HK1080086A

HK1080086A - Novel benzodioxoles

Info

Publication number: HK1080086A
Application number: HK06102987.5A
Authority: HK
Inventors: A‧阿拉尼; K‧贝莱切; W‧古帕; W‧哈普; D‧库贝; T‧吕贝斯; J-M‧普兰凯尔; M‧罗杰斯-埃文斯; G‧施奈德; J‧齐格; O‧罗什
Original assignee: 霍夫曼 - 拉罗奇有限公司
Priority date: 2002-07-29
Filing date: 2003-07-18
Publication date: 2006-04-21

Description

New benzodioxoles

no marking

The present invention relates to novel benzodioxole derivatives, processes for their preparation, pharmaceutical compositions containing them and their use as medicaments. The active compounds of the present invention are useful for the treatment of obesity and other disorders.

The invention relates in particular to compounds of general formula (I) and pharmaceutically acceptable salts thereof:

wherein:

R¹and R²Independently unsubstituted phenyl, or phenyl which is independently mono-, di-or trisubstituted with hydroxy, lower alkyl, lower alkoxy, perfluoro-lower alkyl, perfluoro-lower alkoxy, alkanoyl, cyano, nitro or halogen; or R¹And R²Together with the carbon atom to which they are attached form 10 ', 11 ' -dihydro-2, 5 ' - [5H ]]Dibenzo- [ a, d]A cycloheptene residue;

R³and R⁴Independently hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, perfluoro-lower alkyl, alkanoyl or cyano;

R⁵is hydrogen, lower alkyl, lower alkylsulfonyl, cycloalkyl lower alkyl or hydroxy-lower alkyl;

R⁶is Y-R⁸Lower alkyl, lower alkoxy, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkylaminocarbonyl-lower alkyl, heterocyclyl, cycloalkyl, phenyl or phenyl lower alkyl, wherein the phenyl moiety may optionally be mono-, di-or tri-substituted, independently, by lower alkyl, lower alkoxy, halogen, perfluoro-lower alkyl, hydroxy, alkanoyl or cyano; or

When X is-C (O) -or-SO₂When is, R⁶Is hydrogen; or

R⁵And R⁶Together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered monocyclic or 8-, 9-, 10-or 12-membered bicyclic saturated or unsaturated heterocyclic ring which may optionally contain one or two additional heteroatoms independently selected from O, N and S, said heterocyclic ring being optionally mono-, di-or tri-substituted independently by lower alkyl, lower alkoxycarbonyl, hydroxy lower alkyl, lower alkoxy-lower alkyl, di-lower alkylcarbamoyl, carbamoyl, lower alkylcarbonylamino, oxo, dioxo, alkanoyl, amino lower alkyl, hydroxy, lower alkoxy, halogen, perfluoro-lower alkyl, cyano, heteroaryl, or by phenyl or phenyl lower alkyl, wherein said phenyl moiety may optionally be mono-, di-or tri-substituted independently by lower alkyl, lower alkoxy, lower alkylcarbonylamino, oxo, dioxo, alkanoyl, amino lower alkyl, hydroxy, lower alkoxy, halo, perfluoro-lower alkyl, cyano, heteroaryl, or by phenyl or phenyl lower alkyl, Lower alkoxyMono-, di-or tri-substituted by yl, halogen, perfluoro-lower alkyl, hydroxy, alkanoyl or cyano;

R⁷is hydrogen, halogen, lower alkyl or cyano;

R⁸is phenyl, cycloalkyl, heterocyclyl or heteroaryl;

x is a single bond, -CH₂-、-C(O)-、-SO₂-or-SO₂NH-；

Y is-CH₂-, -C (O) -, -NH-or-SO₂-。

Two different types of cannabinoid receptors (CB1 and CB2) have been isolated and both belong to the G protein-coupled receptor superfamily. Optional CB is also described ₁Spliced form CB_1AIt does not exhibit ligand binding and receptor activation characteristics different from CB1 (d.shire, c.carrillon, m.kaghad, b.calandra, m.rinaldi-Carmona, g.le Fur, d.cpu, p.ferrara, journal of biochemistry (j.biol.chem.)270(8) (1995) 3726-31). The CB1 receptor is located mainly in the brain, whereas the CB2 receptor is distributed mainly around the spleen and cells of the immune system (s.munro, k.l.thomas, m.abu-Shaar, Nature 365(1993) 61-61). Thus, CB 1-selective compounds are desirable in order to avoid side effects.

Δ⁹-tetrahydrocannabinoid (Δ)⁹THC) is the main psychoactive compound in indian cannabis (y. gaioni, r.mechoulam, journal of the american chemical association (j.am.chem.soc.), 86(1964)1646), whereas indian cannabis sativa (cannabis savita) has been used in medicine for several times (r.mechoulam (Ed.): "Cannabinoids as therapeutic Agents" ("Cannabinoids atherotheremic Agents"), 1986, pp.1-20, CRCPress). Delta⁹THC is a non-selective CB1/2 receptor agonist and is used in the united states as dronabinol (mario *) for the reduction of cancer chemotherapy-induced emesis (CIE) and for the reversal of weight loss in AIDS patients by appetite stimulation. In the United kingdom,. DELTA. ⁹-synthetic analogue of THC Naboline (LY-109514, Cesamet *) for CIE (R.G.Pertwee,the pharmaceutical sciences (Pharmaceut. Sci.)3(11) (1997)539-545, E.M.Williamson, F.J.Evans, Drugs (Drugs)60(6) (2000) 1303-1314).

