolyl (notably benzothiazol-2-yl), benzotriazolyl (notably 1 H-benzotriazol-S-yl), benzoxadiazolyl (notably benzo[1 ,2,5]oxadiazol-4-yl), benzothiadiazolyl (notably benzo[1 ,2,5]thiadiazol-4-yl, and benzo[1 ,2,5]thiadiazol-5-yl), and quinolinyl (notably quinolin-8-yl). The above-mentioned heteroaryl groups as used for the substituent "B" are unsubstituted, mono-, di-, or tri-substituted (preferred unsubstituted, mono-, or di-substituted, more preferred unsubstituted, or mono- substituted), wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci. 4)alkoxy; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; cyano; (Ci -3)al koxy-(Ci-4)al kyl ; (Ci-3)alkoxy-(C2-4)alkoxy; nitro; hydroxy; (C2-4)alkenyl; (C2-4)alkenyloxy; -NR4R5, wherein R4 and R5 independently represent hydrogen or (Ci-3)alkyl; unsubstituted 5- or 6-membered monocyclic heteroaryl; and unsubstituted phenyl. In a sub- embodiment, the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (Ci-3)fluoroalkyl; halogen; and -NR4R5, wherein R4 and R5 independently represent hydrogen or (Ci-3)alkyl (especially from (Ci-4)alkyl; (Ci-4)alkoxy; halogen; and -NR4R5). In another particular embodiment, the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, halogen, cyano, (Ci -3)al koxy-(Ci-4)al kyl , (Ci-3)alkoxy-(C2-4)alkoxy, nitro, hydroxy, (C2- 4)alkenyloxy, unsubstituted 5- or 6-membered monocyclic heteroaryl, and unsubstituted phenyl. In a sub- embodiment, the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, halogen, and unsubstituted phenyl (especially from (Ci-4)alkyl, halogen, and unsubstituted phenyl; notably from (Ci-4)alkyl, and halogen). Particular examples of "B" representing "heteroaryl" are 5-phenyl- oxazol-4-yl, 5-methyl-isoxazol-3-yl, 5-ferf.-butyl-[1 ,2,4]oxadiazol-3-yl, [1 ,2,4]oxadiazol-3-yl, thiophen-2-yl, thiazol- 4-yl, 3-chloro-[1 ,2,4]thiadiazol-5-yl, 5-chloro-[1 ,2,3]thiadiazol-4-yl, imidazol-2-yl, pyridin-2-yl, pyridin-3-yl, 6- chloro-pyridin-3-yl, pyridine-4-yl, 1 H-indol-3-yl, 3-methyl-benzo[Jb]thiophen-2-yl, 1-methyl-1H-benzimidazol-2-yl, benzothiazol-2-yl, 1-methyl-1H-benzotriazol-5-yl, benzo[1 ,2,5]oxadiazol-4-yl, benzo[1 ,2,5]thiadiazol-4-yl, benzo[1 ,2,5]thiadiazol-5-yl, and quinolin-8-yl, 3-methyl-thiophen-2-yl, pyridin-4-yl, 4-chloro-1 -methyl- H-pyrazol- 3-yl, 5-chloro-1 ,3-dimethyl-1 H-pyrazol-4-yl, 2,4-dichloro-thiazol-5-yl, 4-methyl-pyridin-3-yl, and 2-ethyl-5-methyl- 3H-imidazol-4-yl.
The term "partially aromatic bicyclic ring system", used alone or in combination, means a phenyl ring or a 5- or 6-membered monocyclic heteroaryl ring (preferably containing one to two heteroatoms) as defined before, wherein said ring is fused to a 5- or 6-membered saturated or partially unsaturated non-aromatic ring optionally containing up to two (i.e. 0, 1 , or 2) heteroatoms independently selected from the group consisting of oxygen and nitrogen (i.e. such partially aromatic bicyclic ring system is a 8-, 9-, or 10-membered bicyclic ring system). If not explicitly indicated otherwise, a partially aromatic bicyclic ring system may be attached to the rest of the molecule either at the aromatic ring or at the saturated or partially unsaturated non-aromatic ring of said bicyclic ring system. For the substituent "A", a partially aromatic bicyclic ring system is attached to the rest of the molecule at the aromatic ring of said bicyclic ring system. The group of partially aromatic bicyclic ring systems comprises three sub-groups, notably "partially aromatic bicyclic heteroaryl ring systems", "carbocyclyl" groups, and "heterocyclyl" groups, as defined hereinafter. The above-mentioned partially aromatic bicyclic ring systems are preferably unsubstituted, or may be mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, halogen and oxo. In a sub-embodiment, for the substituent "A", a preferred sub-group of partially aromatic bicyclic ring systems are partially aromatic bicyclic heteroaryl ring systems as defined below. In another sub-embodiment, for the substituent "B", a preferred sub- group of partially aromatic bicyclic ring systems are heterocyclyl groups as defined below. One subgroup of "partially aromatic bicyclic ring systems" as defined before are "partially aromatic bicyclic heteroaryl ring systems".
The term "partially aromatic bicyclic heteroaryl ring system", used alone or in combination, means a 5- or 6- membered monocyclic heteroaryl ring (preferably containing one to two heteroatoms) as defined before, which is fused to a 5- or 6-membered saturated or partially unsaturated non-aromatic ring optionally containing up to two heteroatoms independently selected from the group consisting of oxygen and nitrogen. For avoidance of any doubt, in case one of said heteroatoms is a nitrogen atom, said nitrogen atom may be a bridgehead atom and thus be part of both the monocyclic heteroaryl ring and the 5- or 6-membered saturated ring, wherein the latter ring in this case may contain one further heteroatom selected from the group consisting of oxygen and nitrogen. Preferably, said fused 5- or 6-membered saturated or partially unsaturated non-aromatic ring is a carbocyclic ring. Partially aromatic bicyclic heteroaryl ring systems are preferably attached to the rest of the molecule at the monocyclic heteroaryl ring of said group. For the substituent "A", a partially aromatic bicyclic heteroaryl ring system is attached to the rest of the molecule at the aromatic ring of said bicyclic ring system. Examples of such a "partially aromatic bicyclic heteroaryl ring system" are 5,6,7, 8-tetrahydro-quinolinyl, 5,6,7,8- tetrahydro-isoquinolinyl, 5,6,7, 8-tetrahydro-quinazolinyl, and 5,6,7,8-tetrahydro-quinoxalinyl. For the substituent "A", a preferred example is 5,6,7, 8-tetrahydro-quinolinyl. The above-mentioned partially aromatic bicyclic heteroaryl ring systems are preferably unsubstituted, or may be mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, halogen and oxo.
Another subgroup of "partially aromatic bicyclic ring systems" as defined before are carbocyclyl groups.
The term "carbocyclyl", used alone or in combination, means a phenyl ring fused to a 5- or 6-membered saturated or partially unsaturated non-aromatic carbocyclic ring. Preferably, said 5- or 6-membered fused carbocyclic ring is saturated. For the substituent "A", a carbocyclyl group is attached to the rest of the molecule at the aromatic ring of said carbocyclyl group. Examples of such "carbocyclyl" groups are tetrahydronaphthalyl and indanyl. The above-mentioned carbocyclyl groups are preferably unsubstituted, or may be mono-, or di- substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci. 4)alkoxy, halogen and oxo. A particular example of such carbocyclyl groups as used for the substituent "A"is indan-5-yl.
Another sub-group of "partially aromatic bicyclic ring systems" as defined before are heterocyclyl groups.
The term "heterocyclyl", used alone or in combination, means a phenyl ring fused to a 5- or 6-membered saturated or partially unsaturated non-aromatic ring containing up to two heteroatoms independently selected from the group consisting of oxygen (preferred) and nitrogen. Heterocyclyl groups are preferably attached to the rest of the molecule at the phenyl ring of said group. For the substituent "A", a heterocyclyl group is attached to the rest of the molecule at the phenyl ring of said group. Examples of heterocyclyl groups are 2,3-dihydro- benzofuranyl, 4H-benzo[1 ,3]dioxinyl, benzo[1 ,3]dioxolyl (especially benzo[1 ,3]dioxol-5-yl), 2,3-dihydro- benzo[1 ,4]dioxinyl, 2H-chromenyl, and chromanyl. For the substituent "A", particular examples are 2,3-dihydro- benzo[1 ,4]dioxinyl. For the substituent "B", particular examples are chromanyl, 3,4-dihydro-2H- benzo[1 ,4]oxazinyl, and (notably) benzo[1 ,3]dioxolyl. The above-mentioned heterocyclyl groups are preferably unsubstituted, or may be mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, halogen and oxo. Benzo[1 ,3]dioxolyl-groups are preferably unsubstituted, or may be mono-substituted in position 6 with chloro. Chromanyl groups are preferably unsubstituted or di-substituted with methyl. 3,4-Dihydro-2H-benzo[1 ,4]oxazinyl groups are preferably substituted with oxo at position 3 and may optionally be further substituted with methyl at the nitrogen atom. A particular example of such heterocyclyl groups as used for the substituent "A"is 2,3-dihydro-benzo[1 ,4]dioxin-6-yl. Particular examples of such heterocyclyl groups as used for the substituent "B"are benzo[1 ,3]dioxol-5-yl, and 6- chloro-benzo[1 ,3]dioxol-5-yl, chroman-2-yl, 2,2-dimethyl-chroman-6-yl, and 3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl.
The term "cyano" refers to a group -CN.
The term "(Ci-3)al koxy-(Ci-4)al kyl" refers to a (Ci-3)alkyl-0-(Ci-4)alkyl group wherein the alkyl groups are as defined before. An example of a (Ci-3)alkoxy-(Ci-4)alkyl group is 2-methoxy-ethyl.
The term "(Ci-3)alkoxy-(C2-4)alkoxy" refers to a (Ci-3)al kyl-0-(C2-4)al kyl-O- group wherein the alkyl groups are as defined before. An example of a (Ci -3)al koxy-(C2-4)al kyl group is 2-methoxy-ethoxy.
The term "nitro" refers to a group -NO2.
The term "(C2-4)alkenyloxy" refers to a (C2-4)alkenyl-0- group wherein the alkenyl group is as defined before. An example of a (C2-4)alkenyloxy group is allyloxy.
Further embodiments of the invention are described hereinafter:
2) A further embodiment of the invention relates to compounds of Formula (I) according to embodiment 1), which are also compounds of Formula
Figure imgf000013_0001
Formula (ICE).
wherein W represents N or CH (preferably CH) (it being well understood that in case W represents N, W does not carry an optional substituent R1). In a sub-embodiment, in case W represents N, Y preferably represents
C=0.
3) A further embodiment of the invention relates to compounds of Formula (I) according to embodiment 2), wherein, in case Y represents CH2, the quaternary carbon atom of the thus formed indan-1-one moiety has the absolute configuration depicted in Formula (IEI) below:
Figure imgf000014_0001
Formula (IEI).
4) Another embodiment relates to compounds of Formula (I) according to embodiment 2), wherein, in case Y represents CH2, the quaternary carbon atom of the thus formed indan-1 -one moiety has the absolute configuration depicted in Formula ( ) below:
Figure imgf000014_0002
Formula ( ).
5) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1 ) to 4),
Figure imgf000014_0003
wherein the asterisks signify the bond to which the group Z is attached to.
6) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1 ) to 5), wherein L1 represents
Figure imgf000014_0004
wherein the asterisk signifies the bond to which the group Z is attached to.
7) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1 ) to 6), wherein X represents CH.
8) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1 ) to 6), wherein X represents N.
9) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1 ) to 8), wherein Y represents CH2.
10) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1 ), 2) or 5) to 8), wherein Y represents C=0. 11) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 10), wherein Z represents a group selected from the group consisting of methylene (-CH2-), ethylene (-CH2-CH2-), propane-1 ,3-diyl (trimethylene), butane-1 ,4-diyl (tetramethylene), ethylen-oxy (-CH2-CH2-O-*), and ethylen-oxy- methylen (-CH2-CH2-O-CH2-*); wherein the asterisks signify the bond to which B is attached to.
12) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 11), wherein Z represents methylene (-CH2-).
13) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 12), wherein (R1)n represents one (preferred) or two optional substituents (i.e. n represents the integer 0, 1 , or 2; preferably 0 or 1) each independently selected from the group consisting of (Ci )alkyl, (Ci-4)alkoxy, hydroxy, trifluoromethyl, and (especially) halogen (notably from (Ci-4)alkyl, (Ci-4)alkoxy, and (especially) halogen).
14) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 13), wherein (R1)n represents one (preferred) or two substituents each independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, hydroxy, trifluoromethyl, and (especially) halogen (notably from (Ci-4)alkyl, (Ci-4)alkoxy, and (especially) halogen).
15) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 13), wherein (R1)n represents one optional substituent in ortho-position (notably of the indan-1 ,3-dione / indan-1-one moiety of the compounds of Formula (I)), wherein said R1 is selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, hydroxy, and (especially) halogen (notably from (Ci-4)alkyl, (Ci-4)alkoxy, and (especially) halogen).
16) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 13), wherein (R1)n represents one optional substituent in meta-position (notably of the indan-1 ,3-dione / indan-1 -one moiety of the compounds of Formula (I)), wherein said R1 is selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, trifluoromethyl, and (especially) halogen (notably from (Ci-4)alkyl, (Ci-4)alkoxy, and (especially) halogen).
17) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 13), wherein (R1)n is absent (i.e. n represents the integer 0).
18) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 17), wherein A represents aryl, wherein said aryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; (C3-6)cycloalkyl; and a 5- or 6-membered ring selected from pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, which ring, in case it is attached to A through a carbon atom or in case it is a piperazinyl ring, may in turn optionally be substituted at the vacant nitrogen atom with (Ci-4)alkyl(notably from (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, and halogen; especially from (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, and halogen); or A represents heteroaryl, wherein said heteroaryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, halogen; (C3-6)cycloalkyl; and morpholinyl (notably from (Ci-4)alkyl, (Ci-4)alkoxy, trifluoromethyl and halogen; especially from (Ci-4)alkyl, (Ci-4)alkoxy, and halogen); or
A represents an unsubstituted partially aromatic bicyclic ring system, wherein A is attached to the rest of the molecule at the aromatic ring of said partially aromatic bicyclic ring system.
19) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 18), wherein A represents aryl, wherein said aryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; (C3-6)cycloalkyl; and a 5- or 6-membered ring selected from pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, which ring, in case it is attached to A through a carbon atom or in case it is a piperazinyl ring, may in turn optionally be substituted at the vacant nitrogen atom with (Ci-4)alkyl(notably from (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, and halogen; especially from (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, and halogen); or
A represents heteroaryl, wherein said heteroaryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, halogen; (C3-6)cycloalkyl; and morpholinyl (notably from (Ci-4)alkyl, (Ci-4)alkoxy, trifluoromethyl and halogen; especially from (Ci-4)alkyl, (Ci-4)alkoxy, and halogen).
20) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 18), wherein A represents aryl, wherein said aryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; (C3-6)cycloalkyl; and a 5- or 6-membered ring selected from pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, which ring, in case it is attached to A through a carbon atom or in case it is a piperazinyl ring, may in turn optionally be substituted at the vacant nitrogen atom with (Ci-4)alkyl(notably from (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, and halogen; especially from (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, and halogen).
21) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 18), wherein A represents heteroaryl, wherein said heteroaryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci. 3)fluoroalkyl, halogen; (C^cycloalkyl; and morpholinyl (notably from (Ci-4)alkyl, (Ci-4)alkoxy, trifluoromethyl and halogen; especially from (Ci-4)alkyl, (Ci-4)alkoxy, and halogen).
22) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 18), wherein A represents an unsubstituted partially aromatic bicyclic ring system, wherein A is attached to the rest of the molecule at the aromatic ring of said partially aromatic bicyclic ring system. 23) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 22), wherein B represents aryl, wherein said aryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; and -NR4R5, wherein R4 and R5 independently represent hydrogen or (Ci-3)alkyl (in another embodiment, from (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, halogen, cyano, (Ci- 3)al koxy-(Ci-4)al kyl , (Ci-3)alkoxy-(C2-4)alkoxy, nitro, hydroxy, (C2-4)alkenyloxy, unsubstituted 5- or 6-membered monocyclic heteroaryl, and unsubstituted phenyl; especially from (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, (Ci-
3) fluoroalkoxy, and halogen); or
B represents heteroaryl, wherein said heteroaryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; halogen; and - NR4R5, wherein R4 and R5 independently represent hydrogen or (Ci-3)al kyl (in another embodiment, from (Ci-
4) alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, halogen, and unsubstituted phenyl; especially from (Ci-4)alkyl, halogen, and unsubstituted phenyl); or
B represents a partially aromatic bicyclic ring system; wherein said partially aromatic bicyclic ring system is unsubstituted, or may be mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, halogen and oxo (notably unsubstituted (preferred), or mono-substituted, wherein the substituent is halogen); or
B represents (C3-7)cycloalkyl (especially cyclopropyl or cyclohexyl).
24) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 23), wherein B represents aryl, wherein said aryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; and -NR4R5, wherein R4 and R5 independently represent hydrogen or (Ci-3)alkyl (in another embodiment, from (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, halogen, cyano, (Ci- 3)al koxy-(Ci-4)al kyl , (Ci-3)alkoxy-(C2-4)alkoxy, nitro, hydroxy, (C2-4)alkenyloxy, unsubstituted 5- or 6-membered monocyclic heteroaryl, and unsubstituted phenyl; especially from (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, (Ci- 3)fluoroalkoxy, and halogen).
25) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 23), wherein B represents heteroaryl, wherein said heteroaryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; halogen; and -NR4R5, wherein R4 and R5 independently represent hydrogen or (Ci-3)al kyl (in another embodiment, from (C -4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, halogen, and unsubstituted phenyl; especially from (Ci-4)alkyl, halogen, and unsubstituted phenyl).
26) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 23), wherein B represents a partially aromatic bicyclic ring system (especially heterocyclyl); wherein said partially aromatic bicyclic ring system is unsubstituted, or may be mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, halogen and oxo (notably unsubstituted (preferred), or mono-substituted, wherein the substituent is halogen).
27) Another embodiment relates to compounds of Formula (I) according to any one of embodiments 1) to 23), wherein B represents (C3-7)cycloalkyl (especially cyclopropyl or cyclohexyl).
28) Another embodiment relates to compounds of Formula (I) according to embodiment 2), wherein one or more (and notably all) of the following characteristics in any combination are present:
• Z represents a group selected from the group consisting of methylene (-CH2-), ethylene (-CH2-CH2-), propane-1 ,3-diyl (trimethylene), butane-1 ,4-diyl (tetramethylene), and ethylen-oxy (-CH2-CH2-O-*); wherein the asterisk signifies the bond to which B is attached to;
· (R1)n is absent; or, in case W represents CH,
o (R1)n represents one substituent in ortho-position of the indan-1 ,3-dione / indan-1-one moiety of the compounds of Formula (I), wherein said R1 is selected from the group consisting of (Ci- 4)alkyl, (Ci-4)alkoxy, hydroxy, and (especially) halogen (notably from (Ci-4)alkyl, (Ci-4)alkoxy, and (especially) halogen); or
o (R1)n represents one substituent in meta-position of the indan-1, 3-dione / indan-1 -one moiety of the compounds of Formula (I), wherein said R1 is selected from the group consisting of (Ci- 4)alkyl, (Ci-4)alkoxy, trifluoromethyl, and (especially) halogen (notably from (Ci-4)alkyl, (Ci. 4)alkoxy, and (especially) halogen);
• A represents aryl, wherein said aryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (Ci.
3) fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; (C3-6)cycloalkyl; (C2-4)alkenyl; and morpholinyl; or
A represents heteroaryl, wherein said heteroaryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci.
4) alkoxy; (Ci-3)fluoroalkyl; halogen; (C3-6)cycloalkyl; phenyl; -NR2R3, wherein R2 and R3 independently represent hydrogen or (Ci-3)alkyl; and a 5- or 6-membered ring selected from pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, which ring, in case it is attached to A through a carbon atom or in case it is a piperazinyl ring, may in turn optionally be substituted at the vacant nitrogen atom with (Ci-4)alkyl; or A represents an unsubstituted partially aromatic bicyclic heteroaryl ring system, wherein A is attached to the rest of the molecule at the aromatic ring of said partially aromatic bicyclic heteroaryl ring system; · B represents aryl, wherein said aryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (Ci. 3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; cyano; (Ci-3)alkoxy-(Ci-4)alkyl; (Ci-3)alkoxy-(C2-4)alkoxy; nitro; hydroxy; (C2-4)alkenyl; (C2-4)alkenyloxy; -NR4R5, wherein R4 and R5 independently represent hydrogen or (Ci-3)alkyl; unsubstituted 5- or 6-membered monocyclic heteroaryl; and unsubstituted phenyl; or B represents heteroaryl, wherein said heteroaryl is unsubstituted, or mono-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; halogen; - NR4R5, wherein R4 and R5 independently represent hydrogen or (Cu)alkyl; and unsubstituted phenyl; or
B represents heterocyclyl; wherein said heterocyclyl is unsubstituted (preferred), or mono-, or di- substituted, wherein the substituents are independently selected from (Ci-4)alkyl, halogen and oxo; or B represents (C^cycloalkyl.
29) Another embodiment relates to compounds of Formula (I) according to embodiment 1), which are also compounds of Formula (lp)
Figure imgf000019_0001
Formula (lp)
wherein one or more (and notably all) of the following characteristics in any combination are present:
X represents CH or N;
Y represents CH2 or C=0;
Z represents -(CH2)m-, wherein m represents the integers 1 to 4 (especially 1), wherein optionally one CH2 group may be replaced by oxygen;
(R1)n represents one or two optional substituents each independently selected from the group consisting of (Ci- 4)alkyl, (Ci-4)alkoxy, hydroxy, trifluoromethyl, (Ci)fluoroalkoxy, and halogen (notably from (Ci-4)alkyl, (Ci-4)alkoxy, and (especially) halogen);
A represents aryl or heteroaryl, wherein said aryl or heteroaryl independently is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci- 4)alkoxy, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, and halogen; or
A represents an unsubstituted partially aromatic bicyclic ring system, wherein A is attached to the rest of the molecule at the aromatic ring of said partially aromatic bicyclic ring system;
B represents aryl or heteroaryl, wherein said aryl or heteroaryl independently is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci- 4)alkoxy, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, halogen, cyano, (Ci -3)al koxy-(Ci-4)al kyl , (Ci-3)alkoxy-(C2-4)alkoxy, nitro, hydroxy, (C2-4)alkenyloxy, unsubstituted 5- or 6-membered monocyclic heteroaryl, and unsubstituted phenyl; or B represents a partially aromatic bicyclic ring system; wherein said partially aromatic bicyclic ring system is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from (Ci-4)alkyl, (Ci-4)alkoxy, halogen and oxo;
or B represents (C3-7)cycloalkyl;
wherein it is well understood that the characteristics described in embodiments 2) to 27) above apply mutatis mutandis also to the compounds of formula (Ip).
30) Another embodiment relates to compounds of Formula (Ip) according to embodiment 29), wherein one or more (and notably all) of the following characteristics in any combination are present:
• Z represents a group selected from the group consisting of methylene (-CH2-), ethylene (-CH2-CH2-), propane-1 ,3-diyl (trimethylene), butane-1 ,4-diyl (tetramethylene), and ethylen-oxy (-CH2-CH2-O-*); wherein the asterisk signifies the bond to which B is attached to;
• (R1)n is absent; or (R1)n represents one substituent in ortho-position of the indan-1,3-dione / indan-1- one moiety of the compounds of Formula (I), wherein said R1 is selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, hydroxy, and (especially) halogen (notably from (Ci-4)alkyl, (Ci-4)alkoxy, and (especially) halogen); or (R1)n represents one substituent in meta-position of the indan-1 ,3-dione / indan-1-one moiety of the compounds of Formula (I), wherein said R1 is selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, trifluoromethyl, and (especially) halogen (notably from (Ci-4)alkyl, (Ci-4)alkoxy, and (especially) halogen);
• A represents aryl, wherein said aryl is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, and halogen; or
A represents heteroaryl, wherein said heteroaryl is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, and halogen; or
A represents an unsubstituted partially aromatic bicyclic heteroaryl ring system, wherein A is attached to the rest of the molecule at the aromatic ring of said partially aromatic bicyclic heteroaryl ring system;
• B represents aryl, wherein said aryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, halogen, cyano, (Ci-3)alkoxy-(Ci-4)alkyl, (Ci-3)alkoxy-(C2-4)alkoxy, nitro, hydroxy, (C2-4)alkenyloxy, unsubstituted 5- or 6- membered monocyclic heteroaryl, and unsubstituted phenyl; or
B represents heteroaryl, wherein said heteroaryl is unsubstituted, or mono-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, halogen, and unsubstituted phenyl; or B represents heterocyclyl; wherein said heterocyclyl is unsubstituted (preferred), or mono-substituted, wherein the substituent is halogen; or
B represents (C3-7)cycloalkyl.
31) Examples of compounds of Formula (I) according to embodiment 1) are selected from the group consisting of:
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1 -yl)-2-phenyl-indan-1 ,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-phenyl-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(3-Fluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(2-Fluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(3,4-Difluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(3-Methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-{4-[2-(2-Methoxy-ethyl)-benzyl]-piperazin-1-yl}-2-phenyl-indan-1 ,3-dione;
2-[4-(1 ,3-Dioxo-2-phenyl-indan-2-yl)-piperazin-1-ylmethyl]-benzonitrile;
2-[4-(6-Chloro-benzo[1,3]dioxol-5-ylmethyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-Phenyl-2-[4-(2-trifluoromethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(3-Fluoro-4-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(3-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(3-Fluoro-4-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(2-Chloro-5-fluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-Phenyl-2-[4-(2-propyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2-Ethoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(2-Allyloxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(2-Nitro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-(4-Benzo[1 ,2,5]thiadiazol-4-ylmethyl-piperazin-1 -yl)-2-phenyl-indan-1 ,3-dione;
2-Phenyl-2-(4-quinolin-8-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-[4-(3-Methyl-benzo[jb]thiophen-2-ylmethyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
4-Fluoro-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione; 2-(4-Benzyl-piperazin-1-yl)-4-fluoro-2-phenyl-indan-1,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-4-fluoro-2-phenyl-indan-1 ,3-dione;
4-Fluoro-2-phenyl-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(4-Cyclopropylmethyl-piperazin-1-yl)-4-fluoro-2-phenyl-indan-1,3-dione;
2-(4-Benzyl-piperazin-1-yl)-4-chloro-2-phenyl-indan-1 ,3-dione;
4-Chloro-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
4-Chloro-2-phenyl-2-(4-pyridin-3-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
4-Chloro-2-phenyl-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-4-methyl-2-phenyl-indan-1 ,3-dione;
4-Methyl-2-phenyl-2-(4-pyridin-3-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
4-Methyl-2-phenyl-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-4-ethyl-2-phenyl-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-4-ethyl-2-phenyl-indan-1,3-dione;
4-Ethyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1,3-dione;
4-Ethyl-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-4-methoxy-2-phenyl-indan-1 ,3-dione;
4- Methoxy-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-5-fluoro-2-phenyl-indan-1 ,3-dione;
5- Fluoro-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
5-Chloro-2-(4-cyclopropylmethyl-piperazin-1-yl)-2-phenyl-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-5-methyl-2-phenyl-indan-1 ,3-dione;
5-Methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-5-methoxy-2-phenyl-indan-1 ,3-dione;
5-Methoxy-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
5-Methoxy-2-phenyl-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(2-methylphenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-chloro-phenyl)-indan-1,3-dione;
2-(3-Chloro-phenyl)-2-(4-cyclohexylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(3-chloro-phenyl)-indan-1 ,3-dione; 2-(3-Chloro-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Chloro-phenyl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-chloro-phenyl)-indan-1,3-dione;
2-(3-Chloro-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-bromo-phenyl)-indan-1,3-dione;
2-(3-Bromo-phenyl)-2-(4-cyclohexylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(3-bromo-phenyl)-indan-1,3-dione; 2-(3-Bromo-phenyl)-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)-indan-1,3-dione;
2-(3-Bromo-phenyl)-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Bromo-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Bromo-phenyl)-2-(4-pyridin-3-ylmethyl-piperazin-1-yl)-indan-1,3-dione;
2-(3-Bromo-phenyl)-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-indan-1,3-dione;
2-(3-Bromo-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-methylphenyl)-indan-1 ,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-methylphenyl)-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(3-methylphenyl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-methylphenyl)-indan-1 ,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methylphenyl)-indan-1 ,3-dione;
2-[4-(4-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methylphenyl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methylphenyl)-indan-1 ,3-dione;
2-[4-(3-Chloro-benzyl)-piperazin-1-yl]-2-(3-methylphenyl)-indan-1 ,3-dione;
2-(4-Pyridin-4-ylmethyl-piperazin-1-yl)-2-(3-methylphenyl)-indan-1 ,3-dione;
2-(4-Thiophen-2-ylmethyl-piperazin-1-yl)-2-(3-methylphenyl)-indan-1,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-methylphenyl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-methylphenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-trifluoromethyl-phenyl)-indan-1,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-methoxy-phenyl)-indan-1 ,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-methoxy-phenyl)-indan-1 ,3-dione;
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1 -yl)-2-(3-methoxy-phenyl)-indan-1 ,3-dione;
2-(3-Methoxy-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan-1 ,3-dione;
2-[4-(4-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan-1 ,3-dione;
2-[4-(3-Chloro-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan-1 ,3-dione;
2-(3-Methoxy-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(3-Methoxy-phenyl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Methoxy-phenyl)-2-[4-(4-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione; 2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(4-methylphenyl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(4-methylphenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(4-methoxy-phenyl)-indan-1 ,3-dione;
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1 -yl)-2-(4-methoxy-phenyl)-indan-1 ,3-dione;
2-(4-Methoxy-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(4-methoxy-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(4-methoxy-phenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-naphthalen-2-yl-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-naphthalen-2-yl-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-naphthalen-2-yl-indan-1,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-naphthalen-2-yl-indan-1,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-naphthalen-2-yl-indan-1,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-naphthalen-2-yl-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-pyridin-2-yl-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-pyridin-2-yl-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-pyridin-2-yl-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-pyridin-2-yl-indan-1 ,3-dione;
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-pyridin-3-yl-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan-1 ,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-pyhdin-3-yl-indan-1 ,3-dione;
2-[4-(4-Methoxy-benzyl)-piperazin-1-yl]-2-pyhdin-3-yl-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-pyhdin-3-yl-indan-1 ,3-dione;
2-[4-(3-Chloro-benzyl)-piperazin-1-yl]-2-pyhdin-3-yl-indan-1 ,3-dione;
2-[4-(3-Methyl-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-pyridin-4-yl-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-pyhdin-4-yl-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-pyridin-4-yl-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(6-chloro-pyridin-2-yl)-indan-1 ,3-dione;
2-(6-Chloro-pyhdin-2-yl)-2-(4-cyclohexylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(6-Chloro-pyridin-2-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Chloro-pyridin-2-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Chloro-pyridin-2-yl)-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione; 2-(6-Chloro-pyndin-2-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(6-chloro-pyridin-2-yl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(6-bromo-pyridin-2-yl)-indan-1 ,3-dione;
2-(6-Bromo-pyridin-2-yl)-2-(4-cyclohexylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(6-Bromo-pyridin-2-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Bromo-pyridin-2-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Bromo-pyridin-2-yl)-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Bromo-pyridin-2-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Bromo-pyridin-2-yl)-2-[4-(2-chloro-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(6-ethyl-pyridin-2-yl)-indan-1 ,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(6-ethyl-pyridin-2-yl)-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(6-ethyl-pyridin-2-yl)-indan-1 ,3-dione;
2-(6-Ethyl-pyridin-2-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Ethyl-pyridin-2-yl)-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Ethyl-pyridin-2-yl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Ethyl-pyridin-2-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(3-Chloro-benzyl)-piperazin-1-yl]-2-(6-ethyl-pyridin-2-yl)-indan-1 ,3-dione;
2-[4-(4-Chloro-benzyl)-piperazin-1-yl]-2-(6-ethyl-pyridin-2-yl)-indan-1 ,3-dione;
2-(6-Ethyl-pyridin-2-yl)-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(6-Ethyl-pyridin-2-yl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(6-Ethyl-pyridin-2-yl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Ethyl-pyridin-2-yl)-2-[4-(4-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(6-ethyl-pyridin-2-yl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(6-ethyl-pyridin-2-yl)-indan-1 ,3-dione;
2-(6-Ethyl-pyridin-2-yl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2,5-Dimethyl-benzyl)-piperazin-1-yl]-2-(6-ethyl-pyridin-2-yl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(6-ethoxy-pyridin-2-yl)-indan-1 ,3-dione;
2-(6-Ethoxy-pyridin-2-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Ethoxy-pyridin-2-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Ethoxy-pyridin-2-yl)-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Ethoxy-pyridin-2-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(6-ethoxy-pyridin-2-yl)-indan-1,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(5-bromo-pyridin-3-yl)-indan-1 ,3-dione;
2-(5-Bromo-pyridin-3-yl)-2-(4-cyclohexylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(5-Bromo-pyridin-3-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(5-Bromo-pyridin-3-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione; 2-(5-Bromo-pyridin-3-yl)-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(5-Bromo-pyridin-3-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(5-Bromo-pyridin-3-yl)-2-[4-(2-chloro-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-quinolin-4-yl-indan-1 ,3-dione;
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-quinolin-4-yl-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-quinolin-4-yl-indan-1 ,3-dione;
2-[4-(3- ethoxy-benzyl)-piperazin-1-yl]-2-quinolin-4-yl-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-quinolin-4-yl-indan-1 ,3-dione;
2-[4-(2- ethyl-benzyl)-piperazin-1-yl]-2-pyrazin-2-yl-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-pyrazin-2-yl-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-pyrazin-2-yl-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-quinoxalin-2-yl-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-quinoxalin-2-yl-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-quinoxalin-2-yl-indan-1 ,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-quinoxalin-2-yl-indan-1,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-quinoxalin-2-yl-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-thiophen-3-yl-indan-1 ,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-thiophen-3-yl-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-thiophen-3-yl-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-thiophen-3-yl-indan-1 ,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-thiophen-3-yl-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-thiophen-3-yl-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1 -yl)-2-thiophen-3-yl-indan-1 ,3-dione;
2-(2,5-Dimethyl-thiazol-4-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1,3-dione; 2-[1-(2-Methyl-benzyl)-piperidin-4-yl]-2-phenyl-indan-1 ,3-dione;
2-[1-(2-Methyl-benzyl)-piperidin-4-yl]-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione;
2-(1-Benzyl-piperidin-4-yl)-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione;
2-[1-(2-Ethyl-benzyl)-piperidin-4-yl]-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1 -yl)-2-phenyl-indan-1 -one;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-phenyl-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-phenyl-indan-1-one;
2-Phenyl-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)-indan-1-one;
2-(4-Cyclopropylmethyl-piperazin-1-yl)-2-phenyl-indan-1-one;
2-Phenyl-2-(4-pyridin-3-ylmethyl-piperazin-1-yl)-indan-1-one;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one; 2-(4-Phenethyl-piperazin-1-yl)-2-phenyl-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-4-methyl-2-phenyl-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-4-methyl-2-phenyl-indan-1-one;
4-Methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-4-methyl-2-phenyl-indan-1-one;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-4-methyl-2-phenyl-indan-1-one;
4- Methyl-2-[4-(4-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-4-bromo-2-phenyl-indan-1-one;
5- Fluoro-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
5-Fluoro-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
5-Fluoro-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
5-Fluoro-2-[4-(4-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-5-fluoro-2-phenyl-indan-1-one;
5- Methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-5-methyl-2-phenyl-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-5-methoxy-2-phenyl-indan-1-one;
6- Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
6- Methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-6-methyl-2-phenyl-indan-1-one;
6-Methoxy-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-6-methoxy-2-phenyl-indan-1-one;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-7-methyl-2-phenyl-indan-1-one;
7- Methoxy-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-methyl-phenyl)-indan-1-one;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(3-methyl-phenyl)-indan-1-one;
2-[4-(3-Methyl-benzyl)-piperazin-1-yl]-2-(3-methyl-phenyl)-indan-1-one;
2-[4-(4-Methyl-benzyl)-piperazin-1-yl]-2-(3-methyl-phenyl)-indan-1-one;
2-(4-Benzyl-piperazin-1 -yl)-2-(3-methyl-phenyl)-indan-1 -one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-methyl-phenyl)-indan-1-one;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methyl-phenyl)-indan-1-one;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methyl-phenyl)-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-2-(3-methoxy-phenyl)-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-methoxy-phenyl)-indan-1-one;
2-(3-Methoxy-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan-1-one;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan-1-one; 2-(3-Methoxy-phenyl)-2-[4-(4-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-2-(3-fluoro-phenyl)-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-fluoro-phenyl)-indan-1-one;
2-(3-Fluoro-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(3-Fluoro-phenyl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1-one;
2-(3-Fluoro-phenyl)-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-indan-1-one;
2-(3-Fluoro-phenyl)-2-[4-(4-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-2-(3-isopropyl-phenyl)-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-isopropyl-phenyl)-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-ethyl-phenyl)-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-2-(4-fluoro-phenyl)-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(4-fluoro-phenyl)-indan-1-one;
2-(4-Fluoro-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(4-methyl-phenyl)-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-2-(3-fluoro-phenyl)-5-methyl-indan-1-one;
2-(3-Fluoro-phenyl)-5-rnethyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(3-Fluoro-phenyl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-5-rnethyl-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-5-methyl-indan-1-one;
2-(3-Ethyl-phenyl)-5-methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one; 2-(1-Benzo[1,3]dioxol-5-ylmethyl-piperidin-4-yl)-2-phenyl-indan-1-one;
2-(1-Benzyl-piperidin-4-yl)-2-phenyl-indan-1-one;
2-(1-Cyclohexylmethyl-piperidin-4-yl)-2-phenyl-indan-1-one;
2-[1-(3-Methoxy-benzyl)-piperidin-4-yl]-2-phenyl-indan-1-one;
2-[1 -(2-Methyl-benzyl)-piperidin-4-yl]-2-phenyl-indan-1 -one;
2-[1-(2-Chloro-benzyl)-piperidin-4-yl]-2-phenyl-indan-1-one;
2-[1-(4-Chloro-benzyl)-piperidin-4-yl]-2-phenyl-indan-1-one;
2-[1 -(3-Methyl-benzyl)-piperidin-4-yl]-2-phenyl-indan-1 -one;
2-[1-(2-Methoxy-benzyl)-piperidin-4-yl]-2-phenyl-indan-1-one;
2-[1-(2-Ethyl-benzyl)-piperidin-4-yl]-2-(3-methyl-phenyl)-indan-1-one;
2-(1-Benzyl-piperidin-4-yl)-2-(3-methyl-phenyl)-indan-1-one;
2-(1-Cyclohexylmethyl-piperidin-4-yl)-2-(3-methyl-phenyl)-indan-1-one;
2-(1-Benzo[1 ,3]dioxol-5-ylmethyl-piperidin-4-yl)-2-(3-methyl-phenyl)-indan-1-one;
2-[1-(4-Methoxy-benzyl)-piperidin-4-yl]-2-(3-methyl-phenyl)-indan-1-one;
2-[1-(2-Methyl-benzyl)-piperidin-4-yl]-2-(3-methyl-phenyl)-indan-1-one;
2-[1-(2-Methoxy-benzyl)-piperidin-4-yl]-2-(3-methyl-phenyl)-indan-1-one;
2-(3-Methyl-phenyl)-2-[1-(2-trifluoromethyl-benzyl)-piperidin-4-yl]-indan-1-one; 2-(3-Methyl-phenyl)-2-[1-(2-propyl-benzyl)-piperidin-4-yl]— indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(1-methyl-1H-pyrazol-3-yl)-indan-1-one;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(1-methyl-1H-pyrazol-3-yl)-indan-1-one;
2-(4-Bromo-thiophen-2-yl)-2-[4-(2-rnethyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(4-Brorno-thiophen-2-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(4-Bromo-thiophen-2-yl)-2-[4-(4-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(5-methyl-isoxazol-3-yl)-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(5-methyl-isoxazol-3-yl)-indan-1-one;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(5-methyl-isoxazol-3-yl)-indan-1-one;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(5-methoxy-pyridin-3-yl)-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(5,6,7,8-tetrahydro-quinolin-2-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(5,6,7,8-tetrahydro-quinolin-2-yl)-indan-1 ,3-dione;
2-(2,6-Dimethyl-pyridin-4-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(2,6-Dimethyl-pyridin-4-yl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione; 2-(4,6-Dimethyl-pyridin-2-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4,6-Dimethyl-pyridin-2-yl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4,6-Dimethyl-pyridin-2-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4,6-Dimethyl-pyridin-2-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(2-methyl-pyridin-4-yl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(2-methyl-pyridin-4-yl)-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(2-methyl-pyridin-4-yl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(2-methyl-pyridin-4-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(2-methyl-pyridin-4-yl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(2-methyl-pyridin-4-yl)-indan-1,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(2-methyl-pyridin-4-yl)-indan-1,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-methyl-pyridin-4-yl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(4-methyl-pyridin-2-yl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(4-methyl-pyridin-2-yl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(4-methyl-pyridin-2-yl)-indan-1 ,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(4-methyl-pyridin-2-yl)-indan-1,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(4-methyl-pyridin-2-yl)-indan-1,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(4-methyl-pyridin-2-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyrazin-2-yl)-indan-1 ,3-dione;
5-Methoxy-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-2-(3-methylphenyl)-indan-1,3-dione;
5-Methoxy-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-2-(3-methylphenyl)-indan-1 ,3-dione;
5-Methoxy-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-2-(3-methylphenyl)-indan-1 ,3-dione; 2-[4-(2,5-Dimethyl-benzyl)-piperazin-1-yl]-5-methoxy-2-(3-rnethylphenyl)-indan-1 ,3-dione; 2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-5-methoxy-(3-methylphenyl)-indan-1,3-dione; 2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-5-methoxy-(3-methylphenyl)-indan-1,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-5-methoxy-(3-methylphenyl)-indan-1 ,3-dione;
5-Methoxy-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-(3-methylphenyl)-indan-1 ,3-dione;
5-Methoxy-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-(3-methylphenyl)-indan-1 ,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-5-methoxy-(3-methylphenyl)-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-5-methoxy-(3-methylphenyl)-indan-1 ,3-dione; 2-(4-Benzyl-piperazin-1-yl)-5-methoxy-(3-methylphenyl)-indan-1 ,3-dione;
4-Hydroxy-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(6-methyl-pyrimidin-4-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyrimidin-4-yl)-indan-1 ,3-dione; 2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyrimidin-4-yl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-5-fluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
4-Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
4-Fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
4-Fluoro-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-phenyl-indan-1 ,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-4-fluoro-2-phenyl-indan-1 ,3-dione;
2-[4-(2,5-Dimethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-phenyl-indan-1,3-dione;
4-Chloro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
4- Methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-4-methyl-2-phenyl-indan-1 ,3-dione;
5-Fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
5- Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-(3-Chloro-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Chloro-phenyl)-2-[4-(2,4-dimethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Chloro-phenyl)-2-[4-(2,5-difluoro-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Bromo-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Bromo-phenyl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Bromo-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Bromo-phenyl)-2-[4-(2-chloro-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Bromo-phenyl)-2-[4-(2,4-dimethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Bromo-phenyl)-2-[4-(2,5-difluoro-benzyl)-piperazin-1-yl]-indan-1 ,3-dione; 2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-m-tolyl-indan-1 ,3-dione;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-m-tolyl-indan-1 ,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-m-tolyl-indan-1 ,3-dione;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione; 2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione; 2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan-1 ,3-dione;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan-1 ,3-dione; 2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan-1 ,3-dione;
4- Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-(4-Benzyl-piperazin-1 -yl)-4-fluoro-2-phenyl-indan-1 -one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-4-fluoro-2-phenyl-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-phenyl-indan-1-one;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-4-fluoro-2-phenyl-indan-1-one;
2-(4-Benzyl-piperazin-1 -yl)-4-methoxy-2-phenyl-indan-1 -one;
4-Methoxy-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-4-methoxy-2-phenyl-indan-1-one;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-4-methoxy-2-phenyl-indan-1-one;
5- Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-7-fluoro-2-phenyl-indan-1-one;
7-Fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-7-fluoro-2-phenyl-indan-1-one;
7-Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-(3-Ethyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-2-(3-ethyl-phenyl)-indan-1-one;
2-(3-lsopropyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(3-Fluoro-5-methyl-phenyl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl-phenyl)-indan-1-one;
2-(3-Fluoro-5-methyl-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-indan-1-one;
2-(3-Fluoro-5-methyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one; 2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-fluoro-5-methyl-phenyl)-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-2-(3-fluoro-5-methyl-phenyl)-indan-1-one;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl-phenyl)-indan-1-one;
2-(3,5-Dimethyl-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan-1-one;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-indan-1-one;
2-(3,5-Dimethyl-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(3,5-Dimethyl-phenyl)-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)-indan-1-one; 2-(3,5-Dimethyl-phenyl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(3,5-Dimethyl-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-indan-1-one;
2-(3,5-Dimethyl-phenyl)-2-[4-(2-rnethyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-indan-1-one;
4-Fluoro-2-(3-fluoro-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan-1-one;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro-phenyl)-indan-1-one;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro-phenyl)-indan-1-one;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl] -fluoro-2-(3-fluoro-phenyl)-indan-1-one; 4-Fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-indan-1-one;
4-Fluoro-2-(3-fluoro-phenyl)-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro-phenyl)-indan-1-one;
4-Fluoro-2-(3-fluoro-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-indan-1-one;
4-Fluoro-2-(3-fluoro-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-4-fluoro-2-(3-fluoro-phenyl)-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-4-fluoro-2-(3-fluoro-phenyl)-indan-1-one;
4-Fluoro-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-2-/n-tolyl-indan-1-one;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-4-fluoro-2-m-tolyl-indan-1-one;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-4-fluoro-2-m-tolyl-indan-1-one;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-m-tolyl-indan-1-one;
4-Fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-/D-tolyl-indan-1-one;
4-Fluoro-2-(4-pyndin-2-ylmethyl-piperazin-1-yl)-2-/r?-tolyl-indan-1-one;
4- Fluoro-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-2-m-tolyl-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-m-tolyl-indan-1-one;
4-Fluoro-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-2-m-tolyl-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-4-fluoro-2-m-tolyl-indan-1-one;
2-(4-Benzyl-piperazin-1 -yl)-4-fluoro-2-/7?-tolyl-indan-1 -one;
5- Fluoro-2-(3-fluoro-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan-1-one; 2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-5-fluoro-2-(3-fluoro-phenyl)-indan-1-one; 5-Fluoro-2-(3-fluoro-phenyl)-2-(4-pyndin-2-ylmethyl-piperazin-1-yl)-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-5-fluoro-2-(3-fluoro-phenyl)-indan-1-one;
5-Fluoro-2-(3-fluoro-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-5-fluoro-2-(3-fluoro-phenyl)-indan-1-one;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-5-fluoro-2-m-tolyl-indan-1-one;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-5-fluoro-2-m-tolyl-indan-1-one;
5-Fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-/D-tolyl-indan-1-one; 2-(4-Cyclohexylmethyl-piperazin-1-yl)-5-fluoro-2-m-tolyl-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-5-fluoro-2-m-tolyl-indan-1-one;
2-(3-Ethyl-phenyl)-5-fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-ethyl-phenyl)-5-fluoro-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-4-fluoro-2-(3-fluoro-5-methyl-phenyl)-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-4-fluoro-2-(3-fluoro-5-methyl-phenyl)-indan-1-one;
4-Fluoro-2-(3-fluoro-5-methyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
4-Fluoro-2-(3-fluoro-5-methyl-phenyl)-2-[4-(4-rnethoxy-benzyl)-piperazin-1-yl]-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro-5-methyl-phenyl)-indan-1-one;
4-Fluoro-2-(3-fluoro-5-methyl-phenyl)-2-[4-(3-rnethyl-benzyl)-piperazin-1-yl]-indan-1-one;
4-Fluoro-2-(3-fluoro-5-methyl-phenyl)-2-(4-pyndin-2-ylmethyl-piperazin-1-yl)-indan-1-one;
4-Fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl-phenyl)-indan-1-one;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro-5-methyl-phenyl)-indan-1-one;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro-5-methyl-phenyl)-indan-1-one; 2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro-5-methyl-phenyl)-indan-1-one;
4-Fluoro-2-(3-fluoro-5-methyl-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-4-fluoro-indan-1-one;
2-(3,5-Dimethyl-phenyl)-4-fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(3,5-Dimethyl-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-4-fluoro-indan-1-one;
2-(3,5-Dimethyl-phenyl)-4-fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-4-fluoro-indan-1-one;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-4-fluoro-indan-1-one;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-4-fluoro-indan-1-one;
2-[1-(5-Fluoro-2-vinyl-benzyl)-piperidin-4-yl]-2-phenyl-indan-1-one;
2-[1-(2-Ethyl-5-fluoro-benzyl)-piperidin-4-yl]-2-phenyl-indan-1-one;
2-[1-(2-Ethyl-5-fluoro-benzyl)-piperidin-4-yl]-2-m-tolyl-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-2-(2,6-dimethyl-pyridin-4-yl)-indan-1 ,3-dione;
2-(2,6-Dimethyl-pyridin-4-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(2,6-Dimethyl-pyridin-4-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(2-methyl-pyridin-4-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(4-methyl-pyndin-2-yl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(6-methyl-pyrazin-2-yl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyrazin-2-yl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyrazin-2-yl)-indan-1 ,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(6-methyl-pyrazin-2-yl)-indan-1,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-fluoro-phenyl)-indan-1 ,3-dione; -(3-Fluoro-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-indan-1 ,3-dione;
-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-indan-1 ,3-dione;
-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-indan-1 ,3-dione;
-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-indan-1 ,3-dione;
-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-indan-1 ,3-dione;
-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-vinyl-phenyl)-indan-1,3-dione;
-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-vinyl-phenyl)-indan-1 ,3-dione;
-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-vinyl-phenyl)-indan-1 ,3-dione;
-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-vinyl-phenyl)-indan-1 ,3-dione;
-(4-Benzyl-piperazin-1-yl)-2-(3-difluoromethyl-phenyl)-indan-1 ,3-dione;
-(3-Difluoromethyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-(3-Difluoromethyl-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(3-difluoromethyl-phenyl)-indan-1 ,3-dione;-(3-Difluoromethyl-phenyl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-difluoromethyl-phenyl)-indan-1 ,3-dione;
-(4-Benzyl-piperazin-1-yl)-2-(3-ethoxy-phenyl)-indan-1 ,3-dione;
-(3-Ethoxy-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1,3-dione;
-(3-Ethoxy-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-(3-Ethoxy-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-ethoxy-phenyl)-indan-1,3-dione;
-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-ethoxy-phenyl)-indan-1 ,3-dione;
-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-ethoxy-phenyl)-indan-1 ,3-dione;
-(3-Ethoxy-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
-(3-Cyclopropyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-(3-Cyclopropyl-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;-(3-Cyclopropyl-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-(3-Cyclopropyl-phenyl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1,3-dione;
-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-propoxy-phenyl)-indan-1 ,3-dione;
-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-propoxy-phenyl)-indan-1,3-dione;
-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-propoxy-phenyl)-indan-1 ,3-dione;
-(4-Benzyl-piperazin-1-yl)-2-(3-propoxy-phenyl)-indan-1 ,3-dione;
-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-trifluoromethoxy-phenyl)-indan-1,3-dione;
-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-trifluoromethoxy-phenyl)-indan-1 ,3-dione;
-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-trifluoromethoxy-phenyl)-indan-1 ,3-dione;
-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-trifluoromethoxy-phenyl)-indan-1,3-dione; 2-[4-(4-Methyl-pyridin-3-ylmethyl)-piperazin-1-yl]-2-(3-trifluoromethoxy-phenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-morpholin-4-yl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-morpholin-4-yl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-morpholin-4-yl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-morpholin-4-yl-phenyl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-morpholin-4-yl-phenyl)-indan-1 ,3-dione;
2-(3-Fluoro-5-methyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-fluoro-5-methyl-phenyl)-indan-1 ,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-fluoro-5-methyl-phenyl)-indan-1 ,3-dione;
2-(3-Fluoro-5-methyl-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl-phenyl)-indan-1 ,3-dione;
2-(3-Fluoro-5-methyl-phenyl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Fluoro-5-methyl-phenyl)-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl-phenyl)-indan-1 ,3-dione;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl-phenyl)-indan-1 ,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl-phenyl)-indan-1 ,3-dione;
2-(3-Fluoro-5-methyl-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4-Chroman-2-ylmethyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-[4-(4-Chloro-1-methyl-1 H-pyrazol-3-ylmethyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-2-[4-(2-fluoro-5-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4-Benzo[1 ,3]dioxol-4-ylmethyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione;
2-[4-(2,5-Dimethoxy-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione;
2-[4-(5-Bromo-2-methoxy-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione; 2-[4-(5-Chloro-1 ,3-dimethyl-1 H-pyrazol-4-ylmethyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione; 2-[4-(4-Dimethylamino-2-methoxy-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-2-[4-(3-methyl-thiophen-2-ylmethyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-2-[4-(5-fluoro-2-methoxy-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-(3,5-Dimethyl-phenyl)-2-[4-(3-oxo-3,4-dihydro-2H-benzo[ ,4]oxazin-6-ylmethyl)-piperazin-1-yl]-indan-1 ,3- dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3,5-difluoro-phenyl)-indan-1 ,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3,5-difluoro-phenyl)-indan-1,3-dione;
2-(3,5-Difluoro-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Difluoro-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Difluoro-phenyl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Difluoro-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Difluoro-phenyl)-2-[4-(2,4-dimethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3,5-difluoro-phenyl)-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3,5-difluoro-phenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-fluoro-5-methoxy-phenyl)-indan-1 ,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-fluoro-5-methoxy-phenyl)-indan-1 ,3-dione;
2-(3-Fluoro-5-methoxy-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methoxy-phenyl)-indan-1 ,3-dione;
2-(3-Fluoro-5-methoxy-phenyl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-(3-Fluoro-5-methoxy-phenyl)-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(3-Fluoro-5-methoxy-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methoxy-phenyl)-indan-1 ,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methoxy-phenyl)-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methoxy-phenyl)-indan-1,3-dione;
2-(3-Fluoro-5-methoxy-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-methoxy-5-methyl-phenyl)-indan-1 ,3-dione;
2-(3-Methoxy-5-methyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-methoxy-5-methyl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-methoxy-5-methyl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-methoxy-5-methyl-phenyl)-indan-1 ,3-dione;
2-(3,5-Dimethoxy-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Dimethoxy-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Dimethoxy-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3,5-dimethoxy-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2',3'-dihydro-1'H-[2,5']biindenyl-1,3-dione; -[4-(2-ΜΘΪήοχγ- θηζνΙ)-ρίρβΓ3ζίη-1-γΙ]-2\3'-άίήνάΓθ-1Ή-[2,5'] ίίη βηγΙ-1 ,3-οΙίοηβ;
-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-quinolin-2-yl-indan-1 ,3-dione;
-(4-Benzyl-piperazin-1 -yl)-2-quinolin-2-yl-indan-1 ,3-dione;
-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-quinolin-2-yl-indan-1 ,3-dione;
-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-quinolin-2-yl-indan-1 ,3-dione;
-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-quinolin-2-yl-indan-1,3-dione;
-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-quinolin-2-yl-indan-1 ,3-dione;
-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(1-methyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione;
-[4-(2-Methoxy-benzyl)-piperazin-1 -yl]-2-(1 -methyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione;
-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(1-methyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione;
-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(1 -methyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione;-(4-Benzyl-piperazin-1-yl)-2-(5-fluoro-pyridin-3-yl)-indan-1,3-dione;
-(5-Fluoro-pyridin-3-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(5-fluoro-pyridin-3-yl)-indan-1 ,3-dione;
-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(5-fluoro-pyridin-3-yl)-indan-1 ,3-dione;
-(4-Benzyl-piperazin-1-yl)-2-(5-methyl-pyridin-3-yl)-indan-1 ,3-dione;
-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(5-methyl-pyridin-3-yl)-indan-1 ,3-dione;
-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(5-methyl-pyridin-3-yl)-indan-1 ,3-dione;
-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(5-methyl-pyridin-3-yl)-indan-1 ,3-dione;
-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-3-yl)-indan-1 ,3-dione;
-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-3-yl)-indan-1 ,3-dione;
-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-3-yl)-indan-1 ,3-dione;
-[4-(2-Ethyl-benzyl)-piperazin-1 -yl]-2-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione;
-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione;-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)-indan-1,3-dione;
-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1 -yl]-2-(1 ,3,5-tri methyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione;-(5-Methoxy-pyridin-3-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(5-methoxy-pyridin-3-yl)-indan-1 ,3-dione;
-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(5-methoxy-pyridin-3-yl)-indan-1,3-dione;
-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(1-methyl-1 H-indazol-3-yl)-indan-1 ,3-dione;
-[4-(2-Methoxy-benzyl)-piperazin-1 -yl]-2-(1 -methyl-1 H-indazol-3-yl)-indan-1 ,3-dione;
-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(1-methyl-1 H-indazol-3-yl)-indan-1 ,3-dione;
-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(5-trifluoromethyl-pyridin-3-yl)-indan-1 ,3-dione;
-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(5-trifluoromethyl-pyridin-3-yl)-indan-1 ,3-dione; 2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(1-phenyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione;
2-[4-(2- ethyl-benzyl)-piperazin-1-yl]-2-(1-phenyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(1-phenyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(2-pyrrolidin-1-yl-pyridin-4-yl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(6-rnethyl-pyridin-3-yl)-indan-1-one;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(6-rnethyl-pyridin-3-yl)-indan-1-one;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-[5-((S)-1-methyl-pyrrolidin-2-yl)-pyridin-3-yl]-indan-1-one;
2-(2-Ethyl-6-methyl-pyridin-4-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-(2-Ethyl-6-methyl-pyhdin-4-yl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(2,6-Diethyl-pyridin-4-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(2,6-Diethyl-pyridin-4-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(2,6-Diethyl-pyridin-4-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(2,6-Diethyl-pyridin-4-yl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(2,6-diethyl-pyridin-4-yl)-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(2,6-diethyl-pyridin-4-yl)-indan-1 ,3-dione;
2-(2-lsopropyl-6-methyl-pyridin-4-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(2-isopropyl-6-methyl-pyridin-4-yl)-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(2-isopropyl-6-methyl-pyridin-4-yl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(2-isopropyl-6-methyl-pyridin-4-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(2-isopropyl-6-methyl-pyridin-4-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(5-methyl-pyridin-2-yl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(6-methyl-pyridin-2-yl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-2-yl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-2-yl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-2-yl)-indan-1 ,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-2-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-2-yl)-indan-1 ,3-dione;
2-(2-Chloro-6-methyl-pyridin-4-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(2-Chloro-6-methyl-pyridin-4-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(2-Chloro-6-methyl-pyridin-4-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(2-Chloro-6-methyl-pyridin-4-yl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(2-chloro-6-methyl-pyridin-4-yl)-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(2-chloro-6-methyl-pyridin-4-yl)-indan-1 ,3-dione;
2-(3,5-Dimethyl-pyridin-2-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(5-ethyl-pyridin-2-yl)-indan-1 ,3-dione;
2-(5-Ethyl-pyridin-2-yl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione; 2-(2-Dimethylamino-pyrimidin-4-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1,3-di
2-(2-Ethoxy-pyrirnidin-4-yl)-2-[4-(2-methyl-benzyl)-piperaziri-1-yl]-indan-1 ,3-dione;
2-(2-Ethoxy-pynmidin-4-yl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Methylamino-pyridin-2-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(6-methylamino-pyridin-2-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(6-methylamino-pyridin-2-yl)-indan-1 ,3-dione;
2-(6-Dimethylamino-pyridin-2-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Dimethylamino-pyridin-2-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Dimethylamino-pyridin-2-yl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1,3-dione; 2-(6-Ethylamino-pyridin-2-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Ethylamino-pyridin-2-yl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-5-methyl-2-m-tolyl-indan-1 ,3-dione;
5-Methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-m-tolyl-indan-1,3-dione;
2-(3-Fluoro-phenyl)-5-methoxy-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Fluoro-phenyl)-5-methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-5-methyl-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-5-methyl-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-4-fluoro-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-4-fluoro-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-4-fluoro-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-4-fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-4-fluoro-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-4-fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-4-fluoro-indan-1 ,3-dione; 2-(4-Benzyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-4-fluoro-indan-1 ,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-4-fluoro-indan-1 ,3-dione;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-4-fluoro-indan-1 ,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-4-fluoro-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-4-fluoro-indan-1 ,3-dione;
2-(1-Benzyl-piperidin-4-yl)-2-(6-methyl-pyridin-2-yl)-indan-1-one;
2-[1-(2-Ethyl-benzyl)-piperidin-4-yl]-2-(6-methyl-pyridin-2-yl)-indan-1-one;
2-[1-(2-Methyl-benzyl)-piperidin-4-yl]-2-(6-methyl-pyridin-2-yl)-indan-1-one;
2-[1-(5-Fluoro-2-rnethyl-benzyl)-piperidin-4-yl]-2-(6-rnethyl-pyridin-2-yl)-indan-1-one;
2-[1-(2-Methyl-benzyl)-azetidin-3-yl]-2-phenyl-indan-1-one;
6-(4-(2-methylbenzyl)piperazin-1-yl)-6-(m-tolyl)-5H-cyclopenta[b]pyhdine-5,7(6H)-dione;
(R)-4-Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-m-tolyl-indan-1-one; (S)-4-Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-m-tolyl-indan-1-one;
(R)-2-[1-(2-Methyl-benzyl)-piperidin-4-yl]-2-m-tolyl-indan-1-one;
(S)-2-[1-(2-Methyl-benzyl)-piperidin-4-yl]-2-m-tolyl-indan-1-one;
2-[1-(5-Fluoro-2-methyl-benzyl)-piperidin-4-yl]-2-(3-rnethyl-phenyl)-indan-1 ,3-dione;
2-[1-(2-Methyl-benzyl)-piperidin-4-yl]-2-(3-methyl-phenyl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-[3-(4-methyl-piperazin-1-yl)-ph
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-piperidin-1-yl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1 -yl]-2-(3-piperidin-1 -yl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-piperidin-1-yl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-piperidin-1-yl-phenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-piperidin-1-yl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-pyrrolidin-1-yl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-pyrrolidin-1-yl-phenyl)-indan-1 ,3-dione;
2-[4-(4-Methyl-pyridin-3-ylmethyl)-piperazin-1-yl]-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione; and
2-[4-(4-Methyl-pyridin-3-ylmethyl)-piperazin-1-yl]-2-(3-methyl-phenyl)-indan-1 ,3-dione.