Anandamide (arachidonylethanolamide) was identified as an endogenous ligand (agonist) of CB1 (R.G.Pertwee, latest pharmaceutical chemistry (curr.Med.chem.), 6(8) (1999) 635-664; W.A.devane, L.Hanus, A.Breuer, R.G.Pertwee, L.A.Stevenson, G.Griffin, D.Gibson, A.Mandelbaum, A.Etinger, R.Mechoulam, Science 194258 (1992) 6-9). Anandamide and 2-arachidonoyl glycerol (2-AG) on adenylyl cyclase and voltage sensitivity Ca on pre-synaptic nerve endings²⁺Channel negative regulation and activation pair K⁺Inward rectification of channels (v.di Marzo, d.melck, t.bisogno, l.depetrocells, Trends in Neuroscience 21(12) (1998)521-8), thereby affecting neurotransmitter release and/or action, thereby reducing neurotransmitter release (a.c.porter, c.c.felder, pharmacological therapy (pharmacol.ther.), 90(1) (2001) 45-60).

As a⁹Anandamide of THC also increases feeding through a CB1 receptor mediated mechanism. CB1 selective antagonists block the increased food intake associated with the administration of anandamide (C.M.Williams, T.C.Kirkham, < Psychopharmacology > (Psychopharmacology)143(3) (1999)315- > 317; C.C.Felder, E.M.Briley, J.Axelrod, J.T.Simpson, K.Mackie, W.A.Deven, < American national academy of sciences > (Proc.Natl.Acad.Sci.U.S.A.)90(16 (1993)7656-60) and result in appetite suppression and weight loss (G.Colombo, R.Agabio, G.Diaz, C.Lobina, R.Reali, G.L.Gessa, Life (Life sciences 63) PL 113 (1998).

Leptin is the principal signal for hypothalamic sensory nutritional status and regulation of food intake and energy balance. After a short food restriction, CB1 receptor knockout mice had reduced appetite compared to their wild type offspring, and the CB1 antagonist SR141716A reduced wild type food intake, but not knockout mice. In addition, defective leptin signaling is associated with elevated levels of intrinsic cannabinoids in the hypothalamus, but not the cerebellum, of obese db and ob/ob mice and Zucker rats. Rapid leptin treatment of normal rats and ob/ob mice reduced anandamide and 2-arachidonoyl glycerol in the hypothalamus. These findings indicate that intrinsic cannabinoids in the hypothalamus promote CB1 receptor activation to maintain food intake and form part of the neural circuit of leptin regulation (v.di Marzo, s.k.goparaju, l.wang, j.liu, s.bitkai, z.jarai, f.fezza, g.i.miura, r.d.palmiter, t.sugiura, g.kunos., "Nature 410(6830) 822-825).

CB1 selective antagonist/inverse agonist SR-141716A is currently undergoing a phase III clinical trial for the treatment of obesity. In a double-blind placebo-controlled study, SR141716 doses at 5, 10 and 20m per day significantly reduced body weight compared to placebo (f.barth, m.ranaldi-Carmona, m.arnone, h.heshmani, g.le Fur, "Cannabinoid antagonists: From research approaches to potential new drugs" ("Cannabinoid antagonists: From research efforts to potential new drugs" -paper abstracts, 222 ACS nd nasal Meeting, Chicago, IL, united states, 8 months 26-30, 2001).

Other compounds which have been proposed as antagonists of the CB1 receptor, i.e.corresponding inverse agonists, are the aminoalkyl indoles (AAI; M.Pacheco, S.R.Childers, R.Arnold, F.Casino, S.J.Ward, J.Experimental therapeutics of pharmacology (J.Pharmacol. Exp.Ther.) (1) (1991) 170-) 257 (183), such as 6-bromo- (WIN 54661; F.M.Casino, R.Arnold, D.Haycock, J.Kuster, S.J.Ward, NIDA Res.Monogr.105(1991)295-6) or 6-iododoline (AM630, K.Hosota, R.M.Quock, R.M; Hosohata, T.H.Burkey, A.Makrrinyais, P.Connese, R.M.Quock, R.M.H.J.J.J.Ward, T.Burkey, A.J.Ward, J.J.Ward, N.W.J.J.Sciense, J.W.S.S.W.S.S.S.22, J.W.S.S.22 (1995-19, J.W.S.S.S.S.22, J.S.S.J.J.W.S.S.S.S.J.J.W.S.S.S.22.) (1995, J.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S. Arylbenzo [ b ] disclosed in WO9602248, US5596106 are known]Thiophene and benzo [ b]Furan (LY320135, c.c. felder, k.e.joyce, e.m.briley, m.glass, k.p.mackie, k.j.fahey, g.j.cullinan, d.c. huntden, d.w.johnson, m.o.chaney, g.a.koppel, m.brownstein, journal of pharmacological experimental therapy (j.pharmacol.ex)p.Ther.) (1) (1998)291-7), 3-alkyl- (5, 5-diphenyl) imidazolidinediones (M.Kanyon, S.J.Govaerts, E.Hermans, J.H.Poupaert, D.M.Lambert, Bioorganic Pharmacology communications (biorg. Med. chem.Lett.)9(15 (1999) 2233. Lambert 2236), and 3-alkyl-5-arylimidazolidinediones (F.Ooms, J.Wouters, O.Oscar.T.Happaerts, G.Bouchard, P. -A.Carrupt, B.Testa, D.M.Lambert, J.Pharmacology (J.chem.) (45) CB 9. 1748) 1756) antagonize hCb. 1. receptor 1756, respectively ₁The inverse agonist action of the receptor. Substituted 1- (aryl) methyl-azetidine derivatives as CB1 antagonists are disclosed in WO0015609(FR2783246-a1), WO0164634(FR2805817-a1), WO0228346, WO0164632(FR2805818-a1), WO0164633(FR2805810-a 1). In WO0170700, 4, 5-dihydro-1H-pyrazole derivatives are described as CB1 antagonists. In several patent documents, bridged and unbridged 1, 5-diphenyl-3-pyrazole carboxamide derivatives are disclosed as CB1 antagonists/inverse agonists (WO0132663, WO0046209, WO9719063, EP658546, EP656354, US5624941, EP576357, US 3940418). Other different structural classes have recently been disclosed as CB receptor modulators (WO0158869, WO 0224630).

It is an object of the present invention to provide selective direct acting CB1 receptor antagonists, i.e. corresponding inverse agonists. Such antagonists/inverse agonists are useful in medical therapy, in particular in the treatment and/or prevention of diseases associated with the modulation of the CB1 receptor.

The following definitions are used to explain and define the meaning and scope of the various terms used to describe the invention described herein, unless otherwise indicated.

In the present specification, the term "lower" is used to refer to a group consisting of 1 to 6, preferably 1 to 4, carbon atoms.

The term "halogen" refers to fluorine, chlorine, bromine and iodine, preferably to chlorine, fluorine and bromine, most preferably to chlorine and fluorine.

The term "alkyl", alone or in combination with other groups, refers to a branched or straight chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms, preferably 1 to 16 carbon atoms, more preferably 1 to 10 carbon atoms.

The term "lower alkyl" alone or in combination with other groups refers to a branched or straight chain monovalent alkyl group of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. The term is further exemplified by such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl, n-hexyl, 2-ethylbutyl, and the like.

The term "cycloalkyl" refers to a monovalent carbocyclic group of 3 to 6 carbon atoms, preferably 3 to 5 carbon atoms. The term is further exemplified by such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The term "lower alkylsulfonyl" refers to the group R' -SO₂-, wherein R' is lower alkyl.

The term "lower alkylcarbonyl" refers to the group R '-CO-, wherein R' is lower alkyl.

The term "alkoxy" refers to the group R '-O-, wherein R' is alkyl. The term "lower alkoxy" refers to the group R '-O-, wherein R' is lower alkyl. Examples of lower alkoxy groups are: for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and hexyloxy, with methoxy being particularly preferred.

The term "lower alkoxycarbonyl" refers to the group R '-O-C (O) -, wherein R' is lower alkyl.

The term "perfluoro-lower alkyl" refers to a lower alkyl group wherein all hydrogens of the lower alkyl group are replaced with fluorine. Among the preferred perfluoro-lower alkyl groups are trifluoromethyl, pentafluoroethyl and heptafluoropropyl, with trifluoromethyl being especially preferred.

The term "alkanoyl" refers to the groups C (O) -R, wherein R is hydrogen or lower alkyl. Examples of alkanoyl are formyl, acetyl, propionyl and the like.

The term "phenyl-lower alkyl" refers to a phenyl group attached to the remainder of the molecule through a lower alkylene group such as methylene, ethylene, propylene or butylene, preferably methylene and ethylene. Preferred phenyl-lower alkyl residues are benzyl and 1-phenylethyl.

The term "amino lower alkyl" refers to a lower alkyl group substituted with an amino group.

The term "heterocyclyl" refers to a 5-or 6-membered saturated heterocyclic residue containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl residues are morpholino, tetrahydrofuranyl, pyrrolidinyl, piperidinyl and azepanyl.

The term "heteroaryl" refers to an aromatic monovalent mono-or poly-carbocyclic group containing at least one heteroatom selected from N, O and S. Examples of heteroaryl groups are pyridyl, pyrazinyl and pyrimidinyl. Such heteroaryl residues may be optionally mono-, di-or tri-substituted independently by lower alkoxy, lower alkyl, perfluoro-lower alkyl, cyano and alkanoyl, preferably by halogen and perfluoro-lower alkyl.

The term "pharmaceutically acceptable salts" includes salts of the compounds of formula (I) which are non-toxic to living organisms formed with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulfonic acid, salicylic acid, p-toluenesulfonic acid and the like. Preferred salts with acids are formates, maleates, citrates, hydrochlorides, hydrobromides and methanesulfonates, particularly preferably the hydrochloride.