32) A further aspect of the invention relates to compounds of Formula (II) or salts thereof,
Figure imgf000040_0001
Formula (II)
wherein A, Y and (R1)n are as defined in embodiment 1);
wherein it is well understood that the particular characteristics indicated for the compounds of Formula (I) in embodiments 3) and 4), 9) and 10), 13) to 17), and 18) to 22) apply mutatis mutandis to the compounds of Formula (II).
Any reference to a compound of Formula (I) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.
Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases or the like, this is intended to mean also a single compound, salt, disease or the like.
The term "pharmaceutically acceptable salts" refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217. The present invention also includes isotopically, especially 2H (deuterium) labelled compounds of formula (I) which compounds are identical to the compound of formula (I) wherein one or more atoms have been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopically labelled, especially 2H (deuterium) labelled compounds of formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2H (deuterium) may lead to greater metabolic stability, resulting eg. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile. In one embodiment of the invention, the compounds of formula (I) are not isotopically labelled, or labelled with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled. Isotopically labelled compounds of formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
The compounds of the present invention have useful, in particular pharmacologically useful, properties. They bind to the NPS receptor and thus modulate the effects of endogenous NPS.
The compounds of Formula (I) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral or parenteral administration.
The present invention further also relates to pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]) by bringing the described compounds of Formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
The compounds according to Formula (I) according to embodiment 1), including the compound 2-(4-Benzyl- piperazin-1-yl)-2-phenyl-indan-1 ,3-dione are suitable for the prevention and/or treatment of diseases or disorders which respond to the modulation of the NPS receptor. Such diseases or disorders are further described in the following:
In particular the compounds according to Formula (I) are particularly suitable for the prevention or treatment selected from the group consisting of dysthymic disorders including major depression and cyclothymia, affective neurosis, all types of manic depressive disorders, delirium, psychotic disorders, schizophrenia, catatonic schizophrenia, delusional paranoia, adjustment disorders and all clusters of personality disorders; schizoaffective disorders; anxiety disorders including generalized anxiety, obsessive compulsive disorder, posttraumatic stress disorder, panic attacks, all types of phobic anxiety and avoidance; separation anxiety; all types of stress-related syndromes including hyperactivation of the hypothalamo-pituitary axis, irritable bowel syndrome, insomnia, hypertension, infertitly, depression, anxiety; all types of psychoactive substance use, abuse, seeking and reinstatement; all types of psychological or physical addictions, dissociative disorders including multiple personality syndromes and psychogenic amnesias; sexual and reproductive dysfunction; psychosexual dysfunction and addiction; tolerance to narcotics or withdrawal from narcotics; increased anaesthetic risk, anaesthetic responsiveness; hypothalamic-adrenal dysfunctions; disturbed biological and circadian rhythms; sleep disturbances associated with diseases such as neurological disorders including neuropathic pain and restless leg syndrome; sleep apnea; narcolepsy; chronic fatigue syndrome; insomnias related to psychiatric disorders; all types of idiopathic insomnias and parasomnias; sleep-wake schedule disorders including jet-lag; mood disorders, particularly those involving light cycles, such as seasonal affected disorder, all dementias and cognitive dysfunctions in the healthy population and in psychiatric and neurological disorders; mental dysfunctions of aging; all types of amnesia; severe mental retardation; dyskinesias and muscular diseases; muscle spasticity, tremors, movement disorders; spontaneous and medication-induced dyskinesias; neurodegenerative disorders including Huntington's, Creutzfeld-Jacob's, Alzheimer's diseases and Tourette syndrome; Amyotrophic lateral sclerosis; Parkinson's disease; Cushing's syndrome; traumatic lesions; spinal cord trauma; head trauma; perinatal hypoxia; hearing loss; tinnitus; demyelinating diseases; spinal and cranial nerve diseases; ocular damage; retinopathy; epilepsy; seizure disorders; absence seizures, complex partial and generalized seizures; Lennox-Gastaut syndrome; migraine and headache; pain disorders; anaesthesia and analgesia; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; dental pain; pain related to infection e.g. by HIV; post- chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; osteoarthritis; conditions associated with visceral pain such as irritable bowel syndrome; eating disorders; diabetes; toxic and dysmetabolic disorders including cerebral anoxia, diabetic neuropathies and alcoholism; appetite, taste, eating, or drinking disorders; somatoform disorders including hypochondriasis; vomiting/nausea; emesis; gastric dyskinesia; gastric ulcers; Kallman's syndrome (anosmia); impaired glucose tolerance; intestinal motility dyskinesias; hypothalamic diseases; hypophysis diseases; hyperthermia syndromes, pyrexia, febrile seizures, idiopathic growth deficiency; dwarfism; gigantism; acromegaly; all sorts of cancers; all types of testicular dysfunctions, fertility control; reproductive hormone abnormalities; hot flashes; hypothalamic hypogonadism, functional or psychogenic amenorrhea; urinary bladder incontinence; chronic and acute allergic/inflammatory/immune disorders or diseases; all types of dermatitis, acne and cysts, sebaceous gland dysfunctions; cardiovascular disorders; heart and lung diseases, acute and congestive heart failure; hypotension; hypertension; dyslipidemias, hyperlipidemias, insulin resistance; urinary retention; osteoporosis; angina pectoris; myocardial infarction; arrhythmias, coronary diseases, left ventricular hypertrophy; ischemic or haemorrhagic stroke; all types of cerebrovascular disorders including subarachnoid haemorrhage, ischemic and hemorrhagic stroke and vascular dementia; chronic renal failure and other renal diseases; gout; and other diseases related to general IMPS system dysfunctions. ln another preferred embodiment of the invention compounds of Formula (I) are particularly suitable for the prevention or treatment of diseases or disorders selected from the group consisting of sleep disorders; eating disorders; drinking disorders; stress-related syndromes; addiction; psychoactive substance use, abuse, seeking and reinstatement; dementias and cognitive dysfunctions; anxiety disorders; dysthymic disorders; chronic and acute allergic/inflammatory/immune disorders or diseases; all sorts of cancers; and pain.
In another preferred embodiment of the invention compounds of Formula (I) are particularly suitable for the prevention or treatment of diseases or disorders selected from the group consisting of sleep disorders; eating disorders; drinking disorders; stress-related syndromes; addiction; psychoactive substance use, abuse, seeking and reinstatement; dementias and cognitive dysfunctions; anxiety disorders; and dysthymic disorders.
Eating disorders may be defined as comprising metabolic dysfunction; dysregulated appetite control; compulsive obesities; emeto-bulimia or anorexia nervosa; reduced appetite in the elderly; and reduced appetite due to another disease such as cancer. Eating disorders or pathologically modified food intake may result from disturbed appetite (attraction or aversion for food); altered energy balance (intake vs. expenditure); disturbed perception of food quality (high fat or carbohydrates, high payability); disturbed food availability (unrestricted diet or deprivation), disrupted water balance, or from another disease such as cancer.
Drinking disorders may be defined as comprising polydipsias in psychiatric disorders and all other types of excessive fluid intake as well as reduced fluid intake in the elderly.
Sleep disorders may be defined as comprising all types of parasomnias, insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift-work syndrome, delayed or advanced sleep phase syndrome or insomnias related to psychiatric disorders. Insomnias also comprise sleep disorders associated with aging; intermittent treatment of chronic insomnia; situational transient insomnia (new environment, noise) or short-term insomnia due to stress; grief; pain or illness. Insomnia also comprise stress-related syndromes that comprise post-traumatic stress disorders; as well as other types and subtypes of anxiety disorders that comprise generalized anxiety, obsessive compulsive disorder, panic attacks, all types of phobic anxiety and avoidance, and separation anxiety. In another embodiment, stress-related syndromes may especially be defined as comprising hyperactivation of the hypothalamo-pituitary axis, irritable bowel syndrome, hypertension, infertitly; and, stress related syndromes may also be associated with / comprise insomnia, depression or anxiety.
Psychoactive substance use, abuse, seeking and reinstatement may be defined as comprising all types of psychological or physical addictions and their related tolerance and dependence components.
Dementias and cognitive dysfunctions may be defined as comprising deficits in all types of attention, learning and memory functions occurring transiently or chronically in the normal, healthy, young, adult or aging population, and also occurring transiently or chronically in psychiatric, neurologic, cardiovascular and immune disorders. Anxiety disorders may be defined as comprising generalized anxiety, obsessive compulsive disorder, posttraumatic stress disorder, panic attacks, all types of phobic anxiety and avoidance, and separation anxiety.
Dysthymic disorders may be defined as comprising major depression and cyclothymia, affective neurosis, all types of manic depressive disorders, delirium, psychotic disorders, schizophrenia, catatonic schizophrenia, delusional paranoia, adjustment disorders and all clusters of personality disorders and schizoaffective disorders.
Pain may be defined as comprising migraine and headache; pain disorders; anaesthesia and analgesia; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; dental pain; pain related to infection e.g. by HIV; post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; osteoarthritis; conditions associated with visceral pain such as irritable bowel syndrome.
Chronic and acute allergic/inflammatory/immune disorders or diseases may be defined as comprising allergic asthma, rhinitis, allergic rhinitis, chronic obstructive pulmonary disease (COPD), dermatitis, inflammatory bowel disease, rheumatoid arthritis, allergic nephritis, conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, itching, inflammation, ischemia-reperfusion injury, cerebrovascular disorders, pleuritis, ulcerative colitis, eosinophil-related diseases comprising Churg- Strauss syndrome and sinusitis, and basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis, in humans and other mammals.
Cancers may be defined as comprising all sorts of cancers such as large intestine cancer, rectal cancer, breast cancer, lung cancer, non-small cell lung cancer, prostate cancer, esophagal cancer, stomach cancer, liver cancer, bile duct cancer, spleen cancer, kidney cancer, urinary bladder cancer, uterine cancer, ovarian cancer, cervical cancer, testicular cancer, thyroid cancer, pancreas cancer, brain tumor, blood tumor, basophil adenoma, prolactinoma, hyperprolactinemia, adenomas, endometrial cancer; and especially colon cancer.
In a further preferred embodiment of the invention compounds of Formula (I) are particularly suitable for the prevention or treatment of sleep disorders. In a sub-embodiment, the compounds of Formula (I) can be used for the preparation of a medicament and/or are particularly suitable for the prevention or treatment of sleep disorders selected from the group consisting of all types of parasomnias, insomnias, narcolepsy and other disorders of excessive sleepiness; sleep-related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift-work syndrome; delayed or advanced sleep phase syndrome; and insomnias related to psychiatric disorders.
In another preferred embodiment of the invention compounds of Formula (I) are particularly suitable for the prevention or treatment of dementias and cognitive dysfunctions.
In another embodiment of the invention compounds of Formula (I) are particularly suitable for the prevention or treatment of eating disorders. ln another embodiment of the invention compounds of Formula (I) are particularly suitable for the prevention or treatment of psychoactive substance use, abuse, seeking and reinstatement.
In another embodiment of the invention compounds of Formula (I) are particularly suitable for the prevention or treatment of stress-related syndromes as well as other types and subtypes of anxiety disorders.
In another embodiment of the invention compounds of Formula (I) are particularly suitable for the prevention or treatment of dysthymic disorders.
In another embodiment of the invention compounds of Formula (I) are particularly suitable for the prevention or treatment of pain.
In another embodiment of the invention compounds of Formula (I) are particularly suitable for the prevention or treatment of chronic and acute allergic/inflammatory/immune disorders or diseases. In a sub-embodiment, such disorders or diseases are notably selected from the group consisting of allergic asthma, rhinitis, allergic rhinitis, COPD, dermatitis, inflammatory bowel disease, and rheumatoid arthritis.
In another embodiment of the invention compounds of Formula (I) are particularly suitable for the prevention or treatment of cancer.
Whenever a compound is mentioned as suitable for the prevention or treatment of a certain disease or disorder it is understood that such compound may be used for the preparation of a medicament for the prevention or treatment of said disease or disorder.
Another aspect of the invention concerns a method for the prevention or the treatment of a disease or disorder as mentioned above in a patient comprising the administration to said patient of a pharmaceutically active amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
Besides, any preferences indicated for the compounds of Formula (I) (whether for the compounds themselves, salts thereof, compositions containing the compounds or salts thereof, uses of the compounds or salts thereof, etc.) apply mutatis mutandis to compounds of formulae (IEI), and/or (h) and/or (IP) and/or (ICE) and vice versa.
Unless used regarding temperatures, the term "about" placed before a numerical value "X" refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X. In the particular case of temperatures, the term "about" placed before a temperature "Y" refers in the current application to an interval extending from the temperature Y minus 10 °C to Y plus 10 °C, and preferably to an interval extending from Y minus 5 °C to Y plus 5 °C. Besides, the term "room temperature" (r.t.) as used herein refers to a temperature of about 25°C.
Preparation of compounds of Formula (I)
A further aspect of the invention is a process for the preparation of compounds of Formula (I). Compounds according to Formula (I) of the present invention can be prepared from commercially available or well known starting materials according to the methods described in the experimental part, by analogous methods; or according to the general sequence of reactions outlined below, wherein Ar1, A, B, X, L1, Y, Z, and (R1)n are as defined for Formula (I). Other abbreviations used herein are explicitly defined, or are as defined in the experimental section. In some instances the generic groups Ar1, A, B, X, L1, Y, Z, and (R1)n might be incompatible with the assembly illustrated in the schemes below and so will require the use of protecting groups (PG). The use of protecting groups is well known in the art (see for example "Protective Groups in Organic Synthesis", T.W. Greene, P.G.M. Wuts, Wiley-lnterscience, 1999). For the purposes of this discussion, it will be assumed that such protecting groups as necessary are in place. The compounds obtained may also be converted into salts, especially pharmaceutically acceptable salts thereof in a manner known per se.
Compounds of Formula (I) can be obtained by reacting a compound of Structure 1 , 2, 3, or 4, or a salt thereof, with a reagent of Structure 5, wherein Hal represents CI, Br or I; in the presence of a base such as NEt.3, DIPEA, K2CO3, CS2CO3, in the presence or absence of tetrabutylammonium iodide, in a solvent such as DMF or DCM in a temperature range from r.t. to about 80°C.
Figure imgf000046_0001
ucture 3
Figure imgf000046_0002
Structure 4 Structure 5 Structure 6
Alternatively, a compound of Formula (I) can be obtained by reacting a compound of Structure 1 , 2, 3, or 4, or a salt thereof, with an aldehyde of Structure 6, wherein 71 represents -(CH2)m-r, or -(CH2)i-2-0-; and a reducing agent such as NaBhU, NaBH(OAc)3, or NaBhhCN; in a solvent such as DCM, DCE, THF. In case the compound of Structure 1 , 2, 3, or 4 is a salt, the reaction is performed in the presence of a base such as NEt.3, or DIPEA. The corresponding compounds of Structure 5 and 6 are commercially available or synthesized from commercially available starting materials using well known methods.
Compounds of Structure 1 , especially those of Formula (II) as described in embodiment 33) above, are key intermediates in the process of preparation of compounds of Formula (I).
Alternatively, in case L1 represents a piperazinyl or a 1 ,4-diazepanyl group, compounds of Formula (I) can be obtained by reacting a compound of Structure 7, wherein Hal represents CI or Br, with a compound of Structure 8 or 9 in the presence of a base such as NEt.3, DIPEA, CS2CO3 or K2CO3 in a solvent such as dioxane, THF, DCM or DMF.
Figure imgf000047_0001
Structure 7 Structure 8 Structure 9
Figure imgf000047_0002
Structure 10 Structure 11
Alternatively, a compound of Structure 8 or 9 can be silylated on the free amine, preferably trimethylsilylated, and coupled to a compound of Structure 7 in a solvent such as dioxane in the presence of a base, such as NEt or DIPEA, at r.t. up to reflux temperature, preferably around 60°C, to give compounds of Formula (I).
In case L1 represents piperazinyl or 1 ,4-diazepanyl, a compound of Structure 1 can be obtained by methods described in the literature (U. Mikstais and A.Arens, Chemistry of Heterocyclic Compounds 1968, 811-813) e.g. a compound of Structure 7 is treated with piperazine hydrochloride in a solvent such as MeOH or is treated with a compound of Structure 10 or 11 , wherein PG represents an amino protective group such as Boc or Cbz, to give accordingly a compound of Structure 12 or 13, from which the PG can be removed applying known methods, to yield the corresponding compound of Structure 1 or 2.
Alternatively, a compound of Structure 10 or 11 can be silylated on the free amine, preferably trimethylsilylated, and coupled to a compound of Structure 7 in a solvent such as dioxane in the presence of a base, such as NEt or DIPEA, at r.t. up to reflux temperature, preferably around 60°C, to give compounds of Structure 12 and 13 respectively.
Figure imgf000047_0003
Structure 12 Structure 13
Figure imgf000047_0004
Structure 15
Figure imgf000048_0001
Structure 16
In particular cases a compound of Structure 12 is obtained by functional group modification on another compound of Structure 12 as in the particular cases of compounds of Structure 14 or 15 which can be obtained from compounds of Structure 16 in the known conditions of a Suzuki reaction.
Compounds of Structure 7 can be prepared by halogenating a compound of Structure 17 in the presence of a halogen donating reagent such as SO2CI2, POCI3, PEto, Efo, NBS or NCS, in a solvent such as Et.20, DCM, or AcOH.
Compounds of Structure 17 can be prepared according to known procedures, e.g. in case Y represents C=0 by using a procedure from C. G. Thomson et al., Bioorg. Med. Chem. Letters 2006, 16, 1388-1391 , starting with the respective phthalic acid anhydride in a reaction with commercially available or well known diversely substituted phenylacetic acid derivatives in AC2O and in the presence of Et3N at reflux, followed by treatment with NaOMe in MeOH at reflux. In case A represents heteroaryl or a partially aromatic bicyclic ring system, a compound of Structure 17 can be accessed using analogous methods starting with appropriately substituted acetic acid derivatives in a reaction with the respective phthalic acid anhydride in AC2O, or by treatment of indan-1 ,3-dione derivatives with azine N-oxides in the presence of AC2O, or in a reaction of diethyl phthalate with a methyl substituted heteroaryl derivative using NaH as condensing agent in a refluxing solvent such as DME in analogy to J. F. Wolfe ef a/., J. Org. Chem. 1974, 39, 2006. Alternatively a compound of Structure 17 can be accessed by reaction of appropriately substituted phthalide derivative of Structure 18 with a subtituted carboxaldehyde of Structure 19 following a procedure described in US2005/0059663 or by K. A. Menear ef a/., J. Med. Chem.
-6591 with a base such as MeONa in a solvent such as MeOH or ethylpropionate.
Figure imgf000048_0002
Structure 17 Structure 18 Structure 19
Compounds of Structure 18 and 19 are commercially available or can be obtained by methods well know in the art. For example when A represents pyridyl, compounds of Structure 19 can be obtained in a well know manner from the corresponding carboxylic acids whose syntheses are described for example in WO2009/024905. ln case Y represents CH2, a compound of Structure 17 can be prepared according to known protocols, either by cyclizing a compound of Structure 20 under Friedel-Crafts conditions (B. B. Datta and J. C. Bardhan, J. Chem. Soc. 1962, 3974-3977) or in a two-step reaction sequence, wherein in a first step a compound of Structure 21 is halogenated under well known conditions to a compound of Structure 22, which is then reacted with a Grignard rea ent of Structure 23 (A. S. Hussey and R. R. Herr, J. Org. Chem. 1959, 24, 843-845).
Figure imgf000049_0001
Structure 20 Structure 21 Structure 22 Structure 23
Compounds of Structure 20 and 21 are commercially available or well known in the art, or can be accessed in analogy to the methods described in the experimental part below.
A compound of Structure 1 wherein L1 represents 4-piperidinyl, or of Structure 3 or 4, can be obtained from a compound of Structure 24, 25 or 26, respectively after cleavage of an amino protecting group PG, such as e.g. Boc, by applying known methods.
Figure imgf000049_0002
Structure 24 Structure 25 Structure 26
A compound of Structure 24, wherein A represents phenyl and Y represents C=0, can be obtained in a Pd- catalyzed reaction, wherein a compound of Structure 27 is treated with a 1 ,1 ,1 -trifluoro-methanesulfonic acid phenyl ester derivative and a base such as NaOfBu, in the presence of a catalyst such as 1 ,1 '-bis(di-ferf.- butylphosphino)ferrocene palladium dichloride in anhydrous, degassed solvent such as dioxane at elevated temperature (Grasa, G. A.; Colacot, T. J. Org. Lett. 2007, 9(26), 5489-5492).
A compound of Structure 27 can be obtained in a reaction of a compound of Structure 28 with a compound of Structure 29, wherein PG represents an amino protecting group such as Boc, in the presence of equimolar 2,6-dimethyl- l,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester and catalytic amount of DL -proline in a solvent such as DMSO (Ramachary, D.B; Kishor, M.; Reddy, G. B. Org. Biomol. Chem. 2006, 1641-1646).
Figure imgf000049_0003
Structure 27 Structure 28 Structure 29
Compounds of Structure 28 and Structure 29 are commercially available or accessible by applying well known procedures.
In case Y represents CH2, a compound of Structure 1 wherein L1 represents 4-piperidinyl, or of Structure 3 or 4, can be generated from a compound of Structure 30, 31 or 32, respectively, via hydrolysis of the imine and concomitant removal of the amino protecting group PG under well known conditions. A compound of Structure 30, 31 or 32 can be obtained in an intramolecular cyclization reaction by means of ferf-BuLi from a compound of Structure 33, 34 or 35, respectively. Such a compound of Structure 33, 34 or 35 can be prepared according to known procedures, e.g. by alkylating a compound of Structure 36, 37 or 38, respectively, with a compound of Structure 39 using a reagent such as NaH or LDA.
Generally, a compound of Structure 36, 37 or 38 can be obtained using the methods described in the experimental part below, by analogous methods, or by applying methods known to a person skilled in the art.
Figure imgf000050_0001
Structure 30 Structure 31 Structure 32
Figure imgf000050_0002
Structure 34 Structure 37 Structure 35 Structure 38
Alternatively, in case in a compound of Structure 1 X represents N, and Y represents CH2, a compound of Formula (I) can be obtained from a compound of Structure 40 under conditions analogous to those for converting compounds of Structure 30 to a compound of Structure 1.
Compounds of Structures 40 can be synthesized either by alkylating compounds of Structure 41 or by cyclizing compounds of Structure 42 using methods described herein before. Compounds of Structure 41 can be obtained by anhydrous Boc cleavage, e.g. HCI in AcOEt at r.t., after cyclization of compounds of Structure 43 using methods described before for the compounds of Structure 33. In some instances, conditions of PG removal may lead directly to the corresponding compounds of Structure 1. Compounds of Structure 42 are produced by PG removal on compounds of Structure 43 and subsequent alkylation under conditions analogous to those described for compounds of Structure 1. Compounds of Structure 43 are produced by a Strecker synthesis involving the corresponding aldehyde under known conditions, followed by alkylation of the aminonitrile intermediate analogously to the alkylation of compounds of Structure 36. The corresponding aldehydes are commercially available or synthesized from commercially available halides or carboxylic acid derivatives using well-known methods.
Figure imgf000051_0001
Structure 40 Structure 41
Figure imgf000051_0002
Structure 42 Structure 43
In case precursors of generic groups A or B containing a heteroaryl group as required in the syntheses described above are not commercially available, these precursors may be synthesized using well known methods, see for example T. Eicher, S. Hauptmann "The chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications", 2nd Edition 2003, Wiley, ISBN 978-3-527-30720-3; and A. R. Katrizky, C. W. Rees, E. F. V. Scriven (Eds.) "Comprehensive Heterocyclic Chemistry II" 1996, Elsevier, ISBN 0-08-042072-9.
Whenever the compounds of Formula (I) are obtained in the form of mixtures of enantiomers, the enantiomers can be separated using methods known to one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Regis Whelk-01 (R,R) (10 μιτι) column, a Daicel ChiralCel OD-H (5-10 μιτι) column, or a Daicel ChiralPak IA (10 μιτι) or AD-H (5 μιτι) column. Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH or /PrOH, in presence or absence of an amine such as NEt3, diethylamine) and eluent B (hexane), at a flow rate of 0.8 to 150 mL/min. Experimental section:
Abbrevations (as used herein and in the description above):
AcOEt ethyl acetate
AcOH acetic acid
Ac20 acetic acid anhydride
aq. aqueous
Boc iert.-butyloxycarbonyl
BSA Bovine serum albumine
Bu butyl (such as in fBuLi = ferf.-BuLi = tertiary butyl lithium)
Cbz benzyloxycarbonyl
CC column chromatography on silica gel
CHO Chinese hamster ovary
comb. combined
cone. concentrated
DCM dichloromethane
DCE 1,2-dichloroethane
DEA diethylamine
DIPEA N-ethyldiisopropylamine
DME 1 ,2-dimethoxyethane
DMEM Dulbecco's modified essential medium
DMF dimethylformamide
DMSO dimethylsulfoxide
Et ethyl
Et20 diethyl ether
EtOH ethanol
FC flash column chromatography on silica gel
FCS Foetal calf serum
FLIPR Fluorescent imaging plate reader
h hour(s)
HBSS Hank's balanced salt soln.
HEPES 4-(2-hydroxyethyl)-piperazine-1-ethanesulfonic acid
HPLC high performance liquid chromatography
/PrOH iso-propanol
LC liquid chromatography LDA lithium diisopropylamide
M molarity [mol L"1]
Me methyl
MeCN acetonitrile
MeOH methanol
MS mass spectroscopy
min. minute(s)
N normality
NaBH(OAc)3 sodium triacetoxyborohydride
NaOfBu sodium ted. (tertiary) butoxide
NaOMe sodium methoxide
NBS N-bromo-succinimide
NCS N-chloro-succinimide
NEt.3 triethylamine
org. organic
PG protecting group
PL-HCO3 Stratospheres™ Solid Phase Extraction cartridges containing a HC03- quaternary amine salt prep. preparative
r.t. room temperature
sat. saturated
sec secundary
soln. solution
TFA trifluoroacetic acid
TBAI tetrabutylammonium iodide
THF tetrahydrofuran
TMSCN trimethylsilylcyanide
fR retention time
Chemistry
The following examples illustrate the preparation of biologically active compounds of the invention but do not at all limit the scope thereof.
General remarks:
For avoidance of any doubt, chiral compounds whose syntheses lead to a mixture of diastereoisomers (either as a mixture of two racemates or as a mixture of epimers) have not been separated, unless stated otherwise. For avoidance of any doubt, chiral compounds have been synthesized in racemic form unless explicitly stated otherwise. All temperatures are stated in °C. All solvents and reagents are used as obtained from commercial sources unless otherwise indicated. The starting materials are obtained from commercial sources or synthesized using standard literature procedures. In mixtures, relations of parts of solvent or eluent or reagent mixtures in liquid form are given as volume ratios (vlv), unless indicated otherwise.
Compounds are characterized by:
Analytical LC-MS Methods:
(LC-1) Agilent 1100 G1312A binary pump equipped with Agilent 1100 G1315B DAD detector, Thermo Finnigan MSQ Surveyor (MS, lonisation: ESI+ (positive ion)), Sedere Sedex 85 (ELSD), Dionex P580 (makeup pump MS), Gilson 215 (auto sampler). Column: Zorbax-AQ (4.6 x 50 mm, 5 μ \).
(LC-2)Agilent 1100 G1312A binary pump equipped with Agilent 1100 G1315B DAD detector, Thermo MSQ Plus (MS, lonisation: ESI+ (positive ion)), Sedere Sedex 85 (ELSD), Dionex P580 (makeup pump MS) and Gilson 215 (auto sampler). Column: Zorbax-AQ (4.6 x 50 mm, 5 μτη).
(LC-4) Agilent 1100 G1312A binary pump equipped with Agilent 1100 G1315B DAD detector, Thermo MSQ Plus (MS, lonisation: ESI+ (positive ion)), Sedere Sedex 85 (ELSD), Dionex P580 (makeup pump MS) and Gilson 215 (auto sampler). Column: Zorbax Extend-C18 (4.6 x 50 mm, 5 μτη).
(LC-5) Dionex HPG-3400A binary pump equipped with Dionex DAD-3000 detector, Thermo MSQ Plus (MS, lonisation: ESI+ (positive ion) or ESI- (negative ion)), Sedere Sedex 85 (ELSD), Dionex TCC-3200 (thermostated column compartment), Dionex ISO-3100A (makeup pump MS) and Gilson 215 (auto sampler). Column: Acentis Express C18 (4.6 x 30 mm, 2.7 μπ\), Zorbax SB-AQ, (4.6 x20 mm, 1.8 mi) or Waters Xbridge C18 (4.6 x 50 mm, 5 / m).
(LC-6), (LC-8), (LC-9), (LC-10), (LC-11), (LC-13), (LC-14) and (LC-15) Dionex P580 binary pump equipped with Dionex PDA-100 photodiode array detector and a Jasco OR-1590 Chiral Detector, using a Daicel ChiralPak AD- H column (4.6 x 250 mm, 5 μιτι).
(LC-7) Dionex P580 binary pump equipped with Dionex PDA-100 photodiode array detector and a Jasco OR- 1590 Chiral Detector, using a Daicel ChiralPak IA column (4.6 x 250 mm, 5 μιτι).
(LC-12a,b,c,d) Dionex HPG-3000 pump equipped with a Dionex Ultimate 3000 photodiode array detector, a Thermo MSQ MS mass detector and a PolymerLab ELS2100 ELSD Detector, using a Dionex TCC-3000 Column compartment, a CTC Pal HTS Sampler for LC and a Ascentis C18 (3 x 30 mm 2.7μπ\) (Methods LC- 12a, 12b and 12c) or a Waters X-Bridge C18 (2,1 x 20mm 2,5 μνη) (Method LC-12d)
Conditions: For acidic methods LC-1 , LC-2 and LC-5: eluent A: MeCN, eluent B: 0.04% TFA in water; 5% to 95% MeCN over 1 min, flow rate 4.5 mL / min, fR given in min. For basic method LC-4: eluent A: MeCN, eluent B: 13 mM NH3 in water; 5% to 95% MeCN over 45 s, flow rate 4.5 mL / min, fR given in min. For basic method LC-6: eluent A: /PrOH with 0.1 % DEA, eluent B: hexane, isocratic (85%B) over 15 mn, flow rate 0.8 mL / min, fR given in min. For basic method LC-7: eluent A: EtOH with 0.1 % DEA, eluent B: hexane, isocratic (50%B) over 15 mn, flow rate 0.8 mL / min, fR given in min. For basic method LC-8: eluent A: /PrOH with 0.1 % DEA, eluent B: hexane, isocratic (95%B) over 15 mn, flow rate 0.8 mL / min, fR given in min. For basic method LC-9: eluent A: /PrOH with 0.1 % DEA, eluent B: hexane, isocratic (90%B) over 15 mn, flow rate 0.8 mL / min, fR given in min. For basic method LC-10: Eluent: EtOH with 0.1 % DEA over 30 mn, flow rate 0.8 mL / min, fR given in min. For basic method LC-11 : eluent A: iPrOH with 0.1 % DEA, eluent B: hexane, isocratic (30%B) over 15 mn, flow rate 0.8 mL / min, tR given in min. LC-12a: eluent A: MeCN, eluent B: 5 mM HC02NH4 + 2% AcCN in water; 5% to 95% MeCN over 2.5 min, flow rate 3 mL / min, tR given in min. LC-12b: eluent A: MeCN, eluent B: 5 mM HC02NH4 + 2% AcCN in water; 5% to 95% MeCN over 1.4 min, flow rate 3 mL / min, tR given in min. LC-12c: eluent A: MeCN, eluent B: 5 mM HC02NH4 + 2% AcCN in water; 5% to 95% MeCN over 2 min, flow rate 3 mL / min, tR given in min. LC-12d: eluent A: MeCN + 0.04% HC02H, eluent B: water + 0.05% HC02H; 5% to 95% MeCN over 1.4 min, flow rate 3 mL / min, tR given in min. LC-13: eluent A: iPrOH with 0.1 % DEA, eluent B: hexane, isocratic (80%B), flow rate 0.8 mL / min, tR given in min. LC-14: eluent A: EtOH with 0.1 % DEA, eluent B: hexane, isocratic (80%B), flow rate 0.8 mL / min, tR given in min. LC-15: eluent A: iPrOH with 0.1 % DEA, eluent B: hexane, isocratic (98%B), flow rate 0.8 mL / min, tR given in min.
In case a substance gives no observable ionization peak in its mass-spectrum, m/z n.a. is mentioned in the analytical description of this substance. In this case, n.a. means: not applicable. For bromine containing compounds, the experimental m/z is the one of the major experimentally observed bromine isotope peak that differs correspondingly from the molecular weight as known to the person skilled in the art.
NMR spectroscopy:
Bruker Avance II spectrometer equipped with a 400 MHz Ultrashield™ Magnet and a BBO 5mm probehead or a PAXTI 1 mm probehead. Chemical shifts (δ) are reported in parts per million (ppm) relative to proton resonances resulting from incomplete deuteration of the NMR solvent, e.g. for dimethylsulfoxide δ(Η) 2.49 ppm, for chloroform δ(Η) 7.24 ppm. The abbreviations s, d, f, q and m refer to singlet, doublet, triplet, quartet, multiplet and br to broad, respectively. Coupling constants J are reported in Hz. In case NMR spectra are measured using 1 mm Microprobe® tubes and a PAXTI 1 mm probehead, the compounds are dissolved in non-deuterated DMSO. The spectra are then measured with double irradiation for suppression of the DMSO and H20 peaks. In that case only a selection of representative NMR peaks of the compound is given.
Compounds are purified by:
Flash chromatography on silica gel:
Biotage SP4 or Flashmaster II chromatography apparatus (FC) or standard column flash chromatography on silica gel (CC) (Silica-Gel 60, particle size 0.035-0.070 mm from Fluka). Conditions: eluent A: Heptane, eluent B: AcOEt unless stated otherwise.
Preparative LC-MS Methods:
Prep. LC-MS (A): Gilson 333/334 binary high pressure gradient pump system equipped with Dionex UVD340U DAD detector, Polymerlabs PL-ELS 1000 ELS detector, Finnigan AQA MS detector, Sedere Sedex V.F.S variable flow splitter, 2 x Dionex P680 isocratic make up pump and Gilson 215 autosampler and fraction collector. Column: Xbridge Prep C18 (30 x 75 mm OBD). Conditions: eluent A MeCN, eluent B 0.5% aq. formic acid, 40% to 100% MeCN over 3.5 min, flow rate 75 mL / min.
Prep. LC-MS (B): Gilson 333/334 binary high pressure gradient pump system equipped with Dionex UVD340U DAD detector, Polymerlabs PL-ELS 1000 ELS detector, Finnigan AQA MS detector, Sedere Sedex V.F.S variable flow splitter, 2 x Dionex P680 isocratic make up pump and Gilson 215 autosampler and fraction collector. Column: Xbridge Prep C18 (30 x 75 mm OBD). Conditions: eluent A MeCN, eluent B 0.5% cone. aq. NH3, 40% to 100% MeCN over 3.5 min, flow rate 75 mL / min.
Prep. LC-MS (C): Waters HPLC apparatus equipped with Waters 600 controller, Waters 276 sample manager, Waters 996 Photodiode array detector, Waters SOF and Waters micromass ZQTM mass spectrometer. Column: Phenomenex® Luna column, (50 x 21.2 mm, 10 μτη, C18 (2), 100 A Axia). Conditions: eluent A 0.4 % formic acid in MeCN, eluent B 1 % aq. formic acid, linear gradient over 3.5 min, flow rate 50 mL / min.
Prep. LC-MS (D): Preparative chiral separations are performed on a HPLC instrument equipped with Dionex P580 binary pump, photodiode array detector Dionex PDA-100. Column: Diacel ChiralPak AD-H (20 x 250 mm, 5 μίτι) or ChiralPak IA (20 x 250 mm, 10 μηι). Conditions: eluent A: EtOH with 0.1 % DEA or iPrOH with 0.1 % DEA, eluent B hexane isocratic (%B) conditions, run time 30 min., flow rate 10 mL / min., detection at 210 nm. The compounds are dissolved in EtOH before loading.
Synthesis of Compounds of Formula (I):
Example 1.01
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-phenyl-indan-1 ,3-dione
A soln. of 2-bromo-2-phenyl-indan-1 ,3-dione (0.061 mmol) in dioxane (1 mL) is added onto 1-benzo[1 ,3]dioxol- 5-ylmethyl-piperazine (0.067 mmol) followed by NEk (0.073 mmol). The resulting soln. is stirred at r.t. over night then water is added and the resulting aq. phase is extracted three times with DCM. The org. layers are comb, and - if necessary - dried (MgS04) and filtered. The solvent is evaporated and the title compound is obtained by prep. LC-MS (B) as a yellow powder:
fR (LC-2) 0.88; ESI-MS: m/z 441.02 [M+H]+. 1H-NMR (DMSO-d6): 2.33 (d, J = 0.8, 4 H), 2.61 (t, J = 4.3, 4 H), 3.34 (s, 2 H), 5.97 (s, 2 H), 6.71 (m, 1 H), 6.81 (m, 2 H), 7.35 (m, 5 H), 8.04 (m, 4 H).
Example 1.02
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-phenyl-indan-1 ,3-dione
A mixture of 2-phenyl-2-piperazin-1-yl-indan-1 ,3-dione hydrochloride (0.146 mmol), cydohexylmethyl bromide (0.16 mmol) and Cs2C03 (0.32 mmol) in DMF (0.5 mL) is stirred at r.t. for 18 h, then at 60 °C for 24h. Then DCM and water are added at r.t.. After phase separation the aq. layer is extracted twice with DCM. The comb, org. layer is concentrated under reduced pressure and the title compound is obtained by prep. LC-MS (B) separation as a yellow powder: iR (LC-1) 0.87; ESI-MS: m/z 403.23 [M+H]+. 1H-NMR (CDCI3): 0.89 (m, 2 H), 1.20 (m, 3 H), 1.48 (m, 1 H), 1.70 (m, 5 H), 2.21 (d, J = 7.0, 2 H), 2.52 (s, 4 H), 2.82 (s, 4 H), 7.30 (t, J = 6.8, 3 H), 7.53 (dd, J = 8.3, 2.0, 2 H), 7.87 (dd, J = 5.8, 3.0, 2 H), 7.98 (dd, J = 5.5, 3.0, 2 H).
a) 2-Phenyl-2-oioerazin-1-yl-indan-1,3-dione hydrochloride
The subtitle compound is prepared according to a procedure adapted from U. Mikstais and A. Arens, Chemistry of Heterocyclic Compounds 1968, 811-813: 2-halo-2-phenyl-indan-1 ,3-dione (50 mmol) is treated with piperazine dihydrochloride (55 mmol) and NEt.3 (50 mmol) in MeOH (100 mL) and allowed to stir overnight at r.t.. After evaporation of the solvent in vaccuo, the solid residue is suspended in DCM and filtered. To the resulting soln. is added 1 N aq. HCI soln.. The resulting aq. phase is extracted three times with DCM. The pH of the aq. phase is then set to pH=14 by slow addition of 1 N aq. NaOH soln.. The resulting aq. phase is extracted twice with DCM. To the comb. org. phases is added cone. aq. HCI. The precipitated white solid is filtered and dried under high vaccum to yield the title compound as a white solid.
Example 1.03
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione
To a stirred mixture of 2-phenyl-2-piperazin-1 -yl-indan-1 ,3-dione hydrochloride (0.225 mmol), NaBH(OAc)3 (1.16 mmol), and DIPEA (0.305 mmol) in DCM (5 mL) is added 2-methyl-benzaldehyde (0.305 mmol). The resulting soln. is continued to stir at r.t. over night. Then water and sat. aq. NaHCC>3 soln. are added and the resulting aq. layer is extracted twice with DCM. The comb. org. layer is dried (MgSC ) and filtered. The solvent is evaporated and the title compound is obtained after separation by prep. LC-MS (B) as a white powder:
fR (LC-5) 0.61 ; ESI-MS: m/z 411.3 [M+H]+. 1H-NMR (CDCI3): 2.34 (s, 3 H), 2.47 (s, 4 H), 2.76 (t, J = 4.3, 4 H), 3.48 (m, 2 H), 7.11 (m, 3 H), 7.24 (d, J = 6.8, 1 H), 7.32 (m, 3 H), 7.55 (m, 2 H), 7.87 (m, 2 H), 7.99 (m, 2 H).
Compounds of Examples 1.04- 1.79 listed in Table 1 below are prepared by applying either one of the above- mentioned methods described for Example 1.01 , 1.02 or 1.03.
Table 1: Examples 1.04- 1.79
Figure imgf000057_0001
0.6
2-[4-(4-Fluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione 415.27
(LC-5)
0.6
2-[4-(3-Fluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione 415.25
(LC-5)
2-[4-(2,4-Difluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3- 0.6
433.17 dione (LC-5)
2-[4-(2,3-Difluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3- 0.6
433.2 dione (LC-5)
2-[4-(3-Difluoromethoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan- 0.63
463.19 1 ,3-dione (LC-5)
2-Phenyl-2-[4-(2-trifluoromethoxy-benzyl)-piperazin-1-yl]-indan- 0.66
481.09 1 ,3-dione (LC-5)
0.59
2-[4-(2-Fluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione 415.2
(LC-5)
2-[4-(2-Methoxy-benzyl)-piperazin-1 -yl]-2-phenyl-indan-1 ,3- 0.61
427.23 dione (LC-5)
2-[4-(3,4-Difluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3- 0.61
433.19 dione (LC-5)
2-[4-(3-Methoxy-benzyl)-piperazin-1 -yl]-2-phenyl-indan-1 ,3- 0.6
427.23 dione (LC-5)
2-[4-(4-lsopropyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3- 0.69
439.28 dione (LC-5)
0.62
2-[4-(3-Methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione 411.24
(LC-5)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3- 0.6
433.23 dione (LC-5)
2-[4-(2-Difluoromethoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan- 0.63
463.2 1 ,3-dione (LC-5)
2-{4-[2-(2-Methoxy-ethyl)-benzyl]-piperazin-1-yl}-2-phenyl- 0.64
455.28 indan-1 ,3-dione (LC-5)
2-{4-[3-(2-Methoxy-ethoxy)-benzyl]-piperazin-1-yl}-2-phenyl- 0.6
471.28 indan-1 ,3-dione (LC-5)
4-[4-(1 ,3-Dioxo-2-phenyl-indan-2-yl)-piperazin-1-ylmethyl]- 0.57
422.22 Denzonitrile (LC-5) 3-[4-(1 ,3-Dioxo-2-phenyl-indan-2-yl)-piperazin-1-ylmethyl]- 0.57
422.21 Denzonitrile (LC-5)
0.63
2-[4-(4-Methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione 411.27
(LC-5)
0.63
2-[4-(4-Chloro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione 431.19
(LC-5)
2-[4-(2-Bromo-5-methoxy-benzyl)-piperazin-1-yl]-2-phenyl- 0.64
507.13 indan-1 ,3-dione (LC-5)
2-[4-(1 ,3-Dioxo-2-phenyl-indan-2-yl)-piperazin-1-ylmethyl]- 0.58
422.2 Denzonitrile (LC-5)
2-[4-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethyl)-piperazin-1-yl]-2- 0.62
475.15 phenyl-indan-1 ,3-dione (LC-5)
2-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-2-phenyl-indan-1 ,3- 0.69
473.25 dione (LC-5)
2-Phenyl-2-[4-(2-trifluoromethyl-benzyl)-piperazin-1-yl]-indan- 0.65
465.15 1 ,3-dione (LC-5)
2-[4-(4-Methyl-3-trifluoromethyl-benzyl)-piperazin-1-yl]-2- 0.68
479.21 phenyl-indan-1 ,3-dione (LC-5)
2-Phenyl-2-[4-(4-pyrazol-1-yl-benzyl)-piperazin-1-yl]-indan-1 ,3- 0.6
463.24 dione (LC-5)
2-Phenyl-2-[4-(4-[1 ,2,3]thiadiazol-4-yl-benzyl)-piperazin-1-yl]- 0.61
481.34 indan-1 ,3-dione (LC-5)
2-Phenyl-2-[4-(4-trifluoromethyl-benzyl)-piperazin-1-yl]-indan- 0.65
465.31 1 ,3-dione (LC-5)
2-[4-(2-Fluoro-6-methoxy-benzyl)-piperazin-1-yl]-2-phenyl- 0.62
445.17 indan-1 ,3-dione (LC-5)
2-[4-(3-Fluoro-4-methoxy-benzyl)-piperazin-1-yl]-2-phenyl- 0.61
445.23 indan-1 ,3-dione (LC-5)
2-[4-(4-Methoxy-3-trifluoromethyl-benzyl)-piperazin-1-yl]-2- 0.66
495.18 phenyl-indan-1 ,3-dione (LC-5)
2-(4-Biphenyl-4-ylmethyl-piperazin-1-yl)-2-phenyl-indan-1 ,3- 0.7
473.29 dione (LC-5)
2-[4-(2-Fluoro-5-trifluoromethyl-benzyl)-piperazin-1-yl]-2- 0.79
483.13 phenyl-indan-1 ,3-dione (LC-5) 2-[4-(2-Methyl-3-trifluoromethyl-benzyl)-piperazin-1-yl]-2- 0.82
479.21 phenyl-indan-1 ,3-dione (LC-5)
2-[4-(3-Chloro-2,6-difluoro-benzyl)-piperazin-1-yl]-2-phenyl- 0.77
467.06 indan-1 ,3-dione (LC-5)
2-[4-(2-Chloro-6-fluoro-3-methyl-benzyl)-piperazin-1-yl]-2- 0.78
463.14 phenyl-indan-1 ,3-dione (LC-5)
2-[4-(3-Chloro-2-fluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan- 0.78
449.24 1 ,3-dione (LC-5)
2-[4-(2,3-Difluoro-4-methyl-benzyl)-piperazin-1-yl]-2-phenyl- 0.78
447.2 indan-1 ,3-dione (LC-5)
2-[4-(2-Fluoro-4-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan- 0.77
429.16 1 ,3-dione (LC-5)
2-[4-(3-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan- 0.77
429.19 1 ,3-dione (LC-5)
2-[4-(2,3-Dichloro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3- 0.8
465.01 dione (LC-5)
2-[4-(4-Fluoro-2-trifluoromethyl-benzyl)-piperazin-1-yl]-2- 0.81
483.11 phenyl-indan-1 ,3-dione (LC-5)
2-Phenyl-2-[4-(2,3,5-trifluoro-benzyl)-piperazin-1-yl]-indan-1 ,3- 0.76
451.05 dione (LC-5)
2-[4-(3-Fluoro-4-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan- 0.76
429.16 1 ,3-dione (LC-5)
2-[4-(2-Fluoro-6-trifluoromethyl-benzyl)-piperazin-1-yl]-2- 0.78
483.10 phenyl-indan-1 ,3-dione (LC-5)
2-[4-(2,4-Dichloro-5-fluoro-benzyl)-piperazin-1-yl]-2-phenyl- 0.82
483.03 indan-1 ,3-dione (LC-5)
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3- 0.80
425.19 dione (LC-5)
2-[4-(2-Chloro-3-trifluoromethyl-benzyl)-piperazin-1-yl]-2- 0.82
499.06 phenyl-indan-1 ,3-dione (LC-5)
2-[4-(2-Chloro-5-fluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan- 0.77
449.18 1 ,3-dione (LC-5)
2-[4-(2,5-Dichloro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3- 0.79
465.16 dione (LC-5) 2-[4-(2-Chloro-3,6-difluoro-benzyl)-piperazin-1-yl]-2-phenyl- 0.76
467.03 indan-1 ,3-dione (LC-5)
2-[4-(2-Chloro-6-fluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan- 0.75
449.22 1 ,3-dione (LC-5)
2-[4-(6-Chloro-2-fluoro-3-methyl-benzyl)-piperazin-1-yl]-2- 0.79
463.18 phenyl-indan-1 ,3-dione (LC-5)
2-Phenyl-2-[4-(2,3,6-trifluoro-benzyl)-piperazin-1-yl]-indan-1 ,3- 0.75
451.09 dione (LC-5)
2-[4-(2-Chloro-5-trifluoromethyl-benzyl)-piperazin-1-yl]-2- 0.82
499.06 phenyl-indan-1 ,3-dione (LC-5)
2-[4-(5-Chloro-2-trifluoromethyl-benzyl)-piperazin-1-yl]-2- 0.85
499.08 phenyl-indan-1 ,3-dione (LC-5)
2-[4-(2,6-Difluoro-benzyl)-piperazin-1 -yl]-2-phenyl-indan-1 ,3- 0.73
433.21 dione (LC-5)
0.94
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione 425.17
(LC-2)
2-[4-(2-lsopropyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3- 0.92
439.07 dione (LC-1)
0.92
2-Phenyl-2-[4-(2-propyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione 439.06
(LC-1)
2-[4-(2-Hydroxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1,3- 0.82
413.04 dione (LC-1)
0.89
2-[4-(2-Ethoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione 441.07
(LC-1)
2-[4-(2-Allyloxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3- 0.91
453.11 dione (LC-1)
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan- 0.87
429.11 1 ,3-dione (LC-1)
0.84
2-[4-(2-Nitro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione 441.98
(LC-1)
2-(4-Cyclopropylmethyl-piperazin-1-yl)-2-phenyl-indan-1 ,3- 0.54
361.29 dione (LC-5)
2-(4-Benzo[1 ,2,5]thiadiazol-4-ylmethyl-piperazin-1-yl)-2-phenyl- 0.59
455.18 indan-1 ,3-dione (LC-5) 2-(4-Benzo[1 ,2,5]thiadiazol-5-ylmethyl-piperazin-1-yl)-2-phenyl- 0.58
1.76 455.17
indan-1 ,3-dione (LC-5)
2-(4-Benzo[1 ,2,5]oxadiazol-4-ylmethyl-piperazin-1-yl)-2-phenyl- 0.59
1.77 439.19
indan-1 ,3-dione (LC-5)
2-Phenyl-2-(4-quinolin-8-ylmethyl-piperazin-1-yl)-indan-1 ,3- 0.62
1.78 448.23
dione (LC-5)
2-[4-(1-Methyl-1 H-benzotriazol-5-ylmethyl)-piperazin-1-yl]-2- 0.54
1.79 452.25
phenyl-indan-1 ,3-dione (LC-5)
Compounds of Examples 2.01- 2.09 listed in Table 2 below are prepared by applying either one of the above- mentioned methods described for Example 1.01 , 1.02 or 1.03.
Table 2: Examples 2.01- 2.09
Figure imgf000062_0001
Compounds of Examples 3.01- 3.13 listed in Table 3 below are prepared by applying either one of the above- mentioned methods described for Example 1.01 , 1.02 or 1.03.
Table 3: Examples 3.01- 3.13
Figure imgf000063_0001
Example 4.01
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-4-fluoro-2-phenyl-indan-1,3-dione
The title compound is prepared according to the procedure described for above Example 1.01 by reacting 2- bromo-4-fluoro-2-phenyl-indan-1 ,3-dione with 1-benzo[1 ,3]dioxol-5-ylmethyl-piperazine: iR (LC-1) 0.85; ESI-MS: m/z 458.78 [M+H]+. 1H-NMR (DMSO-d6): 2.32 (d, J = 0.5, 4 H), 2.62 (m, 4 H), 3.39 (s, 2 H), 5.97 (s, 2 H), 6.71 (d, J = 8.0, 1 H), 6.81 (m, 2 H), 7.37 (m, 5 H), 7.88 (m, 2 H), 8.09 (m, 1 H).
a) 2-Halo-4-fluoro-2-Dhenyl-indan-1,3-dione derivatives
2-Bromo-4-fluoro-2-Dhenyl-indan-1,3-dione
The subtitle compound is prepared according to the following procedure adapted from Tanemura, K. ef a/., Chem. Commun. 2004, 470-476:
To a soln. of 4-fluoro-2-phenyl-indan-1 ,3-dione (10 mmol) and NBS (10.5 mmol) in Et^O (10 mL) is added ammonium acetate (1 mmol). The resulting suspension is allowed to stir at r.t. for 30 min. The mixture is filtered, washed with water and extracted with DCM. The comb. org. extracts are dried (MgSC ), filtered and concentrated in vaccuo. Purification by FC affords 4-fluoro-2-phenyl-indan-1 ,3-dione: iR (LC-1) 1.01 ; ESI-MS: m/z n. a. [M+H]+. 1H-NMR (DMSO-d6): 7.46 (m, 3 H), 7.64 (m, 2 H), 7.98 (m, 2 H), 8.18 (td, J = 7.8, 4.8, 1 H). 2-Chloro-4-fluoro-2-phenyl-indan- 3-dione
The subtitle compound is prepared following the brominating protocol as described above using NCS instead of NBS: fR (LC-2) 1.01 ; ESI-MS: m/z n. a. [M+H]+.
b) 4-Fluoro-2-Dhenyl-indan- 1,3-dione
The subtitle compound is prepared according to the procedure adapted from C. G. Thomson ef a/., Bioorg. Med. Chem. Letters 2006, 16(5), 1388-1391 : 3-fluorophthalic acid anhydride (29.7 mmol) is reacted with phenyl acetic acid (59.4 mmol) in AC2O (16 mL) in the presence of NEt.3 (21 mL) at reflux, followed by treatment with 30% sol. of NaOMe in MeOH (48 mL) at reflux.
Example 4.02
4-Fluoro-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1,3-dione
The title compound is prepared according to the procedure described for above Example 1.02 by reacting 4- fluoro-2-phenyl-2-piperazin-1 -yl-indan-1 ,3-dione hydrochloride with 3-methoxybenzyl bromide in DCM in the presence of DIPEA: fR (LC-1) 0.88; ESI-MS: m/z 421.17 [M+H]+.
4-Fluoro-2-phen yl-2-piperazin- 1 - yl-indan- 1 , 3-dione
1) To a stirred soln. of 4-fluoro-2-bromo-2-phenyl-indan-1 ,3-dione (0.1 mmol) and 1-Boc piperazine (0.11 mmol) in dioxane (0.5 mL) is added triethylamine (0.15 mmol). The resulting yellow soln. is continued to stir at r.t. for 36 h. Then water (3 mL) is added and the resulting aq. phase is extracted three times with DCM. The solvent is removed under reduced pressure. The residue is suspended in MeCN (0.5 mL). The formed yellow solid is separated by filtration and dried under high vacuum to yield crude 4-(4-fluoro-1 ,3-dioxo-2-phenyl-indan-2-yl)- piperazine-1-carboxylic acid iert.-butyl ester. iR (LC-1) 1.07; ESI-MS: m/z 424.98 [M+H]+. 1H-NMR (CDCIs): δ 1.44 (s, 9 H), 2.71 (m, 4 H), 3.42 (t, J = 4.5, 4 H), 7.35 (m, 3 H), 7.53 (m, 3 H), 7.80 (m, 1 H), 7.87 (td, J = 7.5, 4.3, 1 H).
2) To a stirred soln. of 4-(4-fluoro-1 ,3-dioxo-2-phenyl-indan-2-yl)-piperazine-1-carboxylic acid fe/t-butyl ester (0.025 mmol) in dioxane (0.5 mL) is added 4N HCI sol. in dioxane (0.5 mL). The resulting sol. is allowed to stir at r.t. for 60 h. Evaporation of the solvent in vacuo yields the subtitle compound hydrochloride as a yellow solid: fR (LC-2) 0.71 ; ESI-MS: m/z 324.94 [M+H-HCI]+. 1H-NMR (DMSO-d6): 2.84 (m, 4 H), 3.05 (m, 4 H), 7.41 (m, 5 H), 7.91 (m, 2 H), 8.13 (m, 1 H), 8.92 (m, 2 H).
Example 4.03
2-(4-Benzyl-piperazin-1-yl)-4-fluoro-2-phenyl-indan-1,3-dione
The title compound is prepared using the procedure described for above Example 1.03 in a reaction of 4-fluoro- 2-phenyl-2-piperazin-1-yl-indan-1 ,3-dione hydrochloride with benzaldehyde in DCM in the presence of NaBH(OAc)3 and DIPEA: fR (LC-1) 0.84; ESI-MS: m/z 415.22 [M+H]+. 1H-NMR (DMSO-d6): £2.35 (s, 4 H), 2.63 (m, 4 H), 3.45 (s, 2 H), 7.31 (m, 10 H), 7.88 (m, 2 H), 8.10 (m, 1 H).
By repeating either one of the procedures used in the synthesis of above-mentioned examples, using appropriate starting materials, the following Example compounds as identified in Tables 4-8 are obtained:
Table 4: Example 4.04- 4.11
Figure imgf000065_0001
2-(4-Cyclopropylmethyl-piperazin-1-yl)-4-fluoro-2-phenyl-indan- 0.79
4.11 379.06 1 ,3-dione (LC-1)
Table 5: Example 5.01- 5.11
Figure imgf000066_0001
1 ,3-dione (LC-1)
Table 6: Example 6.01-6.11
Figure imgf000066_0002
2-(4-Cyclohexylmethyl-piperazin-1-yl)-4-methyl-2-phenyl-indan- 0.91
6.02 417.31 1 ,3-dione (LC-1)
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1-yl)-4-methyl-2- 0.87
6.03 455.24 phenyl-indan-1 ,3-dione (LC-1)
4-Methyl-2-phenyl-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)-indan- 0.82
6.04 412.26 1 ,3-dione (LC-1)
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-4-methyl-2-phenyl- 0.88
6.05 441.27 indan-1 ,3-dione (LC-1)
2-[4-(4-Methoxy-benzyl)-piperazin-1-yl]-4-methyl-2-phenyl- 0.87
6.06 441.26 indan-1 ,3-dione (LC-1)
4-Methyl-2-(4-phenethyl-piperazin-1-yl)-2-phenyl-indan-1 ,3- 0.89
6.07 425.29 dione (LC-1)
4-Methyl-2-phenyl-2-[4-(3-phenyl-propyl)-piperazin-1-yl]-indan- 0.9
6.08 439.28 1 ,3-dione (LC-1)
4-Methyl-2-phenyl-2-(4-pyridin-3-ylmethyl-piperazin-1-yl)-indan- 0.74
6.09 412.26 1 ,3-dione (LC-1)
4-Methyl-2-phenyl-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-indan- 0.73
6.10 412.26 1 ,3-dione (LC-1)
2-(4-Cyclopropylmethyl-piperazin-1-yl)-4-methyl-2-phenyl- 0.82
6.1 1 375.28 indan-1 ,3-dione (LC-1)
Table 7: Example 7.01- 7.14
Figure imgf000067_0001
4-Ethyl-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan- 0.90
7.06 455.07 1 ,3-dione (LC-1)
4-Ethyl-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan- 0.92
7.07 455.03 1 ,3-dione (LC-1)
2-[4-(3-Chloro-benzyl)-piperazin-1-yl]-4-ethyl-2-phenyl-indan- 0.92
7.08 458.79 1 ,3-dione (LC-1)
2-[4-(4-Chloro-benzyl)-piperazin-1-yl]-4-ethyl-2-phenyl-indan- 0.92
7.09 458.83 1 ,3-dione (LC-1)
4-Ethyl-2-phenyl-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-indan- 0.92
7.10 455.05 1 ,3-dione (LC-1)
4-Ethyl-2-phenyl-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)- 0.88
7.1 1 430.98 indan-1 ,3-dione (LC-1)
4-Ethyl-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan- 0.92
7.12 439.06 1 ,3-dione (LC-1)
4-Ethyl-2-[4-(4-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan- 0.92
7.13 439.06 1 ,3-dione (LC-1)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-4-ethyl-2-phenyl-indan- 0.92
7.14 458.91 1 ,3-dione (LC-1)
Table 8: Example 8.01- 8.14
Figure imgf000068_0001
4-Methoxy-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-2-phenyl- 0.85
8.07 457.03
indan-1 ,3-dione (LC-1)
2-[4-(3-Chloro-benzyl)-piperazin-1-yl]-4-methoxy-2-phenyl- 0.86
8.08 460.99
indan-1 ,3-dione (LC-1)
2-[4-(4-Chloro-benzyl)-piperazin-1-yl]-4-methoxy-2-phenyl- 0.86
8.09 460.99
indan-1 ,3-dione (LC-1)
4-Methoxy-2-phenyl-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)- 0.69
8.10 428.05
indan-1 ,3-dione (LC-1)
4-Methoxy-2-phenyl-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)- 0.81
8.1 1 432.98
indan-1 ,3-dione (LC-1)
4-Methoxy-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-2-phenyl- 0.86
8.12 441.03
indan-1 ,3-dione (LC-1)
4-Methoxy-2-[4-(4-methyl-benzyl)-piperazin-1-yl]-2-phenyl- 0.86
8.13 441.04
indan-1 ,3-dione (LC-1)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-4-methoxy-2-phenyl- 0.85
8.14 461
indan-1 ,3-dione (LC-1)
Appropriate 2-phenyl-indan-2-piperazin-1-yl-1 ,3-dione derivatives are prepared as hydrochloride salts according to the procedure for above described Example 4.01.
Figure imgf000069_0001
Appropriate 2-halo-2-phenyl-indan-1 ,3-dione derivatives are prepared according to a procedure adapted from Tanemura, K. ei a/., Chem. Commun. 2004, 470-476 by reacting the corresponding 2-phenyl-indan-1 ,3-dione derivative with NBS.
fR [min] LC-MS MS Data m/z
2-Halo-2-phenyl-indan-1 ,3-dione derivative
Method [M+H]+
2-Bromo-4-chloro-2-phenyl-indan-1 ,3-dione 1.04 (LC-1) n.a.
2-Bromo-4-methyl-2-phenyl-indan-1 ,3-dione 1.05 (LC-1) n.a.
2-Bromo-4-ethyl-2-phenyl-indan- ,3-dione 1.08 (LC-1) n.a. 2-Bromo-4-methoxy-2-phenyl-indan-1 ,3-dione 0.98 (LC-1) n.a.
The following 2-phenyl-indan-1 ,3-dione derivatives are commercially available, or are prepared according to a known procedure, e.g. by an adapted procedure from C. G. Thomson ef a/., Bioorg. Med. Chem. Letters 2006, 16(5), 1388-1391 , from their respective phthalic acid anhydride derivatives in reaction with phenyl acetic acid in AC2O in the presence of NEt.3 at reflux, followed by treatment with NaOMe in MeOH at reflux: 4-chloro-2-phenyl- indan-1 ,3-dione, 4-methyl-2-phenyl-indan-1 ,3-dione, 4-ethyl-2-phenyl-indan-1 ,3-dione, 4-methoxy-2-phenyl- indan-1 ,3-dione.
Analytical data for 4-ethyl-2-phenyl-indan-1 ,3-dione: fR (LC-1) 1.01 ; ESI-MS: m/z n. a. [M+H]+. 1H-NMR (DMSO- d ): £1.16 (U = 7.4, 3 H), 2.96 (q, J = 7.4, 2 H), 7.13 (d, J = 6.8, 1 H), 7.20 (d, J = 7.3, 1 H), 7.35 (m, 3 H), 7.49 (m, 1 H), 7.87 (m, 3 H).
By repeating either one of the procedures used in the synthesis of above-mentioned examples, using appropriate starting materials, the following Example compounds as identified in Tables 9-13 are obtained:
Table 9: Example 9.01- 9.06
Figure imgf000070_0002
Table 10: Example 10.01- 10.11
Figure imgf000070_0001
5-Chloro-2-(4-cyclohexylmethyl-piperazin-1-yl)-2-phenyl-indan- 0.92
10.02 437.08 1 ,3-dione (LC-1)
5-Chloro-2-phenyl-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)-indan- 0.84
10.03 431.99 1 ,3-dione (LC-1)
5-Chloro-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-2-phenyl- 0.9
10.04 460.16 indan-1 ,3-dione (LC-1)
5-Chloro-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-2-phenyl- 0.89
10.05 461.04 indan-1 ,3-dione (LC-1)
5-Chloro-2-(4-phenethyl-piperazin-1 -yl)-2-phenyl-indan-1 ,3- 0.91
10.06 445.04 dione (LC-1)
5-Chloro-2-phenyl-2-[4-(3-phenyl-propyl)-piperazin-1-yl]-indan- 0.92
10.07 458.89 1 ,3-dione (LC-1)
5-Chloro-2-phenyl-2-(4-pyridin-3-ylmethyl-piperazin-1-yl)-indan- 0.76
10.08 432.01 1 ,3-dione (LC-1)
5-Chloro-2-phenyl-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-indan- 0.75
10.09 432.00 1 ,3-dione (LC-1)
5-Chloro-2-(4-cyclopropylmethyl-piperazin-1-yl)-2-phenyl- 0.83
10.10 395.01 indan-1 ,3-dione (LC-1)
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1-yl)-5-chloro-2- 0.89
10.1 1 474.76 phenyl-indan-1 ,3-dione (LC-1)
Table 11: Example 11.01- 11.23
Figure imgf000071_0001
2-[4-(4-Methoxy-benzyl)-piperazin-1-yl]-5-methyl-2-phenyl- 0.87
441.25 indan-1 ,3-dione (LC-1)
5-Methyl-2-(4-phenethyl-piperazin-1-yl)-2-phenyl-indan-1 ,3- 0.89
425.27 dione (LC-1)
5-Methyl-2-phenyl-2-[4-(3-phenyl-propyl)-piperazin-1-yl]-indan- 0.91
439.27 1 ,3-dione (LC-1)
5-Methyl-2-phenyl-2-(4-pyridin-3-ylmethyl-piperazin-1-yl)-indan- 0.75
412.25 1 ,3-dione (LC-1)
5-Methyl-2-phenyl-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-indan- 0.74
412.21 1 ,3-dione (LC-1)
2-(4-Cyclopropylmethyl-piperazin-1-yl)-5-methyl-2-phenyl- 0.82
375.27 indan-1 ,3-dione (LC-1)
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-5-methyl-2-phenyl- 0.89
441.04 indan-1 ,3-dione (LC-1)
5-Methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan- 0.89
425.05 1 ,3-dione (LC-1)
5-Methyl-2-[4-(4-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan- 0.89
425.04 1 ,3-dione (LC-1)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-5-methyl-2-phenyl-indan- 0.88
445.01 1 ,3-dione (LC-1)
2-[4-(3-Chloro-benzyl)-piperazin-1-yl]-5-methyl-2-phenyl-indan- 0.89
445.01 1 ,3-dione (LC-1)
2-[4-(4-Chloro-benzyl)-piperazin-1-yl]-5-methyl-2-phenyl-indan- 0.89
445.03 1 ,3-dione (LC-1)
2-(4-Benzo[1 ,2,5]thiadiazol-4-ylmethyl-piperazin-1-yl)-5-methyl- 0.86
469.04 2-phenyl-indan-1 ,3-dione (LC-1)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-5-methyl-2-phenyl- 0.88
447.03 indan-1 ,3-dione (LC-1)
5-Methyl-2-[4-(5-methyl-isoxazol-3-ylmethyl)-piperazin-1-yl]-2- 0.82
416.04 phenyl-indan-1 ,3-dione (LC-1)
5-Methyl-2-phenyl-2-(4-thiazol-4-ylmethyl-piperazin-1-yl)-indan- 0.8
418.00 1 ,3-dione (LC-1)
5-Methyl-2-(4-[1,2,4]oxadiazol-3-ylmethyl-piperazin-1-yl)-2- 0.79
403.03 phenyl-indan-1 ,3-dione (LC-1) 5-Methyl-2-[4-(3-rnethyl-benzyl)-piperazin-1-yl]-2-phenyl-indan- 0.89
11.23 425.05
1 ,3-dione (LC-1)
(R)-2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-5-me^ and (S)-2-(4- benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-5-methyl-2-phenyl-indan-1,3-dione
The two enantiomers of 2-(4-benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1 -yl)-5-methyl-2-phenyl-indan-1 ,3-dione (Example 11.03) are separated by chiral prep. LC-MS (D). Conditions: ChiralPak AD-H column, Eluent : EtOH with 0.1 % DEA
Example 11.03A: Enantiomer A: fR (LC-10) 18.12.
Example 11.03B: Enantiomer B: fR (LC-10) 23.40.
Table 12: Example 12.01- 12.13
Figure imgf000073_0001
5-Methoxy-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-2-phenyl- 0.88
12.1 1 441.04
indan-1 ,3-dione (LC-1)
5-Methoxy-2-[4-(4-methyl-benzyl)-piperazin-1-yl]-2-phenyl- 0.88
12.12 441.03
indan-1 ,3-dione (LC-1)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-5-methoxy-2-phenyl- 0.88
12.13 460.99
indan-1 ,3-dione (LC-1)
Table 13: Example 13.01- 13.06
Figure imgf000074_0001
Appropriate 2-phenyl-indan-2-piperazin-1 -yl-1 ,3-dione derivatives are prepared as hydrochloride salts according to the procedure for above described Example 4.01 :
fR [min] LC-MS MS Data m/z
2-Phenyl-indan-2-piperazin-1-yl-1,3-dione deivative
Method [M+H]+
5-Fluoro-2-phenyl-2-piperazin-1-yl-indan-1 ,3-dione 0.73 (LC-1) 324.96
5-Chloro-2-phenyl-2-piperazin-1 -yl-indan-1 ,3-dione 0.77 (LC-1) 340.96
5-Methyl-2-phenyl-2-piperazin-1 -yl-indan-1 ,3-dione 0.74 (LC-1) 320.98
5-Methoxy-2-phenyl-2-piperazin-1 -yl-indan-1 ,3-dione 0.77 (LC-1) 350.98
2-Phenyl-2-piperazin-1-yl-5-trifluoromethyl-indan-1 ,3-dione 0.79 (LC-1) 375.00 The following 2-halo-2-phenyl-indan-1 ,3-dione derivatives are prepared according to a procedure adapted from Tanemura, K. ei a/., Chem. Commun. 2004, 470-476 by reacting the corresponding 2-phenyl-indan-1 ,3-dione derivatives with NBS or NCS:
Figure imgf000075_0002
The following 2-phenyl-indan-1 ,3-dione derivatives are commercially available or are prepared according to a known procedures, e.g. by an adapted procedure from C. G. Thomson ei a/., Bioorg. Med. Chem. Letters 2006, 16(5), 1388-1391 , from their respective phthalic acid anhydride derivative in reaction with phenyl acetic acid in AC2O in the presence of NEt3 at reflux, followed by treatment with NaOMe in MeOH at reflux: 5-fluoro-2-phenyl- indan-1 ,3-dione, 5-chloro-2-phenyl-indan-1 ,3-dione, 5-methyl-2-phenyl-indan-1 ,3-dione, 5-methoxy-2-phenyl- indan-1 ,3-dione, 2-phenyl-5-trifluoromethyl-indan-1 ,3-dione.
By repeating either one of the procedures used in the synthesis of above-mentioned examples, using appropriate starting materials, the following Example compounds as identified in Tables 14-25 are obtained:
Table 14: Example 14.01- 14.08
Figure imgf000075_0001
2-[4-(3-Chloro-benzyl)-piperazin-1-yl]-2-(2-methylphenyl)- 0.89
14.06 445.02 indan-1 ,3-dione (LC-1)
2-(4-Pyridin-4-ylmethyl-piperazin-1-yl)-2-(2-methylphenyl)- 0.73
14.07 412.05 indan-1 ,3-dione (LC-1)
2-(4-Thiophen-2-ylmethyl-piperazin-1-yl)-2-(2-methylphenyl)- 0.86
14.08 417.01 indan-1 ,3-dione (LC-1)
Table 15: Example 15.01- 15.07
Figure imgf000076_0001
1-yl]-indan-1 ,3-dione (LC-1)
Table 16: Example 16.01- 16.12
Figure imgf000076_0002
2-(3-Bromo-phenyl)-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)- 0.83
16.04 475.97 indan-1 ,3-dione (LC-1)
2-(3-Bromo-phenyl)-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]- 0.9
16.05 506.49 indan-1 ,3-dione (LC-1)
2-(3-Bromo-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]- 0.89
16.06 506.42 indan-1 ,3-dione (LC-1)
2-(3-Bromo-phenyl)-2-(4-cyclopropylmethyl-piperazin-1-yl)- 0.85
16.07 438.93 indan-1 ,3-dione (LC-1)
2-(3-Bromo-phenyl)-2-(4-phenethyl-piperazin-1 -yl)-indan-1 ,3- 0.91
16.08 490.5 dione (LC-1)
2-(3-Bromo-phenyl)-2-[4-(3-phenyl-propyl)-piperazin-1-yl]- 0.93
16.09 504.98 indan-1 ,3-dione (LC-1)
2-(3-Bromo-phenyl)-2-(4-pyridin-3-ylmethyl-piperazin-1-yl)- 0.76
16.10 475.99 indan-1 ,3-dione (LC-1)
2-(3-Bromo-phenyl)-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)- 0.75
16.11 475.99 indan-1 ,3-dione (LC-1)
2-(3-Bromo-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin- 0.92
16.12 508.93 1-yl]-indan-1 ,3-dione (LC-1)
Table 17: Example 17.01- 17.13
Figure imgf000077_0001
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methylphenyl)- 0.89
17.07 441.05 indan-1 ,3-dione (LC-1)
2-[4-(3-Chloro-benzyl)-piperazin-1-yl]-2-(3-methylphenyl)- 0.88
17.08 445.01 indan-1 ,3-dione (LC-1)
2-[4-(4-Chloro-benzyl)-piperazin-1-yl]-2-(3-methylphenyl)- 0.88
17.09 445.03 indan-1 ,3-dione (LC-1)
2-(4-Pyridin-4-ylmethyl-piperazin-1-yl)-2-(3-methylphenyl)- 0.72
17.10 412.04 indan-1 ,3-dione (LC-1)
2-(4-Thiophen-2-ylmethyl-piperazin-1-yl)-2-(3-methylphenyl)- 0.84
17.11 416.99 indan-1 ,3-dione (LC-1)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-methylphenyl)-indan- 0.91
17.12 439.07 1 ,3-dione (LC-1)
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3- 0.9
17.13 442.89 methylphenyl)-indan-1 ,3-dione (LC-1)
Table 18: Example 18.01- 18.07
Figure imgf000078_0001
Table 19: Example 19.01- 19.15
Figure imgf000079_0001
Table 20: Example 20.01- 20.03
Figure imgf000080_0002
Table 21: Example 21.01- 21.09
Figure imgf000080_0001
Table 22: Example 22.01- 22.10
Figure imgf000081_0002
Table 23: Example 23.01- 23.10
Figure imgf000081_0001
2-(4-Methoxy-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]- 0.87
23.04 441.04 indan-1 ,3-dione (LC-1)
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(4-methoxy-phenyl)- 0.86
23.05 457.04 indan-1 ,3-dione (LC-1)
2-[4-(4-Methoxy-benzyl)-piperazin-1-yl]-2-(4-methoxy-phenyl)- 0.85
23.06 457.06 indan-1 ,3-dione (LC-1)
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(4-methoxy-phenyl)- 0.87
23.07 457.07 indan-1 ,3-dione (LC-1)
2-[4-(3-Chloro-benzyl)-piperazin-1-yl]-2-(4-methoxy-phenyl)- 0.87
23.08 461.03 indan-1 ,3-dione (LC-1)
2-[4-(4-Chloro-benzyl)-piperazin-1-yl]-2-(4-methoxy-phenyl)- 0.87
23.09 461.06 indan-1 ,3-dione (LC-1)
2-(4-Methoxy-phenyl)-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)- 0.71
23.10 428.06 indan-1 ,3-dione (LC-1)
Table 24: Example 24.01- 24.09
Figure imgf000082_0001
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-naphthalen-1-yl-indan- 0.92
24.09 481.05 1 ,3-dione (LC-1)
Table 25: Example 25.01-25.15
Figure imgf000083_0001
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-naphthalen-2-yl-indan- 0.95
25.15 474.75
1 ,3-dione (LC-1)
The following 2-phenyl-indan-2-piperazin-1-yl-1 ,3-dione derivatives are prepared according to the procedure for above described Example 4.01 and are obtained as hydrochloride salts:
Figure imgf000084_0001
Appropriate 2-halo-2-phenyl-indan-1 ,3-dione derivatives are prepared according to a procedure adapted from Tanemura, K. ef a/., Chem. Commun. 2004, 470-476 by brominating or chlorinating the corresponding 2-phenyl- indan-1 ,3-dione derivatives with NBS or NCS, respectively: 2-bromo-2-(2-methyl-phenyl)-indan-1 ,3-dione, 2- chloro-2-(2-methylphenyl)-indan-1 ,3-dione, 2-bromo-2-(3-chloro-phenyl)-indan-1 ,3-dione, 2-chloro-2-(3-chloro- phenyl)-indan-1 ,3-dione, 2-bromo-2-(3-bromo-phenyl)-indan-1 ,3-dione, 2-chloro-2-(3-bromo-phenyl)-indan-1 ,3- dione, 2-bromo-2-(3-methyl-phenyl)-indan-1 ,3-dione, 2-chloro-2-(3-methyl-phenyl)-indan-1 ,3-dione, 2-bromo-2- (3-methoxy-phenyl)-indan-1 ,3-dione, 2-chloro-2-(3-methoxy-phenyl)-indan-1 ,3-dione, 2-bromo-2-(4-chloro- phenyl)-indan-1 ,3-dione, 2-bromo-2-(4-bromo-phenyl)-indan-1 ,3-dione, 2-chloro-2-(4-bromo-phenyl)-indan-1 ,3- dione, 2-bromo-2-(4-methyl-phenyl)-indan-1 ,3-dione, 2-chloro-2-(4-methyl-phenyl)-indan-1 ,3-dione, 2-bromo-2- (4-methoxy-phenyl)-indan-1 , 3-dione, 2-chloro-2-(4-methoxy-phenyl)-indan-1 , 3-dione, 2-bromo-2-naphthalen-1- yl-indan-1 ,3-dione, 2-bromo-2-naphthalen-2-yl-indan-1 ,3-dione,
2-bromo-2-(2-methoxy-phenyl)-indan-1 , 3-dione: fR (LC-1) 1.00; ESI-MS: m/z n.a.. 1H-NMR (DMSO-d6): 2.58 (s, 3 H), 7.22 (m, 1 H), 7.40 (m, 2 H), 7.92 (m, 1 H), 8.16 (m, 4 H),
2-chloro-2-(2-methoxy-phenyl)-indan-1 ,3-dione: fR (LC-1) 1.00; ESI-MS: m/z n.a.,
2-bromo-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione: fR (LC-1) 1.07; ESI-MS: m/z n.a.. 1H-NMR (CDCI3): 7.55 (t, 1 H), 7.65 (m, 1 H), 8.01 (m, 4 H), 8.15 (m, 2 H),
2-chloro-2-(3-trifluoromethyl-phenyl)-indan-1 , 3-dione: fR (LC-1) 1.07; ESI-MS: m/z n.a.. The following 2-phenyl-indan-1 ,3-dione derivatives are commercially available, or are prepared according to an adapted procedure from C. G. Thomson ei a/., Bioorg. Med. Chem. Letters 2006, 16(5), 1388-1391 , from their respective phthalic acid anhydrides in reaction with the corresponding phenyl acetic acid derivative in AC2O in the presence of NEt.3 at reflux, followed by treatment with NaOMe in MeOH at reflux: 2-(2-methyl-phenyl)-indan- 1 ,3-dione, 2-(2-methoxy-phenyl)-indan-1 ,3-dione, 2-(3-chloro-phenyl)-indan-1 ,3-dione, 2-(3-bromo-phenyl)- indan-1 ,3-dione, 2-(3-methyl-phenyl)-indan-1 ,3-dione, 2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione, 2-(3- methoxy-phenyl)-indan-1 ,3-dione, 2-(4-chloro-phenyl)-indan-1 ,3-dione, 2-(4-bromo-phenyl)-indan-1 ,3-dione, 2- (4-methyl-phenyl)-indan-1 ,3-dione, 2-(4-methoxy-phenyl)-indan-1 ,3-dione, 2-naphthalen-1-yl-indan-1 ,3-dione, 2- naphthalen-2-yl-indan-1 ,3-dione.
By repeating either one of the procedures used in the synthesis of above-mentioned examples, using appropriate starting materials, the following Example compounds as identified in Tables 26-34 are obtained:
Table 26: Example 26.01- 26.07
fR [min] (LC- MS Data m/z
Example Compound
MS Method) [M+H]+
2-(4-Benzyl-piperazin-1-yl)-2-pyridin-2-yl-indan-1 ,3-dione 0.76
26.01 398.05
(LC-1)
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-pyridin-2-yl-indan- 0.80
26.02 412.09
1 ,3-dione (LC-1)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-pyridin-2-yl-indan- 0.80
26.03 404.07
1 ,3-dione (LC-1)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-pyridin-2-yl-indan-1 ,3- 0.82
26.04 426.01
dione (LC-1)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-pyridin-2-yl-indan- 0.79
26.05 431.96
1 ,3-dione (LC-1)
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-pyridin-2-yl-indan- 0.78
26.06 428.04
1 ,3-dione (LC-1)
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-pyridin-2-yl-indan- 0.79
26.07 428.05
1 ,3-dione (LC-1)
Table 27: Example 27.01- 27.15
fR [min] (LC- MS Data m/z
Example Compound
MS Method) [M+H]+
2-(4-Benzyl-piperazin-1-yl)-2-pyridin-3-yl-indan-1 ,3-dione 0.70
27.01 398.04
(LC-1) 2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-pyridin-3-yl-indan- 0.74
404.08 1 ,3-dione (LC-1)
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-pyridin-3- 0.72
441.97 yl-indan-1 ,3-dione (LC-1)
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan- 0.73
412.05 1 ,3-dione (LC-1)
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan- 0.73
428.08 1 ,3-dione (LC-1)
2-[4-(4-Methoxy-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan- 0.72
428.07 1 ,3-dione (LC-1)
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan- 0.73
428.06 1 ,3-dione (LC-1)
2-[4-(3-Chloro-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan- 0.74
431.99 1 ,3-dione (LC-1)
2-[4-(4-Chloro-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan- 0.75
431.97 1 ,3-dione (LC-1)
2-Pyridin-3-yl-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-indan- 0.58
399.06 1 ,3-dione (LC-1)
2-Pyridin-3-yl-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan- 0.68
404.00 1 ,3-dione (LC-1)
2-[4-(3-Methyl-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan- 0.74
412.08 1 ,3-dione (LC-1)
2-[4-(4-Methyl-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan- 0.74
412.09 1 ,3-dione (LC-1)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan- 0.73
431.98 1 ,3-dione (LC-1)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan-1 ,3- 0.76
426.01 dione (LC-1) Table 28: Example 28.01- 28.14
* [min]
MS Data
Example Compound LC-MS
m/z [M+H]+ Method
2-(4-Benzyl-piperazin-1-yl)-2-(pyridin-4-yl)-indan-1 ,3-dione 0.70
28.01 398.02
(LC-1)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(pyridin-4-yl)-indan- 0.74
28.02 404.10
1 ,3-dione (LC-1)
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(pyridin-4- 0.71
28.03 441.96 yl)-indan-1 ,3-dione (LC-1)
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(pyridin-4-yl)-indan- 0.72
28.04 412.04
1 ,3-dione (LC-1)
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(pyridin-4-yl)-indan- 0.72
28.05 428.05
1 ,3-dione (LC-1)
2-[4-(4-Methoxy-benzyl)-piperazin-1-yl]-2-(pyridin-4-yl)-indan- 0.71
28.06 428.06
1 ,3-dione (LC-1)
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(pyridin-4-yl)-indan- 0.72
28.07 428.06
1 ,3-dione (LC-1)
2-[4-(3-Chloro-benzyl)-piperazin-1-yl]-2-(pyridin-4-yl)-indan- 0.74
28.08 431.96
1 ,3-dione (LC-1)
2-[4-(4-Chloro-benzyl)-piperazin-1-yl]-2-(pyridin-4-yl)-indan- 0.74
28.09 431.97
1 ,3-dione (LC-1)
2-Pyridin-4-yl-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan- 0.68
28.10 404.03
1 ,3-dione (LC-1)
2-[4-(3-Methyl-benzyl)-piperazin-1-yl]-2-(pyridin-4-yl)-indan- 0.73
28.1 1 412.06
1 ,3-dione (LC-1)
2-[4-(4-Methyl-benzyl)-piperazin-1-yl]-2-(pyridin-4-yl)-indan- 0.74
28.12 412.05
1 ,3-dione (LC-1)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(pyridin-4-yl)-indan- 0.73
28.13 431.97
1 ,3-dione (LC-1)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(pyridin-4-yl)-indan- 0.76
28.14 425.99
1 ,3-dione (LC-1) Table 29: Example 29.01- 29.07
Figure imgf000088_0001
Table 30: Example 30.01- 30.07
iR [min] LC- MS Data
Example Compound
MS Method m/z [M+H]+
2-(4-Benzyl-piperazin-1-yl)-2-(6-bromo-pyridin-2-yl)-indan-1 ,3- 0.85
30.01 475.96 dione (LC-1)
2-(6-Bromo-pyridin-2-yl)-2-(4-cyclohexylmethyl-piperazin-1-yl)- 0.87
30.02 483.94 indan-1 ,3-dione (LC-1)
2-(6-Bromo-pyridin-2-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]- 0.90
30.03 503.99 indan-1 ,3-dione (LC-1)
2-(6-Bromo-pyridin-2-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]- 0.87
30.04 489.88 indan-1 ,3-dione (LC-1)
2-(6-Bromo-pyridin-2-yl)-2-[4-(3-methoxy-benzyl)-piperazin-1- 0.86
30.05 508.02 yl]-indan-1 ,3-dione (LC-1)
2-(6-Bromo-pyridin-2-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1- 0.88
30.06 508.03 yl]-indan-1 ,3-dione (LC-1) 2-(6-Bromo-pyridin-2-yl)-2-[4-(2-chloro-benzyl)-piperazin-1-yl]- 0.86
30.07 511.89 indan-1 ,3-dione (LC-1)
Table 31: Example 31.01- 31.17
tR [min]
MS Data
Example Compound LC-MS
m/z [M+H]+ Method
2-(4-Benzyl-piperazin-1-yl)-2-(6-ethyl-pyridin-2-yl)-indan-1 ,3- 0.85
31.01 426.03 dione (LC-1)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(6-ethyl-pyridin-2-yl)- 0.89
31.02 432.10 indan-1 ,3-dione (LC-1)
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(6-ethyl- 0.86
31.03 470.06 pyridin-2-yl)-indan-1 ,3-dione (LC-1)
2-(6-Ethyl-pyridin-2-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]- 0.88
31.04 440.09 indan-1 ,3-dione (LC-1)
2-(6-Ethyl-pyridin-2-yl)-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]- 0.87
31.05 456.09 indan-1 ,3-dione (LC-1)
2-(6-Ethyl-pyridin-2-yl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]- 0.86
31.06 456.11 indan-1 ,3-dione (LC-1)
2-(6-Ethyl-pyridin-2-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]- 0.88
31.07 456.09 indan-1 ,3-dione (LC-1)
2-[4-(3-Chloro-benzyl)-piperazin-1-yl]-2-(6-ethyl-pyridin-2-yl)- 0.88
31.08 460.09 indan-1 ,3-dione (LC-1)
2-[4-(4-Chloro-benzyl)-piperazin-1-yl]-2-(6-ethyl-pyridin-2-yl)- 0.88
31.09 460.02 indan-1 ,3-dione (LC-1)
2-(6-Ethyl-pyridin-2-yl)-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)- 0.72
31.10 426.83 indan-1 ,3-dione (LC-1)
2-(6-Ethyl-pyridin-2-yl)-2-(4-thiophen-2-ylmethyl-piperazin-1- 0.84
31.1 1 431.98 yl)-indan-1 ,3-dione (LC-1)
2-(6-Ethyl-pyridin-2-yl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]- 0.89
31.12 440.06 indan-1 ,3-dione (LC-1)
2-(6-Ethyl-pyridin-2-yl)-2-[4-(4-methyl-benzyl)-piperazin-1-yl]- 0.88
31.13 440.06 indan-1 ,3-dione (LC-1) 2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(6-ethyl-pyridin-2-yl)- 0.87
31.14 460.05 indan-1 ,3-dione (LC-1)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(6-ethyl-pyridin-2-yl)- 0.91
31.15 454.09 indan-1 ,3-dione (LC-1)
2-(6-Ethyl-pyridin-2-yl)-2-[4-(5-fluoro-2-methyl-benzyl)- 0.89
31.16 457.96 piperazin-1 -yl]-indan-1 ,3-dione (LC-1)
2-[4-(2,5-Dimethyl-benzyl)-piperazin-1-yl]-2-(6-ethyl-pyridin-2- 0.91
31.17 454.09 yl)-indan-1 ,3-dione (LC-1)
Table 32: Example 32.01- 32.07
Figure imgf000090_0001
indan-1 ,3-dione (LC-1)
Table 33: Example 33.01- 33.07
fR [min] LC- MS Data
Example Compound
MS Method m/z [M+H]+
2-(4-Benzyl-piperazin-1-yl)-2-(5-bromo-pyridin-3-yl)-indan-1 ,3- 0.82
33.01 477.94 dione (LC-1) 2-(5-Bromo-pyridin-3-yl)-2-(4-cyclohexylmethyl-piperazin-1-yl)- 0.86
33.02 484.04 indan-1 ,3-dione (LC-1)
2-(5-Bromo-pyridin-3-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]- 0.88
33.03 504.01 indan-1 ,3-dione (LC-1)
2-(5-Bromo-pyridin-3-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]- 0.85
33.04 491.97 indan-1 ,3-dione (LC-1)
2-(5-Bromo-pyridin-3-yl)-2-[4-(3-methoxy-benzyl)-piperazin-1- 0.84
33.05 508.01 yl]-indan-1 ,3-dione (LC-1)
2-(5-Bromo-pyridin-3-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1- 0.85
33.06 508.03 yl]-indan-1 ,3-dione (LC-1)
2-(5-Bromo-pyridin-3-yl)-2-[4-(2-chloro-benzyl)-piperazin-1-yl]- 0.86
33.07 511.95 indan-1 ,3-dione (LC-1)
Table 34: Example 34.01- 34.14
* [min]
MS Data
Example Compound LC-MS
m/z [M+H]+ Method
2-(4-Benzyl-piperazin-1-yl)-2-quinolin-4-yl-indan-1 ,3-dione 0.83
34.01 448.05
(LC-1)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-quinolin-4-yl-indan- 0.86
34.02 454.12
1 ,3-dione (LC-1)
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-quinolin-4- 0.84
34.03 492.08 yl-indan-1 ,3-dione (LC-1)
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-quinolin-4-yl-indan- 0.85
34.04 462.12
1 ,3-dione (LC-1)
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-quinolin-4-yl-indan- 0.85
34.05 478.09
1 ,3-dione (LC-1)
2-[4-(4-Methoxy-benzyl)-piperazin-1-yl]-2-quinolin-4-yl-indan- 0.85
34.06 478.08
1 ,3-dione (LC-1)
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-quinolin-4-yl-indan- 0.86
34.07 478.07
1 ,3-dione (LC-1)
2-[4-(3-Chloro-benzyl)-piperazin-1-yl]-2-quinolin-4-yl-indan- 0.87
34.08 482.01
1 ,3-dione (LC-1) 2-[4-(4-Chloro-benzyl)-piperazin-1-yl]-2-quinolin-4-yl-indan- 0.87
34.09 481.99
1 ,3-dione (LC-1)
2-(4-Pyridin-4-ylmethyl-piperazin-1-yl)-2-quinolin-4-yl-indan- 0.69
34.10 449.16
1 ,3-dione (LC-1)
2-Quinolin-4-yl-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan- 0.81
34.11 454.07
1 ,3-dione (LC-1)
2-[4-(3-Methyl-benzyl)-piperazin-1-yl]-2-quinolin-4-yl-indan- 0.86
34.12 462.08
1 ,3-dione (LC-1)
2-[4-(4-Methyl-benzyl)-piperazin-1-yl]-2-quinolin-4-yl-indan- 0.87
34.13 462.08
1 ,3-dione (LC-1)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-quinolin-4-yl-indan- 0.86
34.14 481.94
1 ,3-dione (LC-1)
The following 2-bromo-2-heteroaryl-indan-1 ,3-dione derivatives are prepared according to a procedure adapted from Tanemura, K. et al., Chem. Commun. 2004, 470-476 by brominating the corresponding 2-heteroaryl-indan- 1 ,3-dione derivatives with NBS and are used without any further purification as crude products in the next step: 2-bromo-2-pyridin-2-yl-indan-1 ,3-dione, 2-bromo-2-pyridin-3-yl-indan-1 ,3-dione, 2-bromo-2-pyridin-4-yl-indan- 1 ,3-dione, 2-bromo-2-(6-chloro-pyridin-2-yl)-indan-1 ,3-dione, 2-bromo-2-(6-bromo-pyridin-2-yl)-indan-1 ,3-dione, 2-bromo-2-(6-ethyl-pyridin-2-yl)-indan-1 ,3-dione, 2-bromo-2-(6-ethoxy-pyridin-2-yl)-indan-1 ,3-dione, 2-bromo-2- (5-bromo-pyridin-3-yl)-indan-1 ,3-dione, 2-bromo-2-quinolin-4-yl-indan-1 ,3-dione.
The following 2-heteroaryl-indan-1 ,3-dione derivatives are commercially available; or are prepared according to an adapted procedure from C. G. Thomson ef a/., Bioorg. Med. Chem. Letters 2006, 16(5), 1388-1391 , from their respective heteroaryl-acetic acid derivative and phthalic anhydride in AC2O in the presence of NEt.3 at reflux, followed by treatment with NaOMe in MeOH at reflux; or are prepared by the procedure from J. E. Wolfe ef a/., J. Org. Chem. 2004, 2006-10 from their respective commerically available methyl-substituted heteroaryl precursor and diethyl phthalate in the presence of NaH in refluxing DME: 2-pyridin-2-yl-indan-1 ,3-dione, 2- pyridin-3-yl-indan-1 ,3-dione, 2-pyridin-4-yl-indan-1 ,3-dione, 2-(6-chloro-pyridin-2-yl)-indan-1 ,3-dione, 2-(6-ethyl- pyridin-2-yl)-indan-1 ,3-dione, 2-quinolin-4-yl-indan-1 ,3-dione.
2-(6-Bromo-p yridin-2-yl) -indan- 1.3-dione
NaH (60% in mineral oil, 2.0 g) is suspended under argon in dry DME (80 mL) in a three-necked flask equipped with a magnetic stirrer and a reflux condenser and heated to reflux in an oil bath. A soln. of 2-bromo-6-methyl- pyridine (1.72 g) and diethyl phthalate (2.8 mL) in DME (20 mL) is added dropwise over 20 min. H2 gas evolves, and the reaction mixture turns from white to orange. The reaction mixture is continued to stir at reflux for 52 h, then, is cooled in an ice-water bath. Et^O (50 mL) is added, followed by dropwise addition of AcOH (1.5 mL) yielding a yellow precipitate. The stirred suspension is diluted with water (100 mL) and additional AcOH (1.5 mL) is added. The precipitate is filtered off, washed with Et^O and water. The crude solid is suspended in EtOH (30 mL), filtered off and dried to give desired subtitle compound as a yellow powder: fR (LC-1) 0.93; ESI-MS: m/z 303.75 [M+H]+; Ή NMR (DMSO- cfe): δ 7.42 (d, J = 7.5, 1 H), 7.57 (m, 3 H), 7.60 (m, 2 H), 7.93 (t, J = 8.0, 1 H), 8.26 (d, J = 8.8, 1 H).
2-(6-Ethoxy-p yridin-2- yl) -indan- 1,3-dione
The subtitle compound is prepared applying the same procedure as described above for the synthesis of 2-(6- bromo-pyridin-2-yl)-indan-1 ,3-dione, but using 2-ethoxy-6-methyl-pyridine: fR (LC-1) 0.91 ; ESI-MS: m/z 268.3 [M+H]+; Ή NMR (CDCI3; enol-tautomer) £1.53 (t, J = 7.0, 3 H), 4.30 (q, J = 7.0, 2 H), 6.22 (d, J = 8.0, 1 H), 7.50 (m, 2 H), 7.59 & 7.63 (m, 2 H), 7.75 (t, J = 8.3, 1 H), 8.05 (d, J = 8.5, 1 H), 14.73 (s).