The present invention relates in one embodiment to compounds of general formula (I):

wherein:

R¹and R²Independently unsubstituted phenyl, or independently by hydroxy, lower alkylLower alkoxy, perfluoro-lower alkyl, alkanoyl, cyano or halogen mono-, di-or tri-substituted phenyl;

R⁵is hydrogen or lower alkyl;

R⁶is phenyl or phenyl lower alkyl, wherein the phenyl moiety may be optionally mono-, di-or tri-substituted independently by lower alkyl, lower alkoxy, halogen, perfluoro-lower alkyl, hydroxy, alkanoyl or cyano; or

R⁵And R⁶Together with the nitrogen atom to which they are attached form a 5-, 6-or 7-membered monocyclic or 9-or 10-membered bicyclic saturated or unsaturated heterocyclic ring which may optionally contain one or two other heteroatoms independently selected from O, N and S, said heterocyclic ring being optionally mono-, di-or tri-substituted independently by lower alkyl, lower alkoxycarbonyl, hydroxy lower alkyl, alkanoyl, amino lower alkyl, hydroxy, lower alkoxy, halogen, perfluoro-lower alkyl, cyano, heteroaryl or by phenyl, or phenyl lower alkyl, wherein said phenyl moiety may be optionally mono-, di-or tri-substituted independently by lower alkyl, lower alkoxy, halogen, perfluoro-lower alkyl, hydroxy, alkanoyl or cyano;

x is-CH₂-, -C (O) -or-SO₂-。

In one embodiment, R¹And R²Is unsubstituted phenyl. In another embodiment, R¹And R²Independently is phenyl which is independently mono-, di-or tri-substituted, preferably mono-or di-substituted, with: a hydroxyl group; lower alkyl, such as methyl; lower alkoxy, such as methoxy; perfluoro-lower alkyl, such as trifluoromethyl; perfluoro-lower alkoxy, such as trifluoromethoxy; an alkanoyl group; a cyano group; a nitro group; or halogens such as chlorine, fluorine and bromine.

In another embodiment, R¹And R²Independently unsubstituted phenyl, or phenyl which is independently mono-, di-or trisubstituted with: lower alkyl, such as methyl; lower alkoxy, such as methoxy; perfluoro-lower alkyl, such as trifluoromethyl; perfluoro-lower alkoxy, such as trifluoromethoxy; a cyano group; a nitro group; or halogens such as chlorine, fluorine and bromine.

In another embodiment, the invention relates to a compound of general formula (I) as defined above, wherein R is¹And R²Independently is phenyl, which is independently mono-, di-or tri-substituted with hydroxy, lower alkyl, lower alkoxy, perfluoro-lower alkyl, alkanoyl, cyano or halogen; r¹And R²Preferred substituents of the phenyl residue are: lower alkyl, such as methyl; lower alkoxy, such as methoxy; and halogens such as fluorine and chlorine. Preferably R¹And R²Independently phenyl which is independently mono-or di-substituted by halogen, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine, or by lower alkoxy, preferably methoxy.

R¹And R²The substituted phenyl residues of (a) are preferably substituted as described above in ortho and/or para position, more preferably in para position.

In another embodiment, R ¹And R²Together with the carbon atom to which they are attached form 10 ', 11 ' -dihydro-2, 5 ' - [5H ]]Dibenzo [ a, d ]]A cycloheptene residue.

In one embodiment, the invention relates to a compound of general formula (I) as defined above, wherein R is³And R⁴Independently hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, perfluoro-lower alkyl, alkanoyl or cyano. Preferred halogen residues R³And R⁴Fluorine, chlorine and bromine, fluorine being particularly preferred. R³And R⁴The above preferred lower alkyl residue is methyl. R³And R⁴The above preferred lower alkoxy residue is methoxy. R³And R⁴The above preferred perfluoro-lower alkyl residue is trifluoromethyl.

In another embodiment, the invention relates to a compound of general formula (I) as defined above, wherein R is³And R⁴Independently hydrogen, hydroxy or halogen, such as fluorine, chlorine or bromine. R³And R⁴Preferred substituents are hydrogen and fluorine, with hydrogen being particularly preferred.

In one embodiment, the invention relates to a compound of general formula (I) as defined above, wherein R is⁵And R⁶Together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered monocyclic or 8-, 9-, 10-or 12-membered bicyclic saturated or unsaturated heterocyclic ring which may optionally contain one or two additional heteroatoms independently selected from O, N and S, said heterocyclic ring being optionally mono-, di-or tri-substituted independently by lower alkyl, lower alkoxycarbonyl, hydroxy lower alkyl, lower alkoxy-lower alkyl, di-lower alkylcarbamoyl, carbamoyl, lower alkylcarbonylamino, oxo, alkanoyl, amino lower alkyl, hydroxy, lower alkoxy, halogen, perfluoro-lower alkyl, cyano, heteroaryl or by phenyl, or phenyl lower alkyl, wherein said phenyl moiety may optionally be mono-, di-or tri-substituted independently by lower alkyl, lower alkoxy, cyano, alkoxy, amino lower alkyl, alkoxy, cyano, heteroaryl, or by phenyl, or phenyl lower alkyl, wherein said phenyl moiety may optionally be mono, Lower alkoxy, halogen, perfluoro-lower alkyl, hydroxy, alkanoyl or cyano, is mono-, di-or tri-substituted, preferably mono-or di-substituted.

In another embodiment, the invention relates to a compound of general formula (I) as defined above, wherein R is⁵And R⁶Together with the nitrogen atom to which they are attached form a 5-, 6-or 7-membered monocyclic or 9-or 10-membered bicyclic saturated or unsaturated heterocyclic ring which may optionally contain one or two other heteroatoms independently selected from O and N, said heterocyclic ring being optionally mono-or disubstituted independently by lower alkyl, lower alkoxycarbonyl, hydroxy lower alkyl, alkanoyl, hydroxy, or by phenyl or phenyl lower alkyl, wherein said phenyl moiety may be optionally mono-or disubstituted independently by lower alkyl, lower alkoxy, halogen or perfluoro-lower alkyl.

In another preferred embodiment, the invention relates to a compound of general formula (I) as defined above, wherein R is⁵And R⁶Together with the nitrogen atom to which they are attached form a 5-or 6-membered monocyclic saturated heterocyclic ring which may optionally contain one further heteroatom independently selected from O and S, said heterocyclic ring being optionally mono-or di-substituted independently by hydroxy or by halogen, such as fluorine.

In one embodiment, R⁵And R⁶Preferred heterocycles which are formed together with the nitrogen atom to which they are attached are piperazinyl, morpholino, piperidinyl, piperidin-4-one, pyrrolidinyl, thiomorpholino, azepanyl, 1, 2, 3, 4-tetrahydro-isoquinolinyl, 1, 2, 3, 6-tetrahydro-pyridinyl, [1, 4 ] tetrahydro-pyridinyl ]-diazepanyl, 1, 4-dioxa-8-aza-spiro [4-5 ]]Dec-8-yl, 2, 3, 5, 6-tetrahydro- [1, 2']Bipyrazinyl-4-yl and 3-hydroxy-8-aza-bicyclo [3.2.1 ].]Oct-8-yl, which is optionally mono-, di-or tri-substituted, preferably mono-or di-substituted, as described above independently with: lower alkyl groups such as methyl and isopropyl; lower alkoxycarbonyl such as ethoxycarbonyl; hydroxy lower alkyl, such as hydroxymethyl; lower alkoxy-lower alkyl, such as methoxymethyl; di-lower alkylcarbamoyl such as dimethylcarbamoyl; a carbamoyl group; lower alkylcarbonylamino such as acetylamino; oxo; dioxo; alkanoyl groups such as formyl; a hydroxyl group; lower alkoxy groups such as methoxy and ethoxy; halogen, such as fluorine; perfluoro-lower alkyl; such as trifluoromethyl; heteroaryl, such as unsubstituted pyrazinyl; an unsubstituted pyridyl group; pyridyl disubstituted with chloro and/or trifluoromethyl; or phenyl lower alkyl, such as benzyl, wherein the phenyl moiety may be optionally mono-, di-or tri-substituted, preferably mono-or di-substituted, independently by: lower alkyl, such as methyl; lower alkoxy, such as methoxy; halogens such as chlorine and fluorine; or perfluoro-lower alkyl, such as trifluoromethyl.

In another embodiment, R⁵And R⁶Preferred heterocycles which form together with the nitrogen atom to which they are attached are piperazinyl, morpholino, piperidinyl, piperidin-4-one, pyrrolidinyl, 1, 2, 3, 4-tetrahydro-isoquinolinyl, 1, 2, 3, 6-tetrahydro-pyridinyl, [1, 4 ] s]-diazepanyl and 1, 4-dioxa-8-aza-spiro [4.5]Decan-8-yl, especially piperazinyl, morpholinyl and piperidinyl are preferred. In another preferred embodiment, R⁵And R⁶The preferred heterocyclic ring formed with the nitrogen atom to which they are attached is piperidinyl.

R⁵And R⁶Other preferred heterocycles formed together with the nitrogen atom to which they are attached are piperidinyl, morpholino, thiomorpholino and pyrrolidinyl, optionally independently substituted as described above with hydroxy or halogen, such as fluoro, preferably optionally mono-or di-substituted. Most preferred is R⁵And R⁶The preferred heterocyclic ring formed with the nitrogen atom to which they are attached is morpholino.

In one embodiment, R⁵And R⁶The preferred heterocyclic ring formed with the nitrogen atom to which they are attached is unsubstituted.

In another embodiment, R⁵And R⁶The heterocyclic ring formed together with the nitrogen atom to which they are attached is mono-, di-or tri-substituted, preferably mono-or di-substituted, independently by: lower alkyl groups such as methyl and isopropyl; lower alkoxycarbonyl such as ethoxycarbonyl; hydroxy lower alkyl, such as hydroxymethyl; lower alkoxy-lower alkyl, such as methoxymethyl; di-lower alkylcarbamoyl such as dimethylcarbamoyl; a carbamoyl group; lower alkylcarbonylamino such as acetylamino; oxo; dioxo; alkanoyl groups such as formyl; a hydroxyl group; lower alkoxy groups such as methoxy and ethoxy; halogen, such as fluorine; perfluoro-lower alkyl, such as trifluoromethyl; heteroaryl, such as unsubstituted pyrazinyl; an unsubstituted pyridyl group; pyridyl disubstituted with chloro and/or trifluoromethyl; or phenyl lower alkyl, such as benzyl, wherein the phenyl moiety may optionally be independently substituted with Mono-, di-or tri-substituted radicals: lower alkyl, such as methyl; lower alkoxy, such as methoxy; halogens such as chlorine and fluorine; or perfluoro-lower alkyl, such as trifluoromethyl.