2-(5-Bromo-p yridin-3-yl) -indan- 1 , 3-dione
The subtitle compound is prepared according to Example 4.01 (step b), but using 5-bromo-3-pyridylacetic acid: fR (LC-1) 0.74; ESI-MS: m/z 303.74 [M+H]+. 1H-NMR (DMSO-d6): £ 1.92 (s, 1 H), 7.28 (m, 2 H), 7.36 (m, 2 H), 8.24 (t, br, J = 1.8, 1 H), 9.25 (d, J = 1.8, 1 H), 9.66 (d, J = 1.5, 1 H).
By repeating the procedures described in the above-mentioned examples, using appropriate starting materials, the following Example compounds as identified in Tables 35-40 are obtained:
Table 35: Example 35.01- 35.14
fR [min] LC- MS Data
Example Compound
MS Method m/z [M+H]+
2-(4-Benzyl-piperazin-1-yl)-2-pyrazin-2-yl-indan-1 , 3-dione 0.74
35.01 399.04
(LC-1)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-pyrazin-2-yl-indan- 0.78
35.02 405.06
1 , 3-dione (LC-1)
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-pyrazin-2-yl-indan- 0.77
35.03 413.09
1 , 3-dione (LC-1)
2-[4-(3-Chloro-benzyl)-piperazin-1-yl]-2-pyrazin-2-yl-indan- 0.78
35.04 433.00
1 , 3-dione (LC-1)
2-[4-(4-Chloro-benzyl)-piperazin-1-yl]-2-pyrazin-2-yl-indan- 0.78
35.05 432.98
1 , 3-dione (LC-1)
2-[4-(3-Methyl-benzyl)-piperazin-1-yl]-2-pyrazin-2-yl-indan- 0.78
35.06 413.07
1 , 3-dione (LC-1)
2-[4-(4-methyl-benzyl)-piperazin-1-yl]-2-pyrazin-2-yl-indan- 0.78
35.07 413.04
1 , 3-dione (LC-1)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-pyrazin-2-yl-indan- 0.77
35.08 432.97
1 , 3-dione (LC-1) 2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-pyrazin-2-yl-indan-1 ,3- 0.81
35.09 426.02 dione (LC-1)
2-(4-benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-pyrazin-2- 0.75
35.10 442.93 yl-indan-1 ,3-dione (LC-1)
2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-2-pyrazin-2-yl-indan- 0.76
35.11 429.03
1 ,3-dione (LC-1)
2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-2-pyrazin-2-yl-indan- 0.75
35.12 429.05
1 ,3-dione (LC-1)
2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-2-pyrazin-2-yl-indan- 0.77
35.13 429.04
1 ,3-dione (LC-1)
2-pyrazin-2-yl-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan- 0.72
35.14 404.99
1 ,3-dione (LC-1)
Table 36: Example 36.01- 36.07
iR [min] LC- MS Data
Example Compound
MS Method m/z [M+H]+
2-(4-Benzyl-piperazin-1-yl)-2-quinoxalin-2-yl-indan-1 ,3-dione 0.84
36.01 449.05
(LC-1)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-quinoxalin-2-yl-indan- 0.87
36.02 455.13
1 ,3-dione (LC-1)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-quinoxalin-2-yl-indan- 0.89
36.03 477.10
1 ,3-dione (LC-1)
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-quinoxalin-2-yl-indan- 0.86
36.04 463.07
1 ,3-dione (LC-1)
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-quinoxalin-2-yl- 0.85
36.05 479.07 indan-1 ,3-dione (LC-1)
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-quinoxalin-2-yl- 0.86
36.06 479.08 indan-1 ,3-dione (LC-1)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-quinoxalin-2-yl-indan- 0.85
36.07 482.72
1 ,3-dione (LC-1) Table 37: Example 37.01- 37.07
Figure imgf000095_0002
Table 38: Example 38.01- 38.14
Figure imgf000095_0001
2-Benzothiazol-2-yl-2-[4-(3-chloro-benzyl)-piperazin-1-yl]- 0.89
38.07 487.89 indan-1 ,3-dione (LC-1)
2-Benzothiazol-2-yl-2-[4-(4-chloro-benzyl)-piperazin-1-yl]- 0.89
38.08 487.99 indan-1 ,3-dione (LC-1)
2-Benzothiazol-2-yl-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)- 0.73
38.10 454.95 indan-1 ,3-dione (LC-1)
2-Benzothiazol-2-yl-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)- 0.84
38.11 459.96 indan-1 ,3-dione (LC-1)
2-Benzothiazol-2-yl-2-[4-(2-chloro-benzyl)-piperazin-1-yl]- 0.88
38.12 487.91 indan-1 ,3-dione (LC-1)
2-Benzothiazol-2-yl-2-[4-(3-methyl-benzyl)-piperazin-1-yl]- 0.89
38.13 468.01 indan-1 ,3-dione (LC-1)
2-Benzothiazol-2-yl-2-[4-(4-methyl-benzyl)-piperazin-1-yl]- 0.88
38.14 468.06 indan-1 ,3-dione (LC-1)
Table 39: Example 39.01- 39.07
* [min]
MS Data
Example Compound LC-MS
m/z [M+H]+ Method
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-thiophen-3-yl-indan- 0.84
39.01 436.96
1 ,3-dione (LC-1)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-thiophen-3-yl-indan- 0.85
39.02 409.03
1 ,3-dione (LC-1)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-thiophen-3-yl-indan-1 ,3- 0.88
39.03 431.01 dione (LC-1)
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-thiophen-3-yl-indan- 0.85
39.04 417.02
1 ,3-dione (LC-1)
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-thiophen-3-yl-indan- 0.84
39.05 433.01
1 ,3-dione (LC-1)
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-thiophen-3-yl-indan- 0.83
39.06 433.01
1 ,3-dione (LC-1)
2-(4-Benzyl-piperazin-1 -yl)-2-thiophen-3-yl-indan-1 ,3-dione 0.81
39.07 403.00
(LC-1) * [min]
MS Data
Example Compound LC-MS
m/z [M+H]+ Method
2-(2,5-Dimethyl-thiazol-4-yl)-2-[4-(2-methyl-benzyl)-piperazin- 0.86
40.01 446.05
1 -yl]-indan-1 ,3-dione (LC-1)
The intermediates: 2-bromo-2-pyrazin-2-yl-indan-1 ,3-dione, 2-bromo-2-quinoxalin-2-yl-indan-1 ,3-dione, 2- bromo-2-(3-methyl-quinoxalin-2-yl)-indan-1 ,3-dione, 2-benzothiazol-2-yl-2-bromo-indan-1 ,3-dione, 2-bromo-2- thiophen-3-yl-indan-1 ,3-dione and 2-bromo-2-(2,5-dimethyl-thiazol-4-yl)-indan-1 ,3-dione are prepared according to a procedure adapted from Tanemura, K. ef a/., Chem. Commun. 2004, 470-476 by brominating the respective 2-pyrazin-2-yl-indan-1 ,3-dione, 2-quinoxalin-2-yl-indan-1 ,3-dione, and 2-(3-methyl-quinoxalin-2-yl)-indan-1 ,3- dione with NBS and are used without any further purification as crude products in the next step.
The following 2-heteroaryl-indan-1 ,3-dione derivatives are commercially available; or are prepared according to an adapted procedure from C. G. Thomson ef a/., Bioorg. Med. Chem. Letters 2006, 16(5), 1388-1391 , from their respective heteroaryl-acetic acid derivatives and phthalic anhydride in AC2O in the presence of NEt.3 at reflux, followed by treatment with NaOMe in MeOH at reflux; or are prepared by the procedure from J. E. Wolfe ef a/., J. Org. Chem. 2004, 2006-10, from their respective commercially available methyl-substituted heteroaryl precursor and diethyl phthalate in the presence of NaH in refluxing DME: 2-pyrazin-2-yl-indan-1 ,3-dione, 2- quinoxalin-2-yl-indan-1 ,3-dione, 2-(3-methyl-quinoxalin-2-yl)-indan-1 ,3-dione, 2-benzothiazol-2-yl-indan-1 ,3- dione, 2-thiophen-3-yl-indan-1 ,3-dione,
2-(2,5-Dimethyl-thiazol-4-yl)-indan-1,3-dione
The subtitle compound is prepared according to Example 4.01 (step b), but using (2,5-dimethyl-thiazol-4-yl) acetic acid: fR (LC-1) 0.71 ; ESI-MS: m/z 258.53 [M+H]+. 1H-NMR (CDCI3): 8.09 (m, 2 H), 7.92 (m, 3 H), 2.71 (m, 3 H), 2.49 (m, 3 H).
Example 41.01
2-[1-(2-Methyl-benzyl)-piperidin-4-yl]-2-phenyl-indan-1 ,3-dione
The title compound is obtained by reacting 2-phenyl-2-piperidin-4-yl-indan-1 ,3-dione hydrochloride under the conditions described for Example 1.02 or 1.03: fR (LC-1) 0.89; ESI-MS: m/z 410.05 [M+H]+. 1H-NMR (DMSO-d6): £ 1.24 (d, J = 12.3, 2 H), 1.47 (qd, J = 12.3, 3.3, 2 H), 1.89 (m, 2 H), 2.25 (s, 3 H), 2.43 (m, 1 H), 2.75 (d, J = 11.3, 2 H), 3.32 (m, 2 H), 7.12 (m, 4 H), 7.28 (m, 1 H), 7.38 (m, 4 H), 8.12 (s, 4 H)
a) 2-Phenyl-2-oioeridin-4-yl-indan-1,3-dione hydrochloride
To a stirred soln. of 4-(1 ,3-dioxo-2-phenyl-indan-2-yl)-piperidine-1-carboxylic acid ferf.-butyl ester (63 mg, 0.155 mmol) dissolved in 0.4 mL DCM is added 0.4 mL of a 4N HCI soln. in dioxane. The reaction mixture is continued to stir at r.t. for 2h. After evaporation of the solvent in vacuo the subtitle compound is obtained as an orange oil: fR (LC-1) 0.75; ESI-MS: m/z 305.98 [M-HCI]+.
b) 4-(1,3-Dioxo-2-phenyl-indan-2-yl)-piperidine-1-carboxylic acid tert.-butyl ester
As described in Grasa, G. A.; Colacot, T. J. Org. Lett. 2007, 9(26), 5489-5492, a Schlenk tube containing 4-(1 ,3- dioxo-indan-2-yl)-piperidine-1-carboxylic acid tert.-butyl ester (98 mg, 0.3 mmol), 1 ,1 '-bis(di-fert.-butylphosphino) ferrocene palladium dichloride (18 mg, 0.028 mmol, 0.092) and NaOfBu (31 mg, 0.33 mmol) is degassed and 2 mL of anhydrous, degassed dioxane are added, followed by the addition of 1 ,1 ,1-trifluoro-methanesulfonic acid phenyl ester (69.8 mg, 0.05 mL, 0.032 mmol). The reaction mixture is stirred under IS -atmosphere at 100 °C overnight, then, is cooled to r.t. and filtered. After evaporation of the solvent and FC the subtitle compound is obtained as a yellow oil: fR (LC-2) 1.10; ESI-MS: m/z 406.02 [M+H]+. 1H-NMR (DMSO-d6): £ 1.23-1.41 (m, 4 H), 1.36 (s, 9H), 2.72 (m, 3 H), 3.94 (m, 2 H), 7.31 (m, 1 H), 7.44 (m, 4 H), 8.05 (s, 4 H).
c) 4-( 3-Dioxo-indan-2-yl)-piperidine-1-carboxylic acid tert.-butyl ester
As described in Ramachary, D.B; Kishor, M.; Reddy, G. B. Org. Biomoi. Chem. 2006, 1641-1646, to a stirred soln. of indan-l,3-dione (5 g, 34.2 mmol), Boc-piperidone (6.81 g, 34.2 mmol) and 2,6-dimethyl- 1 ,4- dihydro-pyridine-3,5-dicarboxylic acid diethyl ester (8.67 g, 34.2 mmol) in DMSO (60 mL) is added DL-proline (0.79 g, 6.8 mmol). The resulting red soln. is continued to stir at r.t. over night, then, water is added. The aq. layer is separated and extracted four times with DCM. The comb. org. layer is dried over MgSO/t, filtered, and the solvent is evaporated. The residue is purified by CC to give the subtitle compound as a white powder. fR (LC-1) 0.99; ESI-MS: m/z 329.98 [M+H]+. 1H-NMR (CDCIs): £1.45 (s, 9 H), 1.56 (m, 2 H), 1.72 (m, 2 H), 2.39 (m, 1 H), 2.67 (m, 2 H), 2.94 (d, J = 4.0, 1 H), 4.14 (m, 2 H), 7.87 (m, 2 H), 8.00 (m, 2 H).
By repeating the procedures described in the above-mentioned Example 41.01 , but using 2-piperidin-4-yl-2-(3- trifluoromethyl-phenyl)-indan-1 ,3-dione hydrochloride and 2-(piperidin-4-yl)-2-(3-methyl-phenyl)-indan-1 ,3-dione dihydrochloride, the following Example compounds as identified in Table 42 are obtained:
Table 42: Example 42.01- 42.04
Figure imgf000098_0001
phenyl)-indan-1 ,3-dione (LC-1)
2-[1-(2-Ethyl-benzyl)-piperidin-4-yl]-2-(3-trifluoromethyl-phenyl)- 0.95
42.04 492.15
indan-1 ,3-dione (LC-1)
2-[1-(2-Methyl-benzyl)-piperidin-4-yl]-2-(3-methyl-phenyl)-indan- 0.81 (LC-
42.05 424.53
1 ,3-dione 1)
2-[1-(5-Fluoro-2-methyl-benzyl)-piperidin-4-yl]-2-(3-methyl- 0.82 (LC-
42.06 442.54
phenyl)-indan-1 ,3-dione 1) a) 2-Piperidin-4-yl-2-(3-trifluoromethyl-phenyl)-indan-1,3-dione hydrochloride and 2-(piperidin-4-yl)-2-(3-methyl- phenyfl-indan-1 ,3-dione dihydrochloride
are obtained after treating respectively 4-[1 ,3-dioxo-2-(3-trifluoromethyl-phenyl)-indan-2-yl]-piperidine-1- carboxylic acid fert. -butyl ester and 4-[1 ,3-dioxo-2-(3-methyl-phenyl)-indan-2-yl]-piperidine-1-carboxylic acid fe/t-butyl ester with 4N HCI in AcOEt, as described above for Example 41.01.
Analytical data of the free base of: 2-piperidin-4-yl-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione hydrochloride: fR (LC-1) 0.80; ESI-MS: m/z 374.01 [M+H]+. 2-(piperidin-4-yl)-2-(3-methyl-phenyl)-indan-1 ,3-dione dihydrochloride: fR (LC-1) 0.67; ESI-MS: m/z 320.47 [M+H]+. b) 4-[1,3-Dioxo-2-(3-trifluoromethyl-ohenyl)-indan-2^ acid tert.-butyi ester and 4-(1,3- Dioxo-2-[3-methylphenyll-indan-2-yl)-piperidine-1-carboxylic acid tert-butyl ester
are prepared as described above for Example 40.01 by reacting 4-(1 ,3-dioxo-indan-2-yl)-piperidine-1-carboxylic acid fe/t-butyl ester with 1 ,1 ,1-trifluoro-methanesulfonic acid 3-(trifluoromethyl)phenyl ester and 1 ,1 ,1 -trifluoro- methanesulfonic acid 3-methylphenyl ester repectively in the presence of 1 ,1 '-bis(di-fe/t- butylphosphino)ferrocene palladium dichloride and NaOfBu in anhydrous dioxane.
Analytical data of 4-[1 ,3-Dioxo-2-(3-trifluoromethyl-phenyl)-indan-2-yl]-piperidine-1-carboxylic acid tert.-butyl ester: fR (LC-2) 1.14; ESI-MS: m/z 474.05 [M+H]+; 1H-NMR (DMSO-d6): 1.31 (m, 2 H), 1.44 (m, 9 H), 1.58 (m, 2 H), 2.59 (m, 3 H), 4.10 (bs, 2H), 7.48 (t, J = 7.8, 1 H), 7.56 (m, 1 H), 7.83 (m, 2 H), 7.91 (m, 2 H), 8.04 (dd, J = 5.5, 3.0, 2 H).
Analytical data of 4-(1 ,3-dioxo-2-[3-methylphenyl]-indan-2-yl)-piperidine-1-carboxylic acid ferf-butyl ester:
fR (LC-1) 1.02; ESI-MS: m/z 420.51 [M+H]+
Example 43.01
2-(4-Benzyl-piperazin-1-yl)-2-phenyl-indan-1-one
Applying the conditions described for the synthesis of Example 1.01 , 2-bromo-2-phenyl-indan-1-one (0.061 mmol) in dioxane is treated with 1-benzyl-piperazine (0.067 mmol) in the presence of NEt (0.073 mmol) to give the title compound: fR (LC-1) 0.83; ESI-MS: m/z 383.25 [M+H]+; 1H-NMR (CDCI3): & 2.57 (m, 8 H), 3.42 (d, J = 17.3, 1 H), 3.56 (m, 2 H), 3.70 (d, J = 17.6, 1 H), 7.26 (m, 8 H), 7.38 (t, J = 7.3, 1 H), 7.56 (d, J = 8.8, 3 H), 7.68 (m, 2 H).
(R)-2-(4-benzyl-piperazin-1-yl)-2-phenyl-indan-1-one and (S)-2-(4-benzyl-piperazin-1-yl)-2-phenyl-indan-1- one
The two enantiomers of 2-(4-benzyl-piperazin-1 -yl)-2-phenyl-indan-1 -one (Example 43.01) are separated by chiral prep. LC-MS (D). Conditions: ChiralPak AD-H column, Eluent A: /PrOH with 0.1 % DEA, Eluent B: Hexane. Isocratic conditions (85%B).
Example 43.01A: Enantiomer A: fR (LC-6) 9.43.
Example 43.01 B: Enantiomer B: fR (LC-6) 10.93.
2-Bromo-2-phenyl-indan-1-one
The subtitle compound is prepared according to the procedure described for the synthesis of Example 4.01 by brominating 2-phenyl-indan-1-one with NBS: fR (LC-1) 1.03; ESI-MS: m/z 288.74 [M+H]+. 1H-NMR (DMSO-d6): S 4.10 (d, J = 18.6, 1 H), 4.23 (d, J = 18.3, 1 H), 7.37 (m, 1 H), 7.43 ( = 7.3, 2 H), 7.55 (t, J = 7.5, 1 H), 7.64 (d, J = 7.5, 1 H), 7.82 (m, 4 H).
As described in the procedures for above-mentioned Example 43.01 , the following Example compounds as identified in Table 43 and Table 44 are obtained by reacting 2-bromo-2-phenyl-indan-1-one with the appropriate piperazine derivative in the presence of NEt3:
Table 43: Example 43.02- 43.10
fR [min] LC- MS Data
Example Compound
MS Method m/z [M+H]+
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-phenyl- 0.85
43.02 427.11
indan-1-one (LC-1)
2-(4-Cyclohexylmethyl-piperazin-1 -yl)-2-phenyl-indan-1 -one 0.87
43.03 389.29
(LC-1)
2-Phenyl-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)-indan-1-one 0.77
43.04 384.26
(LC-1)
2-(4-Naphthalen-1-ylmethyl-piperazin-1-yl)-2-phenyl-indan-1- 0.87
43.05 433.26
one (LC-1)
2-(4-Cyclopropylmethyl-piperazin-1-yl)-2-phenyl-indan-1-one 0.79
43.06 347.22
(LC-1)
2-Phenyl-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-indan-1-one 0.69
43.07 384.26
(LC-1) 2-Phenyl-2-(4-pyridin-3-ylrnethyl-piperazin-1-yl)-indan-1-one 0.71
43.08 384.25
(LC-1)
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one 0.85
43.09 413.09
(LC-1)
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one 0.86
43.10 397.08
(LC-1)
(R)-2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-phenyl-indan-1-one and (S)-2-(4-benzo[1,3]dioxol- 5-ylmethyl-piperazin-1-yl)-2-phenyl-indan-1-one
The two enantiomers of 2-(4-benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1 -yl)-2-phenyl-indan-1 -one (Example 43.02) are separated by chiral prep. LC-MS (D). Conditions: ChiralPak IA column, Eluent A: EtOH with 0.1 % DEA, Eluent B: Hexane. Isocratic conditions (50%B).
Example 43.02A: Enantiomer A: fR (LC-7) 12.86.
Example 43.02B: Enantiomer B: fR (LC-7) 16.41.
(R)-2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-phenyl-indan-1-one and (S)-2-(4-cyclohexylmethyl-piperazin- 1-yl)-2-phenyl-indan-1-one
The two enantiomers of 2-(4-cyclohexylmethyl-piperazin-1 -yl)-2-phenyl-indan-1 -one (Example 43.03) are separated by chiral prep. LC-MS (D). Conditions: ChiralPak AD-H column, Eluent A: /PrOH with 0.1 % DEA, Eluent B: Hexane. Isocratic conditions (95%B).
Example 43.03A: Enantiomer A: fR (LC-8) 8.56.
Example 43.03B: Enantiomer B: fR (LC-8) 11.03.
Table 44: Example 44.01- 44.03
Figure imgf000101_0001
As described in the procedures for above-mentioned Example 43.01 , the following Example compounds identified in Table 45-52 are obtained by reacting a 2-bromo-2-phenyl-indan-1-one analogue bearing substituent at position 4, 5, 6 or 7 with the appropriate piperazine derivative in the presence of NEt3: Table 45: Example 45.01- 45.07
Figure imgf000102_0002
Table 46: Example 46.01- 46.11
Figure imgf000102_0001
5-Fluoro-2-[4-(4-methyl-benzyl)-piperazin-1-yl]-2-phenyl- 1.11
46.06 415.09 indan-1-one (LC-4)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-5-fluoro-2-phenyl- 1.15
46.07 435.13 indan-1-one (LC-4)
2-(4-Benzyl-piperazin-1-yl)-5-bromo-2-phenyl-indan-1-one 0.89
46.08 461.00
(LC-1)
5-Methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl- 0.89
46.09 410.96 indan-1-one (LC-1)
2-(4-Benzyl-piperazin-1-yl)-5-methyl-2-phenyl-indan-1-one 0.87
46.10 397.08
(LC-1)
2-(4-Benzyl-piperazin-1-yl)-5-methoxy-2-phenyl-indan-1-one 0.85
46.11 413.06
(LC-1)
Table 47: Example 47.01- 47.22
iR [min]
MS Data
Example Compound LC-MS
m/z [M+H]+ Method
2-(4-Benzyl-piperazin-1-yl)-6-fluoro-2-phenyl-indan-1-one 1.08
47.01 401.10
(LC-4)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-6-fluoro-2-phenyl- 1.34
47.02 407.14 indan-1-one (LC-4)
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1-yl)-6-fluoro-2- 1.04
47.03 445.07 phenyl-indan-1-one (LC-4)
6-Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl- 1.16
47.04 415.14 indan-1-one (LC-4)
6-Fluoro-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-2-phenyl- 1.06
47.05 431.09 indan-1-one (LC-4)
6-Fluoro-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-2-phenyl- 1.05
47.06 431.20 indan-1-one (LC-4)
6-Fluoro-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-2-phenyl- 1.07
47.07 431.09 indan-1-one (LC-4)
2-[4-(3-Chloro-benzyl)-piperazin-1-yl]-6-fluoro-2-phenyl- 1.14
47.08 435.06 indan-1-one (LC-4) 2-[4-(4-Chloro-benzyl)-piperazin-1-yl]-6-fluoro-2-phenyl- 1.14
435.07 indan-1-one (LC-4)
6-Fluoro-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-2-phenyl- 1.12
415.12 indan-1-one (LC-4)
6-Fluoro-2-[4-(4-methyl-benzyl)-piperazin-1-yl]-2-phenyl- 1.12
415.09 indan-1-one (LC-4)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-6-fluoro-2-phenyl- 1.15
435.07 indan-1-one (LC-4)
6-Methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl- 0.89
411.06 indan-1-one (LC-1)
2-(4-Benzyl-piperazin-1-yl)-6-methyl-2-phenyl-indan-1-one 0.87
397.04 (LC-1)
6-Methoxy-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-2-phenyl- 0.89
427.28 indan-1-one (LC-1)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-6-methoxy-2-phenyl- 0.91
441.09 indan-1-one (LC-1)
6-Methoxy-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-2-phenyl- 0.88
443.61 indan-1-one (LC-1)
6-Methoxy-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-2-phenyl- 0.89
443.65 indan-1-one (LC-1)
6-Methoxy-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl- 0.89
426.93 indan-1-one (LC-1)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-6-methoxy-2-phenyl- 0. 90
419.46 indan-1-one (LC-1)
2-(4-Benzyl-piperazin-1-yl)-6-methoxy-2-phenyl-indan-1-one 0.87
413.68 (LC-1)
2-(4-Benzyl-piperazin-1-yl)-6-bromo-2-phenyl-indan-1-one 1.15
461.03 (LC-4) Table 48: Example 48.01- 48.11
Figure imgf000105_0001
The following 2-bromo-2-phenyl-indan-1-one derivatives bearing a substituent at position 4, 5, 6 or 7 are prepared from the respective phenyl-indan-1-one derivatives according to the brominating conditions described for Example 43.01 :
2-Bromo-2-phenyl-indan-1-one derivative fR [min] LC-MS MS Data m/z substituted at position 4, 5, 6 or 7 Method [M+H]+
2-Bromo-4-methyl-2-phenyl-indan-1-one 1.14 (LC-1) 302.79
2,4-Dibromo-2-phenyl-indan-1-one 1.09 (LC-1) n. a. 2-Bromo-5-fluoro-2-phenyl-indan-1-one 1.11 (LC-1) 306.76
2-Bromo-5-methyl-2-phenyl-indan-1-one 1.06 (LC-1) 302.8
2,5-Dibromo-2-phenyl-indan-1-one 1.08 (LC-1) n. a.
2-Bromo-5-methoxy-2-phenyl-indan-1-one 1.03 (LC-1) 318.78.
2-Bromo-6-fluoro-2-phenyl-indan-1-one 1.12 (LC-1) 306.64
2-Bromo-6-methyl-2-phenyl-indan-1-one 1.06 (LC-1) 302.65
2,6-Dibromo-2-phenyl-indan-1-one 1.08 (LC-1) n. a.
2-Bromo-6-methoxy-2-phenyl-indan-1-one 1.05 (LC-1) 318.75
2-Bromo-7-methyl-2-phenyl-indan-1-one 1.14 (LC-1) 302.76
2-Bromo-7-methoxy-2-phenyl-indan-1-one 1.00 (LC-1) 318.96
The following 2-phenyl-indan-1-one derivatives bearing a substituent at position 4, 5, 6 or 7 are prepared according to a known procedure by A. S. Hussey and R. R. Herr, J. Org. Chem. 1959, 24, 843-845: In brief, 2- chloro-indan-1-one (5.4 mmol), appropriately substituted at position 4, 5, 6 or 7, is treated with 1 M phenylmagnesium bromide soln. (7.6 mmol) in THF / toluene to give the respectively substituted 2-phenyl-indan- 1-one:
2-Phenyl-indan-1-one derivative fR [min] LC-MS MS Data m/z substituted at position 4, 5, 6 or 7 Method [M+H]+
4-Methyl-2-phenyl-indan-1 -one 1.06 (LC-1) 222.99
4-Bromo-2-phenyl-indan-1-one 0.94 (LC-1) n. a.
5-Fluoro-2-phenyl-indan-1 -one 1.02 (LC-1) 266.96
5-Methyl-2-phenyl-indan-1 -one 1.00 (LC-1) 222.99
5-Bromo-2-phenyl-indan-1 -one 1.04 (LC-1) 288.87
5-Methoxy-2-phenyl-indan-1 -one 0.97 (LC-1) 238.99
6-Fluoro-2-phenyl-indan-1 -one 1.03 (LC-1) 226.94
6-Methyl-2-phenyl-indan-1 -one 1.01 (LC-1) 222.99
6-Bromo-2-phenyl-indan-1 -one 1.03 (LC-1) 288.90
6-Methoxy-2-phenyl-indan-1 -one 0.99 (LC-1) 239.01
7-Methyl-2-phenyl-indan-1 -one 1.09 (LC-1) 222.99
7-Methoxy-2-phenyl-indan-1 -one 0.93 (LC-1) 239.10 The following 2-chloro-indan-1 -one derivatives bearing a substituent at position 4, 5, 6 or 7 are prepared following a method adapted from a known procedure by A. S. Hussey and R. R. Herr, J. Org. Chem. 1959, 24, 843-845: In brief, indan-1-one (32.6 mmol) appropriately substituted at position 4, 5, 6 or 7 is chlorinated in glacial AcOH in the presence of NCS (35.9 mmol) to give the respectively substituted 2-chloro-indan-1-one:
Figure imgf000107_0001
Applying the same procedures as described for above-mentioned Example 43.01 , the following Example compounds as identified in Tables 49-51 are obtained by reacting a 2-bromo-2-phenyl-indan-1-one derivative with the appropriate piperazine derivative in the presence of NEt3:
Table 49: Example 49.01- 49.05
fR [min] LC-MS MS Data
Example Compound
Method m/z [M+H]+
2-(2-Cyclohexylmethyl-piperazin-1-yl)-2-(2-methyl- 0.92
49.01 403.15
phenyl)-indan-1-one (LC-1)
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(2-methyl- 0.90
49.02 410.98
phenyl)-indan-1-one (LC-1)
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(2-methyl- 0.91
49.03 427.05
phenyl)-indan-1-one (LC-1) 2-(4-Benzyl-piperazin-1-yl)-2-(2-methoxy-phenyl)- 0.87
49.04 413.07 indan-1-one (LC-1)
2-(2-Methoxy-phenyl)-2-[4-(2-methyl-benzyl)-piperazin- 0.88
49.05 426.88
1-yl]-indan-1-one (LC-1)
Table 50: Example 50.01- 50.23
iR [min] LC- MS Data
Example Compound
MS Method m/z [M+H]+
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-methyl-phenyl)- 1.18
50.01 411.17 indan-1-one (LC-4)
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(3- 1.06
50.02 441.12 methyl-phenyl)-indan-1 -one (LC-4)
2-[4-(3-Methyl-benzyl)-piperazin-1-yl]-2-(3-methyl-phenyl)- 1.15
50.03 411.15 indan-1-one (LC-4)
2-[4-(4-Methyl-benzyl)-piperazin-1-yl]-2-(3-methyl-phenyl)- 1.14
50.04 411.16 indan-1-one (LC-4)
2-(4-Benzyl-piperazin-1-yl)-2-(3-methyl-phenyl)-indan-1- 1.1
50.05 397.22 one (LC-4)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-methyl-phenyl)- 1.39
50.06 403.39 indan-1-one (LC-4)
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methyl- 1.08
50.07 427.01 phenyl)-indan-1-one (LC-4)
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methyl- 1.09
50.08 427.01 phenyl)-indan-1-one (LC-4)
2-(4-Benzyl-piperazin-1-yl)-2-(3-methoxy-phenyl)-indan-1- 0.82
50.09 413.07 one (LC-1)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-methoxy- 0.86
50.10 418.96 phenyl)-indan-1-one (LC-1)
2-(3-Methoxy-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1- 0.84
50.11 426.95 yl]-indan-1-one (LC-1)
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methoxy- 0.85
50.12 443.07 phenyl)-indan-1-one (LC-1)
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methoxy- 0.83
50.13 442.83 phenyl)-indan-1-one (LC-1) 2-(3-Methoxy-phenyl)-2-[4-(4-methyl-benzyl)-piperazin-1- 0.85
50.14 426.94
yl]-indan-1-one (LC-1)
2-(4-Benzyl-piperazin-1-yl)-2-(3-fluoro-phenyl)-indan-1- 0.87
50.15 401.07
one (LC-1)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-fluoro-phenyl)- 0.90
50.16 406.58
indan-1-one (LC-1)
2-(3-Fluoro-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]- 0.89
50.17 415.05
indan-1-one (LC-1)
2-(3-Fluoro-phenyl)-2-[4-(2-methoxy-benzyl)-piperazin-1- 0.88
50.18 431.03
yl]-indan-1-one (LC-1)
2-(3-Fluoro-phenyl)-2-[4-(3-methoxy-benzyl)-piperazin-1- 0.88
50.19 431.04
yl]-indan-1-one (LC-1)
2-(3-Fluoro-phenyl)-2-[4-(4-methyl-benzyl)-piperazin-1-yl]- 0.89
50.20 415.18
indan-1-one (LC-1)
2-(4-Benzyl-piperazin-1-yl)-2-(3-isopropyl-phenyl)-indan-1- 0.92
50.21 425.06
one (LC-1)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-isopropyl- 0.95
50.22 431.12
phenyl)-indan-1-one (LC-1)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-ethyl-phenyl)- 0.95
50.23 417.14
indan-1-one (LC-1)
(R)-2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-methyl-phenyl)-indan-1-one and (S)-2-[4-(2-Methyl-benzyl)- piperazin-1-yl]-2-(3-methyl-phenyl)-indan-1-one
The two enantiomers of 2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-(3-methyl-phenyl)-indan-1-one (Example 50.01) are separated by chiral prep. LC-MS (D). Conditions: ChiralPak AD-H column, Eluent A: /PrOH with 0.1 % DEA, Eluent B: Hexane. Isocratic conditions (90%B).
Example 50.01A: Enantiomer A: fR (LC-9) 7.33.
Example 50.01B: Enantiomer B: fR (LC-9) 8.53.
Table 51: Example 51.01- 51.10
fR [min] LC- MS Data
Example Compound
MS Method m/z [M+H]+
2-(4-Benzyl-piperazin-1-yl)-2-(4-fluoro-phenyl)-indan-1- 0.85
51.01 400.49
one (LC-1) 2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(4-fluoro-phenyl)- 0.89
51.02 406.54
indan-1-one (LC-1)
2-(4-Fluoro-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]- 0.87
51.03 414.52
indan-1-one (LC-1)
2-(4-Fluoro-phenyl)-2-[4-(3-methoxy-benzyl)-piperazin-1- 0.87
51.04 430.52
yl]-indan-1-one (LC-1)
2-(4-Fluoro-phenyl)-2-[4-(4-methyl-benzyl)-piperazin-1-yl]- 0.88
51.05 414.52
indan-1-one (LC-1)
2-(4-Benzyl-piperazin-1-yl)-2-(4-methyl-phenyl)-indan-1- 0.87
51.06 397.11
one (LC-1)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(4-methyl- 0.90
51.07 403.15
phenyl)-indan-1-one (LC-1)
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(4-methyl-phenyl)- 0.89
51.08 410.95
indan-1-one (LC-1)
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(4-methyl- 0.89
51.09 426.88
phenyl)-indan-1-one (LC-1)
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(4-methyl- 0.88
51.10 427.03
phenyl)-indan-1-one (LC-1)
The following 2-bromo-2-phenyl-indan-1-one derivatives are prepared from their respective 2-phenyl-indan-1- one derivatives according to the brominating conditions as described for Example 43.01 :
fR [min] LC-MS MS Data m/z
2-Bromo-2-phenyl-indan-1-one derivative
Method [M+H]+
2-Bromo-2-(2-methyl-phenyl)-indan-1-one 1.12 (LC-1) 302.87
2-Bromo-2-(2-methoxy-phenyl)-indan-1-one 0.99 (LC-1) 318.82
2-Bromo-2-(3-methyl-phenyl)-indan-1-one 1.14 (LC-1) 302.72
2-Bromo-2-(3-methoxy-phenyl)-indan-1-one 1.09 (LC-1) 318.67
2-Bromo-2-(3-fluoro-phenyl)-indan-1-one 1.11 (LC-1) 306.75
2-Bromo-2-(3-ethyl-phenyl)-indan-1-one 1.08 (LC-1) 316.67
2-Bromo-2-(3-isopropyl-phenyl)-indan-1-one 1.11 (LC-1) 330.91
2-Bromo-2-(4-methyl-phenyl)-indan-1-one 0.93 (LC-1) 301.90
2-Bromo-2-(4-fluoro-phenyl)-indan-1-one 1.11 (LC-1) 306.49 The following 2-phenyl-indan-1-one derivatives are prepared according to a known procedure from A. S. Hussey and R. R. Herr, J. Org. Chem. 1959, 24, 843-845: 2-chloro-indan-1-one (16.6 mmol) is treated with a 1 M soln. of the corresponding (commercial or freshly prepared) phenyl-magnesium bromide derivative (23.3 mmol) in THF / toluene to give the respective 2-phenyl-indan-1-one derivative:
Figure imgf000111_0001
Applying the same procedures as described for above-mentioned Example 43.01 , the following Example compounds as identified in Table 52 are obtained by reacting a 2-bromo-5-methyl-2-phenyl-indan-1-one derivative with the appropriate piperazine derivative in the presence of NEk:
Table 52: Examples 52.01- 52.20
fR [min] LC- MS Data
Example Compound
MS Method m/z [M+H]+
2-(4-Cyclohexylmethyl-piperazin-1-yl)-5-methyl-2-(3-methyl- 0.93
52.01 417.09
phenyl)-indan-1 -one (LC-1)
5-Methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-(3-methyl- 0.92
52.02 425.06
phenyl)-indan-1 -one (LC-1)
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-5-methyl-2-(3-methyl- 0.92
52.03 441.07
phenyl)-indan-1 -one (LC-1)
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-5-methyl-2-(3-methyl- 0.91
52.04 441.06
phenyl)-indan-1 -one (LC-1)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-5-methyl-2-(3-methyl- 0.94
52.05 439.08
phenyl)-indan-1 -one (LC-1) 5-Methyl-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-2-(3-methyl- 0.92
52.06 425.10
phenyl)-indan-1 -one (LC-1)
2-(4-Benzyl-piperazin-1-yl)-2-(3-fluoro-phenyl)-5-methyl- 0.89
52.07 415.04
indan-1-one (LC-1)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-fluoro-phenyl)-5- 0.92
52.08 421.13
methyl-indan-1-one (LC-1)
2-(3-Fluoro-phenyl)-5-methyl-2-[4-(2-methyl-benzyl)- 0.91
52.09 429.06
piperazin-1 -yl]-indan-1 -one (LC-1)
2-(3-Fluoro-phenyl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]- 0.91
52.10 445.08
5-methyl-indan-1-one (LC-1)
2-(3-Fluoro-phenyl)-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]- 0.90
52.11 445.15
5-methyl-indan-1-one (LC-1)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-5- 0.93
52.12 443.66
methyl-indan-1-one (LC-1)
2-(3-Fluoro-phenyl)-5-methyl-2-[4-(3-methyl-benzyl)- 0.92
52.13 429.05
piperazin-1 -yl]-indan-1 -one (LC-1)
2-(4-Benzyl-piperazin-1-yl)-2-(3-ethyl-phenyl)-5-methyl-indan- 0.92
52.14 425.10
1-one (LC-1)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-ethyl-phenyl)-5- 0.95
52.15 431.16
methyl-indan-1-one (LC-1)
2-(3-Ethyl-phenyl)-5-methyl-2-[4-(2-methyl-benzyl)-piperazin- 0.94
52.16 439.06
1-yl]-indan-1-one (LC-1)
2-(3-Ethyl-phenyl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-5- 0.94
52.17 455.05
methyl-indan-1-one (LC-1)
2-(3-Ethyl-phenyl)-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-5- 0.93
52.18 455.13
methyl-indan-1-one (LC-1)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-ethyl-phenyl)-5- 0.97
52.19 453.01
methyl-indan-1-one (LC-1)
2-(3-Ethyl-phenyl)-5-methyl-2-[4-(3-methyl-benzyl)-piperazin- 0.94
52.20 439.10
1-yl]-indan-1-one (LC-1)
The following 2-bromo-5-methyl-2-phenyl-indan-1-one derivatives are prepared from the respective 5-methyl-2- phenyl-indan-1-one derivatives according to the brominating conditions described for Example 43.01 : iR [min] LC-MS MS Data m/z
2-Bromo-5-methyl-2-phenyl-indan-1-one derivative
Method [M+H]+
2-Bromo-5-methyl-2-(3-methyl-phenyl)-indan-1-one 0.94 (LC-1) n. a.
2-Bromo-2-(3-fluoro-phenyl)-5-methyl-indan-1-one 1.07 (LC-1) 320.83
2-Bromo-2-(3-ethyl-phenyl)-5-methyl-indan-1-one 1.11 (LC-1) 330.87
The following 5-methyl-2-phenyl-indan-1-one derivatives are prepared according to a known procedure from A. S. Hussey and R. R. Herr, J. Org. Chem. 1959, 24, 843-845: 2-chloro-5-methyl-indan-1 -one (16.6 mmol) is treated with a 1 M soln. of the corresponding phenyl-magnesium bromide derivative (23.3 mmol) in THF / toluene to give the respective 5-methyl-2-phenyl-indan-1 -one derivative:
Figure imgf000113_0001
2-Chloro-5-methyl-indan-1 -one is prepared according to a known procedure from A. S. Hussey and R. R. Herr, J. Org. Chem. 1959, 24, 843-845: 5-methyl-indan-1-one (32.6 mmol) is chlorinated in glacial AcOH in the presence of NCS (35.9 mmol):
fR (LC-1) 0.91 ; ESI-MS: m/z 180.94 [M+H]+. 1H-NMR (DMSO-d6): 2.48 (s, 3H), 3.27 (dd, J = 17.6, 4.0, 1 H), 3.75 (dd, J = 17.6, 7.8, 1 H), 4.56 (dd, J = 7.8, 4.0, 1 H), 7.27 (m, 2 H), 7.74 (d, J = 8.5, 1 H).
Example 53.01
2-(1-Benzo[1,3]dioxol-5-ylmethyl-piperidin-4-yl)-2-phenyl-indan-1-one
The title compound is prepared according to the procedure described for above Example 1.02 by reacting 2- phenyl-2-piperidin-4-yl-indan-1-one with 5-bromomethyl-benzo[1 ,3]dioxole in DMF in the presence of CS2CO3: fR (LC-1) 0.86; ESI-MS: m/z 426.19 [M+H]+. 1H-NMR (DMSO-d6): £1.57 (m, 2 H), 1.87 (m, 2 H), 2.49 (m, 3 H), 3.38 (m, 2 H), 3.51 (d, J = 17.8, 1 H), 3.69 (d, J = 17.8, 1 H), 3.95 (s, 2 H), 6.00 (s, 2 H), 6.82 (m, 2 H), 6.92 (s, 1 H), 7.23 (m, 1 H), 7.34 (m, 3 H), 7.55 (m, 3 H), 7.62 (m, 1 H), 7.69 (d, J = 7.5, 1 H).
a) 2-Phenyl-2-DiDeridin-4-yl-indan-1-one
A stirred mixture of 4-(1-imino-2-phenyl-indan-2-yl)-piperidine-1-carboxylic acid ferf.-butyl ester (29.9 g, 77 mmol) in THF (65 mL), water (10 mL) and aq. 1 M HCI soln. (500 mL) is heated to 70 °C and kept stirring at this temperature over night. After cooling down to r.t., aq. 5N NaOH is added and the basic soln. is extracted three times with AcOEt. The comb. org. layer is washed with water and brine dried (MgS04) and filtered. The - In solvent is evaporated and the crude product is purified by FC to deliver the subtitle compound as a slightly brownish solid: fR (LC-1 ) 0.73; ESI-MS: m/z 291.99 [M+H]+. 1H-NMR (CDCIs): 1.29 (m, 2 H), 1.47 (m, 2 H), 2.46 (tt, J = 1 1.8, 3.0, 1 H), 2.62 (m, 3 H), 3.08 (m, 2 H), 3.53 (d, J = 17.6, 1 H), 3.65 (d, J = 17.6, 1 H), 7.22 (m, 1 H), 7.33 (m, 3 H), 7.54 (m, 3 H), 7.61 (t, J = 7.8, 1 H), 7.72 (d, J = 7.8, 1 H).
b) 4-(1-lmino-2-phenyl-indan-2-yl)-piperidine-1-carboxylic acid tert.-butyl ester
At -78 °C, fBuLi (1.7 M in hexane, 9.6 mL, 16.4 mmol) is added dropwise to a stirred soln. of 4-[(2-bromo- benzyl)-cyano-phenyl-methyl]-piperidine-1 -carboxylic acid fert. -butyl ester (3.5 g, 7.46 mmol) in dry THF (80 mL). The reaction mixture is continued to stir for 2 h at -78 °C, then, is allowed to warm to r.t. over night. Sat. aq. NH4CI soln. and water are added and the mixture is extracted three times with DCM. The comb. org. layer is washed with water and brine, dried (MgS04) and filtered. The solvent is evaporated and the subtitle compound is obtained after FC as an off-white solid. fR (LC-1 ) 0.89; ESI-MS: m/z 391.08 [M+H]+. 1H-NMR (CDCI3): £ 1.28 (m, 2 H), 1.45 (s, 9 H), 1.60 (m, 2 H), 2.55 (m, 1 H), 2.74 (m, 2 H), 3.38 (d, J = 17.6, 1 H), 3.51 (d, J = 17.6, 1 H), 4.14 (m, 2 H), 7.22 (m, 1 H), 7.34 (m, 3 H), 7.47 (m, 4 H), 7.62 (m, 1 H), 9.53 (m, 1 H).
c) 4-i(2-Bromo-benzyl)-cvano-Dhenyl-methyli-DiDeridine-1-carboxylic acid tert.-butyl ester
A stirred suspension of 4-(cyano-phenyl-methyl)-piperidine-1 -carboxylic acid ferf.-butyl ester (500 mg, 1.66 mmol), NaH (100 mg, 2.50 mmol) and tetrabutylammonium bromide (108 mg, 0.33 mmol) in dry DMF (5 mL) is heated to 50 °C. After 15 min 2-bromobenzyl bromide (437 mg, 1.75 mmol) is added and the mixture is stirred at 50 °C over night. The suspension is cooled to r.t. and the solid is filtered off. The filtrate is concentrated in vacuo. The obtained residue is dissolved in water and sat. aq. NH4CI soln. and extracted three times with AcOEt. The comb. org. layer is dried (MgS04) and filtered. The solvent is evaporated and the subtitle compound is obtained after FC of the residue as a colorless solid: fR (LC-1 ) 1.14; ESI-MS: m/z 469.20 [M+H]+. 1H-NMR (CDCI3): £ 1.31 (m, 2 H), 1.47 (s, 9 H), 1.76 (m, 1 H), 2.20 (m, 2 H), 2.59 (m, 1 H), 2.79 (m, 1 H), 3.31 (d, J = 14.3, 1 H), 3.85 (d, J = 14.3, 1 H), 4.11 (m, 1 H), 4.36 (m, 1 H), 6.84 (m, 1 H), 7.02 (m, 2 H), 7.33 (m, 5 H), 7.48 (m, 1 H).
d) 4-(Cvano-Dhenyl-methyl)-DiDeridine-1-carboxylic acid tert.-butyl ester
NaBH4 (1.58 g, 40.2 mmol) is added to a stirred soln. of 4-(cyano-phenyl-methylene)-piperidine-1-carboxylic acid tert.-butyl ester (4.0 g, 13.4 mmol) in /PrOH (186 mL) and the resulting suspension is heated at reflux for 16 h. Then, the reaction mixture is cooled to r.t. and the volatiles are evaporated. The residue is taken up in MeOH and 10% aq. citric acid soln. is carefully added with stirring. After gas evolution has ceased, water is added and the mixture is extracted three times with AcOEt. The comb. org. layer is washed with water and brine, dried over MgS04, filtered and evaporated. Crystallization of the residue from diisopropylether finally delivers subtitle compound as colorless crystals. fR (LC-1 ) 1.03; ESI-MS: m/z 301.17 [M+H]+. 1H-NMR (CDCI3): δ 1.33 (m, 3 H), 1.47 (s, 9 H), 1.89 (m, 2 H), 2.64 (m, 2 H), 3.66 (d, J = 7.0, 1 H), 4.18 (m, 2 H), 7.31 (m, 2 H), 7.40 (m, 3 H). e) 4-(Cvano-Dhenyl-methylene)-DiDeridine-1-carboxylic acid tert.-butyl ester
To a freshly prepared stirred soln. of Na (6.99 g, 291 mmol) in EtOH (1.5 1) is added benzyl cyanide (29.8 mL, 255 mmol) and after 10 min stirring at r.t. 1-Boc-4-piperidone (243 mmol). The resulting yellow soln. is stirred at r.t. over night. Sat. NH4CI soln. (1000 mL) is added and the mixture is extracted three times with AcOEt (200 mL each). The comb. org. layer is washed with water and brine, dried over MgS04, filtered and concentrated. The oily residue is purified by FC to provide subtitle compound as a colorless solid: fR (LC-1) 1.05; ESI-MS: m/z 299.10 [M+H]+. 1H-NMR (CDCI3): £1.50 (s, 9 H), 2.45 (t, J = 5.5, 2 H), 2.80 (t, J = 5.8, 2 H), 3.45 (t, J = 5.8, 2 H), 3.64 (t, J = 5.8, 2 H), 7.30 (m, 2 H), 7.42 (m, 3 H).
Applying the same procedures as described for above-mentioned Example 53.01, the following Example compounds as identified in Table 53 are obtained by reacting a 2-phenyl-2-piperidin-4-yl-indan-1-one with the appropriately substituted benzyl bromide, substituted benzyl chloride or cycloalkylmethyl bromide in the presence of CS2CO3:
Table 53: Example 53.02- 53.12 fR [min] LC-MS MS Data m/z
Example Compound
Method [M+H]+
53.02 2-(1-Benzyl-piperidin-4-yl)-2-phenyl-indan-1-one 0.84 (LC-1) 382.30
2-(1-Cyclohexylmethyl-piperidin-4-yl)-2-phenyl-indan-1-one 0.89
53.03 388.39
(LC-1)
2-[1-(3-Methoxy-benzyl)-piperidin-4-yl]-2-phenyl-indan-1-one 0.92
53.04 412.59
(LC-1)
2-[1 -(2-Methyl-benzyl)-piperidin-4-yl]-2-phenyl-indan-1 -one 0.87
53.05 396.07
(LC-1)
2-[1-(4-Methyl-benzyl)-piperidin-4-yl]-2-phenyl-indan-1-one 0.89
53.06 396.08
(LC-1)
2-[1-(2-Chloro-benzyl)-piperidin-4-yl]-2-phenyl-indan-1-one 0.88
53.07 416.02
(LC-1)
2-[1-(3-Chloro-benzyl)-piperidin-4-yl]-2-phenyl-indan-1-one 0.88
53.08 416.03
(LC-1)
2-[1-(4-Chloro-benzyl)-piperidin-4-yl]-2-phenyl-indan-1-one 0.93
53.09 416.15
(LC-2)
2-[1-(4-Methoxy-benzyl)-piperidin-4-yl]-2-phenyl-indan-1-one 0.86
53.10 412.09
(LC-1)
2-[1 -(3-Methyl-benzyl)-piperidin-4-yl]-2-phenyl-indan-1 -one 0.88
53.11 396.07
(LC-1) 2-[1-(2-Methoxy-benzyl)-piperidin-4-yl]-2-phenyl-indan-1-one 0.88
53.12 412.10
(LC-1)
(R)-2-(1-Benzyl-piperidin-4-yl)-2-phenyl-indan-1-one and (S)-2-(1-Benzyl-piperidin-4-yl)-2-phenyl-indan-1- one
The two enantiomers of 2-(1-Benzyl-piperidin-4-yl)-2-phenyl-indan-1-one (Example 53.02) are separated by chiral prep. LC-MS (D). Conditions: ChiralPak AD-H column, Eluent : EtOH with 0.1 % DEA.
Example 53.02A Enantiomer A: fR (LC-11) 7.2;
Example 53.02B Enantiomer B: fR (LC-11) 9.1.