In another embodiment, R⁵And R⁶The heterocyclic ring formed together with the nitrogen atom to which they are attached is preferably mono-or disubstituted independently by methyl, propyl, ethoxycarbonyl, hydroxymethyl, formyl, hydroxy, unsubstituted pyrazinyl, unsubstituted pyridyl, pyridyl disubstituted by chlorine and/or trifluoromethyl, or by phenyl or phenylmethyl, wherein the phenyl moiety may be optionally mono-or disubstituted independently by methyl, methoxy, chlorine, fluorine and/or trifluoromethyl.

In a preferred embodiment, R⁵And R⁶The heterocyclic ring formed together with the nitrogen atom to which they are attached is optionally mono-or di-substituted independently by hydroxy or by halogen, such as fluorine.

R⁵And R⁶The substituted 6-membered heterocyclic ring formed with the nitrogen atom to which they are attached is preferably substituted at the 4-position of the ring; the substituted 5-membered ring is preferably substituted at the 3-position of the ring.

In one embodiment, the invention relates to a compound of general formula (I) as defined above, wherein R is ⁵Is hydrogen, lower alkyl, lower alkylsulfonyl, cycloalkyl lower alkyl or hydroxy-lower alkyl. Preferred lower alkyl residues R⁵Lower alkylsulfonyl residues R which are methyl and ethyl, particularly preferably methyl, are preferred⁵Is n-butylsulfonyl. Preferred cycloalkyl lower alkyl residues R⁵Is cyclopropylmethyl. Preferred hydroxy-lower alkyl residues R⁵Is a 2-hydroxyethyl group.

In one embodiment, the invention relates to a compound of general formula (I) as defined above, wherein R is⁶Is Y-R⁸Lower alkyl, lower alkoxy, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkylcarbamoyl-lower alkyl, heterocyclic group, cycloalkyl, lower alkyl-lower alkyl, lower alkoxy-lower alkyl, lower alkyl,Phenyl or phenyl lower alkyl, wherein the phenyl moiety may be optionally mono-, di-or tri-substituted independently by lower alkyl, lower alkoxy, halogen, perfluoro-lower alkyl, hydroxy, alkanoyl or cyano.

In another embodiment, the invention relates to a compound of general formula (I) as defined above, wherein R is⁶Is lower alkyl, lower alkoxy, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkylcarbamoyl-lower alkyl, heterocyclyl, cycloalkyl, phenyl or phenyl lower alkyl, wherein said phenyl moiety may be optionally mono-, di-or tri-substituted, preferably mono-or di-substituted, independently by lower alkyl, lower alkoxy, halogen, perfluoro-lower alkyl, hydroxy, alkanoyl or cyano.

Preferred lower alkyl residues R⁶Ethyl, n-propyl and isopropyl. Preferred lower alkoxy residues R⁶Are tert-butoxy and methoxy. Preferred hydroxy-lower alkyl residues R⁶Is a 2-hydroxyethyl group. Preferred lower alkoxy-lower alkyl residues R⁶Is a methoxyethyl group. Preferred heterocyclyl residues R⁶Morpholino, tetrahydrofuranyl and pyrrolidinyl. Heterocyclyl radical R⁶Preferably a pyrrolidinyl residue R⁶May optionally be mono-substituted by lower alkoxy-lower alkyl, such as methoxymethyl. Preferred cycloalkyl residues R⁶Cyclopropyl, cyclobutyl, cyclopentyl and cycloheptyl. Preferred phenyl lower alkyl residues R⁶Benzyl and phenethyl. Phenyl lower alkyl residue R⁶Preferably a phenethyl residue R⁶The phenyl moiety of (a) may optionally be mono-substituted by lower alkoxy, such as methoxy. Preferred lower alkylcarbamoyl-lower alkyl residues R⁶Is 2, 2-dimethyl-1-methylcarbamoyl-propyl.

In another embodiment, the invention relates to a compound of general formula (I) as defined above, wherein R is⁶Is Y-R⁸。

In another embodiment, the present invention relates to the aboveA compound of the general formula (I) as defined above, wherein when X is-C (O) -or-SO ₂When is, R⁶Is hydrogen.

In one embodiment, the invention relates to a compound of general formula (I) as defined above, wherein R is⁷Is hydrogen, cyano, halogen such as fluorine, or lower alkyl such as methyl. In another embodiment, R⁷Cyano, halogen such as fluorine, or lower alkyl such as methyl. In another embodiment, the invention relates to a compound of general formula (I) as defined above, wherein R is⁷Is hydrogen. Preferably R⁷Halogen, especially fluorine, is preferred.

In another embodiment, the invention relates to a compound of general formula (I) as defined above, wherein R is⁸Is phenyl, cycloalkyl, heterocyclyl or heteroaryl.

Preferred cycloalkyl residues R⁸Is cyclohexyl. For example, when Y is-C (O) -, methyl and n-butyl (e.g. when Y is-SO)₂-when) preferred lower alkyl residues R⁸Is n-propyl. Preferred heterocyclyl residues R⁸Morpholino, piperidinyl and azepanyl. Preferred heteroaryl residues R⁸Is a pyridyl group.

In one embodiment, R⁸Are heterocyclyl residues, such as morpholino, piperidinyl and azepanyl, with piperidinyl being particularly preferred.