Example 54.01
2-(2-Methoxy-phenyl)-2-[1-(2-methyl-benzyl)-piperidin-4-yl]-indan-1-one
The title compound is obtained applying the procedure described for above-mentioned Example 53.01 , by reacting a soln. of 2-(2-methoxy-phenyl)-2-[1-(2-methyl-benzyl)-piperidin-4-yl]-indan-1-ylideneamine in THF / ethylene glycol with aq. 1 M HCI in a microwave reactor at 120°C for 30 min: fR (LC-1) 0.95; ESI-MS: m/z 426.14 [M+H]+. 1H-NMR (CDCI3): 1.39 (m, 2 H), 1.56 (m, 1 H), 1.85 (m, 1 H), 2.18 (m, 2 H), 2.35 (s, 3 H), 2.48 (m, 1 H), 2.98 (m, 2 H), 3.46 (s, 2 H), 3.58 (m, 2 H), 3.67 (s, 3 H), 6.94 (m, 2 H), 7.15 (m, 3 H), 7.24 (m, 1 H), 7.36 (m, 3 H), 7.50 (m, 1 H), 7.58 (m, 1 H), 7.80 (d, J = 7.5, 1 H).
a) 2-(2-Methoxy-ohenyl)-2-[1-(2-methyl-benzyl)-oioeridin-4-yll-M
Applying the procedure described for above-mentioned Example 53.01 , 3-(2-Bromo-phenyl)-2-(2-methoxy- phenyl)-2-[1-(2-methyl-benzyl)-piperidin-4-yl]-propionitrile is reacted with fBuLi at -78 °C. The resulting subtitle compound is used in the next step without further purification. fR (LC-1) 0.70; ESI-MS: m/z 425.08 [M+H]+. b) 3-(2 romo-ohenyl)-2-(2-methoxy-ohenyl)-2-[1-(2-methyl-ben
Applying the procedure described for above-mentioned Example 53.01 , (2-methoxy-phenyl)-[1-(2-methyl- benzyl)-piperidin-4-yl]-acetonitrile is reacted with 2-bromobenzyl bromide in dry DMF in the presence of NaH and tetrabutylammonium bromide at 50 °C to give subtitle compound: tR (LC-1) 0.90; ESI-MS: m/z 504.98 [M+H]+. 1H-NMR (CDCI3): £ 1.13 (m, 1 H), 1.46 (m, 1 H), 1.93 (m, 2 H), 2.12 (m, 2 H), 2.37 (s, 3 H), 2.65 (m, 1 H), 2.85 (d, J = 11.3, 1 H), 3.09 (m, 1 H), 3.45 (s, 2 H), 3.69 (d, J = 14.3, 1 H), 3.78 (d, J = 14.3, 1 H), 3.90 (s, 3 H), 6.73 (m, 1 H), 6.87 (t, J = 7.8, 1 H), 6.91 (d, J = 8.3, 1 H), 6.98 (m, 2 H), 7.14 (m, 3 H), 7.30 (m, 2 H), 7.37 (m, 1 H), 7.49 (m, 1 H).
c) (2-Methoxy-ohenyl)-f1-(2-methyl-benzyl)-oioeridin-4-yll-aceton^
Applying the procedure described for above-mentioned Example 53.01 , (2-methoxy-phenyl)-[1-(2-methyl- benzyl)-piperidin-4-ylidene]-acetonitrile is treated with NaBH4 in /PrOH to give subtitle compound: tR (LC-1) 0.83; ESI-MS: m/z 335.05 [M+H]+. 1H-NMR (CDCI3): £1.31 (m, 3 H), 1.72 (m, 1 H), 1.88 (m, 3 H), 2.29 (s, 3 H), 2.81 (m, 2 H), 3.37 (s, 2 H), 3.83 (s, 3 H), 4.18 (d, J = 7.8, 1 H), 7.00 (t, J = 7.5, 1 H), 7.08 (d, J = 8.3, 1 H), 7.13 (m, 3 H), 7.19 (m, 1 H), 7.30 (dd, J = 7.5, 1.5, 1 H), 7.35 (m, 1 H).
cfj (2-Methoxy-phenyl)-i1-(2-methyl-benzyl)-piperidin-4-yliden
Applying the procedure described for above-mentioned Example 53.01 , (2-methoxy-phenyl)-acetonitrile and 1- (2-methyl-benzyl)-piperidin-4-one are condensed in the presence of freshly prepared NaOEt soln. to give subtitle compound: fR (LC-1) 0.82; ESI-MS: m/z 333.08 [M+H]+. 1H-NMR (DMSO-d6): £2.18 (m, 2 H), 2.33 (s, 3 H), 2.42 (m, 2 H), 2.60 (m, 2 H), 2.68 (m, 2 H), 3.47 (s, 2 H), 3.82 (s, 3 H), 7.01 (t, J = 7.5, 1 H), 7.12 (m, 1 H), 7.17 (m, 4 H), 7.25 (m, 1 H), 7.41 (m, 1 H).
e) 1 -(2-methyl-benzyl)-Diperidin-4-one
A soln. of 4-piperidone monohydrate hydrochloride (7.09 g, 45.23 mmol), 1-bromomethyl-2-methyl-benzene (6.64 mL, 49.76 mmol) and DIPEA (16.26 mL, 94.99 mmol) in DCM (150 mL) is stirred at r.t. for 70 h. The reaction mixture is diluted with sat. aq. NaHCC -soln. and extracted with DCM. The comb. org. layer is dried (MgS04) and concentrated in vacuo. The subtitle comp. is obtained after FC. fR (LC-2) 0.56; ESI-MS: m/z 222.49 [M+H20]+; 1H-NMR (DMSO-d6): £2.34 (m, 4 H), 2.37 (s, 3 H), 2.70 (m, 4 H), 3.56 (s, 2 H), 7.17 (m, 3 H), 7.29 (d, J = 5.5, 1 H).
Example 55.01
2-[1-(2-Ethyl-benzyl)-piperidin-4-yl]-2-(3-methylphenyl)-indan-1-one
The title compound is obtained applying the same procedures as described for above-mentioned Example 53.01 , by reacting 2-piperidin-4-yl-2-(3-methylphenyl)-indan-1-one with 1-bromomethyl-2-ethyl-benzene in the presence of Cs2C03: fR (LC-4) 1.31 ; ESI-MS: m/z 424.03 [M+H]+; 1H-NMR (CDCIs): £1.22 (t, J = 7.5, 3 H), 1.38 (m, 4 H), 1.97 (m, 2 H), 2.33 (m, 1 H), 2.34 (s, 3 H), 2.71 (q, J = 7.5, 2 H), 2.88 (m, 2 H), 3.44 (m, 2 H), 3.49 (d, J = 17.6, 1 H), 3.63 (d, J = 17.8, 1 H), 7.03 (d, J = 7.5, 1 H), 7.12 (m, 1 H), 7.19 (m, 3 H), 7.26 (m, 1 H), 7.35 (m, 3 H), 7.52 (d, J = 7.5, 1 H), 7.60 (t, J = 7.5, 1 H), 7.72 (d, J = 7.5, 1 H).
a) 2-(3-Methyl-Dhenyl)-2-DiDeridin-4-yl-indan- 1 -one
The subtitle compound is obtained applying the procedure described for above-mentioned Example 53.01 , by treating a THF soln. of 4-[1-imino-2-(3-methyl-phenyl)-indan-2-yl]-piperidine-1-carboxylic acid ferf.-butyl ester with aq. 1 M HCI: fR (LC-1) 0.77; ESI-MS: m/z 306.02 [M+H]+. 1H-NMR (CDCI3): £ 1.27 (m, 2 H), 1.48 (m, 2 H), 2.06 (m, 1 H), 2.35 (s, 3 H), 2.45 (m, 1 H), 2.61 (m, 2 H), 3.06 (m, 2 H), 3.51 (d, J = 17.6, 1 H), 3.65 (d, J = 17.6, 1 H), 7.04 (d, J = 7.3, 1 H), 7.20 (t, J = 7.8, 1 H), 7.36 (m, 3 H), 7.52 (m, 1 H), 7.61 (t, J = 7.5, 1 H), 7.73 (d, J = 7.5, 1 H).
b) 4-[1-lmino-2-(3-methyl-ohenyl)-indan-2-yll-oioerffl^ acid tert.-butyl ester
Applying the procedure described for above-mentioned Example 53.01 , 4-[(2-bromo-benzyl)-cyano-(3-methyl- phenyl)-methyl]-piperidine-1-carboxylic acid ferf.-butyl ester is reacted with fBuLi at -78 °C. The resulting subtitle compound is used in the next step without further purification. fR (LC-1) 0.86; ESI-MS: m/z 405.12 [M+H]+. c) 4-[(2-Bromo-benzyl)-cvano-(3-methyl-Dhenyl)-methyll-w^ acid tert.-butyl ester
Applying the procedure described for above-mentioned Example 53.01 , 4-[cyano-(2-methoxy-phenyl)-methyl]- piperidine-1-carboxylic acid ferf.-butyl ester is reacted with 2-bromobenzyl bromide in dry DMF in the presence of NaH and tetrabutylammonium bromide at 50 °C to give subtitle compound: fR (LC-1) 1.16; ESI-MS: m/z 484.65 [M+H]+. 1H-NMR (CDCI3): 1.33 (m, 2 H), 1.47 (s, 9 H), 1.75 (m, 1 H), 2.19 (m, 2 H), 2.35 (s, 3 H), 2.61 (m, 1 H), 2.80 (m, 1 H), 3.31 (d, J = 14.1 , 1 H), 3.82 (d, J = 14.3, 1 H), 4.13 (m, 1 H), 4.36 (m, 1 H), 6.87 (m, 1 H), 7.03 (m, 2 H), 7.13 (m, 3 H), 7.22 (t, J = 7.3, 1 H), 7.48 (dd, J = 7.0, 1.8, 1 H).
cf) 4-iCvano-(3-methyl-Dhenyl)-methyli-DiDeridine-1-carboxylic acid tert.-butyl ester
Applying the procedure described for above-mentioned Example 53.01 , 4-[cyano-(3-methyl-phenyl)-methylene]- piperidine-1-carboxylic acid ferf.-butyl ester is treated with NaBhU in /PrOH to give subtitle compound: fR (LC-1) 1.00; ESI-MS: m/z 315.25 [M+H]+. 1H-NMR (CDCI3): £1.34 (m, 2 H), 1.47 (s, 9 H), 1.61 (m, 1 H), 1.89 (m, 2 H), 2.39 (s, 3 H), 2.65 (m, 2 H), 3.61 (d, J = 7.3, 1 H), 4.18 (m, 2 H), 7.09 (d, J = 7.8, 1 H), 7.12 (s, 1 H), 7.17 (d, J = 7.0, 1 H), 7.29 (m, 1 H).
e) 4-[Cvano-(3-methyl-phenyl)-methylenel-piperidine-1-carboxylic acid tert.-butyl ester
Applying the procedure described for above-mentioned Example 53.01 , (3-methyl-phenyl)-acetonitrile and 1- Boc-4-piperidone is condensed in the presence of freshly prepared NaOEt soln. to give subtitle compound: fR (LC-1) 1.08; ESI-MS: m/z 313.03 [M+H]+. 1H-NMR (CDCI3): £1.50 (s, 9 H), 2.40 (s, 3 H), 2.46 (m, 2 H), 2.78 (m, 2 H), 3.44 (t, J = 5.8, 2 H), 3.63 (t, J = 5.8, 2 H), 7.08 (d, J = 7.5, 1 H), 7.13 (m, 1 H), 7.19 (d, J = 7.8, 1 H), 7.31 (m, 1 H).
Applying the same procedure as described for above-mentioned Example 55.01 , the following Example compounds as identified in Table 55 are obtained by reacting a 2-piperidin-4-yl-2-(3-methyl-phenyl)-indan-1-one with the appropriate substituted benzyl bromide, substituted benzyl chloride or cycloalkyi methyl bromide in the presence of CS2CO3:
Table 55: Example 55.02-55.09
fR [min]
Example Compound LC-MS MS Data
Method m/z [M+H]+
2-(1-Benzyl-piperidin-4-yl)-2-(3-methyl-phenyl)-indan-1-one 0.89
55.02 396.15
(LC-1)
2-(1-Cyclohexylmethyl-piperidin-4-yl)-2-(3-methyl-phenyl)- 0.93
55.03 402.20
indan-1-one (LC-1)
2-(1-Benzo[1 ,3]dioxol-5-ylmethyl-piperidin-4-yl)-2-(3-methyl- 0.90
55.04 440.07
phenyl)-indan-1 -one (LC-1) 2-[1-(4-Methoxy-benzyl)-piperidin-4-yl]-2-(3-methyl-phenyl)- 1.12
55.05 425.90
indan-1-one (LC-4)
2-[1-(2-Methyl-benzyl)-piperidin-4-yl]-2-(3-methyl-phenyl)- 0.92
55.06 410.06
indan-1-one (LC-1)
2-[1-(2-Methoxy-benzyl)-piperidin-4-yl]-2-(3-methyl-phenyl)- 1.19
55.07 425.72
indan-1-one (LC-4)
2-(3-methyl-phenyl)-2-[1-(2-trifluorornethyl-benzyl)-piperidin- 1.24
55.08 464.13
4-yl]-indan-1-one (LC-4)
2-[1-(2-Propyl-benzyl)-piperidin-4-yl]-2-(3-methyl-phenyl)- 0.96
55.09 438.11
indan-1-one (LC-1)
Example 56.01
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(1-methyl-1H-pyrazol-3-yl)-indan-1-one
a) The title compound is obtained by reacting 2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-2-(1-methyl-1 H-pyrazol-3-yl)- indan-1-imine with aq. 2 N aq. HCI / THF at 60 °C for 2 h and subsequent neutralization with aq. NaOH soln.: fR (LC-1) 0.80; ESI-MS: m/z 415.09 [M+H]+. 1H-NMR (CDCI3): 1.24 (t, J = 7.5, 3 H), 2.78 (m, 3 H), 2.96 (m, 2 H), 3.19 (m, 3 H), 3.36 (m, 2 H), 3.66 (d, J = 17.3, 1 H), 3.79 (s, 3 H), 3.94 (d, J = 17.3, 1 H), 4.24 (d, J = 5.0, 2 H), 6.38 (d, J = 1.8, 1 H), 7.24 (d, J = 1.8, 1 H), 7.29 (m, 1 H), 7.36 (m, 3 H), 7.54 (d, J = 7.8, 1 H), 7.63 (t, J = 7.5, 1 H), 7.70 (d, J = 7.8, 1 H), 7.93 (d, J = 7.3, 1 H).
b) 2-[4-(2-Ethyl-benzyl)-Diperazin- 1 -yll-2-( 1 -methyl-1H-Dyrazol-3-yl)-indan-1 -imine
2-(1 -Methyl-1 - -pyrazol-3-yl)-2-piperazin-1 -yl-indan-1 -imine (70 mg) and 2-ethylbenzylbromide (44.3 mg) were dissolved in DCM and DIPEA (0.08 mL). The soln. is stirred at r.t. for 24 h under argon atmosphere. The reaction mixture is diluted with sat. aq. NaHC03 and extracted three times with DCM. The comb, extracts are dried over MgS04 and concentrated in vacuo to give 120 mg of a yellow oil. Purification by prep. LC-MS (B) gives the title compound as white solidified foam: fR (LC-1) 0.63; ESI-MS: m/z 414.12 [M+H]+. 1H NMR (CDCI3): £ 1.23 (t, J = 7.8, 3 H), 2.53 (m, br, 8 H), 2.73 (q, J = 7.5, 2 H), 3.49 (m, 3 H), 3.78 (m, 4 H), 6.36 (d, J = 2.3, 1 H), 7.13 (m, 1 H), 7.20 (m, 2 H), 7.25 (d, J = 2.3, 1 H), 7.29 (m, 3 H), 7.46 (m, 2 H), 7.83 (d, J = 7.5, 1 H).
c) 2-( 1 -Methyl- 1 H-Dyrazol-3-yl)-2-Diperazin- 1 -yl-indan-1 -imine
To 2-(1-methyl-1H-pyrazol-3-yl)-2-(4-Boc-piperazin-1-yl)-indan-1-imine (708.5 mg) is added HCI (ca. 3.3 N) in dry AcOEt (5mL). The reaction mixture is stirred at r.t. for 1 h to give a yellow suspension and then filtered. The solid is rinsed with AcOEt. Aq. 1 N NaOH is added and the mixture is extracted with DCM. The comb. org. layer is dried over Na2S04, filtered and evaporated under reduced pressure to give crude subtitle compound as yellow solidified foam: fR (LC-1) 0.50; ESI-MS: m/z 296.00 [M+H]+. cf) 2-( 1 -Methyl- 1 H-Dyrazol-3-yl)-2-(4-Boc-DiDerazin- 1-yl)-indan-1-imine
To a stirred soln. of 4-[(2-Bromo-benzyl)-cyano-(1 -methyl-1 /-/-pyrazol-3-yl)-methyl]-piperazine-1 -carboxylic acid fe/t-butyl ester (1.1 g) in dry THF (15 mL) is added dropwise a soln. of fBuLi under argon at -78 °C. Then, the orange reaction mixture is continued to stir at -78 °C for 2 h. A sat. aq. soln. of NH4CI is added. At r.t. water is added until the white precipitate dissolves. This mixture is extracted three times with DCM. The comb. org. layers are washed with brine, dried (MgSC>4), filtered, and evaporated under reduced pressure to give crude subtitle compound as yellow solidified foam (1.1 g): fR (LC-1) 0.77; ESI-MS: m/z 396.14 [M+H]+. e) 4-[(2-Bromo-benzyl)-cvano-(1 -methyl-1 H-Dyrazol-3-yl)-methyli-DiDerazine-1-carboxylic acid tert.-butyl ester To a stirred soln. of 4-[cyano-(1-methyl-1 H-pyrazol-3-yl)-methyl]-piperazine-1-carboxylic acid fe/t-butyl ester (1.26 g) in dry DMF (22 mL) is added under argon atmosphere NaH and tetrabutylammonium bromide. The resulting yellow suspension is heated to 50 °C for 20 min, then, 2-bromobenzyl bromide is added and the reaction mixture is kept stirring at 50 °C for 2 h. At r.t., water is added, followed by addition of cone. aq. soln. of NH4CI. The mixture is extracted thee times with AcOEt. The comb. org. layer is dried, filtered, and evaporated to dryness under reduced pressure to give a yellow residue. Subtitle compound (1.1 g) is obtained after purification by CC as a white foam: fR (LC-1) 1.05; ESI-MS: m/z 474.04 [M+H]+. f) 4-[Cvano-(1 -methyl-1 H-Dyrazol-3-yl)-methyli-DiDerazine-1 -carboxylic acid tert.-butyl ester
To a stirred soln. of 1 -methyl-1 H-pyrazole-3-carbaldehyde (454.5 mg) and 1-Boc-piperazine (768.7 mg) in dry MeCN (5 mL) at r.t. under argon is added consecutively SnC (55 mg) and dropwise TMSCN (0. 666 mL, 4.95 mmol). The reaction mixture is heated in a closed microwave-tube at 80 °C for 20 min, filtered over S1O2 and the residue is rinsed with MeCN. The solvent is evaporated to dryness under reduced pressure to give the subtitle compound (1.36 g) as yellow solid foam: fR (LC-1) 0.86; ESI-MS: m/z 306.04 [M+H]+.
Applying the same procedure as described for above-mentioned Example 56.01 , the following Example compound as identified in Table 56 is obtained by reacting 2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(1- methyl-1 -/-pyrazol-3-yl)-indan-1 -imine with aq. HCI in THF:
Table 56: Example 56.02
Figure imgf000120_0001
a) 2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(1-methyl-1 H-pyrazol-3-yl)-indan-1-imine is obtained from 2- (1-methyl-1 H-pyrazol-3-yl)-2-piperazin-1-yl-indan-1-imine with 5-fluoro-2-methyl-benzyl bromide under basic conditions as described in Example 56.01 : fR (LC-1) 0.63; ESI-MS: m/z 418.07 [M+H]+. 1H-NMR (CDCI3): 2.32 (m, 4 H), 2.57 (m, 8 H), 3.49 (m, 3 H), 3.80 (m, 4 H), 6.35 (s, 1 H), 6.87 (m, 1 H), 7.11 (m, 2 H), 7.26 (s, 1 H), 7.32 (m, 1 H), 7.48 (m, 2 H), 7.88 (m, 1 H).
Applying the same procedure as described for above-mentioned Example 56.01 , the following Example compounds as identified in Tables 57-60 are obtained by reacting the appropriate 2-heterocyclic 2-piperazin-1- yl-indan-1-imines with aq. HCI in THF, purified by crystallization, prep. TLC or prep. LC-MS (B):
Table 57: Examples 57.01-57.03
Figure imgf000121_0001
a) 2-(4-Bromo-thiophen-2-yl)-2-[4-benzyl-piperazin-1-yl]-indan-1-imine derivatives are synthesized from 2-(4- bromo-thiophen-2-yl)-2-piperazin-1-yl-indan-1-imine as in Example 56.01 using the corresponding benzyl bromide derivative:
Figure imgf000121_0002
b) 2-(4-Bromo-thiophen-2-yl)-2-piperazin-1 -yl-indan-1 -imine is produced from 2-(4-bromo-thiophen-2-yl)-2-(4- Boc-piperazin-1-yl)-indan-1-imine analogously to Example 56.01 with dry HCI in AcOEt at r.t.: fR (LC-1) 0.61 ; ESI-MS: m/z 375.96 [M+H]+.
c) 2-(4-Bromo-thiophen-2-yl)-2-(4-Boc-piperazin-1-yl)-indan-1 -imine is obtained from 4-[(2-bromo-benzyl)-(4- bromo-thiophen-2-yl)-cyano-methyl]-piperazine-1-carboxylic acid ieri.-butyl ester according to Example 56.01 with fBuLi in THF: fR (LC-1) 0.61 ; ESI-MS: m/z 375.96 [M+H]+. d) 4-[(2-Bromo-benzyl)-(4-bromo-thiophen-2-yl)-cyano-methyl]-piperazine-1-carboxyli acid ieri.-butyl ester is synthesized from 4-[(4-bromo-thiophen-2-yl)-cyano-methyl]-piperazine-1-carboxylic acid ieri.-butyl ester according to Example 56.01 : fR (LC-1) 1.17; ESI-MS: m/z 555.91 [M+H]+. 1H-NMR (CDCIs): £1.50 (s, 9 H), 2.70 (m, 2 H), 2.88 (m, 2 H), 3.20 (d, J = 13, 1 H), 3.56 (s, br, 4 H), 3.95 (d, J = 13.2, 1 H), 6.71 (s, J = 0.8, 1 H), 6.90 (d, J = 7.3, 1 H), 7.16 (m, 2 H), 7.25 (d, J = 0.8, 1 H), 7.54 (m, 1 H).
e) 4-[(4-Bromo-thiophen-2-yl)-cyano-methyl]-piperazine-1-carboxylic acid ieri.-butyl ester is produced by a Strecker reaction between TMSCN, 4-bromothiophen-2-ylcarbaldehyde, and Boc-piperazine according to Example 56.01 : fR (LC-1) 1.06; ESI-MS: m/z 385.92 [M+H]+. 1H-NMR (CDCI3): £ 1.50 (m, 9 H), 2.57 (m, 2 H), 2.66 (m, 2 H), 3.51 (m, 4 H), 4.97 (s, 1 H), 7.22 (s, 1 H), 7.30 (s, 1 H).
2-[4-benzyl-piperazin-1-yl]-2-(5-methyl-isoxazol-3-yl)-indan-1-one derivatives are obtained directly by benzylation of 2-(5-methyl-isoxazol-3-yl)-2-piperazin-1-yl-indan-1-one with the appropriate benzyl bromide derivative analogous to Example 56.01 (step b) after prep. LC-MS (B) purification:
Table 58: Examples 58.01-58.03
Figure imgf000122_0001
a) 2-(5-methyl-isoxazol-3-yl)-2-piperazin-1-yl-indan-1-one is synthesized from 4-[1-imino-2-(5-methyl-isoxazol-3- yl)-indan-2-yl]-piperazine-1-carboxylic acid ieri.-butyl ester by heating in aq. HCI / THF at 70 °C for 2 h according to Example 56.01 : fR (LC-1) 0.67; ESI-MS: m/z 297.97 [M+H]+. 1H-NMR (CDCI3, NH due to solvent exchange and spectral overlap invisible): £2.40 (s, 3 H), 2.48 (m, 4 H), 2.89 (m, 2 H), 2.97 (m, 2 H), 3.58 (d, J = 17.3, 1 H), 3.95 (d, J = 17.5, 1 H), 6.45 (s, 1 H), 7.38 ( = 7.3, 1 H), 7.56 (d, J = 7.8, 1 H), 7.65 (t, J = 7.5, 1 H), 7.73 (d, J = 7.8, 1 H).
b) 4-[1-lmino-2-(5-methyl-isoxazol-3-yl)-indan-2-yl]-piperazine-1-carboxylic acid ieri.-butyl ester is obtained from 4-[(2-bromo-benzyl)-cyano-(5-methyl-isoxazol-3-yl)-methyl]-piperazine-1-carboxylic acid ieri.-butyl ester according to Example 56.01 : fR (LC-1) 0.81 ; ESI-MS: m/z 397.16 [M+H]+.
c) 4-[(2-Bromo-benzyl)-cyano-(5-methyl-isoxazol-3-yl)-methyl]-piperazine-1-carboxylic acid ieri.-butyl ester is produced from 4-[cyano-(5-methyl-isoxazol-3-yl)-methyl]-piperazine-1-carboxylic acid ieri.-butyl ester according to Example 56.01 : fR (LC-1) 1.08; ESI-MS: m/z 474.89 [M+H]+. 1H-NMR (CDCI3): £1.49 (s, 9 H), 2.42 (s, 3 H), 2.57 (m, 2 H), 2.84 (m, 2 H), 3.53 (m, 5 H), 3.86 (d, J = 14.1 , 1 H), 5.96 (s, 1 H), 7.11 (t, J = 7.8, 1 H), 7.22 (t, J = 7.3, 1 H), 7.27 (s, 1 H), 7.52 (d, J = 8.0, 1 H).
d) 4-[Cyano-(5-methyl-isoxazol-3-yl)-methyl]-piperazine-1-carboxylic acid ieri.-butyl ester is the result of a Strecker reaction between TMSCN, 5-methyl-isoxazol-3-carbaldehyde and Boc-piperazine according to Example 56.01 : fR (LC-1) 0.93; ESI-MS: m/z 307.02 [M+H]+.
Table 59: Example 59.01
Figure imgf000123_0001
a) 2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(5-methoxy-pyridin-3-yl)-indan-1-imine is obtained according to Example 56.01 from 2-(5-methoxy-pyridin-3-yl)-2-piperazin-1-yl-indan-1-imine: fR (LC-1) 0.64; ESI-MS: m/z 445.13 [M+H]+. 1H-NMR (CDCI3): £2.31 (s, 3 H), 2.57 (m, 8 H), 3.30 (d, J = 17.3, 1 H), 3.48 (m, 2 H), 3.64 (d, J = 17.1 , 1 H), 3.85 (s, 3 H), 6.85 (m, 1 H), 7.08 (m, 3 H), 7.37 (m, 2 H), 7.53 (m, 1 H), 7.55 (m, 1 H), 7.79 (m, 1 H), 8.17 (s, 1 H), 8.28 (s, 1 H).
b) 2-(5-Methoxy-pyridin-3-yl)-2-piperazin-1-yl-indan-1-imine is produced from 4-[1-imino-2-(5-methoxy-pyridin-3- yl)-indan-2-yl]-piperazine-1-carboxylic acid ieri.-butyl ester according to Example 56.01 : fR (LC-1) 0.48; ESI-MS: m/z 322.98 [M+H]+.
c) 4-[1-lmino-2-(5-methoxy-pyridin-3-yl)-indan-2-yl]-piperazine-1-carboxylic acid ieri.-butyl ester is synthesized from 4-[(2-bromo-benzyl)-cyano-(5-methoxy-pyridin-3-yl)-methyl]-piperazine-1-carboxylic acid ieri.-butyl ester according to Example 56.01 and is used as crude product in the next step: fR (LC-1) 0.75 min, ESI-MS: m/z 423.09 [M+H]+.
d) 4-[(2-Bromo-benzyl)-cyano-(5-methoxy-pyridin-3-yl)-methyl]-piperazine-1-carboxylic acid ieri.-butyl ester is synthesized from 4-[cyano-(5-methoxy-pyridin-3-yl)-methyl]-piperazine-1-carboxylic acid ieri.-butyl ester according to Example 56.01 : fR (LC-1) 1.04 min, ESI-MS: m/z 501.01 [M+H]+.
e) 4-[cyano-(5-methoxy-pyridin-3-yl)-methyl]-piperazine-1-carboxylic acid ieri.-butyl ester is obtained from 5- methoxypyridin-3-carbaldehyde according to Example 56.01 : fR (LC-1) 0.88 min, ESI-MS: m/z 374.09 [M+H+MeCN]+. 1H-NMR (CDCI3): δ 1.49 (s, 9 H), 2.57 (m, 4 H), 3.50 (m, br, 4 H), 3.93 (s, 3 H), 4.90 (s, 1 H), 7.37 (s, 1 H), 8.36 (s, 1 H), 8.42 (s, 1 H). Example 60.01
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(5,6,7,8-tetrahydro-quinolin-2-yl)-indan-1,3-dione
a) NEt3 (25 juL) is added to freshly prepared crude 1-(2-ethyl-benzyl)-4-trimethylsilanyl-piperazine (0.25 mmol) and is diluted with dioxane (1 mL). Crude 2-bromo-2-(5,6,7,8-tetrahydro-quinolin-2-yl)-indan-1 ,3-dione (0.11 mmol) solution is added. The reaction is stirred at r.t. for 20 h. The mixture is dissolved in DCM (2 mL), and washed once with water (1 mL). The org. phase is separated by passage through a phase separator tube filled with Isolute HM-N™, and the tube rinsed with DCM (2 mL). The filtrate is concentrated to dryness under reduced pressure. This material is diluted in MeCN (0.7 mL), filtered through 0.45
Figure imgf000124_0001
syringe filter that is rinsed with 0.5 mL MeCN and the filtrate purified by prep LC-MS (B). After evaporation under reduced pressure pure 2- [4-(2-ethyl-benzyl)-piperazin-1-yl]-2-(5,6J,8-tetrahydro-quinolin-2-yl)-indan-1 ,3-dione is obtained: fR (LC-2) 0.93 min, ESI-MS: m/z 480.02 [M+H]+. 1H-NMR (CDCI3): δ 1.22 (t, J = 7.5 Hz, 3 H), 1.73 (m, 4 H), 2.51 (s, 4 H), 2.61 (m, 2 H), 2.72 (m, 4 H), 2.86 (m, 4 H), 3.50 (s, 2 H), 7.11 (m, 1 H), 7.19 (m, 2 H), 7.28 (m, 1 H), 7.39 (d, J = 8.0 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.84 (m, 2 H), 7.99 (m, 2 H).
b) 2-(5,6,7,8-Tetrahydro-quinolin-2-yl)-indan-1 ,3-dione (61 mg) is suspended in dry Et^O (2 mL) at r.t. under argon. NBS (42 mg) and ammonium acetate (1.7 mg) is added. The brown suspension turns into a light yellow solution with suspension and the reaction is stirred for 1 h. The reaction mixture containing 2-bromo-2-(5, 6,7,8- tetrahydro-quinolin-2-yl)-indan-1 ,3-dione was directly used for the piperazine alkylation described in step a) above: fR (LC-2) 1.05 min, ESI-MS: m/z 357.80 [M+H]+.
c) 2-(5,6,7,8-Tetrahydro-quinolin-2-yl)-indan-1 ,3-dione is obtained according to S Robert-Piessard ef a/., Eur. J. Med. Chem. 1990 25 737 If ' by heating diethyl phthalate (2.8 mL) and 2-methyl-5,6,7,8-tetrahydroquinoline (1.47 g) in the presence of NaH (2.01 g) in dry DME (40 mL) at reflux for 45 h, cooling to 0 °C, destruction of residual NaH with water, acidification to pH 1-2 with 25% aq. HCI, extraction with DCM, and purification by FC (heptane/AcOEt 1 :0 to 7:3), followed by prep. TLC (toluene/AcOEt, 1 :1 , Rf = 0.5): 63 mg: fR (LC-2) 0.96 min, ESI-MS: m/z 277.98 [M+H]+. 1H-NMR (d6-DMSO, enol-tautomer): δ 1.77 (m, 2 H), 1.85 (m, 2 H), 2.68 ( = 6.3 Hz, 2 H), 2.93 (t, J = 6.3 Hz, 2 H), 7.50 (m, 2 H), 7.55 (m, 2 H), 7.85 (d, J = 8.8 Hz, 1 H), 8.19 (d, J = 8.8 Hz, 1 H, 14.14 (s, br, 1 H).
Table 60: Example 60.02
Figure imgf000124_0002
a) 1-(5-Fluoro-2-methyl)-piperazine and N,0-bis(trimethylsilyl)acetamide (150 μΐ) are dissolved in dry DCM (1 mL) under argon. The mixture is heated at reflux for 1 h, cooled down to r.t., and the solution is directly used for the alkylation (step a, Example 60.01) with 2-bromo-2-(5,6,7,8-tetrahydro-quinolin-2-yl)-indan-1 ,3-dione (step b) above).
By repeating the procedures described for Example compounds 60.01 and 60.02, using appropriate starting materials, the following Example compounds as identified in Tables 61-66 are obtained:
Table 61: Examples 61.01-61.02
Figure imgf000125_0002
Table 62: Examples 62.01-62.04
Figure imgf000125_0003
Table 63: Examples 63.01-63.07
Figure imgf000125_0001
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(2-methyl-pyridin-4-yl)- 0.61
63.03 445.97 indan-1 ,3-dione (LC-1)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(2-methyl-pyridin-4-yl)- 0.66
63.04 440.00 indan-1 ,3-dione (LC-1)
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(2-methyl- 0.69
63.05 444.09 pyridin-4-yl)-indan-1 ,3-dione (LC-1)
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(2-methyl-pyridin-4- 0.61
63.06 442.01 yl)-indan-1 ,3-dione (LC-1)
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(2-methyl-pyridin-4- 0.61
63.07 441.99 yl)-indan-1 ,3-dione (LC-1)
Table 64: Examples 64.01-64.02
fR [min] LC- MS Data
Example Compound
MS Method m/z [M+H]+
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-methyl-pyridin-4- 0.64
64.01 426.03 yl)-indan-1 ,3-dione (LC-1)
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methyl-pyridin-4- 0.64
64.02 441.97 yl)-indan-1 ,3-dione (LC-1)
Table 65: Examples 65.01-65.06
fR [min] LC- MS Data
Example Compound
MS Method m/z [M+H]+
2-(4-Benzyl-piperazin-1-yl)-2-(4-methyl-pyridin-2-yl)-indan-1 ,3- 0.76
65.01 412.01 dione (LC-1)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(4-methyl-pyridin-2-yl)- 0.82
65.02 440.09 indan-1 ,3-dione (LC-1)
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(4-methyl-pyridin-2- 0.78
65.03 425.99 yl)-indan-1 ,3-dione (LC-1)
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(4-methyl-pyridin-2- 0.77
65.04 491.93 yl)-indan-1 ,3-dione (LC-1)
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(4-methyl-pyridin-2- 0.78
65.05 441.96 yl)-indan-1 ,3-dione (LC-1)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(4-methyl-pyridin-2- 0.78
65.06 445.84 yl)-indan-1 ,3-dione (LC-1) Table 66: Example 66.01
Figure imgf000127_0002
The following 2-bromo-2-(2,6-dimethyl-pyridin-4-yl)-indan-1 ,3-dione, 2-bromo-2-(4,6-dimethyl-pyridin-2-yl)- indan-1 ,3-dione, 2-bromo-2-(2-methyl-pyridin-4-yl)-indan-1 ,3-dione, 2-bromo-2-(3-methyl-pyridin-4-yl)-indan-1 ,3- dione, 2-bromo-2-(4-methyl-pyridin-2-yl)-indan-1 ,3-dione, 2-bromo-2-(6-methyl-pyrazin-2-yl)-indan-1 ,3-dione are prepared according to a procedure adapted from Tanemura, K. ei a/., Chem. Commun. 2004, 470-476 by brominating the respective 2-(2,6-dimethyl-pyridin-4-yl)-indan-1 ,3-dione, 2-(4,6-dimethyl-pyridin-2-yl)-indan-1 ,3- dione, 2-(2-methyl-pyridin-4-yl)-indan-1 ,3-dione, 2-(3-methyl-pyridin-4-yl)-indan-1 ,3-dione, 2-(4-methyl-pyridin-2- yl)-indan-1 ,3-dione, 2-(6-methyl-pyrazin-2-yl)-indan-1 ,3-dione with NBS and are used without any further purification as crude products in the next step.
The following 2-heteroaryl-indan-1 ,3-dione derivatives are commercially available; or are prepared according to J. Ploquin ei a/., J. Heterocyci. Ch., 1980, 961-73 from their respective methyl-substituted precursor and phthalic anhydride by condensation at elevated temperature: 2-(2,6-dimethyl-pyridin-4-yl)-indan-1 ,3-dione, 2-(4,6- dimethyl-pyridin-2-yl)-indan-1 ,3-dione, 2-(2-methyl-pyridin-4-yl)-indan-1 ,3-dione, 2-(3-methyl-pyridin-4-yl)-indan- 1 ,3-dione, 2-(4-methyl-pyridin-2-yl)-indan-1 ,3-dione, 2-(6-methyl-pyrazin-2-yl)-indan-1 ,3-dione.
By repeating the procedures described for the examples in Tables 14-25, using appropriate starting materials, the following Example compounds as identified in Table 67 are obtained:
- 67.12
Figure imgf000127_0001
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-5-methoxy-(3- 0.91
67.05 473.02
methylphenyl)-indan-1 ,3-dione (LC-1)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-5-methoxy-(3- 0.93
67.06 469.50
methylphenyl)-indan-1 ,3-dione (LC-1)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-5-methoxy-(3- 0.9
67.07 474.79
methylphenyl)-indan-1 ,3-dione (LC-1)
5-Methoxy-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-(3- 0.91
67.08 471.10
methylphenyl)-indan-1 ,3-dione (LC-1)
5-Methoxy-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-(3- 0.91
67.09 455.05
methylphenyl)-indan-1 ,3-dione (LC-1)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-5-methoxy-(3- 0.92
67.10 447.16
methylphenyl)-indan-1 ,3-dione (LC-1)
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1-yl)-5-methoxy-(3- 0.89
67.1 1 485.01
methylphenyl)-indan-1 ,3-dione (LC-1)
2-(4-Benzyl-piperazin-1-yl)-5-methoxy-(3-methylphenyl)-indan- 0.89
67.12 440.97
1 ,3-dione (LC-1)
5-Methoxy-2-piperazin-1-yl-2-(3-methylphenyl)-indan-1 ,3-dione hydrochloride is prepared according to the procedure for above described Example 4.01.
5-Methoxy-2-piperazin-1-yl-2-(3-methylphenyl)-indan-1 ,3-dione hydrochloride: fR (LC-1) 0.77; ESI-MS: m/z 350.98 [M+H-HCI]+. 1H-NMR (CDCI3): 2.27 (s, 3 H), 2.81 (s, 4 H), 3.04 (s, 4 H), 3.98 (s, 3 H), 7.21 (m, 4 H), 7.44 (s, 1 H), 7.58 (m, 1 H), 7.97 (d, J = 8.5, 1 H), 8.90 (d, J = 1.0, 2 H).
2-Bromo-5-methoxy-2-(3-methylphenyl)-indan-1 ,3-dione and 2-chloro-5-methoxy-2-(3-methylphenyl)-indan-1 ,3- dione are prepared according to a procedure adapted from Tanemura, K. et al., Chem. Commun. 2004, 470-476 by brominating 5-methoxy-2-(3-methylphenyl)-indan-1 ,3-dione with NBS and NCS respectively.
2-Bromo-5-methoxy-2-(3-methylphenyl)-indan-1 ,3-dione: fR (LC-1) 1.05; ESI-MS: m/z 346.90 [M+H]+. 1H-NMR (CDCI3): £2.37 (s, 3 H), 4.01 (s, 3 H), 7.17 (m, 1 H), 7.28 (m, 1 H), 7.50 (m, 4 H), 8.09 (m, 1 H).
2-Chloro-5-methoxy-2-(3-methylphenyl)-indan-1 ,3-dione: fR (LC-1) 1.05; ESI-MS: m/z 300.67 [M+H]+.
5-Methoxy-2-(3-methylphenyl)-indan-1 ,3-dione is prepared according to an adapted procedure from C. G. Thomson ei a/., Bioorg. Med. Chem. Letters 2006, 16(5), 1388-1391 , from the respective phthalic acid anhydride in reaction with phenyl acetic acid in AC2O in the presence of NEt.3 at reflux, followed by treatment with NaOMe in MeOH at reflux: 5-Methoxy-2-(3-methylphenyl)-indan-1 ,3-dione: fR (LC-1) 0.98; ESI-MS: mil 266.97 [M+H]+. 1H-NMR (DMSO- ck): 2.34 (s, 3 H), 4.01 (s, 3 H), 4.22 (s, 1 H), 6.99 (s, 2 H), 7.13 (d, J = 7.5, 1 H), 7.26 (m, 1 H), 7.43 (m, 2 H), 8.01 (d, J = 8.3, 1 H).
By repeating the procedures described for the examples in Tables 14-25, using appropriate starting materials, the following Example compounds as identified in Table 68 are obtained:
Table 68: Example 68.01- 68.09
Figure imgf000129_0001
2-Bromo-4-hydroxy-2-phenyl-indan-1 ,3-dione is prepared according to a procedure adapted from Tanemura, K. ei a/., Chem. Commun. 2004, 470-476 by brominating the respective 4-hydroxy-2-phenyl-indan-1 ,3-dione with NBS.
2-Bromo-4-hydroxy-2-phenyl-indan-1 ,3-dione: fR (LC-1) 0.94; ESI-MS: m/z n.a.. 1H-NMR (DMSO-afe): £7.44 (m, 4 H), 7.59 (m, 3 H), 7.93 (m, 1 H), 11.63 (s, 1 H).
4-Hydroxy-2-phenyl-indan-1 ,3-dione is prepared according to an adapted procedure from C. G. Thomson et al., Bioorg. Med. Chem. Letters 2006, 16(5), 1388-1391 , from the respective phthalic acid anhydride derivative in reaction with phenyl acetic acid in AC2O in the presence of NEt.3 at reflux, followed by treatment with NaOMe in MeOH at reflux: fR (LC-1) 0.86; ESI-MS: m/z 239.08 [M+H]+.
Table 69: Example 69.01
Figure imgf000130_0001
a) Triethylamine (42 /A.) is added to the mixture containing 1-(2-ethyl-benzyl)-4-trimethylsilanyl-piperazine (step d below, 0.25 mmol) and is diluted with anhydrous dioxane (1 mL) in a microwave vial equipped with a magnetic stirring bar. Crude 2-bromo-2-pyrimidin-4-yl-indan-1 ,3-dione (0.2 mmol) is added and the resulting mixture is heated up to 60°C for 60 min in the microwave. After cooling to r.t., DCM is added (2 mL) and the resulting mixture washed with water (1 mL). The org. phase is separated by passage through a phase separator cartridge filled with Isolute HM™ and the cartridge rinsed once with DCM (2 mL). The filtrate is concentrated under reduced pressure. The crude material obtained is purified by prep. LC-MS (B) to give 2-[4-(2-ethyl-benzyl)- piperazin-1-yl]-2-pyrimidin-4-yl-indan-1 ,3-dione: fR (LC-2) 0.81 ; ESI-MS: m/z 426.78 [M+H]+; 1H-NMR (CDCI3): δ 1.22 (t, J = 7.5 Hz, 3 H), 2.52 (s, 4 H), 2.72 (q, J = 7.5 Hz, 2 H), 2.82 (t, J = 4.5 Hz, 4 H), 3.51 (s, 2 H), 7.92 (dd, J = 5.8, 3.3 Hz, 2 H), 8.01 (dd, J = 5.3, 1.0 Hz, 1 H), 8.04 (dd, J = 5.8, 3.0 Hz, 2 H), 8.80 (d, J = 5.3 Hz, 1 H), 8.98 (d, J = 0.8 Hz, 1 H).
b) 2-Bromo-2-pyrimidin-4-yl-indan-1 ,3-dione is prepared according to a procedure adapted from Tanemura, K. ef a/., Chem. Commun. 2004, 470-476 by brominating 2-pyrimidin-4-yl-indan-1 ,3-dione with NBS and is used without any further purification as crude products in the next step: fR (LC-2) 0.89; ESI-MS: m/z 343.88 [M+MeCN+H]+.
c) 2-Pyrimidin-4-yl-indan-1 ,3-dione is prepared using an adapted procedure from J. Ploquin ef a/., J. Heterocycl. Chem., 1990, 77, 961-73, by heating in a microwave oven.
d) 1-(2-Ethyl-benzyl)-piperazine (102 mg, 0.5 mmol) and N,0-bis(trimethylsilyl)acetamide (310 β, 1.25 mmol) are dissolved in DCM (2 mL) under argon. Activated molecular sieves (4 A) are added and the mixture was stirred at r.t. over night. The resulting solution containing 1-(2-ethyl-benzyl)-4-trimethylsilanyl-piperazine is directly used for the alkylation described in above step a).
e) Crude 4-(2-ethyl-benzyl)-piperazine-1-carboxylic acid ferf.-butyl ester is dissolved with stirring in 3.3 N HCI in dry AcOEt (20 mL), after 1 h further 3.3 N HCI in dry AcOEt (10 mL) is added to the now white suspension and the mixture further diluted with AcOEt (20 mL). After 2 h, a thick white suspension has formed. The mixture is filtered through a fritted funnel and filter residue washed with little AcOEt. Drying under high vacuum yields 1-(2- ethyl-benzyl)-piperazine bis-hydrochloride salt as white crystals. fR (LC-2) 0.52; ESI-MS: m/z 205.10. [M+H]+; 1H-NMR (D20): 1.15 (t, J = 7.5 Hz, 3 H), 2.72 (q, J = 7.8 Hz, 2 H), 3.20 (m, 1 H), 3.54 (m, 9 H), 3.66 (m, 1 H), 4.41 (s, 2 H), 7.31 (m, 1 H), 7.43 (m, 3 H).
f) Sodium cyanoborhydride is added in portions to an ethanolic solution of 1-Boc-piperazine, 2- ethylbenzaldehyde and a spatula tip of bromocresol Green sodium salt at r.t.. AcOH is added until indicator changed color from blue to green. The mixture is stirred over night at r.t. After evaporation of the solvents under reduced pressure, the residue is distributed in 1 N aq. NaOH (200 mL) and DCM (50mL) and the org. phase separated. The aq. phase is washed with DCM (2x 20 mL), the collected org. phases unified and dried over Na2SC>4, filtered, and evaporated to dryness to yield 4-(2-ethyl-benzyl)-piperazine-1-carboxylic acid fert. -butyl ester as a colorless oil that is used as such in step (e) above: fR (LC-2) 0.77; ESI-MS: m/z 305.07 [M+H]+.
Table 70: Examples 70.01-70.03
Figure imgf000131_0001
Above products are prepared from 2-(6-methyl-pyrimidin-4-yl)-indan-1 ,3-dione by bromination with NBS and reaction with the corresponding freshly prepared 4-trimethylsilylated 1 -substituted piperazine according to Example 69 above:
Figure imgf000131_0002
2-(6-Methyl-py ri mid i n-4-yl) indan-1 , 3-d ione above is prepared according to an adapted procedure from J. Ploquin ef a/., J. Heterocycl. Chem., 1990, 17, 961-73, by heating a solution of phthalic anhydride and 4,6- dimethylpyrimidine in 1 ,2-dichlorobenzene for 20 h at 200°C: 1H-NMR (d6-DMSO, enol-tautomer): 2.47 (s, 3 H), 7.64 (m, 4 H), 8.13 (s, 1 H), 8.72 (s, 1 H), 13.7 (s, br, 1 H). By repeating either one of the procedures used in the synthesis of above-mentioned examples from Tables 1- 19, using appropriate starting materials, the following Example compounds as identified in Table I bis are obtained
Table Ibis : Examples 1.80-19.18
Figure imgf000132_0001
4-Chloro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-phenyl- 0.91
462.97 indan-1 ,3-dione (LC-1)
4-Methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan- 0.9
425.04 1 ,3-dione (LC-1)
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-4-methyl-2-phenyl-indan- 0.91
441.04 1 ,3-dione (LC-1)
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-4-methyl-2- 0.91
442.87 phenyl-indan-1 ,3-dione (LC-1)
5-Fluoro-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan- 0.89
445.06 1 ,3-dione (LC-1)
5-Fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-phenyl- 0.9
447.00 indan-1 ,3-dione (LC-1)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-5-fluoro-2-phenyl-indan- 0.89
449.01 1 ,3-dione (LC-1)
5-Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan- 0.87
429.12 1 ,3-dione (LC-1)
2-[4-(2-Ethyl-5-fluoro-benzyl)-piperazin-1-yl]-5-methyl-2-phenyl- 0.89
457.30 indan-1 ,3-dione (LC-1)
2-(3-Chloro-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan- 0.93
458.68 1 ,3-dione (LC-1)
2-(3-Chloro-phenyl)-2-[4-(2,4-dimethyl-benzyl)-piperazin-1-yl]- 0.93
458.99 indan-1 ,3-dione (LC-1)
2-(3-Chloro-phenyl)-2-[4-(2,5-difluoro-benzyl)-piperazin-1-yl]- 0.89
466.66 indan-1 ,3-dione (LC-1)
2-(3-Bromo-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan- 0.91
488.96 1 ,3-dione (LC-1)
2-(3-Bromo-phenyl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]- 0.91
505.0 indan-1 ,3-dione (LC-1)
2-(3-Bromo-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan- 0.94
504.88 1 ,3-dione (LC-1)
2-(3-Bromo-phenyl)-2-[4-(2-chloro-benzyl)-piperazin-1-yl]-indan- 0.9
510.93 1 ,3-dione (LC-1)
2-(3-Bromo-phenyl)-2-[4-(2,4-dimethyl-benzyl)-piperazin-1-yl]- 0.93
503.06 indan-1 ,3-dione (LC-1) 2-(3-Bromo-phenyl)-2-[4-(2,5-difluoro-benzyl)-piperazin-1-yl]- 0.89
16.18 512.96
indan-1 ,3-dione (LC-1)
0.88
17.14 2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-m-tolyl-indan-1,3-dione 445.11
(LC-1)
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2- n-tolyl-indan-1 ,3- 0.91
17.15 439.11
dione (LC-1)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2- 77-tolyl-indan-1 ,3- 0.87
17.16 447.10
dione (LC-1)
2-[4-(4-Methyl-pyridin-3-ylmethyl)-piperazin-1-yl]-2-(3- 0.72
17.17 426.03
methylphenyl)-indan-1 ,3-dione (LC-1)
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-trifluoromethyl- 0.94
18.08 493.13
phenyl)-indan-1 ,3-dione (LC-1)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-trifluoromethyl- 0.91
18.09 501.00
phenyl)-indan-1 ,3-dione (LC-1)
2-[4-(4-Methyl-pyridin-3-ylmethyl)-piperazin-1-yl]-2-(3- 0.77
18.10 480.12
trifluoromethyl-phenyl)-indan-1 ,3-dione (LC-1)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan- 0.9
19.16 455.09
1 ,3-dione (LC-1)
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)- 0.9
19.17 455.09
indan-1 ,3-dione (LC-1)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)- 0.86
19.18 463.10
indan-1 ,3-dione (LC-1)
(R)-2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-4-methyl-2-phenyl-indan-1 ,3-dione and (S)-2-(4- benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-4-methyl-2-phenyl-indan-1 ,3-dione
The two enantiomers of 2-(4-benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1 -yl)-4-methyl-2-phenyl-indan-1 ,3-dione (Example 6.03) are separated by chiral prep. LC-MS (D). Conditions: ChiralPak AD-H column, Eluent : EtOH with 0.1% DEA / Heptane (20:80)
Example 6.03A: Enantiomer A: fR (LC-14) 11.83.
Example 6.03B: Enantiomer B: fR (LC-14) 15.98.