In one embodiment, the invention relates to compounds of general formula (I) as defined above, wherein X is a single bond, -CH ₂-、-C(O)-、-SO₂-or-SO₂NH-。

In another embodiment, the invention relates to compounds of general formula (I) as defined above, wherein X is a single bond, R is³、R⁴And R⁷Is hydrogen, and R¹、R²、R⁵And R⁶As defined above.

In a preferred embodiment, the invention relates to compounds of general formula (I) as defined aboveWherein X is-C (O) -or-SO₂- (O) -is particularly preferred.

In another embodiment, the invention relates to a compound of general formula (I) as defined above, wherein Y is-CH₂-, -C (O) -, -NH-or-SO₂-. Preferably Y is-CH₂-or-NH-.

In a preferred embodiment, the invention relates to compounds of general formula (I) and pharmaceutically acceptable salts thereof, wherein R¹And R²Independently phenyl which is mono-or disubstituted independently by lower alkoxy, such as methoxy, or preferably by halogen, such as fluorine, chlorine and bromine; r³And R⁴Each is hydrogen; r⁵And R⁶Together with the nitrogen atom to which they are attached form a 5-or 6-membered monocyclic saturated heterocyclic ring which may optionally contain one additional heteroatom selected from O and S, such as piperidinyl, morpholino, thiomorpholino and pyrrolidinyl, said heterocyclic ring being optionally mono-or disubstituted independently by hydroxy or by halogen, such as fluoro; r ⁷Is halogen, such as fluorine; x is-C (O) -.

Preferred compounds of general formula (I) are selected from the following compounds and pharmaceutically acceptable salts thereof:

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -piperidine;

1- (4-chloro-phenyl) -4- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -piperazine;

1- (2, 3-dimethyl-phenyl) -4- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -piperazine;

1- (2, 4-dichloro-phenyl) -4- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -piperazine;

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4- (4-fluoro-phenyl) -piperazine;

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4- (3-chloro-phenyl) -piperazine;

4- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -morpholine;

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4-phenyl-piperazine;

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -pyrrolidine;

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4- (3-methoxy-phenyl) -piperazine;

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4- (4-methoxy-phenyl) -piperazine;

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4- (2-methoxy-phenyl) -piperazine;

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4- (2-chloro-phenyl) -piperazine;

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4- (2-fluoro-phenyl) -piperazine;

2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonic acid phenethyl-amide;

1-benzo [1, 3] dioxol-5-yl-4- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -piperazine;

4-benzyl-1- (2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonyl) -piperidine;

2- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -1, 2, 3, 4-tetrahydro-isoquinoline;

2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonic acid benzyl-methyl-amide;

2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonic acid benzylamide;

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4-methyl- [1, 4] diazepane;

1- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -4- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) - [1, 4] diazepane;

2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonic acid phenylamide;

2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonic acid [2- (4-methoxy-phenyl) -ethyl ] -amide;

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4-methyl-piperazine;

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4- (4-fluoro-phenyl) -1, 2, 3, 6-tetrahydro-pyridine;

4- (4-chloro-phenyl) -1- (2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonyl) -1, 2, 3, 6-tetrahydro-pyridine;

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4-phenyl-1, 2, 3, 6-tetrahydro-pyridine;

racemic 1- [2- (2-chloro-phenyl) -2- (4-methoxy-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -piperidine;

racemic 1- [2- (2-chloro-phenyl) -2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -piperidine;

racemic 1- [2- (2-chloro-phenyl) -2-p-tolyl-benzo [1, 3] dioxol-5-sulfonyl ] -piperidine;

Racemic 1- [2- (4-chloro-phenyl) -2- (4-methoxy-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -piperidine;

racemic 1- [2- (4-chloro-phenyl) -2-p-tolyl-benzo [1, 3] dioxol-5-sulfonyl ] -piperidine;

1- [2, 2-bis- (4-chloro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -piperidine;

racemic 1- [2- (4-fluoro-phenyl) -2-phenyl-benzo [1, 3] dioxol-5-sulfonyl ] -piperidine;

racemic 1- [2- (4-methoxy-phenyl) -2-phenyl-benzo [1, 3] dioxol-5-sulfonyl ] -piperidine;

racemic 1- [2- (4-chloro-phenyl) -2-p-tolyl-benzo [1, 3] dioxol-5-sulfonyl ] -4- (4-fluoro-phenyl) -1, 2, 3, 6-tetrahydro-pyridine;

racemic 1- [2- (4-chloro-phenyl) -2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -piperidine;

racemic 1- [2- (2, 4-dichloro-phenyl) -2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -piperidine;

1- [2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -piperidine;

racemic 1- [2- (3-chloro-phenyl) -2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -piperidine;

Racemic 1- [2- (4-chloro-phenyl) -2- (2-chloro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -piperidine;

racemic (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (3-hydroxy-pyrrolidin-1-yl) -methanone;

4- (2, 2-diphenyl-benzo [1, 3] dioxol-5-carbonyl) -piperazine-1-carbaldehyde;

(2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (4-hydroxymethyl-piperidin-1-yl) -methanone;

(1, 4-dioxa-8-aza-spiro [4.5] dec-8-yl) - (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -methanone;

(2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone;

(2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (4-methyl-piperazin-1-yl) -methanone;

(2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (4-isopropyl-piperazin-1-yl) -methanone;

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-carbonyl) -piperidin-4-one;

(2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (4-hydroxy-piperidin-1-yl) -methanone;