Example 72.01
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-vinyl-phenyl)-indan-1 ,3-dione
To a stirred mixture of 2-piperazin-1-yl-2-(3-vinyl-phenyl)-indan-1 ,3-dione hydrochloride (0.054 mmol) and NaBH(OAc)3 (0.119 mmol) in DCM (0.3 mL) is added 2-methyl-benzaldehyde (0.06 mmol). The resulting soln. is continued to stir at r.t. over night. Then DCM and water are added and the resulting aq. layer is extracted twice with DCM. The comb. org. layer is dried (MgSC ) and filtered. The solvent is evaporated and the title compound is obtained after purification by prep. LC-MS (B) as a yellow powder: fR (LC-1) 0.92; ESI-MS: m/z 437.1 [M+H]+. 1H-NMR (CDCI3): δ 2.34 (s, 3 H), 2.46 (s, 4 H), 2.76 (t, 4 H), 3.45 (s, 2 H), 5.26 (d, 1 H), 5.74 (d, 1 H), 6.69 (dd, 1 H), 7.12 (m, 3 H), 7.25 (m, 1 H), 7.29 (m, 1 H), 7.38 (m, 1 H), 7.44 (m, 1 H), 7.55 (t, 1 H), 7.88 (m, 2 H), 7.99 (m, 2 H)
a) 2-Piperazin- 1 -yl-2-(3-vinyl-Dhenyl)-indan-1,3-dione hydrochloride
To a soln. of 4-[1 ,3-dioxo-2-(3-vinyl-phenyl)-indan-2-yl]-piperazine-1-carboxylic acid ferf-butyl ester (0.243 mmol) in DCM (4 ml) is added 4N soln. of HCI in 1 ,4-dioxane (3ml). The resulting soln. is continued to stir at r.t. for 1.5 h. The solvent is evaporated and the title compound is obtained as a yellow powder: fR (LC-1) 0.77; ESI- MS: m/z 333.03 [M+H]+.
b) 4-f1,3-Dioxo-2-(3-vinyl-Dhenyl)-indan-2-yll-oioerazine-1^a^oxylic acid tert-butyl ester
To a stirred suspension of 4-[2-(3-bromo-phenyl)-1 ,3-dioxo-indan-2-yl]-piperazine-1-carboxylic acid ferf-butyl ester (0.412 mmol), cesium carbonate (1.236 mmol) and potassium vinyltrifluoroborate (0.412 mmol) in THF (8 ml) is added [1 ,1-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane complex (0.041 mmol) and water (1 ml). The resulting soln. is heated to reflux for 6 h. After cooling, water is added and the resulting aq. phase is neutralized by slow addition of 1 N aq. HCI soln. and extrated three times with Et.20. The comb. org. phase is washed with 1 N aq. HCI soln. and brine and dried over IS^SC The solvent is evaporated and the subtitle compound is obtained after purification by FC as a yellow powder. fR (LC-1) 1.10; ESI-MS: m/z 433.11 [M+H]+.
c) 4-f2-(3 romo-ohenyl)-1,3-dioxo-indan-2-yll-oioerazine-1-carboxylic acid tert-butyl ester
To a solution of 2-bromo-2-(3-bromophenyl)-indane-1 ,3-dione (1.842 mmol) in dry 1 ,4-dioxane (25 ml) is added
1- Boc-piperazine (2.026 mmol) and NEt3 (2.21 mmol). The resulting soln. is continued to stir at r.t. over night. Then DCM and water are added and the resulting aq. layer is extracted twice with DCM. The comb. org. layer is dried (IS^SC ) and filtered. The solvent is evaporated and Et^O is added to the resulting solid. After trituration and filtration, the subtitle compound is obtained as a yellow powder: fR (LC-1) 1.11 ; ESI-MS: m/z 485.04 [M+H]+. Example 73.02
2- (3-Difluoromethyl^henyl)-2-[4-(2-m^
To a solution of 2-bromo-2-(3-difluoromethylphenyl)-indane-1 ,3-dione (0.1 mmol) in DCM (0.9 ml) is added 1-(2- methylbenzyl)piperazine (0.1 mmol) and DIPEA (0.3 mmol). The resulting soln. is continued to stir at r.t. over night. The mixture is then filtered through a PL-HCO3 cartridge which is then washed with a 1 :1 (MeOH/DCM) mixture. The solvent is evaporated in vacuuo and the residue dissolved in a 3:2 (MeOH/DCM) mixture (0.5 ml). The title compound is obtained after purification by prep. LC-MS (B) as a yellow powder: iR (LC-12a) 1.84; ESI-MS: m/z 460.82 [M+H]+. 1H-NMR (DMSO): δ 7.04 (m, 1 H), 7.10 (t, J = 7.4 Hz, 2 H), 7.22 (m, 1 H), 7.33 (t, J = 7.8 Hz, 2 H), 7.57 (m, 4 H), 7.85 (d, J = 8.8 Hz, 1 H), 7.91 (d, J = 8.2 Hz, 1 H), 7.96 (s, 1 H).
a) 2-Bromo-2-(3-difluoromethylohenyl)-indane-1, 3-dione
To solution of 2-(3-difluoromethylphenyl)-indane-1 ,3-dione (11.8 mmol) and NBS (12.4 mmol) in Et20 is added ammonium acetate (1.81 mmol). The resulting suspension is continued to stir for 1 h. Water is added and the resulting aq. phase is extracted three times with brine. The comb. org. phase is washed with brine and dried over MgSC>4. The solvent is evaporated and the subtitle compound is obtained after purification by FC as an off- white powder: fR (LC-1) 1.03; ESI-MS: m/z n.a. [M+H]+.
b) 2-( 3-Difluorometh ylphen yi) -indane- 1 , 3-dione
To a solution phthalide (11.18 mmol) in ethyl propionate (20 ml) is added 3-(difluoromethyl)benzaldehyde. The mixture is heated to 30°C and 5.4N NaOMe in MeOH soln. (20.25 mmol) is added dropwise over 5 min. Upon completion of the addition, the mixture is refluxed for 1 h. It is then cooled to r.t. and DCM and water are added. The resulting aq. phase is set to pH = 2 by careful addition of 2N aq. HCI soln. It is extracted three times with DCM. The comb. org. phase is dried over IS^SC . The subtitle compound is obtained as a red powder and is used as such in the next step. fR (LC-1) 0.96; ESI-MS: m/z 313.98 [M+H]+.
By repeating either one of the procedures used in the synthesis of examples 1.01 , 1.02, 1.03, 72.01 or 73.01 , using appropriate starting materials, the following Example compounds as identified in Tables 71-86 are obtained
Table 71: Examples 71.01-71.12
* [min]
MS Data m/z
Example Compound (LC-MS
[M+H]+ Method)
0.61
71.01 2-(4-Benzyl-piperazin-1-yl)-2-(3-fluoro-phenyl)-indan-1 , 3-dione 415.09
(LC-5)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-fluoro-phenyl)- 0.65
71.02 421.24
indan-1 , 3-dione (LC-5)
2-(3-Fluoro-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]- 0.63
71.03 429.12
indan-1 , 3-dione (LC-5)
2-(3-Fluoro-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]- 0.62
71.04 445.16
indan-1 , 3-dione (LC-5)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-indan- 0.64
71.05 443.2
1 , 3-dione (LC-5)
71.06 2-(3-Fluoro-phenyl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]- 0.64 429.14 indan-1,3-dione (LC-5)
2-(3-Fluoro-phenyl)-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)- 0.56
71.07 416.12 indan-1,3-dione (LC-5)
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-fluoro- 0.64
71.08 447.1 phenyl)-indan-1 ,3-dione (LC-5)
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)- 0.66
71.09 443.13 indan-1,3-dione (LC-5)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)- 0.62
71.10 451.02 indan-1,3-dione (LC-5)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-indan- 0.63
71.11 449.16
1,3-dione (LC-5)
2-(3-Fluoro-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)- 0.6
71.12 421.03 indan-1,3-dione (LC-5)
Table 72: Examples 72.01-72.04
Figure imgf000137_0001
Table 73: Examples 73.01-73.06 fR [min] MS Data
Example Compound LC-MS m/z
Method [M+H]+
2-(4-Benzyl-piperazin-1-yl)-2-(3-difluoromethyl-phenyl)-indan- 1.6 (LC-
73.01 446.76
1,3-dione 12a)
2-(3-Difluoromethyl-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)- 1.89 (LC-
73.03 478.74 piperazin-1-yl]-indan-1 ,3-dione 12a)
73.04 2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(3- 1.52 (LC- 490.73 difluoromethyl-phenyl)-indan-1 ,3-dione 12a)
2-(3-Difluoromethyl-phenyl)-2-[4-(2-methoxy-benzyl)- 1.43 (LC-
73.05 476.75 piperazin-1-yl]-indan-1 ,3-dione 12a)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-difluoromethyl- 1.86 (LC-
73.06 480.66 phenyl)-indan-1 ,3-dione 12a)
Table 74: Examples 74.01-74.11 fR [min] MS Data
Example Compound LC-MS m/z
Method [M+H]+
2-(4-Benzyl-piperazin-1-yl)-2-(3-ethoxy-phenyl)-indan-1 ,3- 0.63 (LC-
74.01 441.16 dione 5)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-ethoxy-phenyl)- 0.67 (LC-
74.02 447.24 indan-1 ,3-dione 5)
2-(3-Ethoxy-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]- 0.66 (LC-
74.03 455.18 indan-1 ,3-dione 5)
2-(3-Ethoxy-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]- 0.68 (LC-
74.04 469.15 indan-1 ,3-dione 5)
2-(3-Ethoxy-phenyl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]- 0.66 (LC-
74.05 455.23 indan-1 ,3-dione 5)
2-(3-Ethoxy-phenyl)-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)- 0.59 (LC-
74.06 442.22 indan-1 ,3-dione 5)
2-(3-Ethoxy-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin- 0.67 (LC-
74.07 473.14
1-yl]-indan-1 ,3-dione 5)
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-ethoxy-phenyl)- 0.68 (LC-
74.08 469.23 indan-1 ,3-dione 5)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-ethoxy-phenyl)- 0.65 (LC-
74.09 477.08 indan-1 ,3-dione 5)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-ethoxy-phenyl)- 0.65 (LC-
74.10 475.21 indan-1 ,3-dione 5)
2-(3-Ethoxy-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)- 0.62 (LC-
74.1 1 447.16 indan-1 ,3-dione 5) Table 75: Examples 75.01-75.04
Figure imgf000139_0001
Table 76: Examples 76.01-76.04
Figure imgf000139_0002
Table 77: Examples 77.01-77.08 fR [min] MS Data
Example Compound LC-MS m/z
Method [M+H]+
2-(4-Benzyl-piperazin-1-yl)-2-(3-trifluoromethoxy-phenyl)-indan- 0.92 (LC-
77.01 481.12
1 ,3-dione 1)
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-trifluoromethoxy- 0.94 (LC-
77.02 495.1 phenyl)-indan-1 ,3-dione 1) 2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-trifluoromethoxy- 0.94 (LC-
77.03 511.16 phenyl)-indan-1 ,3-dione 1)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-trifluoromethoxy- 0.93 (LC-
77.04 515.28 phenyl)-indan-1 ,3-dione 1)
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(3- 0.92 (LC-
77.05 525.14 trifluoromethoxy-phenyl)-indan-1 ,3-dione 1)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-trifluoromethoxy- 0.96 (LC-
77.06 509.15 phenyl)-indan-1 ,3-dione 1)
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3- 0.95 (LC-
77.07 513.14 trifluoromethoxy-phenyl)-indan-1 ,3-dione 1)
2-[4-(4-Methyl-pyridin-3-ylmethyl)-piperazin-1-yl]-2-(3- 0.79 (LC-
77.08 496.18 trifluoromethoxy-phenyl)-indan-1 ,3-dione 1)
Table 78: Examples 78.01-78.05
Figure imgf000140_0001
yl-phenyl)-indan-1 ,3-dione LC-1
Table 79: Examples 79.01-79.12 fR [min] MS Data
Example Compound LC-MS m/z
Method [M+H]+
2-(3-Fluoro-5-methyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin- 0.91 (LC-
79.01 442.83
1-yl]-indan-1 ,3-dione 1)
79.02 2-(4-Benzyl-piperazin-1-yl)-2-(3-fluoro-5-methyl-phenyl)-indan- 0.9 (LC- 429.40 1,3-dione 5)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-fluoro-5-methyl- 0.94 (LC-
79.03 435.40 phenyl)-indan-1 ,3-dione 5)
2-(3-Fluoro-5-methyl-phenyl)-2-[4-(4-methoxy-benzyl)- 0.91 (LC-
79.04 459.60 piperazin-1-yl]-indan-1 ,3-dione 5)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl- 0.99 (LC-
79.05 457.60 phenyl)-indan-1 ,3-dione 5)
2-(3-Fluoro-5-methyl-phenyl)-2-[4-(3-methyl-benzyl)-piperazin- 0.94 (LC-
79.06 443.20
1-yl]-indan-1 ,3-dione 5)
2-(3-Fluoro-5-methyl-phenyl)-2-(4-pyridin-2-ylmethyl- 0.84 (LC-
79.07 430.40 piperazin-1-yl)-indan-1 ,3-dione 5)
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-5- 1.0 (LC-
79.08 461.60 methyl-phenyl)-indan-1 ,3-dione 5)
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl- 0.98 (LC-
79.09 457.60 phenyl)-indan-1 ,3-dione 5)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl- 0.98 (LC-
79.10 465.50 phenyl)-indan-1 ,3-dione 5)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl- 0.98 (LC-
79.11 463.40 phenyl)-indan-1 ,3-dione 5)
2-(3-Fluoro-5-methyl-phenyl)-2-(4-thiophen-2-ylmethyl- 0.9 (LC-
79.12 435.30 piperazin-1-yl)-indan-1 ,3-dione 5)
Table 80: Examples 80.01-80.27 fR [min] MS Data
Example Compound LC-MS m/z
Method [M+H]+
2-(3,5-Dimethyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]- 0.92 (LC-
80.01 439.13 indan-1 ,3-dione 1)
2-(3,5-Dimethyl-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)- 0.93 (LC-
80.02 457.11 piperazin-1-yl]-indan-1 ,3-dione 1)
2-(4-Chroman-2-ylmethyl-piperazin-1-yl)-2-(3,5-dimethyl- 0.93 (LC-
80.03 481.21 phenyl)-indan-1 ,3-dione 1)
2-(4-Benzyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-indan-1 ,3- 0.65 (LC-
80.04 425.24 dione 5) 2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)- 0.65 (LC-
80.05 430.76 indan-1 ,3-dione 5)
2-(3,5-Dimethyl-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1- 0.66 (LC-
80.06 455.15 yl]-indan-1 ,3-dione 5)
2-(3,5-Dimethyl-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]- 0.7 (LC-
80.07 453.25 indan-1 ,3-dione 5)
2-(3,5-Dimethyl-phenyl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]- 0.67 (LC-
80.08 439.17 indan-1 ,3-dione 5)
2-(3,5-Dimethyl-phenyl)-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)- 0.6 (LC-
80.09 426.19 indan-1 ,3-dione 5)
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl- 0.7 (LC-
80.10 453.12 phenyl)-indan-1 ,3-dione 5)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl- 0.66 (LC-
80.11 461.12 phenyl)-indan-1 ,3-dione 5)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)- 0.67 (LC-
80.12 459.09 indan-1 ,3-dione 5)
2-(3,5-Dimethyl-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1- 0.63 (LC-
80.13 431.10 yl)-indan-1 ,3-dione 5)
2-(3,5-Dimethyl-phenyl)-2-[4-(2-ethyl-5-methyl-3H-imidazol-4- 0.69
80.14 457.51 ylmethyl)-piperazin-1-yl]-indan-1 ,3-dione (LC-12b)
2-[4-(4-Chloro-1-methyl-1 H-pyrazol-3-ylmethyl)-piperazin-1-yl]- 0.97
80.15 463.43
2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione (LC-12b)
2-(3,5-Dimethyl-phenyl)-2-[4-(2-fluoro-5-methoxy-benzyl)- 1.14
80.16 473.00 piperazin-1-yl]-indan-1 ,3-dione (LC-12b)
2-(4-Benzo[1 ,3]dioxol-4-ylmethyl-piperazin-1-yl)-2-(3,5- 1.04
80.17 469.46 dimethyl-phenyl)-indan-1 ,3-dione (LC-12b)
2-[4-(2,5-Dimethoxy-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl- 0.94
80.18 485.50 phenyl)-indan-1 ,3-dione (LC-12b)
2-[4-(2,2-Dimethyl-chroman-6-ylmethyl)-piperazin-1-yl]-2-(3,5- 1.08
80.19 509.50 dimethyl-phenyl)-indan-1 ,3-dione (LC-12b)
2-[4-(5-Bromo-2-methoxy-benzyl)-piperazin-1-yl]-2-(3,5- 1.09
80.20 533.36 dimethyl-phenyl)-indan-1 ,3-dione (LC-12b)
2-[4-(5-Chloro-1 ,3-dimethyl-1 H-pyrazol-4-ylmethyl)-piperazin-1- 0.9 (LC-
80.21 477.44 yl]-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione 12b) 2-[4-(4-Dimethylamino-2-methoxy-benzyl)-piperazin-1-yl]-2- 0.85
80.22 498.50
(3,5-dimethyl-phenyl)-indan-1 ,3-dione (LC-12b)
2-(3,5-Dimethyl-phenyl)-2-[4-(5-isopropyl-2-methoxy-benzyl)- 1.05
80.23 497.54 piperazin-1-yl]-indan-1 ,3-dione (LC-12b)
2-(3,5-Dimethyl-phenyl)-2-[4-(3-methyl-thiophen-2-ylmethyl)- 1.18
80.24 445.48 piperazin-1-yl]-indan-1 ,3-dione (LC-12b)
2-(3,5-Dimethyl-phenyl)-2-[4-(5-fluoro-2-methoxy-benzyl)- 1.02
80.25 473.65 piperazin-1-yl]-indan-1 ,3-dione (LC-12b)
2-[4-(2,4-Dichloro-thiazol-5-ylmethyl)-piperazin-1-yl]-2-(3,5- 1.36
80.26 500.36 dimethyl-phenyl)-indan-1 ,3-dione (LC-12b)
2-(3,5-Dimethyl-phenyl)-2-[4-(3-oxo-3,4-dihydro-2H- 0.84
80.27 496.47 benzo[1 ,4]oxazin-6-ylmethyl)-piperazin-1-yl]-indan-1 ,3-dione (LC-12b)
Table 81: Examples 81.01-81.12 fR [min] MS Data
Example Compound LC-MS m/z
Method [M+H]+
2-(4-Benzyl-piperazin-1 -yl)-2-(3,5-difluoro-phenyl)-indan-1 ,3- 0.62 (LC-
81.01 433.04 dione 5)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3,5-difluoro-phenyl)- 0.66 (LC-
81.02 439.19 indan-1 ,3-dione 5)
2-(3,5-Difluoro-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]- 0.65 (LC-
81.03 447.12 indan-1 ,3-dione 5)
2-(3,5-Difluoro-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]- 0.64 (LC-
81.04 463.09 indan-1 ,3-dione 5)
2-(3,5-Difluoro-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]- 0.65 (LC-
81.05 461.07 indan-1 ,3-dione 5)
2-(3,5-Difluoro-phenyl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]- 0.65 (LC-
81.06 447.22 indan-1 ,3-dione 5)
2-(3,5-Difluoro-phenyl)-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)- 0.57 (LC-
81.07 433.58 indan-1 ,3-dione 5)
2-(3,5-Difluoro-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)- 0.66 (LC-
81.08 465.05 piperazin-1 -yl]-indan-1 ,3-dione 5)
2-(3,5-Difluoro-phenyl)-2-[4-(2,4-dimethyl-benzyl)-piperazin-1- 0.68 (LC-
81.09 461.08 yl]-indan-1 ,3-dione 5) 2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3,5-difluoro-phenyl)- 0.63 (LC-
81.10 469.16 indan-1 ,3-dione 5)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3,5-difluoro-phenyl)- 0.64 (LC-
81.11 466.93 indan-1 ,3-dione 5)
2-(3,5-Difluoro-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)- 0.61 (LC-
81.12 439.16 indan-1 ,3-dione 5)
Table 82: Examples 82.01-82.12 fR [min] MS Data
Example Compound LC-MS m/z
Method [M+H]+
2-(4-Benzyl-piperazin-1-yl)-2-(3-fluoro-5-methoxy-phenyl)- 0.63 (LC-
82.01 445.18 indan-1 ,3-dione 5)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-fluoro-5-methoxy- 0.66 (LC-
82.02 451.10 phenyl)-indan-1 ,3-dione 5)
2-(3-Fluoro-5-methoxy-phenyl)-2-[4-(2-methyl-benzyl)- 0.65 (LC-
82.03 459.20 piperazin-1 -yl]-indan-1 ,3-dione 5)
2-(3-Fluoro-5-methoxy-phenyl)-2-[4-(4-methoxy-benzyl)- 0.64 (LC-
82.04 475.15 piperazin-1 -yl]-indan-1 ,3-dione 5)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methoxy- 0.68 (LC-
82.05 473.17 phenyl)-indan-1 ,3-dione 5)
2-(3-Fluoro-5-methoxy-phenyl)-2-[4-(3-methyl-benzyl)- 0.66 (LC-
82.06 459.23 piperazin-1 -yl]-indan-1 ,3-dione 5)
2-(3-Fluoro-5-methoxy-phenyl)-2-(4-pyridin-2-ylmethyl- 0.58 (LC-
82.07 446.11 piperazin-1 -yl)-indan-1 ,3-dione 5)
2-(3-Fluoro-5-methoxy-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)- 0.66 (LC-
82.08 477.16 piperazin-1 -yl]-indan-1 ,3-dione 5)
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-5- 0.68 (LC-
82.09 473.23 methoxy-phenyl)-indan-1 ,3-dione 5)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methoxy- 0.64 (LC-
82.10 481.02 phenyl)-indan-1 ,3-dione 5)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methoxy- 0.65 (LC-
82.11 479.08 phenyl)-indan-1 ,3-dione 5)
2-(3-Fluoro-5-methoxy-phenyl)-2-(4-thiophen-2-ylmethyl- 0.61 (LC-
82.12 451.13 piperazin-1 -yl)-indan-1 ,3-dione 5) Table 83: Examples 83.01-83.05
Figure imgf000145_0001
Table 84: Examples 84.01-84.11 fR [min] MS Data
Example Compound LC-MS m/z
Method [M+H]+
2-(4-Benzyl-piperazin-1-yl)-2-(3,5-dimethoxy-phenyl)-indan- 0.86 (LC-
84.01 457.60
1,3-dione 5)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3,5-dimethoxy- 0.9 (LC-
84.02 463.60 phenyl)-indan-1 ,3-dione 5)
2-(3,5-Dimethoxy-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1- 0.89 (LC-
84.03 471.40 yl]-indan-1 ,3-dione 5)
2-(3,5-Dimethoxy-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin- 0.87 (LC-
84.04 487.40
1-yl]-indan-1 ,3-dione 5)
2-(3,5-Dimethoxy-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1- 0.94 (LC-
84.05 485.40 yl]-indan-1 ,3-dione 5)
2-(3,5-Dimethoxy-phenyl)-2-[4-(3-methyl-benzyl)-piperazin-1- 0.9 (LC-
84.06 471.40 yl]-indan-1 ,3-dione 5)
2-(3,5-Dimethoxy-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)- 0.94 (LC-
84.07 489.30 piperazin-1-yl]-indan-1 ,3-dione 5) 2-(3,5-Dimethoxy-phenyl)-2-[4-(2,4-dimethyl-benzyl)- 0.94 (LC-
84.08 485.60 piperazin-1-yl]-indan-1 ,3-dione 5)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3,5-dimethoxy- 0.91 (LC-
84.09 493.50 phenyl)-indan-1 ,3-dione 5)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3,5-dimethoxy- 0.92 (LC-
84.10 491.40 phenyl)-indan-1 ,3-dione 5)
2-(3,5-Dimethoxy-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin- 0.85 (LC-
84.11 463.60
1-yl)-indan-1 ,3-dione 5)
Table 85: Examples 85.01-85.05
Figure imgf000146_0001
Table 86: Examples 86.01-86.03 fR [min] MS Data
Example Compound LC-MS m/z
Method [M+H]+
2-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yl)-2-[4-(2-methyl-benzyl)- 0.86 (LC-
86.01 469.12 piperazin-1-yl]-indan-1 ,3-dione 1)
2-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yl)-2-[4-(2-ethyl-benzyl)- 0.89 (LC-
86.02 482.76 piperazin-1-yl]-indan-1 ,3-dione 1)
2-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yl)-2-[4-(2,5-dimethyl- 0.89 (LC-
86.03 482.73 benzyl)-piperazin-1 -yl]-indan-1 ,3-dione 1) Appropriate 2-phenyl-indan-2-piperazin-1-yl-1 ,3-dione derivatives are prepared as hydrochloride salts from the corresponding 4-( 1 , 3-d ioxo- i nda n-2-yl)- pi perazi ne- 1 -carboxyl ic acid tert-butyl ester according to the procedure a) for above described Example 72.01 or by reaction of piperazine monohydrochloride with the corresponding 2- phenyl-2-bromo-indan-1 ,3-dione according to the procedure a) for the above described example 1.02
Figure imgf000147_0001
The following substituted 4-(1 ,3-dioxo-indan-2-yl)-piperazine-1-carboxylic acid ieri-butyl ester derivative is obtained by Suzuki coupling of the corresponding bromide with the corresponding potassium trifluoroborate salt as described in the procedure b) in the synthesis of example 72.01
Figure imgf000147_0002
The following substituted 4-(1 ,3-dioxo-indan-2-yl)-piperazine-1 -carboxylic acid ieri-butyl ester derivatives are obtained by substitution of the corresponding 2-phenyl-2-bromo-indan-1 ,3-dione with N-Boc piperazine according to the procedure c) described in the synthesis of compound 72.01 fR [min] MS Data
Substituted 4-(1 ,3-dioxo-indan-2-yl)-piperazine-1 -carboxylic
LC-MS m/z acid tert-butyl ester
Method [M+H]+
4-[2-(3-Bromo-phenyl)-1 ,3-dioxo-indan-2-yl]-piperazine-1 -carboxylic acid tert-butyl 1.11
485.04 ester (LC-1)
4-[2-(3,5-Dimethyl-phenyl)-1 ,3-dioxo-indan-2-yl]-piperazine-1-carboxylic acid tert- 1.15
435.51 butyl ester (LC-2) Appropriate 2-halo-2-phenyl-indan-1 ,3-dione derivatives are prepared according to a procedure adapted from Tanemura, K. ef a/., Chem. Commun. 2004, 470-476 by reacting the corresponding 2-phenyl-indan-1 ,3-dione derivative with NBS or NCS.
Figure imgf000148_0001
2-Bromo-2-(3-momholin-4-yl-Dhenyl)-indan-1,3-dione
To a cooled to 0°C solution of 2-(3-morpholin-4-yl-phenyl)-indan-1 ,3-dione (0.1 mmol) in THF (1 ml), is added phenyl trimethylammonium bromide tribromide (0.110 mmol). After one hour, the crude reaction mixture is evaporated in vaccuo and the resulting solid used as such in the next step. fR (LC-1) 1.00; ESI-MS: m/z 387.96 [M+H]+.
The following 2-phenyl-indan-1 ,3-dione derivatives are commercially available, or are prepared according to a known procedure, e.g. by an adapted procedure from C. G. Thomson ef a/., Bioorg. Med. Chem. Letters 2006, 16(5), 1388-1391 , from their respective phthalic acid anhydride derivatives in reaction with phenyl acetic acid in AC2O in the presence of NEt.3 at reflux, followed by treatment with NaOMe in MeOH at reflux, or by an adapted procedure from US2005/0059663 from phthalide in reaction with their respective benzaldehyde derivatives with NaOMe in MeOH and ethyl propionate at reflux as described in procedure b) for the synthesis of example 73.02 fR [min]
MS Data
2-phenyl-indan-1 ,3-dione derivative LC-MS
m/z [M+H]+ Method
2-(3-Fluoro-phenyl)-indan-1 ,3-dione 0.96 (LC-1) 270.95 2-(3-Difluoromethyl-phenyl)-indan-1 ,3-dione 0.96 (LC-1) 313.98
2-(3-Ethoxy-phenyl)-indan-1 ,3-dione 0.97 (LC-1) 266.98
2-(3-Propoxy-phenyl)-indan-1 ,3-dione 1.01 (LC-1) 280.96
2-(3-Tnfluoromethoxy-phenyl)-indan-1 ,3-dione 1.01 (LC-1) 306.9
2-(3-Fluoro-5-methyl-phenyl)-indan-1 ,3-dione 0.97 (LC-1) 254.96
2-(3,5-Dimethyl-phenyl)-indan-1 ,3-dione 0.99 (LC-1) 250.98
2-(3,5-Difluoro-phenyl)-indan-1 ,3-dione 0.96 (LC-1) 258.97
2-(3-Fluoro-5-methoxy-phenyl)-indan-1 ,3-dione 0.96 (LC-1) 270.96
2-(3-Methoxy-5-methyl-phenyl)-indan-1 ,3-dione 0.96 (LC-1) 266.94
2-(3,5-Dimethoxy-phenyl)-indan-1 ,3-dione 0.94 (LC-1) 282.94
2',3'-Dihydro-1'H-[2,5']biindenyl-1 ,3-dione 1.00 (LC-1) 263.01
2-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yl)-indan-1 ,3-dione 0.92 (LC-1) 280.94
2-(3-Morpholin-4-yl-phenyl)-indan-1 ,3-dione 0.85 (LC-1) 308.02
By repeating either one of the procedures used in the synthesis of above-mentioned examples from Tables 26- 34 or 35-40 using appropriate starting materials, the following Example compounds as identified in Tables 87-98 are obtained:
Table 87: Examples 87.01-87.14 fR [min] LC- MS Data m/z
Example Compound
MS Method [M+H]+
2-Quinolin-2-yl-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan- 0.85
254.00
87.01 1 ,3-dione (LC-1)
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-quinolin-2-yl- 0.87
492.07
87.02 indan-1 ,3-dione (LC-1)
0.87
2-(4-Benzyl-piperazin-1-yl)-2-quinolin-2-yl-indan-1 ,3-dione 448.06
87.03 (LC-1)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-quinolin-2-yl-indan-1 ,3- 0.9
454.12
87.04 dione (LC-1)
2-(4-Pyridin-4-ylmethyl-piperazin-1-yl)-2-quinolin-2-yl-indan-1 ,3- 0.73
449.07
87.05 dione (LC-1) 2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-quinolin-2-yl-indan-1 ,3- 0.91
476.10
87.06 dione (LC-1)
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-quinolin-2-yl-indan- 0.89
478.03
87.07 1 ,3-dione (LC-1)
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-quinolin-2-yl-indan-1 ,3- 0.89
462.01
87.08 dione (LC-1)
2-[4-(3-Chloro-benzyl)-piperazin-1-yl]-2-quinolin-2-yl-indan-1 ,3- 0.89
482.03
87.09 dione (LC-1)
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-quinolin-2-yl-indan- 0.87
478.12
87.10 1 ,3-dione (LC-1)
2-[4-(3-Methyl-benzyl)-piperazin-1-yl]-2-quinolin-2-yl-indan-1 ,3- 0.89
462.12
87.1 1 dione (LC-1)
2-[4-(4-Chloro-benzyl)-piperazin-1-yl]-2-quinolin-2-yl-indan-1 ,3- 0.89
481.96
87.12 dione (LC-1)
2-[4-(4-Methoxy-benzyl)-piperazin-1-yl]-2-quinolin-2-yl-indan- 0.87
478.11
87.13 1 ,3-dione (LC-1)
2-[4-(4-Methyl-benzyl)-piperazin-1-yl]-2-quinolin-2-yl-indan-1 ,3- 0.89
462.15
87.14 dione (LC-1)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-quinolin-2-yl-indan-1 ,3- 0.88
481.98
87.15 dione (LC-1)
Table 88: Examples 88.01-88.05
* [min]
MS Data m/z
Example Compound LC-MS
[M+H]+ Method
2-(4-Benzyl-piperazin-1 -yl)-2-(1 -methyl-1 H-pyrazol-4-yl)-indan- 0.74
88.01 401.09
1 ,3-dione (LC-1)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(1 -methyl-1 H-pyrazol-4- 0.81
88.02 429.13 yl)-indan-1 ,3-dione (LC-1)
2-[4-(2-Methoxy-benzyl)-piperazin-1 -yl]-2-(1 -methyl-1 H-pyrazol- 0.77
88.03 431.10
4-yl)-indan-1 ,3-dione (LC-1)
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(1 -methyl-1 H-pyrazol-4- 0.77
88.04 415.11 yl)-indan-1 ,3-dione (LC-1)
88.05 2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(1-methyl-1 H- 0.78 433.09
Figure imgf000151_0001
Table 89: Examples 89.01-89.04
iR [min]
MS Data m/z
Example Compound LC-MS
[M+H]+ Method
2-(4-Benzyl-piperazin-1-yl)-2-(5-fluoro-pyridin-3-yl)-indan-1 ,3- 0.80
89.01 416.06 dione (LC-1)
2-(5-Fluoro-pyridin-3-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]- 0.84
89.02 430.09 indan-1 ,3-dione (LC-1)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(5-fluoro-pyridin-3-yl)- 0.87
89.03 444.14 indan-1 ,3-dione (LC-1)
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(5-fluoro- 0.84
89.04 448.13 pyridin-3-yl)-indan-1 ,3-dione (LC-1)
Table 90: Examples 90.01-90.04
Figure imgf000151_0002
Table 91: Examples 91.01-91.03
Figure imgf000152_0002
Table 92: Examples 92.01-92.04
Figure imgf000152_0003
Table 93: Examples 93.01-93.05
Figure imgf000152_0001
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(1 ,3,5-trimethyl-1 H- 0.83
93.04 442.89 pyrazol-4-yl)-indan-1 ,3-dione (LC-1)
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1 -yl]-2-(1 ,3,5- 0.84
93.05 461.19 trimethyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione (LC-1)
Table 94: Examples 94.01-94.04
*R [min]
MS Data m/z
Example Compound LC-MS
[M+H]+ Method
2-(4-Benzyl-piperazin-1-yl)-2-(5-methoxy-pyridin-3-yl)-indan- 0.78
94.01 428.11
1 ,3-dione (LC-1)
2-(5-Methoxy-pyridin-3-yl)-2-[4-(2-methyl-benzyl)-piperazin- 0.81
94.02 442.06
1-yl]-indan-1 ,3-dione (LC-1)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(5-methoxy-pyridin-3- 0.84
94.03 456.14 yl)-indan-1 ,3-dione (LC-1)
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(5- 0.82
94.04 460.12 methoxy-pyridin-3-yl)-indan-1 ,3-dione (LC-1)
Table 95: Examples 95.01-95.05
Figure imgf000153_0001
Table 96: Examples 96.01-96.02
Figure imgf000154_0001
Table 98: Examples 97.01-97.05
MS Data fR [min] LC-
Example Compound m/z
MS Method
[M+H]+
2-(4-Benzyl-piperazin-1-yl)-2-(2-pyrrolidin-1-yl-pyridin-4-yl)- 0.66
98.01 466.87 indan-1 ,3-dione (LC-1)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(2-pyrrolidin-1-yl- 0.71
98.02 495.20 pyridin-4-yl)-indan-1 ,3-dione (LC-1)
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(2-pyrrolidin-1-yl- 0.69
98.03 497.21 pyridin-4-yl)-indan-1 ,3-dione (LC-1) 2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(2-pyrrolidin-1-yl- 0.68
98.04 481.20
pyridin-4-yl)-indan-1 ,3-dione (LC-1)
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(2- 0.70
98.05 498.82
pyrrolidin-1 -yl-pyridin-4-yl)-indan-1 ,3-dione (LC-1)
The following 2-bromo-2-heteroaryl-indan-1 ,3-dione derivatives are prepared according to a procedure adapted from Tanemura, K. et al., Chem. Commun. 2004, 470-476 by brominating the corresponding 2-heteroaryl-indan- 1 ,3-dione derivatives with NBS and are used without any further purification as crude products in the next step: 2-bromo-2-quinolin-2-yl-indan-1 ,3-dione, 2-bromo-2-(1-methyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione, 2-bromo-2-(5- fluoro-pyridin-3-yl)-indan-1 ,3-dione, 2-bromo-2-(5-methyl-pyridin-3-yl)-indan-1 ,3-dione, 2-bromo-2-(6-methyl- pyridin-3-yl)-indan-1 ,3-dione, 2-bromo-2-(2,5-dimethyl-oxazol-4-yl)-indan-1 ,3-dione, 2-bromo-2-(1 ,3,5-trimethyl- 1 H-pyrazol-4-yl)-indan-1 ,3-dione, 2-bromo-2-(5-methoxy-pyridin-3-yl)-indan-1 ,3-dione, 2-bromo-2-(1-methyl-1 H- indazol-3-yl)-indan-1 ,3-dione, 2-bromo-2-(5-trifluoromethyl-pyridin-3-yl)-indan-1 ,3-dione, 2-bromo-2-(1-phenyl- 1 H-pyrazol-4-yl)-indan-1 ,3-dione, 2-bromo-2-(2-pyrrolidin-1 -yl-pyridin-4-yl)-indan-1 ,3-dione.
The following 2-heteroaryl-indan-1 ,3-dione derivatives are commercially available; or are prepared according to an adapted procedure from C. G. Thomson ei a/., Bioorg. Med. Chem. Letters 2006, 16(5), 1388-1391 , from their respective heteroaryl-acetic acid derivative and phthalic anhydride in AC2O in the presence of NEt.3 at reflux, followed by treatment with NaOMe in MeOH at reflux; or are prepared by the procedure from J. E. Wolfe ei a/., J. Org. Chem. 2004, 2006-10 from their respective commercially available methyl-substituted heteroaryl precursor and diethyl phthalate in the presence of NaH in refluxing DME; or are prepared according to a procedure adapted from K. A. Menear ei a/., J. Med. Chem. 2008, 51 (20), 6581-6591 , from their respective heteroarylcarboxaldehyde and phthalide with NaOMe in MeOH at reflux: 2-quinolin-2-yl-indan-1 ,3-dione, 2-(1- methyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione, 2-(5-fluoro-pyridin-3-yl)-indan-1 ,3-dione, 2-(5-methyl-pyridin-3-yl)- indan-1 ,3-dione, 2-(6-methyl-pyridin-3-yl)-indan-1 ,3-dione, 2-(2,5-dimethyl-oxazol-4-yl)-indan-1 ,3-dione, 2- (1 ,3,5-trimethyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione, 2-(5-methoxy-pyridin-3-yl)-indan-1 ,3-dione, 2-(1-methyl-1 H- indazol-3-yl)-indan-1 ,3-dione, 2-(5-trifluoromethyl-pyridin-3-yl)-indan-1 ,3-dione, 2-(1-phenyl-1 H-pyrazol-4-yl)- indan-1 ,3-dione, 2-(2-pyrrolidin-1-yl-pyridin-4-yl)-indan-1 ,3-dione.
By repeating either one of the procedures used in the synthesis of above-mentioned examples from Tables 45- 52, the following Example compounds as identified in Tables 45bis-52bis are obtained by reacting a substituted 2-bromo-2-phenyl-indan-1-one derivative with the appropriate piperazine derivative in the presence of NEt.3: Table 45bis: Examples 45.08-45.36 fR [min] MS Data
Example Compound LC-MS m/z
Method [M+H]+
1.28
45.08 2-(4-Benzyl-piperazin-1-yl)-4-chloro-2-phenyl-indan-1-one 417.47
(LC-12b)
4-Chloro-2-(4-cyclohexylmethyl-piperazin-1-yl)-2-phenyl- 1.39
45.09 423.5 indan-1-one (LC-12b)
4-Chloro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl- 1.43
45.10 431.47 indan-1-one (LC-12b)
4-Chloro-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-2-phenyl- 1.23
45.11 447.4 indan-1-one (LC-12b)
4-Chloro-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-2-phenyl-indan- 1.49
45.12 445.4
1-one (LC-12b)
4-Chloro-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-2-phenyl- 1.35
45.13 431.46 indan-1-one (LC-12b)
4-Chloro-2-phenyl-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)- 1.03
45.14 418.45 indan-1-one (LC-12b)
4-Chloro-2-[4-(2,5-difluoro-benzyl)-piperazin-1-yl]-2-phenyl- 1.34
45.15 453.4 indan-1-one (LC-12b)
4-Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl- 0.90
45.16 415.26 indan-1-one (LC-1)
0.62
45.17 2-(4-Benzyl-piperazin-1-yl)-4-fluoro-2-phenyl-indan-1-one 401.41
(LC-5)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-4-fluoro-2-phenyl- 0.66
45.18 407.47 indan-1-one (LC-5)
4-Fluoro-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-2-phenyl- 0.63
45.19 431.4 indan-1-one (LC-5)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-phenyl-indan- 0.67 (LC-
45.20 429.44
1-one 5)
4-Fluoro-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-2-phenyl- 0.65
45.21 415.44 indan-1-one (LC-5)
4-Fluoro-2-phenyl-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)- 0.57
45.22 402.45 indan-1-one (LC-5)
45.23 2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-4-fluoro-2-phenyl- 0.63 437.36 indan-1-one (LC-5)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-4-fluoro-2-phenyl-indan- 0.64
45.24 435.35
1-one (LC-5)
4-Fluoro-2-phenyl-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)- 0.61
45.25 407.39 indan-1-one (LC-5)
0.62
45.26 2-(4-Benzyl-piperazin-1-yl)-4-methoxy-2-phenyl-indan-1-one 413.16
(LC-5)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-4-methoxy-2-phenyl- 0.66
45.27 419.08 indan-1-one (LC-5)
4-Methoxy-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl- 0.64
45.28 427.16 indan-1-one (LC-5)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-4-methoxy-2-phenyl- 0.64
45.29 447.08 indan-1-one (LC-5)
4-Methoxy-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-2-phenyl- 0.63
45.30 443.18 indan-1-one (LC-5)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-4-methoxy-2-phenyl- 0.67
45.31 441.14 indan-1-one (LC-5)
4-Methoxy-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-2-phenyl- 0.65
45.32 427.12 indan-1-one (LC-5)
4-Methoxy-2-phenyl-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)- 0.57
45.33 414.17 indan-1-one (LC-5)
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-4-methoxy-2- 0.66
45.34 445.07 phenyl-indan-1-one (LC-5)
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-4-methoxy-2- 0.68
45.35 441.09 phenyl-indan-1-one (LC-5)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-4-methoxy-2-phenyl- 0.63
45.36 449.21 indan-1-one (LC-5)
Table 46bis: Examples 46.12-46.21 fR [min] MS Data
Example Compound LC-MS m/z
Method [M+H]+
0.84
46.12 2-(4-Benzyl-piperazin-1-yl)-5-fluoro-2-phenyl-indan-1-one 401.05
(LC-1) 2-(4-Cyclohexylmethyl-piperazin-1-yl)-5-fluoro-2-phenyl-indan- 0.87
46.13 406.47
1-one (LC-1)
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-5-fluoro-2- 0.86
46.14 445.05 phenyl-indan-1-one (LC-1)
5-Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan- 0.89
46.15 414.89
1-one (LC-1)
5-Fluoro-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-2-phenyl- 0.86
46.16 431.00 indan-1-one (LC-1)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-5-methoxy-2-phenyl- 0.64
46.17 419.49 indan-1-one (LC-5)
5-Methoxy-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-2-phenyl- 0.62
46.18 443.40 indan-1-one (LC-5)
5-Methoxy-2-phenyl-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)- 0.56
46.19 414.43 indan-1-one (LC-5)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-5-methoxy-2-phenyl- 0.62
46.20 449.57 indan-1-one (LC-5)
5-Methoxy-2-phenyl-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)- 0.60
46.21 419.39 indan-1-one (LC-5)
Table 48bis: Examples 48.12-48.21 fR [min] MS Data
Example Compound LC-MS m/z
Method [M+H]+
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-7-fluoro-2-phenyl-indan- 0.63
48.12 434.92
1-one (LC-5)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-7-fluoro-2-phenyl- 0.61
48.13 437.12 indan-1-one (LC-5)
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-7-fluoro-2-phenyl- 0.66
48.14 429.1 indan-1-one (LC-5)
7-Fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2- 0.64
48.15 433.16 phenyl-indan-1-one (LC-5)
7-Fluoro-2-phenyl-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)-indan- 0.55
48.16 401.7
1-one (LC-5)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-7-fluoro-2-phenyl-indan-1- 0.66
48.17 429.09 one (LC-5) 7-Fluoro-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-2-phenyl- 0.62
48.18 431.13 indan-1-one (LC-5)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-7-fluoro-2-phenyl-indan- 0.64
48.19 407.12
1-one (LC-5)
0.61
48.20 2-(4-Benzyl-piperazin-1 -yl)-7-fluoro-2-phenyl-indan-1 -one 401.22
(LC-5)
7-Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan- 0.88
48.21 415.24
1-one (LC-1)
Table 50bis: Examples 50.24-50.51 fR [min] MS Data
Example Compound LC-MS m/z
Method [M+H]+
0.9
50.24 2-(4-Benzyl-piperazin-1-yl)-2-(3-chloro-phenyl)-indan-1-one 417.09
(LC-1)
2-(3-Ethyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]- 0.9
50.25 425.06 indan-1-one (LC-1)
0.89
50.26 2-(4-Benzyl-piperazin-1 -yl)-2-(3-ethyl-phenyl)-indan-1 -one 410.96
(LC-1)
2-(3-lsopropyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]- 0.93
50.27 439.11 indan-1-one (LC-1)
2-(3-Fluoro-5-methyl-phenyl)-2-[4-(3-methyl-benzyl)-piperazin- 0.67
50.28 429.25
1-yl]-indan-1-one (LC-5)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl- 0.70
50.29 443.17 phenyl)-indan-1-one (LC-5)
2-(3-Fluoro-5-methyl-phenyl)-2-[4-(4-methoxy-benzyl)- 0.65
50.30 445.07 piperazin-1-yl]-indan-1-one (LC-5)
2-(3-Fluoro-5-methyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin- 0.67
50.31 429.13
1-yl]-indan-1-one (LC-5)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-fluoro-5-methyl- 0.68
50.32 421.25 phenyl)-indan-1-one (LC-5)
2-(4-Benzyl-piperazin-1-yl)-2-(3-fluoro-5-methyl-phenyl)-indan- 0.65
50.33 415.22
1-one (LC-5)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl- 0.67
50.34 449.03 phenyl)-indan-1-one (LC-5) 2-(3,5-Dimethyl-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1- 0.64
417.06 yl)-indan-1-one (LC-5)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)- 0.67
445.09 indan-1-one (LC-5)
2-(3,5-Dimethyl-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)- 0.69
443.14 piperazin-1-yl]-indan-1-one (LC-5)
2-(3,5-Dimethyl-phenyl)-2-(4-pyridin-2-ylmethyl-piperazin-1- 0.61
412.18 yl)-indan-1-one (LC-5)
2-(3,5-Dimethyl-phenyl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]- 0.68
425.16 indan-1-one (LC-5)
2-(3,5-Dimethyl-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1- 0.66
441.2 yl]-indan-1-one (LC-5)
2-(3,5-Dimethyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]- 0.68
425.18 indan-1-one (LC-5)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)- 0.69
417.09 indan-1-one (LC-5)
2-(4-Benzyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-indan-1- 0.66
411.23 one (LC-5)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3,5-diethyl-phenyl)- 0.72
473.14 indan-1-one (LC-5)
2-(3,5-Diethyl-phenyl)-2-[4-(2,5-difluoro-benzyl)-piperazin-1- 0.71
475.08 yl]-indan-1-one (LC-5)
2-(3,5-Diethyl-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)- 0.73
471.23 piperazin-1-yl]-indan-1-one (LC-5)
2-(3,5-Diethyl-phenyl)-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)- 0.66
440.21 indan-1-one (LC-5)
2-(3,5-Diethyl-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]- 0.75
467.19 indan-1-one (LC-5)
2-(3,5-Diethyl-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]- 0.71
469.12 indan-1-one (LC-5)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3,5-diethyl-phenyl)- 0.74
445.31 indan-1-one (LC-5)
0.70
2-(4-Benzyl-piperazin-1-yl)-2-(3,5-diethyl-phenyl)-indan-1-one 439.19
(LC-5) Table 52bis: Examples 52.21-52.93 fR [min] MS Data
Example Compound LC-MS m/z
Method [M+H]+
4-Fluoro-2-(3-fluoro-phenyl)-2-(4-thiophen-2-ylmethyl- 0.64
52.21 425.36 piperazin-1-yl)-indan-1-one (LC-12d)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro- 0.72
52.22 453.34 phenyl)-indan-1-one (LC-12d)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro- 0.71
52.23 455.54 phenyl)-indan-1-one (LC-12d)
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro- 0.72
52.24 447.54 phenyl)-indan-1-one (LC-12d)
4-Fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3- 0.74
52.25 451.58 fluoro-phenyl)-indan-1 -one (LC-12d)
4-Fluoro-2-(3-fluoro-phenyl)-2-(4-pyridin-2-ylmethyl-piperazin- 0.58
52.26 420.37
1-yl)-indan-1-one (LC-12d)
4-Fluoro-2-(3-fluoro-phenyl)-2-[4-(3-methyl-benzyl)-piperazin- 0.67
52.27 433.39
1-yl]-indan-1-one (LC-12d)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro- 0.74
52.28 447.6 phenyl)-indan-1-one (LC-12d)
4-Fluoro-2-(3-fluoro-phenyl)-2-[4-(4-methoxy-benzyl)- 0.65
52.29 449.47 piperazin-1-yl]-indan-1-one (LC-12d)
4-Fluoro-2-(3-fluoro-phenyl)-2-[4-(2-methyl-benzyl)-piperazin- 0.68
52.30 433.41
1-yl]-indan-1-one (LC-12d)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-4-fluoro-2-(3-fluoro- 0.71
52.31 425.42 phenyl)-indan-1-one (LC-12d)
2-(4-Benzyl-piperazin-1-yl)-4-fluoro-2-(3-fluoro-phenyl)-indan- 0.64
52.32 419.39
1-one (LC-12d)
4-Fluoro-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-2-m-tolyl- 0.64
52.33 421.35 indan-1-one (LC-12d)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-4-fluoro-2-m-tolyl-indan- 0.73
52.34 449.34
1-one (LC-12d)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-4-fluoro-2-m-tolyl- 0.73
52.35 451.59 indan-1-one (LC-12d) 2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-m-tolyl- 0.73
443.31 indan-1-one (LC-12d)
4-Fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-m- 0.75
447.41 tolyl-indan-1-one (LC-12d)
4-Fluoro-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)-2-m-tolyl- 0.60
416.43 indan-1-one (LC-12d)
4-Fluoro-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-2-m-tolyl- 0.70
429.43 indan-1-one (LC-12d)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-m-tolyl-indan- 0.74
443.29 1-one (LC-12d)
4-Fluoro-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-2-m-tolyl- 0.67
445.38 indan-1-one (LC-12d)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-4-fluoro-2-m-tolyl- 0.69
421.48 indan-1-one (LC-12d)
0.65
2-(4-Benzyl-piperazin-1-yl)-4-fluoro-2-m-tolyl-indan-1-one 415.46
(LC-12d)
(R)-or (S)-4-Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2- 0.91
429.1 m-tolyl-indan-1-one (LC-1)
5-Fluoro-2-(3-fluoro-phenyl)-2-(4-thiophen-2-ylmethyl- 0.65
425.05 piperazin-1-yl)-indan-1-one (LC-5)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-5-fluoro-2-(3-fluoro- 0.64
455.01 phenyl)-indan-1-one (LC-5)
5-Fluoro-2-(3-fluoro-phenyl)-2-(4-pyridin-2-ylmethyl-piperazin- 0.58
420.1 1-yl)-indan-1-one (LC-5)
5-Fluoro-2-(3-fluoro-phenyl)-2-[4-(3-methyl-benzyl)-piperazin- 0.66
433.11 1-yl]-indan-1-one (LC-5)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-5-fluoro-2-(3-fluoro- 0.68
447.08 phenyl)-indan-1-one (LC-5)
5-Fluoro-2-(3-fluoro-phenyl)-2-[4-(4-methoxy-benzyl)- 0.64
449.04 piperazin-1-yl]-indan-1-one (LC-5)
2-(4-Benzyl-piperazin-1-yl)-5-fluoro-2-(3-fluoro-phenyl)-indan- 0.63
419.06 1-one (LC-5)
5-Fluoro-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-2-m-tolyl- 0.63
421.14 indan-1-one (LC-5) 2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-5-fluoro-2-m-tolyl-indan- 0.66
448.99 1-one (LC-5)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-5-fluoro-2-m-tolyl- 0.65
451.08 indan-1-one (LC-5)
5-Fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-m- 0.67
447.08 tolyl-indan-1-one (LC-5)
5-Fluoro-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)-2-m-tolyl- 0.59
416.13 indan-1-one (LC-5)
5-Fluoro-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-2-m-tolyl- 0.67
429.19 indan-1-one (LC-5)
5-Fluoro-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-2-m-tolyl- 0.65
445.15 indan-1-one (LC-5)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-5-fluoro-2-m-tolyl- 0.68
421.21 indan-1-one (LC-5)
0.64
2-(4-Benzyl-piperazin-1-yl)-5-fluoro-2-m-tolyl-indan-1-one 415.23
(LC-5)
2-(3-Ethyl-phenyl)-5-fluoro-2-(4-thiophen-2-ylmethyl-piperazin- 0.66
434.92 1-yl)-indan-1-one (LC-5)
2-(3-Ethyl-phenyl)-5-fluoro-2-[4-(5-fluoro-2-methyl-benzyl)- 0.70
461.08 piperazin-1-yl]-indan-1-one (LC-5)
2-(3-Ethyl-phenyl)-5-fluoro-2-(4-pyridin-2-ylmethyl-piperazin-1- 0.62
430.13 yl)-indan-1-one (LC-5)
2-(3-Ethyl-phenyl)-5-fluoro-2-[4-(3-methyl-benzyl)-piperazin-1- 0.69
443.25 yl]-indan-1-one (LC-5)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-ethyl-phenyl)-5- 0.71
457.19 fluoro-indan-1-one (LC-5)
2-(3-Ethyl-phenyl)-5-fluoro-2-[4-(4-methoxy-benzyl)-piperazin- 0.68
459.22 1-yl]-indan-1-one (LC-5)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-ethyl-phenyl)-5- 0.70
435.20 fluoro-indan-1-one (LC-5)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-5- 0.66
449.19 methyl-indan-1-one (LC-5)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-5- 0.65
450.94 methyl-indan-1-one (LC-5) 2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)- 0.69
443.19 5-methyl-indan-1-one (LC-5)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-ethyl-phenyl)-5- 0.69
459.06 methyl-indan-1-one (LC-5)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-ethyl-phenyl)-5- 0.69
461.18 methyl-indan-1-one (LC-5)
2-(3-Ethyl-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1- 0.71
457.18 yl]-5-methyl-indan-1-one (LC-5)
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-ethyl-phenyl)-5- 0.72
453.14 methyl-indan-1-one (LC-5)
2-(4-Benzyl-piperazin-1-yl)-4-fluoro-2-(3-fluoro-5-methyl- 0.69
433.44 phenyl)-indan-1-one (LC-12d)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-4-fluoro-2-(3-fluoro-5- 0.72
439.47 methyl-phenyl)-indan-1 -one (LC-12d)
4-Fluoro-2-(3-fluoro-5-methyl-phenyl)-2-[4-(2-methyl-benzyl)- 0.74
447.45 piperazin-1-yl]-indan-1-one (LC-12d)
4-Fluoro-2-(3-fluoro-5-methyl-phenyl)-2-[4-(4-methoxy- 0.68
463.53 benzyl)-piperazin-1 -yl]-indan-1 -one (LC-12d)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro-5- 0.76
461.53 methyl-phenyl)-indan-1 -one (LC-12d)
4-Fluoro-2-(3-fluoro-5-methyl-phenyl)-2-[4-(3-methyl-benzyl)- 0.69
447.44 piperazin-1-yl]-indan-1-one (LC-12d)
4-Fluoro-2-(3-fluoro-5-methyl-phenyl)-2-(4-pyridin-2-ylmethyl- 0.63
434.42 piperazin-1-yl)-indan-1-one (LC-12d)
4-Fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3- 0.79
465.54 fluoro-5-methyl-phenyl)-indan-1-one (LC-12d)
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro- 0.79
461.59 5-methyl-phenyl)-indan-1 -one (LC-12d)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro- 0.76
469.57 5-methyl-phenyl)-indan-1 -one (LC-12d)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro-5- 0.77
467.51 methyl-phenyl)-indan-1 -one (LC-12d)
4-Fluoro-2-(3-fluoro-5-methyl-phenyl)-2-(4-thiophen-2- 0.68
439.38 ylmethyl-piperazin-1-yl)-indan-1-one (LC-12d) 2-(4-Benzyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-4-fluoro- 0.69
52.87 429.46
indan-1-one (LC-12d)
2-(3,5-Dimethyl-phenyl)-4-fluoro-2-[4-(2-methyl-benzyl)- 0.75
52.88 443.34
piperazin-1-yl]-indan-1-one (LC-12d)
2-(3,5-Dimethyl-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-4- 0.73
52.89 457.31
fluoro-indan-1-one (LC-5)
2-(3,5-Dimethyl-phenyl)-4-fluoro-2-[4-(5-fluoro-2-methyl- 0.80
52.90 461.63
benzyl)-piperazin-1 -yl]-indan-1 -one (LC-12d)
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl- 0.77
52.91 457.69
phenyl)-4-fluoro-indan-1 -one (LC-12d)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl- 0.78
52.92 465.61
phenyl)-4-fluoro-indan-1 -one (LC-12d)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)- 0.78
52.93 463.42
4-fluoro-indan-1-one (LC-12d)
The two enantiomers of 4-fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-m-tolyl-indan-1-one (Example 52.44) are separated by chiral prep. LC-MS (D). Conditions: ChiralPak AD-H column, Eluent : iPrOH with 0.1 % DEA / Heptane (2:98):
Example 52.44B: Enantiomer B: fR (LC-15) 12.6.
The following substituted 2-bromo-2-phenyl-indan-1-one derivatives are prepared from the respective substituted 2-phenyl-indan-1-one derivatives according to the brominating conditions described for Example 43.01 :
fR [min] MS Data
2-Halo-2-phenyl-indanone derivative LC-MS m/z
Method [M+H]+
2-Bromo-4-chloro-2-phenyl-indan-1-one 1.08 (LC-1) n.a.
2-Bromo-4-fluoro-2-phenyl-indan-1-one 1.05 (LC-1) 303.99
2-Bromo-4-methoxy-2-phenyl-indan-1-one 1.05 (LC-1) 316.82
2-Bromo-7-fluoro-2-phenyl-indan-1-one 1.03 (LC-1) n.a.
2-Bromo-2-(3-chloro-phenyl)-indan-1-one 1.07 (LC-1) 324.86
2-Bromo-2-(3-ethyl-phenyl)-indan-1-one 1.08 (LC-1) 314.78
2-Bromo-2-(3-isopropyl-phenyl)-indan-1-one 1.11 (LC-1) 330.56
2-Bromo-2-(3-fluoro-5-methyl-phenyl)-indan-1-one 1.08 (LC-1) n.a. 2-Bromo-2-(3,5-dimethyl-phenyl)-indan-1-one 1.09 (LC-1) 314.82
2-Bromo-2-(3,5-diethyl-phenyl)-indan-1-one 1.13 (LC-1) 344.72
2-Bromo-4-fluoro-2-(3-fluoro-phenyl)-indan-1-one 1.07 (LC-1) 323.22
2-Bromo-4-fluoro-2-m-tolyl-indan-1-one 1.08 (LC-1) 318.79
2-Bromo-5-fluoro-2-(3-fluoro-phenyl)-indan-1-one 1.05 (LC-1) 321.88
2-Bromo-5-fluoro-2-m-tolyl-indan-1-one 1.07 (LC-1) 321.92
2-Bromo-2-(3-ethyl-phenyl)-5-fluoro-indan-1-one 1.10 (LC-1) 332.71
2-Bromo-2-(3-fluoro-phenyl)-5-methyl-indan-1-one 1.07 (LC-1) 322.01
2-Bromo-2-(3-ethyl-phenyl)-5-methyl-indan-1-one 1.11 (LC-1) 330.87
2-Bromo-4-fluoro-2-(3-fluoro-5-methyl-phenyl)-indan-1-one 1.10 (LC-1) n.a.
2-Bromo-2-(3,5-dimethyl-phenyl)-4-fluoro-indan-1-one 1.11 (LC-1) n.a.
The following substituted 2-phenyl-indan-1-one derivatives are prepared according to a known procedure from A. S. Hussey and R. R. Herr, J. Org. Chem. 1959, 24, 843-845: where a substituted 2-chloro-indan-1-one (16.6 mmol) is treated with a 1 M soln. of the corresponding phenyl-magnesium bromide derivative (23.3 mmol) in THF / toluene to give the respective substituted 2-phenyl-indan-1-one derivative: fR [min] LC-MS MS Data m/z
2-phenyl-indanone derivative
Method [M+H]+
4-Chloro-2-phenyl-indan-1 -one 1.02 (LC-1) 242.94
4-Fluoro-2-phenyl-indan-1-one 0.99 (LC-1) 226.08
4-Methoxy-2-phenyl-indan-1-one 0.99 (LC-1) 238.99
7-Fluoro-2-phenyl-indan-1-one 0.97 (LC-1) 226.25
2-(3-Chloro-phenyl)-indan-1 -one 1.01 (LC-1) 242.97
2-(3-Ethyl-phenyl)-indan-1 -one 1.04 (LC-1) 237.00
2-(3-lsopropyl-phenyl)-indan-1-one 1.06 (LC-1) 251.00
2-(3-Fluoro-5-methyl-phenyl)-indan-1-one 1.02 (LC-1) 241.00
2-(3,5-Dimethyl-phenyl)-indan-1-one 1.03 (LC-1) 237.00
2-(3,5-Diethyl-phenyl)-indan-1-one 1.09 (LC-1) 265.00
4-Fluoro-2-(3-fluoro-phenyl)-indan-1-one 1.00 (LC-1) 244.90 4-Fluoro-2-m-tolyl-indan-1-one 1.03 (LC-1) 240.98
5-Fluoro-2-(3-fluoro-phenyl)-indan-1-one 0.99 (LC-1) 244.92
5-Fluoro-2-m-tolyl-indan-1-one 1.02 (LC-1) 241.00
2-(3-Ethyl-phenyl)-5-fluoro-indan-1-one 1.05 (LC-1) 254.99
2-(3-Fluoro-phenyl)-5-methyl-indan-1-one 1.02 (LC-1) 241.00
2-(3-Ethyl-phenyl)-5-methyl-indan-1-one 1.06 (LC-1) 251.00
4-Fluoro-2-(3-fluoro-5-methyl-phenyl)-indan-1-one 1.03 (LC-1) 259.00
2-(3,5-Dimethyl-phenyl)-4-fluoro-indan-1-one 1.06 (LC-1) 254.90
The following Example compounds as identified in Table 53bis are obtained by reacting a 2-phenyl-2-piperidin- 4-yl-indan-1-one with the appropriately substituted benzyl halogenide in the presence of DIPEA and catalytic tetrabutylammonium iodide:
Table 53bis: Examples 53.13-53.15
Figure imgf000167_0001
The appropriately substituted benzyl halogenide used in the syntheses of above Examples compounds 53.13, 53.14, 1.81 and 1.82 are synthesized according to the following procedures:
2-Chloromethyl-4-fluoro-1 -vinyl-benzene fR (LC-1) 1.00; ESI-MS: m/z n.a. [M+H]+ is obtained by chlorination of (5-fluoro-2-vinyl-phenyl)-methanol using SOCI2 in DCM.
(5-Fluoro-2-vinyl-phenyl)-methanol fR (LC-1) 0.81 ; ESI-MS: m/z n.a. [M+H]+ is obtained by deprotection of ferf- butyl-(5-fluoro-2-vinyl-benzyloxy)-dimethyl-silane with TBAF (tetrabutylammonium fluoride) in THF.
fert-Butyl-(5-fluoro-2-vinyl-benzyloxy)-dimethyl-silane fR (LC-1) 1.19; ESI-MS: m/z 266.94 [M+H]+is derived from (2-bromo-5-fluoro-benzyloxy)-fert-butyl-dimethyl-silane in the conditions of a Stille coupling in presence of tributylvinylstannane and palladium Jb/s triphenylphosphine dichloride in dry DMF. (2-Bromo-5-fluoro-benzyloxy)-ieri-butyl-dimethyl-silane iR (LC-1) 1.3; ESI-MS: m/z n.a. [M+H]+is obtained from commercially available 2-bromo-5-fluorobenzyl alcohol via reaction with tert-butyl-dimethylsilyl chloride and imidazole in THF.
2-Chloromethyl-1-ethyl-4-fluoro-benzene iR (LC-1) 1.02; ESI-MS: m/z n.a. [M+H]+ is is obtained by chlorination of (2-Ethyl-5-fluoro-phenyl)-methanol using SOCI2 in DCM.
(2-Ethyl-5-fluoro-phenyl)-methanol iR (LC-1) 0.83; ESI-MS: m/z 242.15 [M+H]+ is obtained by deprotection of fert-Butyl-(2-ethyl-5-fluoro-benzyloxy)-dimethyl-silane with TBAF in THF.
fert-Butyl-(2-ethyl-5-fluoro-benzyloxy)-dimethyl-silane (LC-1) 1.20; ESI-MS: m/z n.a. [M+H]+is obtained by catalytic hydrogenation of afore-mentionned tert-butyl-(5-fluoro-2- vinyl-benzyloxy)-dimethyl-silane in presence of platinium oxide in THF.
The following Example compound as identified in Table 55bis is obtained by reacting the HCI salt of 2-piperidin- 4-yl-2-/77-tolyl-indan-1 -one with the appropriately substituted benzyl chloride in the presence of DIPEA and catalytic TBAI:
Table 55bis: Example 55.10
Figure imgf000168_0001
The two enantiomers of 2-[1-(2-methyl-benzyl)-piperidin-4-yl]-2-m-tolyl-indan-1-one (Example 55.06) are separated by chiral prep. LC-MS (D). Conditions: ChiralPak AD-H column, Eluent : iPrOH with 0.1 % DEA / Heptane (20:80):
Example 55.06B: Enantiomer B: fR (LC-13) 7.9.
The following Example compounds as identified in Table 99 are obtained in six steps from 6-methylpyridine-3- carbaldehyde, N-Boc-4-piperidone according to the procedures described for the synthesis of Example 56.01 except that the penultimate piperidine intermediate undergoes a reductive amination in the presence of sodium cyanoborohydride and cat. AcOH in EtOH with corresponding benzaldehydes instead of by nucleophilic substitution with benzyl halogenides as in 56.01 b): Table 99: Examples 99.01-99.06
Figure imgf000169_0001
The following intermediates in the syntheses of Example from above-mentionned Table 99 are obtained according to the procedures described for the syntheses of above-mentionned examples compounds described in Tables 56-59 using the appropriate starting materials
MS Data fR [min] LC-
Intermediates in the synthesis of Examples 99.01-99.06 m/z
MS Method
[M+H]+
2-(4-Benzyl-piperazin-1-yl)-2-(6-methyl-pyridin-3-yl)-indan-1-ylideneamine 0.54 (LC-1) 397.14
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(6-methyl-pyridin-3-yl)-indan-1-
0.58 (LC-1) 403.15 ylideneamine
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-3-yl)-indan-1-
0.59 (LC-1) 425.10 ylideneamine
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-3-yl)-indan-1-
0.57 (LC-1) 427.11 ylideneamine
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-3-yl)-indan-1-
0.56 (LC-1) 411.14 ylideneamine 2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-3-yl)-indan-1-
0.57 (LC-1) 427.09 ylideneamine
2-(6-Methyl-pyridin-3-yl)-2-piperazin-1-yl-indan-1-ylidenearnine 0.67 (LC-1) 407.13
4-[1-lmino-2-(6-methyl-pyridin-3-yl)-indan-2-yl]-piperidine-1-carboxylic acid
0.32 (LC-1) 306.96 ferf-butyl ester
4-[(2-Bromo-benzyl)-cyano-(6-methyl-pyridin-3-yl)-methyl]-piperazine-1-
0.89 (LC-1) 485.02 carboxylic acid ferf-butyl ester
4-[Cyano-(6-methyl-pyridin-3-yl)-rnethyl]-piperazine-1-carboxylic acid ferf-
0.72 (LC-1) 317 butyl ester
Table 100: Example 100.01
Figure imgf000170_0001
Above product is obtained as a mixture of diastereomeric epimers and is prepared in 5 steps from (SJ- nicotinecarbaldehyde, 1-Boc-piperazine and trimethylsilylcyanide according to Example 56.01 - except in the order of steps leading to the direct imine precursor of 100.1 as can be deducted of the intermediates below:
MS Data fR [min] LC-
Intermediates in the synthesis of Example 100.01 m/z
MS Method
[M+H]+
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-[5-((S)-1-methyl-pyrrolidin-2- yl)-pyridin-3-yl]-indan-1-ylideneamine 0.56 (LC-1) 498.16
3-(2-Bromo-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-[5-((S)-1- methyl-pyrrolidin-2-yl)-pyridin-3-yl]-propionitrile 0.71 (LC-1) 576.1
3-(2-Bromo-phenyl)-2-[5-((S)-1-methyl-pyrrolidin-2-yl)-pyridin-3-yl]-2-piperazin- 1-yl-propionitrile 0.59 (LC-1) 453.86
4-{ (2-Bromo-benzyl)-cyano-[5-((S)-1-rnethyl-pyrrolidin-2-yl)-pyridin-3-yl]- methyl}-piperazine-1 -carboxyl ic acid ferf-butyl ester 0.84 (LC-1) 556.07
4-{Cyano-[5-((S)-1-methyl-pyrrolidin-2-yl)-pyridin-3-yl]-rnethyl}-piperazine-1- carboxylic acid ferf-butyl ester 0.70 (LC-1) 386.14
All these intermediates are obtained as mixtures of diastereomeric epimers
By repeating either one of the procedures used in the synthesis of above-mentioned examples from Tables 61- 66, using appropriate starting materials, the following Example compounds as identified in Table 61 bis are obtained
Table 61bis: Examples 61.03-66.07
MS Data fR [min] LC-
Example Compound m/z
MS Method
[M+H]+
2-(4-Benzyl-piperazin-1-yl)-2-(2,6-dimethyl-pyridin-4-yl)-indan- 0.64
61.03 426.07
1 ,3-dione (LC-1)
2-(2,6-Dimethyl-pyridin-4-yl)-2-[4-(2-methyl-benzyl)-piperazin- 0.67
61.04 440.14
1 -yl]-indan-1 ,3-dione (LC-1)
2-(2,6-Dimethyl-pyridin-4-yl)-2-[4-(2-methoxy-benzyl)- 0.67
61.05 456.11
piperazin-1 -yl]-indan-1 ,3-dione (LC-1)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(2-methyl-pyridin-4-yl)-
63.08 indan-1 ,3-dione 0.63 (LC-1) 418.07
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(4-methyl-pyridin-2-yl)-
65.07 indan-1 ,3-dione 0.8 (LC-1) 418.02
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(4-methyl-
65.08 0.83 (LC-1) 444.03
pyridin-2-yl)-indan-1 ,3-dione 2-(4-Benzyl-pi perazi n- 1 -yl)-2-(6-methyl-py razi n-2-yl)-i ndan- 1 , 3-
66.02 0.79 (LC-1) 413.10
dione
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(6-methyl-pyrazin-2-
66.03 0.83 (LC-1) 418.93
yl)-indan-1 ,3-dione
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyrazin-2-
66.04 0.82 (LC-1) 426.90
yl)-indan-1 ,3-dione
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyrazin-2-yl)-
66.05 0.85 (LC-1) 440.98
indan-1 ,3-dione
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(6-methyl-pyrazin-2-
66.06 0.82 (LC-1) 442.75
yl)-indan-1 ,3-dione
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(6-methyl-pyrazin-2-
66.07 0.81 (LC-1) 442.8
yl)-indan-1 ,3-dione
By repeating either one of the procedures used in the synthesis of above-mentioned examples from Tables 61- 66, using appropriate starting materials, the following Example compounds as identified in Tables 101-113 are obtained
Table 101: Examples 101.01-101.02
MS Data fR [min] LC-
Example Compound m/z
MS Method
[M+H]+
2-(2-Ethyl-6-methyl-pyridin-4-yl)-2-[4-(2-methyl-benzyl)-
101.01 0.68 (LC-1) 454.1
piperazin-1 -yl]-indan-1 ,3-dione
2-(2-Ethyl-6-methyl-pyridin-4-yl)-2-[4-(5-fluoro-2-methyl-
101.02 0.69 (LC-1) 472.11
benzyl)-piperazin-1 -yl]-indan-1 ,3-dione -102.06
Figure imgf000172_0001
2-(2,6-Diethyl-pyridin-4-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-
102.03 0.7 (LC-1) 468.15 indan-1 ,3-dione
2-(2,6-Diethyl-pyridin-4-yl)-2-[4-(5-fluoro-2-methyl-benzyl)-
102.04 0.71 (LC-1) 486.21 piperazin-1-yl]-indan-1 ,3-dione
2-(4-Benzyl-piperazin-1-yl)-2-(2,6-diethyl-pyridin-4-yl)-indan-1 ,3-
102.05 0.67 (LC-1) 454.16 dione
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(2,6-diethyl-pyridin-4-yl)-
102.06 0.7 (LC-1) 488.1 indan-1 ,3-dione
Table 103: Examples 103.01-103.05
Figure imgf000173_0002
-104.08
Figure imgf000173_0001
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(5-methyl-pyridin-2-yl)-
104.04 0.87 (LC-1) 440.07 indan-1 ,3-dione
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(5-methyl-pyridin-2-yl)-
104.05 0.83 (LC-1) 442.00 indan-1 ,3-dione
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(5-methyl-pyridin-2-yl)-
104.06 0.83 (LC-1) 426.01 indan-1 ,3-dione
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(5-methyl-pyridin-2-yl)-
104.07 0.82 (LC-1) 442.01 indan-1 ,3-dione
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(5-methyl-
104.08 0.85 (LC-1) 444.07 pyridin-2-yl)-indan-1 ,3-dione -105.07
Figure imgf000174_0001
Table 106: Examples 106.01-106.06
Figure imgf000175_0002
-107.07
Figure imgf000175_0001
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-pyridin-2-
107.07 0.88 (LC-1) 460.04 yl)-indan-1 ,3-dione
-108.08
Figure imgf000176_0001
indan-1 ,3-dione
-109.06
Figure imgf000176_0002
2-(2-Dirnethylarnino-pyrirnidin-4-yl)-2-[4-(5-fluoro-2-methyl-
109.04 0.85 (LC-1) 474.04 benzyl)-piperazin-1-yl]-indan-1 ,3-dione
2-(4-Benzyl-piperazin-1-yl)-2-(2-dimethylamino-pyrimidin-4-yl)-
109.05 0.81 (LC-1) 442.0 indan-1 ,3-dione
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(2-dimethylamino-
109.06 0.83 (LC-1) 476.02 pyrimidin-4-yl)-indan-1 ,3-dione -110.07
Figure imgf000177_0001
yl)-indan-1 ,3-dione -111.04
Figure imgf000177_0002
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(6-methylamino-
11 1.03 0.76 (LC-1) 457.02
pyridin-2-yl)-indan-1 ,3-dione
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(6-
11 1.04 0.77 (LC-1 ) 458.94
methylamino-pyridin-2-yl)-indan-1 ,3-dione -112.04
Figure imgf000178_0001
-113.02
Figure imgf000178_0002
The following 2-bromo-2-(2-ethyl-6-methyl-pyridin-4-yl)-indan-1 ,3-dione, 2-bromo-2-(2,6-diethyl-pyridin-4-yl)- indan-1 ,3-dione, 2-bromo-2-(2-lsopropyl-6-methyl-pyridin-4-yl)-indan-1 ,3-dione, 2-bromo-2-(5-methyl-pyridin-2- yl)-indan-1 ,3-dione, 2-bromo-2-(6-methyl-pyridin-2-yl)-indan-1 ,3-dione, 2-bromo-2-(2-chloro-6-methyl-pyridin-4- yl)-indan-1 ,3-dione, 2-bromo-2-(3,5-dimethyl-pyridin-2-yl)-indan-1 ,3-dione, 2-bromo-2-(5-ethyl-pyridin-2-yl)- indan-1 ,3-dione, 2-bromo-2-(2-dimethylamino-pyrimidin-4-yl)-indan-1 ,3-dione, 2-bromo-2-(2-ethoxy-pyrimidin-4- yl)-indan-1 ,3-dione, 2-bromo-2-(6-methylamino-pyridin-2-yl)-indan-1 ,3-dione, 2-bromo-2-(6-dimethylamino- pyridin-2-yl)-indan-1 ,3-dione, 2-bromo-indan-2-(6-ethylamino-pyridin-2-yl)- 1 ,3-dione are prepared according to a procedure adapted from Tanemura, K. ei a/., Chem. Commun. 2004, 470-476 by brominating the respective 2- heteroaryl-indan-1 ,3-dione derivative and are used without further purification in the next step.
The following 2-heteroaryl-indan-1 ,3-dione derivatives are commercially available; or are prepared according to an adapted procedure from C. G. Thomson ei a/., Bioorg. Med. Chem. Letters 2006, 16(5), 1388-1391 , from their respective heteroaryl-acetic acid derivative and phthalic anhydride in AC2O in the presence of NEt.3 at reflux, followed by treatment with NaOMe in MeOH at reflux; or are prepared by the procedure from J. E. Wolfe ei a/., J. Org. Chem. 2004, 2006-10 from their respective commercially available methyl-substituted heteroaryl precursor and diethyl phthalate in the presence of NaH in refluxing DME; or are prepared according to a procedure adapted from K. A. Menear ei a/., J. Med. Chem. 2008, 51 (20), 6581-6591 , from their respective heteroarylaldehyde and phthalide with NaOMe in MeOH at reflux: 2-(2-ethyl-6-methyl-pyridin-4-yl)-indan-1 ,3- dione, 2-(2,6-diethyl-pyridin-4-yl)-indan-1 ,3-dione, 2-(2-isopropyl-6-methyl-pyridin-4-yl)-indan-1 ,3-dione, 2-(5- methyl-pyridin-2-yl)-indan-1 ,3-dione, 2-(6-methyl-pyridin-2-yl)-indan-1 ,3-dione, 2-(2-chloro-6-methyl-pyridin-4- yl)-indan-1 ,3-dione, 2-(3,5-dimethyl-pyridin-2-yl)-indan-1 ,3-dione, 2-(5-ethyl-pyridin-2-yl)-indan-1 ,3-dione, 2-(2- dimethylamino-pyrimidin-4-yl)-indan-1 ,3-dione, 2-(2-ethoxy-pyrimidin-4-yl)-indan-1 ,3-dione, 2-(6-methylamino- pyridin-2-yl)-indan-1 ,3-dione, 2-(6-dimethylamino-pyridin-2-yl)-indan-1 ,3-dione, indan-2-(6-ethylamino-pyridin-2- yl)- 1 ,3-dione.
fR [min] LC- MS Data
Selected analytical data
MS Method m/z [M+H]+
2-Bromo-2-(2-ethyl-6-methyl-pyridin-4-yl)-indan-1 ,3-dione 0.76 (LC-1) 343.91
2-(2-Ethyl-6-methyl-pyridin-4-yl)-indan-1 ,3-dione 0.79 (LC-1) 266.01
2-(2-lsopropyl-6-methyl-pyridin-4-yl)-indan-1 ,3-dione 0.83 (LC-1) 279.99
2-Bromo-2-(2-chloro-6-methyl-pyridin-4-yl)-indan-1 ,3-dione 0.72 (LC-1) 352.09
2-(2-Chloro-6-methyl-pyridin-4-yl)-indan-1 ,3-dione 0.79 (LC-1 271.92
2-Bromo-2-(6-chloro-pyridin-2-yl)-indan-1 ,3-dione 1.0 (LC-1) 337.71
2-(6-Chloro-pyridin-2-yl)-indan-1 ,3-dione 0.93 (LC-1) 257.9
2-Bromo-2-(2-ethoxy-pyrimidin-4-yl)-indan-1 ,3-dione 0.97 (LC-1) 348.79
2-(2-Ethoxy-pyrimidin-4-yl)-indan-1 ,3-dione 0.94 (LC-1) 268.96
2-(6-Dimethylamino-pyridin-2-yl)-indan-1 ,3-dione 0.87 (LC-1) 266.98
2-(6-Ethylamino-pyridin-2-yl)-indan-1 ,3-dione 0.86 (LC-1) 266.98 Example 114.01
5-Methyl-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-2-An-tolyl-indan-1,3-dione
To a stirred mixture of 2-bromo-2-(m-tolyl)-indan-1 ,3-dione (0.06 mmol) and 1-(thiophen-2-ylmethyl)piperazine (0.072 mmol) in 1 ,4-dioxane (1 mL) is added DIPEA (0.06 mmol). The resulting soln. is continued to stir at r.t. over night. The reaction mixture is then filtered over a PL-HCO3 cartridge. The solvent is evaporated and the title compound is obtained after purification by prep. LC-MS (A) as a yellow powder: fR (LC-5) 0.63; ESI-MS: m/z 431.08 [M+H]+. 1H-NMR (H-DMSO): δ 6.94 (m, 2 H), 7.15 (m, 3 H), 7.24 (m, 1 H), 7.41 (d, 1 H), 7.82 (s, 1 H), 7.89 (q, 2 H), 8.15 (s, 1 H).
By repeating either one of the procedures used in the synthesis of above-mentioned examples, using appropriate starting materials, the following Example compounds as identified in Tables 114-117 are obtained
Table 114: Examples 114.02-114.12 fR [min] MS Data
Example Compound LC-MS m/z
Method [M+H]+
2-(4-Benzyl-piperazin-1-yl)-5-methyl-2-m-tolyl-indan-1 ,3- 0.65 (LC-
114.02 425.16
dione 5)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-5-methyl-2-m-fo/y/- 0.68 (LC-
114.03 431.2
indan-1 ,3-dione 5)
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-5-methyl-2-m-tolyl- 0.69 (LC-
114.04 453.28
indan-1 ,3-dione 5)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-5-methyl-2-m-tolyl- 0.65 (LC-
114.05 461.08
indan-1 ,3-dione 5)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-5-methyl-2-m-tolyl- 0.66 (LC-
114.06 459.09
indan-1 ,3-dione 5)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-5-methyl-2-m-tolyl-indan- 0.69 (LC-
114.07 453.25
1 ,3-dione 5)
2-[4-(4-Methoxy-benzyl)-piperazin-1-yl]-5-methyl-2-m-tolyl- 0.65 (LC-
114.08 455.1
indan-1 ,3-dione 5)
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-5-methyl-2-m- 0.67 (LC-
114.09 457.16
tolyl-indan-1 ,3-dione 5)
5-Methyl-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)-2-m-tolyl- 0.60 (LC-
114.10 426.06
indan-1 ,3-dione 5)
5-Methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-m-tolyl- 0.67 (LC-
114.11 439.16
indan-1 ,3-dione 5) 5-Methyl-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-2-m-tolyl- 0.67 (LC-
114.12 439.17 indan-1 ,3-dione 5)
Table 115: Examples 115.01-115.11 fR [min] MS Data
Example Compound LC-MS m/z
Method [M+H]+
2-(3-Fluoro-phenyl)-5-methoxy-2-(4-thiophen-2-ylmethyl- 0.62 (LC-
115.01 451.01 piperazin-1-yl)-indan-1 ,3-dione 5)
2-(3-Fluoro-phenyl)-5-methoxy-2-(4-pyridin-2-ylmethyl- 0.58 (LC-
115.02 446.08 piperazin-1-yl)-indan-1 ,3-dione 5)
2-(3-Fluoro-phenyl)-5-methoxy-2-[4-(2-methyl-benzyl)- 0.65 (LC-
115.03 459.17 piperazin-1-yl]-indan-1 ,3-dione 5)
2-(3-Fluoro-phenyl)-5-methoxy-2-[4-(4-methoxy-benzyl)- 0.64 (LC-
115.04 475.22 piperazin-1-yl]-indan-1 ,3-dione 5)
2-(4-Benzyl-piperazin-1-yl)-2-(3-fluoro-phenyl)-5-methoxy- 0.63 (LC-
115.05 445.2 indan-1 ,3-dione 5)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-fluoro-phenyl)-5- 0.66 (LC-
115.06 451.1 methoxy-indan-1 ,3-dione 5)
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)- 0.68 (LC-
115.07 473.23
5-methoxy-indan-1 ,3-dione 5)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-5- 0.64 (LC-
115.08 481.01 methoxy-indan-1 ,3-dione 5)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-5- 0.65 (LC-
115.09 479.07 methoxy-indan-1 ,3-dione 5)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-5- 0.68 (LC-
115.10 473.16 methoxy-indan-1 ,3-dione 5)
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-fluoro- 0.66 (LC-
115.11 477.09 phenyl)-5-methoxy-indan-1 ,3-dione 5)
Table 116: Examples 116.01-116.12 fR [min] MS Data
Example Compound LC-MS m/z
Method [M+H]+ 2-(3-Fluoro-phenyl)-5-methyl-2-(4-thiophen-2-ylmethyl- 0.62 (LC-
116.01 434.95 piperazin-1-yl)-indan-1 ,3-dione 5)
2-(3-Fluoro-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-5- 0.65 (LC-
116.02 459.13 methyl-indan-1 ,3-dione 5)
2-(3-Fluoro-phenyl)-5-methyl-2-(4-pyridin-2-ylmethyl- 0.59 (LC-
116.03 430.17 piperazin-1-yl)-indan-1 ,3-dione 5)
2-(3-Fluoro-phenyl)-5-methyl-2-[4-(2-methyl-benzyl)- 0.66 (LC-
116.04 443.14 piperazin-1-yl]-indan-1 ,3-dione 5)
2-(3-Fluoro-phenyl)-5-methyl-2-[4-(3-methyl-benzyl)- 0.66 (LC-
116.05 443.1 piperazin-1-yl]-indan-1 ,3-dione 5)
2-(4-Benzyl-piperazin-1-yl)-2-(3-fluoro-phenyl)-5-methyl- 0.64 (LC-
116.06 429.16 indan-1,3-dione 5)
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-fluoro-phenyl)-5- 0.67 (LC-
116.07 435.13 methyl-indan-1 ,3-dione 5)
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)- 0.68 (LC-
116.08 457.19
5-methyl-indan-1 ,3-dione 5)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-5- 0.64 (LC-
116.09 465.23 methyl-indan-1 ,3-dione 5)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-5- 0.65 (LC-
116.10 463.08 methyl-indan-1 ,3-dione 5)
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-5- 0.68 (LC-
116.11 4557.18 methyl-indan-1 ,3-dione 5)
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-fluoro- 0.66 (LC-
116.12 461.09 phenyl)-5-methyl-indan-1 ,3-dione 5)
Table 117: Examples 117.01-117.12 fR [min] MS Data
Example Compound LC-MS m/z
Method [M+H]+
2-(3,5-Dimethyl-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]- 0.95 (LC-
117.01 471.1
4-fluoro-indan-1 ,3-dione 1)
2-(3,5-Dimethyl-phenyl)-4-fluoro-2-(4-pyridin-4-ylmethyl- 0.77 (LC-
117.02 443.99 piperazin-1-yl)-indan-1 ,3-dione 1)
2-(3,5-Dimethyl-phenyl)-4-fluoro-2-[4-(2-methoxy-benzyl)- 0.92 (LC-
117.03 473.13 piperazin-1-yl]-indan-1 ,3-dione 1) 2-(3,5-Dimethyl-phenyl)-4-fluoro-2-[4-(2-methyl-benzyl)- 0.92 (LC-
117.04 457.12
piperazin-1-yl]-indan-1 ,3-dione 1)
2-(3,5-Dimethyl-phenyl)-4-fluoro-2-[4-(3-methoxy-benzyl)- 0.91 (LC-
117.05 473.07
piperazin-1-yl]-indan-1 ,3-dione 1)
2-(3,5-Dimethyl-phenyl)-4-fluoro-2-[4-(5-fluoro-2-methyl- 0.93 (LC-
117.06 474.89
benzyl)-piperazin-1 -yl]-indan-1 ,3-dione 1)
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(3,5-
117.07 0.9 (LC-1) 487.18
dimethyl-phenyl)-4-fluoro-indan-1 ,3-dione
2-(4-Benzyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-4-fluoro-
117.08 0.9 (LC-1) 442.8
indan-1 ,3-dione
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)- 0.93 (LC-
117.09 449.13
4-fluoro-indan-1 ,3-dione 1)
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl- 0.94 (LC-
117.10 471.02
phenyl)-4-fluoro-indan-1 ,3-dione 1)
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl- 0.91 (LC-
117.11 479.13
phenyl)-4-fluoro-indan-1 ,3-dione 1)
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)- 0.91 (LC-
117.12 477.11
4-fluoro-indan-1 ,3-dione 1)
Appropriate 2-halo-2-phenyl-indan-1 ,3-dione derivatives are prepared according to a procedure adapted from Tanemura, K. ef a/., Chem. Commun. 2004, 470-476 by reacting the corresponding 2-phenyl-indan-1 ,3-dione derivative with NBS.
Figure imgf000183_0001
The following 2-phenyl-indan-1 ,3-dione derivatives are commercially available, or are prepared according to a known procedure, e.g. by an adapted procedure from C. G. Thomson ef a/., Bioorg. Med. Chem. Letters 2006, 16(5), 1388-1391 , from their respective phthalic acid anhydride derivatives in reaction with phenyl acetic acid in AC2O in the presence of NEt.3 at reflux, followed by treatment with NaOMe in MeOH at reflux, or by an adapted procedure from US2005/0059663 from phthalide in reaction with their respective benzaldehyde derivatives with NaOMe in MeOH and ethyl propionate at reflux as described in the synthesis of example 73.01.
Figure imgf000184_0001
Table 118: Examples 118.01-118.04
Figure imgf000184_0002
The above Example compounds are obtained from 2-(6-methylpyridin-2-yl) acetonitrile and N-Boc-4-piperidone according to Example 53.01 e)-b) followed by a two-step hydrolysis according to Example 56.01 b)-a) using the following intermediates:
fR [min] LC- MS Data m/z
Intermediates in the synthesis of Examples 118.01-118.04
MS Method [M+H]+
2-(6-Methyl-pyridin-2-yl)-2-piperidin-4-yl-indan-1-one 0.62 (LC-1) 307.01
4-[1-lmino-2-(6-methyl-pyridin-2-yl)-indan-2-yl]-piperidine-1-carboxylic acid
0.87 (LC-1) 405.92 ferf-butyl ester
4-[(2-Bromo-benzyl)-cyano-(6-methyl-pyridin-2-yl)-methyl]-piperidine-1-
1.14 (LC-1) 485.83 carboxylic acid ferf-butyl ester 4-[Cyano-(6-methyl-pyridin-2-yl)-methyl]-piperidine-1 -carboxylic acid tert-
0.92 (LC-1 ) 316.06 butyl ester
4-[Cyano-(6-methyl-pyridin-2-yl)-rnethylene]-piperidine-1 -carboxylic acid
0.87 (LC-1 ) 314.04 ferf-butyl ester
Example 119.07
2-(4-Benzyl-[1,4]diazepan-1-yl)-2-(3-fluoro-phenyl)-indan-1-one
To a stirred yellow solution of 2-[1 ,4]diazepan-1 -yl-2-(3-fluoro-phenyl)-indan-1 -one (0.1 mmol) and AcOH (0.1 ml) in DCM (1 mL) is added benzaldehyde (0.168 mmol) and silica-gel supported sodium cyanoborohydride (0.250 mmol). The resulting soln. is continued to stir at r.t. 3h, then at 50°C over 3 h.. Silica-gel supported sodium cyanoborohydride (0.250 mmol) is added again. The resulting soln. is continued to stir at 50°C over 3h, then at r.t. over night. Then DCM and sat. aq. KH2PO4 soln. are added. The org. layer is dried (MgSC^) and filtered. The solvent is evaporated and the title compound is obtained after purification by FC with a heptane/ ethyl acetate / Et3N mixture as eluent as a yellow foam:
fR (LC-1 ) 0.89; ESI-MS: m/z 415.1 1 [M+H]+. 1H-NMR (D6-DMSO): δ 1.70 (m, 2 H), 2.58 (m, 3 H), 2.67 (m, 1 H), 2.73 (t, 2 H), 3.33 (m, 2H), 3.57 (m, 2 H), 3.65 (s, 2 H), 7.06 (m, 1 H), 7.27 (m, 7 H), 7.45 (m, 2 H), 7.58 (d, 1 H), 7.78 (m, 2 H).
a) 2-\1 AlDiazepan- 1 - yl-2-( 3-fluoro-phen yl)-indan- 1-one
To a soln. of benzyl 4-(2-(3-fluorophenyl)-1 -oxo-2,3-dihydro-1 H-inden-2-yl)- ,4-diazepane-1 -carboxylate (0.61 1 mmol) in EtOH (8 ml) is added 10% (w/w) palladium on charcoal. The resulting black suspension is continued to stir under H2 atmosphere at room temperature over 5 days. The crude mixture is filtered over Celite and the solvent removed under reduced pressure. The subtitle compound is obtained after purification by FC as yellow oil: fR (LC-1 ) 0.76; ESI-MS: m/z 325.04 [M+H]+.
b) Benzyl 4-(2-(3-fluorophenyl)-1-oxo-2,3-dihvdro-1 H-inden-2-yl)-1 A-diazepane-1 -carboxylate
To a stirred soln. of 2-bromo-2-(3-fluorophenyl)-indan-1-one (0.983 mmol) in DMF (3 ml) is added DIPEA (2.94 mmol) and benzyl 1 ,4-diazepane-1 -carboxylate. The resulting soln. is continued to stir at r.t. for 2h. Sat. aq. KH2PO4 soln. is added and the resulting aq. phase is extrated three times with DCM. The comb. org. phase is dried over MgSC . The solvent is evaporated and the subtitle compound is obtained after purification by FC as a yellow foam. fR (LC-1 ) 1.07; ESI-MS: m/z 459.09 [M+H]+.
Example 119.08
2-(4-Benzyl-[1 ,4]diazepan-1-yl)-2-phenyl-indan-1-one
To a solution of 2-bromo-2-phenyl-indan-1 -one (0.279 mmol) and DCM (0.1 ml) in EtOH (1 ml) is added 1 - benzyl-1 ,4-diazepane (0.696 mmol). The resulting soln. is continued to stir at r.t. over night. Sat. aq. KH2PO4 soln. is added and the resulting org. phase is extracted twice with DCM. The solvent is evaporated under a stream of air. The title compound is obtained after purification by prep. LC-MS (B) as a yellow foam: fR (LC-1) 0.85; ESI-MS: m/z 397.29 [M+H]+.
By repeating either one of the procedures used in the synthesis of examples 119.07 or 119.08, using appropriate starting materials, the following Example compounds as identified in Table 119 are obtained
Table 119: Examples 119.01-119.08
Figure imgf000186_0001
Appropriate 2-(1 ,4-diazepan-1 -yl)-2-phenyl-indan-1 -one derivatives are prepared from the corresponding benzyl 4-(1-oxo-2-phenyl-2,3-dihydro-1 H-inden-2-yl)-1 ,4-diazepane-1-carboxylate according to the procedure for above described Example 119.07
Figure imgf000186_0002
Example 120.01
2-(1-(Benzo[d][1,3]dioxol-5-ylmethyl)pyrrolidin-3-yl)-2-phenyl-2,3-dihydro-1 H-inden-1-one
To a stirred solution of 2-phenyl-2-pyrrolidin-3-yl-indan-1-one hydrochloride (0.042 mmol) and DIPEA (0.092 ml) in DCM (1 mL) is added piperonyl bromide (0.042 mmol). The resulting soln. is continued to stir at r.t. Then DCM, water and sat. aq. KH2PO4 soln. are added. The resulting aq. phase is extracted three times with DCM. The solvent is evaporated and the title compound is obtained after purification by prep. LC-MS (C) as a yellow powder: fR (LC-1 ) 0.87; ESI-MS: m/z 412.05 [M+H]+. 1H-NMR (H6-DMSO): δ 5.96 (s, 2 H), 6.71 (m, 1 H), 6.80 (d, 2 H), 7.21 (d, 1 H), 7.31 (m, 4 H), 7.46 (t, 1 H), 7.65 (d, 1 H), 7.73 (m, 2 H)
a) 2-Phenyl-2-pyrrolidin-3-yl-indan-1-one hydrochloride
To a solution of 3-(1 -lmino-2-phenyl-indan-2-yl)-pyrrolidine-1 -carboxylic acid tert-butyl ester (0.138 mmol) in THF (0.5 ml) is added water (0.1 ml) and 1 M aq. HCI soln. (0.5 ml). The resulting yellow solution is continued to stir at 70°C for 5 h. After cooling, the solvent is evaporated and the subtitle compound is without further purification as a yellow solid: fR (LC-2) 0.78; ESI-MS: m/z 278.62 [M+H]+.
b) 3-(1-lmino-2-phenyl-indan-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester
According to a procedure described in WO2005/059107, to a solution of 3-[(2-bromo-benzyl)-cyano-phenyl- methyl]-pyrrolidine-1 -carboxylic acid tert-butyl ester (0.632 mmol) in dry THF, cooled to -78°C, is added dropwise a 1.7 M tert-BuLi soln. in pentane under inert atmosphere. The resulting soln. is allowed to warm to r.t. and continued to stir at r.t. overnight. It is then cooled to 0°C, sat. aq. NH4CI soln. and water is added and the resulting solution extracted three times with DCM. The comb. org. phase is washed with brine and dried over Na2SC>4. The solvent is evaporated and the subtitle compound is obtained after purification by FC as a colourless oil: fR (LC-1 ) 0.83; ESI-MS: m/z 377.12 [M+H]+
c) 3-[(2-Bromo-benzyl)-cvano-phenyl-methyli-pyrrolidine-1-carboxylic acid tert-butyl ester
To a solution of 3-(cyano-phenyl-methyl)-pyrrolidine-1 -carboxylic acid tert-butyl ester (1.536 mmol) and terabutylammonium bromide (0.307 mmol) in dry DMF (4 ml) is added portionwise NaH (2.305 mmol). After 10 min, 2-bromobenzyl bromide (1.613 mmol) is added to the orange solution. The soln. is heated up to 53°C and continued to stir at this temperature over night. The mixture is allowed to cool to r.t. and the resulting suspension is filtered over a sintered funnel .The solvent is removed under reduce pressure. The residue is taken up in a mixture of water and 10% aq. citric acid solution. The resulting aq. phase is extracted three times with AcOEt. The comb. org. phase is dried over IS^SC . The solvent is evaporated and the subtitle compound is obtained after purification by FC as a yellow amorphous solid: fR (LC-1 ) 1.12; ESI-MS: m/z 441.86 [M+H]+
d) 3-(Cvano-phenyl-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester
To a solution of LDA (9.888 mmol) in dry THF (5 ml) cooled to -78°C is added dropwise benzylcyanide (9.888 mmol). To the resulting yellow suspensions was added dropwise a solution of tert-butyl 3-(tosyloxy) pyrrol id ine-1 - carboxylate (6.18 mmol) in THF (16 ml). The reaction mixture is allowed to warm up to r.t.and is continued to stir at this temperature over night. The solvent is removed under reduced pressure and the residue taken up in a mixture of water and DCM. The resulting aq. phase is extracted three times with DCM. The comb. org. phase is is dried over IS^SC . The solvent is evaporated and the subtitle compound is obtained after purification by FC as a yellow oil: fR (LC-1 ) 1.00; ESI-MS: m/z 287.01 [M+H]+ By repeating the procedures used in the synthesis of above-mentioned examples, using appropriate starting materials, the following Example compounds as identified in Tables 120-121 are obtained
Table 120: Examples 120.01-120.03
Figure imgf000188_0001
Example compounds of table 120 are obtained as mixture of two diastereomeric racemates
Table 121: Examples 121.01-121.04 fR [min] MS Data
Example Compound LC-MS m/z
Method [M+H]+
121.01 2-(1-Benzyl-azetidin-3-yl)-2-phenyl-indan-1-one 0.86 (LC-1) 354.04
121.02 2-[1-(2-Methyl-benzyl)-azetidin-3-yl]-2-phenyl-indan-1-one 0.88 (LC-1) 368.06
121.03 2-(1 -Phenethyl-azetidin-3-yl)-2-phenyl-indan-1 -one 0.88 (LC-1) 368.09
121.04 2-Phenyl-2-[1-(3-phenyl-propyl)-azetidin-3-yl]-indan-1-one 0.91 (LC-1) 382.11
The following compounds which are intermediates in the syntheses of the Example compounds as identified in Table 121 are obtained using the procedures described in the synthesis of compound 120.01 using the appropriate starting materials. fR [min] MS Data
Intermediates in the synthesis of compounds 121.01 - LC-MS m/z
121.04
Method [M+H]+
2-Azetidin-3-yl-2-phenyl-indan-1-one 0.74 (LC-1) 264.02
3-(1-lmino-2-phenyl-indan-2-yl)-azetidine-1-carboxylic acid tert-butyl ester 0.82 (LC-1) 363.12
3-[(2-Bromo-benzyl)-cyano-phenyl-methyl]-azetidine-1-carboxylic acid tert-
1.11 (LC-1) 425.88 butyl ester
3-(Cyano-phenyl-methyl)-azetidine-1-carboxylic acid tert-butyl ester 0.97 (LC-1) 273.02 Example 122.01
6-(4-(2-Methylbenzyl)piperazin-1-yl)-6-(m-tolyl)-5H-cyclopenta[b]pyridine-5,7(6H)-dion
To a solution of 6-(m-tolyl)-5H-cyclopenta[b]pyridine-5,7(6H)-dione (0.160 mmol) in dry ether (5 ml) is added ammonium acetate (0.016 mmol) and NBS (0.176 mmol). The mixure is allowed to stir at r.t. for 1 h. To the resulting solution containing intermediate 6-bromo-6-(m-tolyl)-5H-cyclopenta[b]pyridine-5,7(6H)-dione is added 1-(2-methylbenzyl)piperazine (0.479 mmol). Stirring is continued for 2 h at r.t. Water is added and the phases are separated. The resulting aq. phase is extracted twice with ether. The comb. org. phase is dried over MgS04. The solvent is evaporated and the title compound is obtained after purification by prep. LC-MS (B) as a yellow powder: fR (LC-1) 0.84; ESI-MS: m/z 426.03 [M+H]+. 1H-NMR (D6-DMSO): δ 2.26 (s, 3 H), 2.28 (s, 3 H), 2.35 (m, 4 H), 2.61 (t, J = 4.5 Hz, 4 H), 3.40 (s, 2 H), 7.14 (m, 7 H), 7.26 (m, 1 H), 7.99 (dd, J = 8.0, 4.8 Hz, 1 H), 8.47 (dd, J = 7.8, 1.5 Hz, 1 H), 9.26 (dd, J = 4.5, 1.5 Hz, 1 H)
a) 6-(m-Tolyl)-5H-cvcloDenta[blDyricline-5, 7(6H)-dione
To a solution of furo[3,4-b]pyridin-5(7H)-one (2.842 mmol) in ethyle propionate (5 ml) is added 2- methylbenzaldehyde (2.984 mmol). The mixture is heated up to 30°c and 5.4M NaOMe in MeOH is added (5.146 mmol) dropwise over 5 min. The resulting mixture is heated up to reflux and continued to stir a for 1 h. The mixture is cooled down to r.t. and diuted with water and DCM. The pH of the aq. phase is adjusted to pH = 1-2 by slow addition of 2N aq.HCI soln. The resulting aq. phase is extracted twice with DCM. The comb. org. phase is dried over IS^SC . The solvent is evaporated and the subtitle compound is obtained as a yellow powder. It is used as such in the next step. fR (LC-1) 0.75; ESI-MS: m/z 237.94 [M+H]+.
By repeating either one of the procedures used in the synthesis of examples 1.01 , 1.02, 1.03, 72.01 or 73.01 , using appropriate starting materials, the following Example compounds as identified in Tables 123-125 are obtained
Table 123: Examples 123.01-123.03
fR [min] MS Data
Compound Example LC-MS m/z
Method [M+H]+
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-pyrrolidin-1-yl-
123.01 0.92 (LC-1) 480.06
phenyl)-indan-1 ,3-dione
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-pyrrolidin-1-yl-
123.02 0.9 (LC-1) 494.17
phenyl)-indan-1 ,3-dione Table 124: Examples 124.01-124.05
Figure imgf000190_0001
Table 125: Examples 125.01-125.05
Figure imgf000190_0002
Appropriate 2-halo-2-phenyl-indan-1 ,3-dione derivatives are prepared according to the procedure described for the synthesis of 2-bromo-2-(3-morpholin-4-yl-phenyl)-indan-1 ,3-dione iR [min] LC- MS Data
2-Halo-2-phenyl-indan-1 ,3-dione derivative
MS Method m/z [M+H]+
2-bromo-2-(3-[pyrrolidin-1-yl]phenyl)-indan-1 ,3-dione 1.08 (LC-1) 369.94
2-bromo-2-(3-[piperidin-1-yl]phenyl)-indan-1 ,3-dione 0.83 (LC-1) 385.91
2-bromo-2-(3-[4-methylpiperazin-1-yl]phenyl)-indan-1 ,3-dione 0.77 (LC-1) 398.95
The following 2-phenyl-indan-1 ,3-dione derivatives are prepared according to a procedure adapted from US2005/0059663 from phthalide in reaction with their respective benzaldehyde derivatives with NaOMe in MeOH and ethylpropionate at reflux as described in procedure b) for the synthesis of example 73.02
Figure imgf000191_0002
Table 126 summarizes NMR characterization data of selected example compounds.
Table 126. NMR data of selected example compounds
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
* NMR measured in non-deuterated DMSO, only selected peaks given Bioloqical assays
The neuropeptide S receptor antagonistic activity of the compounds of Formula (I) may be determined in accordance with one or more of the following experimental methods.
Impedance measurements using LS174T cells
The colon carcinoma cell line LS174T which endogenously expresses human NPS receptors are seeded out in 180 μΙ onto 96 well Eplates (ACEA Biosciences Inc., San Diego) at 200.000 cells per well in growth medium (MEM with Earle's salt) containing 10% FBS, 100 U/mL penicillin, 100 ug/mL streptomycin, 2 mM L-glutamine, 0.1 mM non essential amino acids and 1 mM sodium pyruvate and placed in the impedance device (ACEA Biosciences Inc. San Diego) for impedance sampling and incubated overnight at 37°C in 5% CO2.
Human neuropeptide S (NPS) as an agonist is prepared as a 1 mM stock solution in MeOH: water (1 :1), diluted in MEM/0.1 %BSA/10mM Hepes, pH 7.4 to generate a 10x stock (50 nM) for use in the assay at a final concentration of 5 nM.
Antagonists are prepared as 10 mM stock solutions in DMSO, then a dilution series is obtained by serial dilution in MEM/0.1 %BSA/10mM Hepes, pH 7.4 containing 1.0 % DMSO. On the day of the assay, antagonists (1 Ofold concentrated) are added to the plate in a volume of 20 μΙ/well, incubated for 30-60 min and finally 22 μΙ/well of 5 nM (final concentration) human NPS is added. Impedance changes are measured during the whole experimental period and the magnitude of each NPS-induced impedance peak is compared to the height of the impedance peak induced by 5 nM NPS with vehicle in place of antagonist. For each antagonist, the IC50 value (the concentration of compound needed to inhibit 50 % of the agonistic response) is determined. The calculated IC50 values of the compounds may fluctuate depending on the daily cellular assay performance. Fluctuations of this kind are known to those skilled in the art.
Radioligand displacement measurements using cells endogenously expressing NPS receptors
The colon carcinoma cell line Colo205 which endogenously expresses human NPS receptors is seeded out into polypropylene 96 well plates at 250000 cells per well in 200 μΙ binding buffer (DMEM, 25 mM Hepes, 0.1% BSA pH 7.4). - Then 22.5 μΙ binding buffer are dispensed into all the wells intended to contain compounds and in defined wells for maximum binding (= max control) determination, and 22.5 μΙ NPS (f.c. = 1 μΜ) in binding buffer are dispensed into defined wells for non specific binding (= min control) determination. Then, 2.5 μΙ of a 10fold compound dilution series (100x) in DMSO or DMSO (in the control wells) are added. Finally 25 μΙ 125l- NPS in binding buffer (160 pM final, Anawa) are dispensed into each well. The plates are sealed and incubated for 2 hours at 4°C under shaking. Then the cells are filtered through GF/C filterplates (Unifilter, Perkin Elmer) previously pre-soaked for 1 hour with 0.1% PEI in water using the cell harvester (Filtermate, Packard), and washed 4 times with wash buffer (50 mM Tris-HCI pH 7.5, 0.1 % BSA). The filerplates are then dried for 1 hour at 40-50°C and 40 μΙ of MicroScint 20 (Perkin Elmer) are added before counting in a 96 wells counter (TopCount, Packard). Antagonists are prepared as 10 mM stock solutions in DMSO, then diluted 10fold in 96 well plates using DMSO to obtain 100x stocks.
Intracellular calcium measurements
Human embryonic kidney (HEK) cells expressing the human neuropeptide S receptor asparagine107 (hNPSR- 107N; Gene Bank Accession NM207172.1) or the human neuropeptide S receptor isoleucine107 (hNPSR-1071, sequence according to Gene Bank Accession NM 207172.1 , however with a SNP leading to an asparagine-to- isoleucin exchange at amino acid position 107) are grown in cell culture medium (DMEM) containing 1 mg/mL G418, 100 U/mL penicillin, 100 μg/mL streptomycin and 10 % fetal calf serum (FCS). The cells are seeded at 25Ό00 cells / well into poly-L-lysine coated 384-well black with clear bottom sterile plates (BD Falcon). The seeded plates are incubated overnight at 37°C in 5% CO2.
Human neuropeptide S (NPS) as an agonist is prepared as a 1 mM stock solution in MeOH: water (1 :1), diluted in HBSS containing 0.0375% NaHC03 and 20 mM HEPES, pH 7.4 for use in the assay at the appropriate final concentration (40 nM for hNPSR-107N).
Antagonists are prepared as 10 mM stock solutions in DMSO, then diluted in 384-well plates using DMSO followed by a transfer of the dilutions into in HBSS containing 0.0375% NaHC03 and 20 mM HEPES, pH7.4. On the day of the assay, 50 μΙ of staining buffer (HBSS containing 1% FCS, 20 mM HEPES, 0.0375% NaHC03, 5 mM probenecid (Sigma) and 3 μΜ of the fluorescent calcium indicator fluo-4 AM (1 mM stock solution in DMSO, containing 10% pluronic)) is added to each well. The 384-well cell-plates are incubated for 30 min at 37° C in 5% CO2 followed by equilibration at r.t. for 30 - 60 min before measurement.
Within the Fluorescent Imaging Plate Reader (FLIPR Tetra, Molecular Devices), antagonists are added to the plate in a volume of 25 μΙ/well, incubated for 10 min and finally 25 μΙ/well of human NPS is added. Fluorescence is measured for each well at 1 second intervals, and the height of each NPS-induced fluorescence peak is compared to the height of the fluorescence peak induced by 40 nM NPS with vehicle in place of antagonist. For each antagonist, the IC50 value (the concentration of compound needed to inhibit 50 % of the agonistic response) is determined and may be normalized using the obtained IC50 value of an on-plate reference compound (non-normalized values in Table 124 are indicated by an asterisk*). The calculated IC50 values of the compounds may fluctuate depending on the daily cellular assay performance. Fluctuations of this kind are known to those skilled in the art. Antagonistic activities of selected compounds with respect to the hNPSR-107N are displayed in Table 124. In case a compound has been measured more than one time in this assay, the geometric mean value of all IC50 values is given. Table 127 in which Ex. means Compound of Example Number; IC50 means hNPSR-107N IC50 [nM]; and Ref 01 corresponds to the compound 2-(4-Benzyl-piperazin-1-yl)-2-phenyl-indan-1 ,3-dione (CAS Registry No. 898480-
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
7.13 1500 29.01 124 50.16 15 73.02 2 111.02 14
7.14 178 29.02 236 50.17 1 73.03 8 111.03 96
8.01 626 29.03 8 50.18 66 73.04 13 111.04 5
8.02 923 29.04 6 50.19 160 73.05 12 112.01 220
8.03 1170 29.05 1 1 1 50.20 285 73.06 27 112.02 59
8.04 147 29.06 21 50.21 521 74.01 1 1 112.03 19
8.05 1260 29.07 31 50.22 312 74.02 22 112.04 7
8.06 2620 30.01 17 50.23 94 74.03 4 113.01 14
8.07 719 30.02 323 50.24 79 74.04 7 113.02 5
8.08 751 30.03 5 50.25 4 74.05 44 114.01 453
8.09 1620 30.04 4 50.26 23 74.06 100 114.02 74
8.10 3420 30.05 79 50.27 7 74.07 6 114.03 454
8.11 515 30.06 8 50.28 92 74.08 14 114.04 134
8.12 1630 30.07 26 50.29 18 74.09 2 114.05 104
8.13 2460 31.01 4 50.30 161 74.10 34 114.06 151
8.14 674 31.02 71 50.31 4 74.11 49 114.07 89
9.01 269* 31.03 5 50.32 60 75.01 2 114.08 442
9.02 486* 31.04 1 50.33 17 75.02 4 114.09 38
9.03 148* 31.05 9 50.34 23 75.03 7 114.10 770
9.04 1802* 31.06 76 50.35 54 75.04 2 114.11 44
9.05 170* 31.07 2 50.36 12 76.01 6 114.12 282
9.06 292* 31.08 93 50.37 18 76.02 7 115.01 867
9.07 61 31.09 162 50.38 95 76.03 13 115.02 298
9.08 16 31.10 610 50.39 25 76.04 10 115.03 102
9.09 878 31.11 216 50.40 39 77.01 86 115.04 608
9.10 43 31.12 15 50.41 7 77.02 8 115.05 323
10.01 1462* 31.13 33 50.42 30 77.03 18 115.06 552
10.02 1504* 31.14 5 50.43 7 77.04 140 115.07 143
10.03 1601 * 31.15 1 50.44 42 77.05 104 115.08 238
Figure imgf000208_0001
Figure imgf000209_0001
14.04 779 37.06 1040 52.40 23 81.10 28 125.03 14
14.05 1950 37.07 7940 52.41 261 81.11 57 125.04 8
14.06 3630 38.01 1690 52.42 48 81.12 86 125.05 6
14.07 4030 38.02 2190 52.43 66 82.01 9
* : a non-normalized value.
a : a remaining activity in % is given. For example: 54% (11.2)a means the respective compound shows 54% remaining activity at a concentration of 11.2 μΜ.
b: The IC50 value of the respective compound in the hNPSR-107N intracellular calcium measurement assay is greater than the limit of detection of the assay.
n.a.: data not available.

Claims

Claims
1. A compound of Formula (I)
Figure imgf000211_0001
Formula (I)
wherein
Ar1 represents a fused benzene or a fused pyridine ring;
(R1)n represents one or two optional substituents each independently selected from the group consisting of (C 4)alkyl, (Ci-4)alkoxy, hydroxy, trifluoromethyl, (Ci)fluoroalkoxy, and halogen; wherein any R1 is attached to carbon atom of Ar1;
L1 re resents a group selected from the group consisting of:
Figure imgf000211_0002
wherein X represents CH or N; and the asterisks signify the bond to which the group Z is attached to;
Y represents CH2 or C=0;
Z represents -(CH2)m-, wherein m represents the integers 1 to 4, wherein optionally one CH2 group may be replaced by oxygen;
A represents aryl or heteroaryl, wherein said aryl or heteroaryl independently is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci- 4)alkoxy; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; (C3-6)cycloalkyl; (C2-4)alkenyl; phenyl; -NR2R3, wherein R2 and R3 independently represent hydrogen or (Ci-3)alkyl; and a 5- or 6-membered ring selected from pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, which ring, in case it is attached to A through a carbon atom or in case it is a piperazinyl ring, may in turn optionally be substituted at the vacant nitrogen atom with (Ci-4)alkyl; or
A represents an unsubstituted partially aromatic bicyclic ring system, wherein A is attached to the rest of the molecule at the aromatic ring of said partially aromatic bicyclic ring system;
B represents aryl or heteroaryl, wherein said aryl or heteroaryl independently is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci- 4)alkoxy; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; halogen; cyano; (Ci-3)alkoxy-(Ci-4)alkyl; (Ci-3)alkoxy-(C2-4)alkoxy; nitro; hydroxy; (C2-4)alkenyl; (C2-4)alkenyloxy; -NR4R5, wherein R4 and R5 independently represent hydrogen or (Ci-3)alkyl; unsubstituted 5- or 6-membered monocyclic heteroaryl; and unsubstituted phenyl; or
B represents a partially aromatic bicyclic ring system; wherein said partially aromatic bicyclic ring system is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from (Ci-4)alkyl, (Ci-4)alkoxy, halogen and oxo;
or B represents (C^cycloalkyl;
or a salt thereof;
with the exception of the following compound: 2-(4-Benzyl-piperazin-1 -yl)-2-phenyl-indan-1 ,3-dione.
2. A compound according to claim 1 , which is also a compound of Formula (ICE)
Figure imgf000212_0001
Formula (ICE).
wherein W represents N or CH;
or a salt thereof.
3. A com ound according to claim 1 , wherein L1 represents
Figure imgf000212_0002
wherein the asterisk signifies the bond to which the group Z is attached to;
or a salt thereof.
4. A compound according to any one of claims 1 to 3, wherein Y represents CH2;
or a salt thereof.
5. A compound according to any one of claims 1 to 3, wherein Y represents C=0;
or a salt thereof.
6. A compound according to any one of claims 1 to 5, wherein
Z represents a group selected from the group consisting of methylene (-CH2-), ethylene (-CH2-CH2-), propane- 1 ,3-diyl (trimethylene), butane-1 ,4-diyl (tetramethylene), ethylen-oxy (-CH2-CH2-O-*), and ethylen-oxy-methylen (-CH2-CH2-O-CH2-*); wherein the asterisks signify the bond to which B is attached to;
or a salt thereof.
7. A compound according to any one of claims 1 to 6, wherein (R1)n is absent;
or a salt thereof.
8. A compound according to any one of claims 1 to 7, wherein A represents aryl, wherein said aryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (Ci-3)fluoroalkyl; (Ci. 3)fluoroalkoxy; halogen; (C3-6)cycloalkyl; and a 5- or 6-membered ring selected from pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, which ring, in case it is attached to A through a carbon atom or in case it is a piperazinyl ring, may in turn optionally be substituted at the vacant nitrogen atom with (Ci-4)alkyl; or
A represents heteroaryl, wherein said heteroaryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, halogen; (C^cycloalkyl; and morpholinyl; or
A represents an unsubstituted partially aromatic bicyclic ring system, wherein A is attached to the rest of the molecule at the aromatic ring of said partially aromatic bicyclic ring system,
or a salt thereof.
9. A compound according to any one of claims 1 to 8, wherein
A represents aryl, wherein said aryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (Ci-3)fluoroalkyl; (Ci. 3)fluoroalkoxy; halogen; (C3-6)cycloalkyl; and a 5- or 6-membered ring selected from pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, which ring, in case it is attached to A through a carbon atom or in case it is a piperazinyl ring, may in turn optionally be substituted at the vacant nitrogen atom with (Ci-4)alkyl; or
A represents heteroaryl, wherein said heteroaryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (Ci-3)fluoroalkyl, halogen; (C^cycloalkyl; and morpholinyl;
or a salt thereof.
10. A compound according to any one of claims 1 to 9, wherein;
B represents aryl, wherein said aryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; (Ci.3)fluoroalkyl; (Ci. 3)fluoroalkoxy; halogen; and -NR4R5, wherein R4 and R5 independently represent hydrogen or (Ci-3)alkyl; or
B represents heteroaryl, wherein said heteroaryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; halogen; and - NR4R5, wherein R4 and R5 independently represent hydrogen or (Ci-3)alkyl; or
B represents a partially aromatic bicyclic ring system; wherein said partially aromatic bicyclic ring system is unsubstituted, or may be mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, halogen and oxo; or
B represents (C3-7)cycloalkyl;
or a salt thereof.
11. A compound according to claim 1 selected from the group consisting of
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-phenyl-indan-1 ,3-dione; 2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-phenyl-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(3-Fluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(2-Fluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(3,4-Difluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(3-Methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-{4-[2-(2-Methoxy-ethyl)-benzyl]-piperazin-1-yl}-2-phenyl-indan-1 ,3-dione;
2-[4-(1 ,3-Dioxo-2-phenyl-indan-2-yl)-piperazin-1-ylmethyl]-benzonitrile;
2-[4-(6-Chloro-benzo[1,3]dioxol-5-ylmethyl)-piperazin-1-yl]-2-phenyl-indan-1,3-dione;
2-Phenyl-2-[4-(2-trifluoromethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(3-Fluoro-4-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(3-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(3-Fluoro-4-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(2-Chloro-5-fluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-Phenyl-2-[4-(2-propyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2-Ethoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(2-Allyloxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(2-Nitro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-(4-Benzo[1 ,2,5]thiadiazol-4-ylmethyl-piperazin-1 -yl)-2-phenyl-indan-1 ,3-dione;
2-Phenyl-2-(4-quinolin-8-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-[4-(3-Methyl-benzo[Jb]thiophen-2-ylmethyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
4-Fluoro-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-4-fluoro-2-phenyl-indan-1,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-4-fluoro-2-phenyl-indan-1 ,3-dione;
4-Fluoro-2-phenyl-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(4-Cyclopropylmethyl-piperazin-1-yl)-4-fluoro-2-phenyl-indan-1,3-dione;
2-(4-Benzyl-piperazin-1-yl)-4-chloro-2-phenyl-indan-1 ,3-dione;
4-Chloro-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
4-Chloro-2-phenyl-2-(4-pyridin-3-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione; 4-Chloro-2-phenyl-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-4-methyl-2-phenyl-indan-1 ,3-dione;
4-Methyl-2-phenyl-2-(4-pyridin-3-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
4-Methyl-2-phenyl-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-4-ethyl-2-phenyl-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-4-ethyl-2-phenyl-indan-1,3-dione; 4-Ethyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1,3-dione;
4- Ethyl-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-4-methoxy-2-phenyl-indan-1 ,3-dione;
4-Methoxy-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-5-fluoro-2-phenyl-indan-1 ,3-dione;
5- Fluoro-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
5-Chloro-2-(4-cyclopropylmethyl-piperazin-1-yl)-2-phenyl-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-5-methyl-2-phenyl-indan-1 ,3-dione;
5-Methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-5-methoxy-2-phenyl-indan-1 ,3-dione;
5-Methoxy-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
5-Methoxy-2-phenyl-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(2-methylphenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-chloro-phenyl)-indan-1,3-dione;
2-(3-Chloro-phenyl)-2-(4-cyclohexylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(3-chloro-phenyl)-indan-1 ,3-dione;
2-(3-Chloro-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Chloro-phenyl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-chloro-phenyl)-indan-1,3-dione;
2-(3-Chloro-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-bromo-phenyl)-indan-1,3-dione;
2-(3-Bromo-phenyl)-2-(4-cyclohexylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(3-bromo-phenyl)-indan-1,3-dione; 2-(3-Bromo-phenyl)-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)-indan-1,3-dione;
2-(3-Bromo-phenyl)-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Bromo-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Bromo-phenyl)-2-(4-pyridin-3-ylmethyl-piperazin-1-yl)-indan-1,3-dione;
2-(3-Bromo-phenyl)-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-indan-1,3-dione;
2-(3-Bromo-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-methylphenyl)-indan-1 ,3-dione; 2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-methylphenyl)-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(3-methylphenyl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-methylphenyl)-indan-1 ,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methylphenyl)-indan-1 ,3-dione;
2-[4-(4-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methylphenyl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methylphenyl)-indan-1 ,3-dione;
2-[4-(3-Chloro-benzyl)-piperazin-1-yl]-2-(3-methylphenyl)-indan-1 ,3-dione;
2-(4-Pyridin-4-ylmethyl-piperazin-1-yl)-2-(3-methylphenyl)-indan-1 ,3-dione;
2-(4-Thiophen-2-ylmethyl-piperazin-1-yl)-2-(3-methylphenyl)-indan-1,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-methylphenyl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-methylphenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione; 2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-methoxy-phenyl)-indan-1 ,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-methoxy-phenyl)-indan-1 ,3-dione;
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1 -yl)-2-(3-methoxy-phenyl)-indan-1 ,3-dione;
2-(3-Methoxy-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan-1 ,3-dione;
2-[4-(4-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan-1 ,3-dione;
2-[4-(3-Chloro-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan-1 ,3-dione;
2-(3-Methoxy-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(3-Methoxy-phenyl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Methoxy-phenyl)-2-[4-(4-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(4-methylphenyl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(4-methylphenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(4-methoxy-phenyl)-indan-1 ,3-dione;
2-(4-Benzo[ ,3]dioxol-5-ylmethyl-piperazin-1 -yl)-2-(4-methoxy-phenyl)-indan-1 ,3-dione;
2-(4-Methoxy-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione; 2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(4-rnethoxy-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(4-methoxy-phenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-naphthalen-2-yl-indan-1 ,3-dione;
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-naphthalen-2-yl-indan-1 ,3-dione; 2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-naphthalen-2-yl-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-naphthalen-2-yl-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-naphthalen-2-yl-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-naphthalen-2-yl-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-pyridin-2-yl-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-pyridin-2-yl-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-pyridin-2-yl-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-pyridin-2-yl-indan-1 ,3-dione;
2-(4-Benzo[1 ,3]dioxol-5-ylmethyl-piperazin-1 -yl)-2-pyridin-3-yl-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan-1 ,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan-1 ,3-dione;
2-[4-(4-Methoxy-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan-1 ,3-dione;
2-[4-(3-Chloro-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan-1 ,3-dione;
2-[4-(3-Methyl-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-pyridin-3-yl-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-pyridin-4-yl-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-pyridin-4-yl-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-pyridin-4-yl-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(6-chloro-pyridin-2-yl)-indan-1 ,3-dione;
2-(6-Chloro-pyridin-2-yl)-2-(4-cyclohexyl methyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(6-Chloro-pyridin-2-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Chloro-pyridin-2-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Chloro-pyhdin-2-yl)-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione; 2-(6-Chloro-pyndin-2-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(6-chloro-pyridin-2-yl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(6-bromo-pyridin-2-yl)-indan-1 ,3-dione;
2-(6-Bromo-pyridin-2-yl)-2-(4-cyclohexylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(6-Bromo-pyridin-2-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione; 2-(6-Bromo-pyridin-2-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Bromo-pyridin-2-yl)-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione; 2-(6-Bromo-pyridin-2-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Bromo-pyridin-2-yl)-2-[4-(2-chloro-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(6-ethyl-pyridin-2-yl)-indan-1 ,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(6-ethyl-pyridin-2-yl)-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(6-ethyl-pyridin-2-yl)-indan-1,3-dione;
2-(6-Ethyl-pyridin-2-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Ethyl-pyridin-2-yl)-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Ethyl-pyridin-2-yl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Ethyl-pyridin-2-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(3-Chloro-benzyl)-piperazin-1-yl]-2-(6-ethyl-pyridin-2-yl)-indan-1 ,3-dione;
2-[4-(4-Chloro-benzyl)-piperazin-1-yl]-2-(6-ethyl-pyridin-2-yl)-indan-1 ,3-dione;
2-(6-Ethyl-pyridin-2-yl)-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(6-Ethyl-pyridin-2-yl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(6-Ethyl-pyridin-2-yl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Ethyl-pyridin-2-yl)-2-[4-(4-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(6-ethyl-pyridin-2-yl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(6-ethyl-pyridin-2-yl)-indan-1 ,3-dione;
2-(6-Ethyl-pyhdin-2-yl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2,5-Dimethyl-benzyl)-piperazin-1-yl]-2-(6-ethyl-pyridin-2-yl)-indan-1 ,3-dione; 2-(4-Benzyl-piperazin-1-yl)-2-(6-ethoxy-pyridin-2-yl)-indan-1 ,3-dione;
2-(6-Ethoxy-pyridin-2-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Ethoxy-pyridin-2-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Ethoxy-pyhdin-2-yl)-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Ethoxy-pyhdin-2-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione; 2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(6-ethoxy-pyridin-2-yl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(5-bromo-pyridin-3-yl)-indan-1 ,3-dione;
2-(5-Bromo-pyridin-3-yl)-2-(4-cyclohexylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(5-Bromo-pyridin-3-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(5-Bromo-pyridin-3-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(5-Bromo-pyridin-3-yl)-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(5-Bromo-pyridin-3-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(5-Bromo-pyridin-3-yl)-2-[4-(2-chloro-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-quinolin-4-yl-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-quinolin-4-yl-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-quinolin-4-yl-indan-1 ,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-quinolin-4-yl-indan-1 ,3-dione; 2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-quinolin-4-yl-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-pyrazin-2-yl-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-pyrazin-2-yl-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-pyrazin-2-yl-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-quinoxalin-2-yl-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-quinoxalin-2-yl-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-quinoxalin-2-yl-indan-1 ,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-quinoxalin-2-yl-indan-1,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-quinoxalin-2-yl-indan-1,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-thiophen-3-yl-indan-1 ,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-thiophen-3-yl-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-thiophen-3-yl-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-thiophen-3-yl-indan-1 ,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-thiophen-3-yl-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-thiophen-3-yl-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-thiophen-3-yl-indan-1,3-dione;
2-(2,5-Dimethyl-thiazol-4-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-[1-(2-Methyl-benzyl)-piperidin-4-yl]-2-phenyl-indan-1 ,3-dione;
2-[1-(2-Methyl-benzyl)-piperidin-4-yl]-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione; 2-(1-Benzyl-piperidin-4-yl)-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione;
2-[1-(2-Ethyl-benzyl)-piperidin-4-yl]-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1 -yl)-2-phenyl-indan-1 -one;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-phenyl-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-phenyl-indan-1-one;
2-Phenyl-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)-indan-1-one;
2-(4-Cyclopropylmethyl-piperazin-1 -yl)-2-phenyl-indan-1 -one;
2-Phenyl-2-(4-pyridin-3-ylmethyl-piperazin-1-yl)-indan-1-one;
2-[4-(2-Methoxy-benzyl)-piperazin-1 -yl]-2-phenyl-indan-1 -one;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-(4-Phenethyl-piperazin-1-yl)-2-phenyl-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-4-methyl-2-phenyl-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-4-methyl-2-phenyl-indan-1-one;
4-Methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-4-methyl-2-phenyl-indan-1-one;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-4-methyl-2-phenyl-indan-1-one;
4-Methyl-2-[4-(4-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one; 2-(4-Benzyl-piperazin-1-yl)-4-bromo-2-phenyl-indan-1-one;
5-Fluoro-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
5-Fluoro-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
5-Fluoro-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
5-Fluoro-2-[4-(4-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-5-fluoro-2-phenyl-indan-1-one;
5- Methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-5-methyl-2-phenyl-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-5-methoxy-2-phenyl-indan-1-one;
6-Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
6- Methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-6-methyl-2-phenyl-indan-1-one;
6- Methoxy-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-6-methoxy-2-phenyl-indan-1-one;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-7-methyl-2-phenyl-indan-1-one;
7- Methoxy-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-methyl-phenyl)-indan-1-one;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(3-methyl-phenyl)-indan-1-one; 2-[4-(3-Methyl-benzyl)-piperazin-1-yl]-2-(3-methyl-phenyl)-indan-1-one;
2-[4-(4-Methyl-benzyl)-piperazin-1-yl]-2-(3-methyl-phenyl)-indan-1-one;
2-(4-Benzyl-piperazin-1 -yl)-2-(3-methyl-phenyl)-indan-1 -one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-methyl-phenyl)-indan-1-one;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methyl-phenyl)-indan-1-one;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methyl-phenyl)-indan-1-one;
2-(4-Benzyl-piperazin-1 -yl)-2-(3-methoxy-phenyl)-indan-1 -one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-rnethoxy-phenyl)-indan-1-one;
2-(3-Methoxy-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan-1-one;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan-1-one; 2-(3-Methoxy-phenyl)-2-[4-(4-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(4-Benzyl-piperazin-1 -yl)-2-(3-fluoro-phenyl)-indan-1 -one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-fluoro-phenyl)-indan-1-one;
2-(3-Fluoro-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(3-Fluoro-phenyl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1-one;
2-(3-Fluoro-phenyl)-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-indan-1-one;
2-(3-Fluoro-phenyl)-2-[4-(4-methyl-benzyl)-piperazin-1-yl]-indan-1-one; 2-(4-Benzyl-piperazin-1-yl)-2-(3-isopropyl-phenyl)-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-isopropyl-phenyl)-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-ethyl-phenyl)-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-2-(4-fluoro-phenyl)-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(4-fluoro-phenyl)-indan-1-one;
2-(4-Fluoro-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(4-methyl-phenyl)-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-2-(3-fluoro-phenyl)-5-methyl-indan-1-one;
2-(3-Fluoro-phenyl)-5-methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(3-Fluoro-phenyl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-5-rnethyl-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-5-methyl-indan-1-one;
2-(3-Ethyl-phenyl)-5-methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(1-Benzo[1,3]dioxol-5-ylmethyl-piperidin-4-yl)-2-phenyl-indan-1-one;
2-(1-Benzyl-piperidin-4-yl)-2-phenyl-indan-1-one;
2-(1-Cyclohexylmethyl-piperidin-4-yl)-2-phenyl-indan-1-one;
2-[1-(3-Methoxy-benzyl)-piperidin-4-yl]-2-phenyl-indan-1-one;
2-[1-(2-Methyl-benzyl)-piperidin-4-yl]-2-phenyl-indan-1-one;
2-[1-(2-Chloro-benzyl)-piperidin-4-yl]-2-phenyl-indan-1-one;
2-[1-(4-Chloro-benzyl)-piperidin-4-yl]-2-phenyl-indan-1-one;
2-[1-(3-Methyl-benzyl)-piperidin-4-yl]-2-phenyl-indan-1-one;
2-[1-(2-Methoxy-benzyl)-piperidin-4-yl]-2-phenyl-indan-1-one;
2-[1-(2-Ethyl-benzyl)-piperidin-4-yl]-2-(3-methyl-phenyl)-indan-1-one;
2-(1-Benzyl-piperidin-4-yl)-2-(3-methyl-phenyl)-indan-1-one;
2-(1-Cyclohexylmethyl-piperidin-4-yl)-2-(3-methyl-phenyl)-indan-1-one;
2-(1-Benzo[1 ,3]dioxol-5-ylmethyl-piperidin-4-yl)-2-(3-rnethyl-phenyl)-indan-1-one;
2-[1-(4-Methoxy-benzyl)-piperidin-4-yl]-2-(3-methyl-phenyl)-indan-1-one;
2-[1-(2-Methyl-benzyl)-piperidin-4-yl]-2-(3-methyl-phenyl)-indan-1-one;
2-[1-(2-Methoxy-benzyl)-piperidin-4-yl]-2-(3-methyl-phenyl)-indan-1-one;
2-(3-Methyl-phenyl)-2-[1-(2-trifluoromethyl-benzyl)-piperidin-4-yl]-indan-1-one;
2-(3-Methyl-phenyl)-2-[1-(2-propyl-benzyl)-piperidin-4-yl]— indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(1-methyl-1 H-pyrazol-3-yl)-indan-1-one;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(1-methyl-1H-pyrazol-3-yl)-indan-1-one;
2-(4-Bromo-thiophen-2-yl)-2-[4-(2-rnethyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(4-Brorno-thiophen-2-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(4-Bromo-thiophen-2-yl)-2-[4-(4-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(5-methyl-isoxazol-3-yl)-indan-1-one; 2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(5-methyl-isoxazol-3-yl)-indan-1-one;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(5-methyl-isoxazol-3-yl)-indan-1-one;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(5-methoxy-pyridin-3-yl)-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(5,6,7,8-tetrahydro-quinolin-2-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(5,6,7,8-tetrahydro-quinolin-2-yl)-indan-1 ,3-dione;
2-(2,6-Dimethyl-pyridin-4-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(2,6-Dimethyl-pyridin-4-yl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4,6-Dimethyl-pyridin-2-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-(4,6-Dimethyl-pyridin-2-yl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione; 2-(4,6-Dimethyl-pyridin-2-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4,6-Dimethyl-pyridin-2-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(2-methyl-pyridin-4-yl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(2-methyl-pyridin-4-yl)-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(2-methyl-pyridin-4-yl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(2-methyl-pyridin-4-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(2-methyl-pyridin-4-yl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(2-methyl-pyridin-4-yl)-indan-1,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(2-methyl-pyridin-4-yl)-indan-1,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-methyl-pyridin-4-yl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(4-methyl-pyhdin-2-yl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(4-methyl-pyridin-2-yl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(4-methyl-pyridin-2-yl)-indan-1 ,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(4-methyl-pyridin-2-yl)-indan-1,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(4-methyl-pyridin-2-yl)-indan-1,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(4-methyl-pyridin-2-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyrazin-2-yl)-indan-1 ,3-dione;
5-Methoxy-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-2-(3-methylphenyl)-indan-1,3-dione;
5-Methoxy-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-2-(3-methylphenyl)-indan-1 ,3-dione;
5-Methoxy-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-2-(3-methylphenyl)-indan-1,3-dione;
2-[4-(2,5-Dimethyl-benzyl)-piperazin-1-yl]-5-methoxy-2-(3-methylphenyl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-5-methoxy-(3-methylphenyl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-5-methoxy-(3-methylphenyl)-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-5-methoxy-(3-methylphenyl)-indan-1 ,3-dione;
5-Methoxy-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-(3-methylphenyl)-indan-1 ,3-dione;
5-Methoxy-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-(3-methylphenyl)-indan- ,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-5-methoxy-(3-methylphenyl)-indan-1 ,3-dione; 2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-5-methoxy-(3-methylphenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-5-methoxy-(3-methylphenyl)-indan-1 ,3-dione;
4-Hydroxy-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(6-methyl-pyrimidin-4-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyhmidin-4-yl)-indan-1 ,3-dione; and
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyrimidin-4-yl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-5-fluoro-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
4-Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
4-Fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
4-Fluoro-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-phenyl-indan-1 ,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-4-fluoro-2-phenyl-indan-1,3-dione;
2-[4-(2,5-Dimethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-phenyl-indan-1,3-dione;
4-Chloro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
4- Methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-4-methyl-2-phenyl-indan-1 ,3-dione;
5- Fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
5-Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1 ,3-dione;
2-(3- ■Chloro- ■phenyl)-2-[4-
2-(3- ■Chloro- ■phenyl)-2-[4-
2-(3- ■Chloro- ■phenyl)-2-[4-
2-(3- ■Bromo- ■phenyl)-2-[4-
2-(3- ■Bromo- ■phenyl)-2-[4-
2-(3- ■Bromo- ■phenyl)-2-[4-
2-(3- ■Bromo- ■phenyl)-2-[4-
2-(3- ■Bromo- ■phenyl)-2-[4-
2-(3- ■Bromo- ■phenyl)-2-[4-
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-m-tolyl-indan-1 ,3-dione;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-m-tolyl-indan-1 ,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-m-tolyl-indan-1 ,3-dione;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan-1 ,3-dione;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan- ,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-indan-1 ,3-dione; 4-Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-4-fluoro-2-phenyl-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-4-fluoro-2-phenyl-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-phenyl-indan-1-one;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-4-fluoro-2-phenyl-indan-1-one;
2-(4-Benzyl-piperazin-1 -yl)-4-methoxy-2-phenyl-indan-1 -one;
4-Methoxy-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-4-methoxy-2-phenyl-indan-1-one;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-4-rnethoxy-2-phenyl-indan-1-one; 5-Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-7-fluoro-2-phenyl-indan-1-one;
7-Fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-7-fluoro-2-phenyl-indan-1-one;
7-Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-phenyl-indan-1-one;
2-(3-Ethyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-2-(3-ethyl-phenyl)-indan-1-one;
2-(3-lsopropyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(3-Fluoro-5-rnethyl-phenyl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl-phenyl)-indan-1-one; 2-(3-Fluoro-5-rnethyl-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-indan-1-one;
2-(3-Fluoro-5-rnethyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(4-Cyclohexylrnethyl-piperazin-1-yl)-2-(3-fluoro-5-methyl-phenyl)-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-2-(3-fluoro-5-methyl-phenyl)-indan-1-one;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl-phenyl)-indan-1-one; 2-(3,5-Dimethyl-phenyl)-2-(4-thiophen-2-ylrnethyl-piperazin-1-yl)-indan-1-one;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-indan-1-one;
2-(3,5-Dimethyl-phenyl)-2-[4-(5-fluoro-2-rnethyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(3,5-Dimethyl-phenyl)-2-(4-pyridin-2-ylrnethyl-piperazin-1-yl)-indan-1-one;
2-(3,5-Dimethyl-phenyl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(3,5-Dimethyl-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-indan-1-one;
2-(3,5-Dimethyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3,5-dirnethyl-phenyl)-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-indan-1-one;
4-Fluoro-2-(3-fluoro-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan-1-one; 2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro-phenyl)-indan-1-one;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro-phenyl)-indan-1-one; 2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro-phenyl)-indan-1-one;
4-Fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-indan-1-one;
4-Fluoro-2-(3-fluoro-phenyl)-2-(4-pyridin-2-ylrnethyl-piperazin-1-yl)-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro-phenyl)-indan-1-one;
4-Fluoro-2-(3-fluoro-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-indan-1-one;
4-Fluoro-2-(3-fluoro-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-4-fluoro-2-(3-fluoro-phenyl)-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-4-fluoro-2-(3-fluoro-phenyl)-indan-1-one;
4-Fluoro-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-2-m-tolyl-indan-1-one;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-4-fluoro-2-m-tolyl-indan-1-one;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-4-fluoro-2-m-tolyl-indan-1-one;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-m-tolyl-indan-1-one;
4-Fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-m-tolyl-indan-1-one;
4-Fluoro-2-(4-pyridin-2-ylrnethyl-piperazin-1-yl)-2-rn-tolyl-indan-1-one;
4-Fluoro-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-2-m-tolyl-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-m-tolyl-indan-1-one;
4- Fluoro-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-2-m-tolyl-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-4-fluoro-2-m-tolyl-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-4-fluoro-2-m-tolyl-indan-1-one;
5-Fluoro-2-(3-fluoro-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan-1-one;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-5-fluoro-2-(3-fluoro-phenyl)-indan-1-one;
5- Fluoro-2-(3-fluoro-phenyl)-2-(4-pyridin-2-ylrnethyl-piperazin-1-yl)-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-5-fluoro-2-(3-fluoro-phenyl)-indan-1-one;
5-Fluoro-2-(3-fluoro-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-5-fluoro-2-(3-fluoro-phenyl)-indan-1-one;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-5-fluoro-2-m-tolyl-indan-1-one;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-5-fluoro-2-m-tolyl-indan-1-one;
5-Fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-m-tolyl-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-5-fluoro-2-m-tolyl-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-5-fluoro-2-m-tolyl-indan-1-one;
2-(3-Ethyl-phenyl)-5-fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-ethyl-phenyl)-5-fluoro-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-4-fluoro-2-(3-fluoro-5-methyl-phenyl)-indan-1-one;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-4-fluoro-2-(3-fluoro-5-methyl-phenyl)-indan-1-one; 4-Fluoro-2-(3-fluoro-5-methyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
4-Fluoro-2-(3-fluoro-5-methyl-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-indan-1-one; 2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro-5-methyl-phenyl)-indan-1-one;
4-Fluoro-2-(3-fluoro-5-methyl-phenyl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
4-Fluoro-2-(3-fluoro-5-methyl-phenyl)-2-(4-pyndin-2-ylmethyl-piperazin-1-yl)-indan-1-one;
4-Fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl-phenyl)-indan-1-one; 2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro-5-methyl-phenyl)-indan-1-one;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro-5-methyl-phenyl)-indan-1-one;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-4-fluoro-2-(3-fluoro-5-methyl-phenyl)-indan-1-one;
4-Fluoro-2-(3-fluoro-5-methyl-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-4-fluoro-indan-1-one;
2-(3,5-Dimethyl-phenyl)-4-fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-(3,5-Dimethyl-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-4-fluoro-indan-1-one;
2-(3,5-Dimethyl-phenyl)-4-fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1-one;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-4-fluoro-indan-1-one;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-4-fluoro-indan-1-one;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-4-fluoro-indan-1-one;
2-[1-(5-Fluoro-2-vinyl-benzyl)-piperidin-4-yl]-2-phenyl-indan-1-one;
2-[1-(2-Ethyl-5-fluoro-benzyl)-piperidin-4-yl]-2-phenyl-indan-1-one;
2-[1-(2-Ethyl-5-fluoro-benzyl)-piperidin-4-yl]-2-m-tolyl-indan-1-one;
2-(4-Benzyl-piperazin-1-yl)-2-(2,6-dimethyl-pyridin-4-yl)-indan-1 ,3-dione;
2-(2,6-Dimethyl-pyridin-4-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(2,6-Dimethyl-pyridin-4-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(2-iTiethyl-pyridin-4-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(4-methyl-pyridin-2-yl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(6-methyl-pyrazin-2-yl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyrazin-2-yl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyrazin-2-yl)-indan-1 ,3-dione;
2-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(6-methyl-pyrazin-2-yl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-fluoro-phenyl)-indan-1 ,3-dione;
2-(3-Fluoro-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-indan-1 ,3-dione;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-indan-1 ,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-vinyl-phenyl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-vinyl-phenyl)-indan-1,3-dione; 2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-vinyl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-vinyl-phenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-difluoromethyl-phenyl)-indan-1 ,3-dione;
2-(3-Difluoromethyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Difluoromethyl-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(3-difluoromethyl-phenyl)-indan-1 ,3-dione;
2-(3-Difluoromethyl-phenyl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-difluoromethyl-phenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-ethoxy-phenyl)-indan-1 ,3-dione;
2-(3-Ethoxy-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-(3-Ethoxy-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Ethoxy-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-ethoxy-phenyl)-indan-1,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-ethoxy-phenyl)-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-ethoxy-phenyl)-indan-1 ,3-dione;
2-(3-Ethoxy-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(3-Cyclopropyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Cyclopropyl-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Cyclopropyl-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Cyclopropyl-phenyl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-propoxy-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-propoxy-phenyl)-indan-1,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-propoxy-phenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-propoxy-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-trifluoromethoxy-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-trifluoromethoxy-phenyl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-trifluoromethoxy-phenyl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-trifluoromethoxy-phenyl)-indan-1,3-dione;
2-[4-(4-Methyl-pyridin-3-ylmethyl)-piperazin-1-yl]-2-(3-trifluoromethoxy-phenyl)-indan-1 ,3-dione; 2-(4-Benzyl-piperazin-1-yl)-2-(3-morpholin-4-yl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-morpholin-4-yl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(3-morpholin-4-yl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-morpholin-4-yl-phenyl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-morpholin-4-yl-phenyl)-indan-1 ,3-dione; 2-(3-Fluoro-5-methyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-fluoro-5-methyl-phenyl)-indan-1 ,3-dione; 2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-fluoro-5-methyl-phenyl)-indan-1 ,3-dione;
2-(3-Fluoro-5-methyl-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl-phenyl)-indan-1 ,3-dione;
2-(3-Fluoro-5-methyl-phenyl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Fluoro-5-methyl-phenyl)-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl-phenyl)-indan-1 ,3-dione;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl-phenyl)-indan-1 ,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl-phenyl)-indan-1,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methyl-phenyl)-indan-1 ,3-dione;
2-(3-Fluoro-5-methyl-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4-Chroman-2-ylmethyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-[4-(4-Chloro-1-methyl-1 H-pyrazol-3-ylmethyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione; 2-(3,5-Dimethyl-phenyl)-2-[4-(2-fluoro-5-rnethoxy-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-(4-Benzo[1,3]dioxol-4-ylmethyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione;
2-[4-(2,5-Dimethoxy-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione;
2-[4-(5-Bromo-2-methoxy-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione;
2-[4-(5-Chloro-1 ,3-dimethyl-1 H-pyrazol-4-ylmethyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione; 2-[4-(4-Dimethylamino-2-methoxy-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-2-[4-(3-methyl-thiophen-2-ylmethyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-2-[4-(5-fluoro-2-methoxy-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-(3,5-Dimethyl-phenyl)-2-[4-(3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethyl)-piperazin-1-yl]-indan-1 ,3- dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3,5-difluoro-phenyl)-indan-1 ,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3,5-difluoro-phenyl)-indan-1,3-dione; 2-(3,5-Difluoro-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Difluoro-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Difluoro-phenyl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Difluoro-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Difluoro-phenyl)-2-[4-(2,4-dimethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3,5-difluoro-phenyl)-indan-1,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3,5-difluoro-phenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-fluoro-5-methoxy-phenyl)-indan-1 ,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3-fluoro-5-methoxy-phenyl)-indan-1 ,3-dione;
2-(3-Fluoro-5-methoxy-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methoxy-phenyl)-indan-1 ,3-dione;
2-(3-Fluoro-5-methoxy-phenyl)-2-[4-(3-methyl-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-(3-Fluoro-5-methoxy-phenyl)-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(3-Fluoro-5-methoxy-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1,3-dione; 2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methoxy-phenyl)-indan-1 ,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methoxy-phenyl)-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-fluoro-5-methoxy-phenyl)-indan-1,3-dione;
2-(3-Fluoro-5-methoxy-phenyl)-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-methoxy-5-methyl-phenyl)-indan-1 ,3-dione;
2-(3-Methoxy-5-methyl-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-methoxy-5-methyl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-methoxy-5-methyl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3-methoxy-5-methyl-phenyl)-indan-1 ,3-dione;
2-(3,5-Dimethoxy-phenyl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-(3,5-Dimethoxy-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Dimethoxy-phenyl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3,5-dimethoxy-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2',3'-dihydro-1'H-[2,5']biindenyl-1,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2',3'-dihydro-1'H-[2,5']biindenyl-1 ,3-dione;
2-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-quinolin-2-yl-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1 -yl)-2-quinolin-2-yl-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-quinolin-2-yl-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-quinolin-2-yl-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-quinolin-2-yl-indan-1,3-dione; 2-[4-(3- ethoxy-benzyl)-piperazin-1-yl]-2-quinolin-2-yl-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(1-methyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(1-methyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(1-methyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(1-methyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(5-fluoro-pyridin-3-yl)-indan-1 ,3-dione;
2-(5-Fluoro-pyridin-3-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(5-fluoro-pyridin-3-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(5-fluoro-pyridin-3-yl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(5-methyl-pyridin-3-yl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(5-methyl-pyridin-3-yl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(5-methyl-pyridin-3-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(5-methyl-pyridin-3-yl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-3-yl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-3-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-3-yl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1 -yl]-2-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1 -yl]-2-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione;
2-(5-Methoxy-pyridin-3-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(5-methoxy-pyridin-3-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(5-methoxy-pyndin-3-yl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(1-methyl-1 H-indazol-3-yl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(1-methyl-1 H-indazol-3-yl)-indan-1,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(1-methyl-1 H-indazol-3-yl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(5-trifluoromethyl-pyridin-3-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(5-trifluoromethyl-pyridin-3-yl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(1-phenyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(1-phenyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(1-phenyl-1 H-pyrazol-4-yl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(2-pyrrolidin-1-yl-pyridin-4-yl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-3-yl)-indan-1-one;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-3-yl)-indan-1-one;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-[5-((S)-1-methyl-pyrrolidin-2-yl)-pyridin-3-yl]-indan-1-one;
2-(2-Ethyl-6-methyl-pyridin-4-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1,3-dione; -(2-Ethyl-6-methyl-pyridin-4-yl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;-(2,6-Diethyl-pyridin-4-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-(2,6-Diethyl-pyridin-4-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-(2,6-Diethyl-pyridin-4-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-(2,6-Diethyl-pyridin-4-yl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-(4-Benzyl-piperazin-1-yl)-2-(2,6-diethyl-pyridin-4-yl)-indan-1 ,3-dione;
-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(2,6-diethyl-pyridin-4-yl)-indan-1 ,3-dione;
-(2-lsopropyl-6-methyl-pyridin-4-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-(4-Benzyl-piperazin-1-yl)-2-(2-isopropyl-6-methyl-pyridin-4-yl)-indan-1 ,3-dione;
-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(2-isopropyl-6-methyl-pyridin-4-yl)-indan-1 ,3-dione;
-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(2-isopropyl-6-methyl-pyridin-4-yl)-indan-1 ,3-dione;
-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(2-isopropyl-6-methyl-pyridin-4-yl)-indan-1 ,3-dione;-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(5-methyl-pyridin-2-yl)-indan-1 ,3-dione;
-(4-Benzyl-piperazin-1-yl)-2-(6-methyl-pyhdin-2-yl)-indan-1 ,3-dione;
-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-2-yl)-indan-1 ,3-dione;
-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-2-yl)-indan-1,3-dione;
-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-2-yl)-indan-1 ,3-dione;
-[4-(3-Methoxy-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-2-yl)-indan-1,3-dione;
-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(6-methyl-pyridin-2-yl)-indan-1 ,3-dione;
-(2-Chloro-6-methyl-pyridin-4-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-(2-Chloro-6-methyl-pyridin-4-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-(2-Chloro-6-methyl-pyridin-4-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-(2-Chloro-6-methyl-pyridin-4-yl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;-(4-Benzyl-piperazin-1-yl)-2-(2-chloro-6-methyl-pyhdin-4-yl)-indan-1 ,3-dione;
-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(2-chloro-6-methyl-pyridin-4-yl)-indan-1 ,3-dione;
-(3,5-Dimethyl-pyridin-2-yl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-(4-Benzyl-piperazin-1-yl)-2-(5-ethyl-pyridin-2-yl)-indan-1 ,3-dione;
-(5-Ethyl-pyridin-2-yl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-(2-Dimethylamino-pyrimidin-4-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1,3-dione;
-(2-Ethoxy-pyhmidin-4-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-(2-Ethoxy-pyhmidin-4-yl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-(6-Methylamino-pyhdin-2-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-(6-methylamino-pyridin-2-yl)-indan-1 ,3-dione;
-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(6-methylamino-pyridin-2-yl)-indan-1 ,3-dione;-(6-Dimethylamino-pyridin-2-yl)-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
-(6-Dimethylamino-pyridin-2-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione; 2-(6-Dimethylamino-pyridin-2-yl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Ethylamino-pyridin-2-yl)-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(6-Ethylamino-pyridin-2-yl)-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-5-methyl-2-m-tolyl-indan-1 ,3-dione;
5-Methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-m-tolyl-indan-1,3-dione;
2-(3-Fluoro-phenyl)-5-methoxy-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3-Fluoro-phenyl)-5-methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-5-methyl-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-fluoro-phenyl)-5-methyl-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-2-[4-(2-ethyl-benzyl)-piperazin-1-yl]-4-fluoro-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-4-fluoro-2-(4-pyridin-4-ylmethyl-piperazin-1-yl)-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-4-fluoro-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-4-fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-4-fluoro-2-[4-(3-methoxy-benzyl)-piperazin-1-yl]-indan-1 ,3-dione;
2-(3,5-Dimethyl-phenyl)-4-fluoro-2-[4-(5-fluoro-2-methyl-benzyl)-piperazin-1-yl]-indan-1,3-dione;
2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-4-fluoro-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-4-fluoro-indan-1 ,3-dione;
2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-(3,5-dimethyl-phenyl)-4-fluoro-indan-1,3-dione;
2-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-4-fluoro-indan-1 ,3-dione;
2-[4-(2,5-Difluoro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-4-fluoro-indan-1 ,3-dione;
2-[4-(2-Chloro-benzyl)-piperazin-1-yl]-2-(3,5-dimethyl-phenyl)-4-fluoro-indan-1 ,3-dione;
2-(1-Benzyl-piperidin-4-yl)-2-(6-methyl-pyridin-2-yl)-indan-1-one;
2-[1-(2-Ethyl-benzyl)-piperidin-4-yl]-2-(6-methyl-pyridin-2-yl)-indan-1-one;
2-[1-(2-Methyl-benzyl)-piperidin-4-yl]-2-(6-methyl-pyridin-2-yl)-indan-1-one;
2-[1-(5-Fluoro-2-methyl-benzyl)-piperidin-4-yl]-2-(6-methyl-pyridin-2-yl)-indan-1-one;
2-[1-(2-Methyl-benzyl)-azetidin-3-yl]-2-phenyl-indan-1-one;
6-(4-(2-methylbenzyl)piperazin-1-yl)-6-(m-tolyl)-5H-cyclopenta[b]pyridine-5J(6H)-dione;
(R)-4-Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-m-tolyl-indan-1-one;
(S)-4-Fluoro-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-2-m-tolyl-indan-1-one;
(R)-2-[1-(2-Methyl-benzyl)-piperidin-4-yl]-2-m-tolyl-indan-1-one; and
(S)-2-[1-(2-Methyl-benzyl)-piperidin-4-yl]-2-m-tolyl-indan-1-one;
2-[1-(5-Fluoro-2-methyl-benzyl)-piperidin-4-yl]-2-(3-methyl-phenyl)-indan-1 ,3-dione;
2-[1-(2-Methyl-benzyl)-piperidin-4-yl]-2-(3-methyl-phenyl)-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-indan-1 ,3-dione; 2-[4-(2-Methoxy-benzyl)-piperazin-1-yl]-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-indan-1 ,3-dione; 2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-indan-1 ,3-dione;
2-[4-(5-Fluoro-2-methyl-benzyl)-piperazin-1-yl]-2-(3-piperidin-1-yl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methoxy-benzyl)-piperazin-1 -yl]-2-(3-piperidin-1 -yl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-piperidin-1-yl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-piperidin-1-yl-phenyl)-indan-1 ,3-dione;
2-(4-Benzyl-piperazin-1-yl)-2-(3-piperidin-1-yl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Ethyl-benzyl)-piperazin-1-yl]-2-(3-pyrrol idin-1-yl-phenyl)-indan-1 ,3-dione;
2-[4-(2-Methyl-benzyl)-piperazin-1-yl]-2-(3-pyrrolidin-1-yl-phenyl)-indan-1 ,3-dione;
2-[4-(4-Methyl-pyridin-3-ylmethyl)-piperazin-1-yl]-2-(3-trifluoromethyl-phenyl)-indan-1 ,3-dione; and
2-[4-(4-Methyl-pyridin-3-ylmethyl)-piperazin-1-yl]-2-(3-methyl-phenyl)-indan-1 ,3-dione;
or a salt of such a compound.
12. A pharmaceutical composition containing, as active principle, a compound of Formula (I) according to claim 1, including the compound 2-(4-Benzyl-piperazin-1 -yl)-2-phenyl-indan-1 ,3-dione; or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.
13. A compound according to claim 1 , including the compound 2-(4-Benzyl-piperazin-1-yl)-2-phenyl-indan-1 ,3- dione; or a pharmaceutically acceptable salt thereof, for use as a medicament.
14. A compound according to claim 1 , including the compound 2-(4-Benzyl-piperazin-1-yl)-2-phenyl-indan-1 ,3- dione; or a pharmaceutically acceptable salt thereof, for the prevention or treatment of a disease selected from the group consisting of sleep disorders; eating disorders; drinking disorders; stress-related syndromes; addiction; psychoactive substance use, abuse, seeking and reinstatement; dementias and cognitive dysfunctions; anxiety disorders; dysthymic disorders; chronic and acute allergic/inflammatory/immune disorders or diseases; all sorts of cancers; and pain.
PCT/IB2011/054998 2011-11-09 2011-11-09 Indanone and indandione derivatives and heterocyclic analogs Ceased WO2013068785A1 (en)

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US12054479B1 (en) 2022-03-14 2024-08-06 Slap Pharmaceuticals Llc Multicyclic compounds
CN114671829A (en) * 2022-04-22 2022-06-28 合肥工业大学 Heterodiad with indanone and dibenzoazepine as parent nucleus, hydrochloride thereof, preparation method and application thereof
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