(2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -pyrrolidin-1-yl-methanone;

Racemic ethyl 1- (2, 2-diphenyl-benzo [1, 3] dioxole-5-carbonyl) -piperidine-3-carboxylate;

[4- (5-chloro-2-methoxy-phenyl) -piperazin-1-yl ] - (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -methanone;

(2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (4-m-tolyl-piperazin-1-yl) -methanone;

(2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone;

(2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (4-o-tolyl-piperazin-1-yl) -methanone;

racemic ethyl 1- (2, 2-diphenyl-benzo [1, 3] dioxole-5-carbonyl) -piperidine-2-carboxylate;

[4- (2, 3-dichloro-phenyl) -piperazin-1-yl ] - (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -methanone;

[4- (4-chloro-3-trifluoromethyl-phenyl) -piperazin-1-yl ] - (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -methanone;

racemic (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (3-hydroxymethyl-piperidin-1-yl) -methanone;

(2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (2, 3, 5, 6-tetrahydro- [1, 2' ] bipyrazinyl-4-yl) -methanone;

(2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (4-pyridin-2-yl-piperazin-1-yl) -methanone;

(4-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (4-methyl-piperazin-1-yl) -methanone;

(4-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone;

(4-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone;

(4, 7-dichloro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone;

(4, 7-dichloro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone;

(4, 7-dichloro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (4-methyl-piperazin-1-yl) -methanone;

(7-bromo-4-chloro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (4-methyl-piperazin-1-yl) -methanone;

(7-bromo-4-chloro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone;

(7-bromo-4-chloro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone;

(7-hydroxy-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone;

(2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - [4- (4-fluoro-phenyl) -3, 6-dihydro-2H-pyridin-1-yl ] -methanone;

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-ylmethyl) -4- (4-fluoro-phenyl) -1, 2, 3, 6-tetrahydro-pyridine.

Other preferred compounds of general formula (I) are selected from the following compounds and pharmaceutically acceptable salts thereof:

n- (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -benzenesulfonamide;

n, N-bis (methylsulfonyl) -2, 2-diphenyl-1, 3-benzodioxol-5-amine;

n, N-bis (butylsulfonyl) -2, 2-diphenyl-1, 3-benzodioxol-5-amine;

cyclohexanecarboxylic acid (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -amide;

butane-1-sulfonic acid (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -amide;

n- (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -butyramide;

morpholine-4-carboxylic acid (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -amide;

piperidine-1-sulfonic acid (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -amide;

piperidine-1-carboxylic acid (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -amide;

[2- (4-chloro-phenyl) -2- (2-fluoro-4-methoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

4- [2- (4-chloro-phenyl) -2- (2-fluoro-4-methoxy-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -morpholine;

[2- (4-methoxy-phenyl) -2- (3-nitro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

4- [2- (4-methoxy-phenyl) -2- (3-nitro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -morpholine;

4- [2- (4-methoxy-phenyl) -5- (morpholine-4-carbonyl) -benzo [1, 3] dioxol-2-yl ] -benzonitrile;

4- [2- (4-methoxy-phenyl) -5- (morpholine-4-sulfonyl) -benzo [1, 3] dioxol-2-yl ] -benzonitrile;

[2- (2-fluoro-4-methoxy-phenyl) -2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

4- [2- (2-fluoro-4-methoxy-phenyl) -2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -morpholine;

(6-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

[ 6-fluoro-2- (4-fluoro-phenyl) -2-phenyl-benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

[2- (2-chloro-phenyl) -6-fluoro-2- (4-methoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

(6-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone;

[ 6-fluoro-2- (4-fluoro-phenyl) -2-phenyl-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[2- (2-chloro-phenyl) -6-fluoro-2- (4-methoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

(6-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - [4- (4-fluoro-phenyl) -piperazin-1-yl ] -methanone;

[ 6-fluoro-2- (4-fluoro-phenyl) -2-phenyl-benzo [1, 3] dioxol-5-yl ] - [4- (4-fluoro-phenyl) -piperazin-1-yl ] -methanone;

[2- (2-chloro-phenyl) -6-fluoro-2- (4-methoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] - [4- (4-fluoro-phenyl) -piperazin-1-yl ] -methanone;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-methoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-methoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-methoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] - [4- (4-fluoro-phenyl) -piperazin-1-yl ] -methanone;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

(6-methyl-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone;

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

(6-bromo-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone;

(+) - [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

(-) - [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[2- (2, 4-dichloro-phenyl) -2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[2- (2, 4-dichloro-phenyl) -2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

(6-chloro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone;

(6-chloro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone;

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid ethyl-methyl-amide;

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid methyl-propyl-amide;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (2-methyl-pyrrolidin-1-yl) amide;

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-ylcarboxylic acid azepan-1-ylamide;

azetidin-1-yl- [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -methanone;

azepan-1-yl- [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -methanone;

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (2, 2-dimethyl-1-methylcarbamoyl-propyl) -amide;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (2S-methoxymethyl-pyrrolidin-1-yl) -methanone;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (2R-hydroxymethyl-pyrrolidin-1-yl) -methanone;

1- [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-carbonyl ] -pyrrolidine-2R-carboxylic acid dimethylamide;

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid cyclobutylamide;

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-carboxylic acid morpholin-4-ylamide;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (2, 3, 5, 6-tetrahydro- [1, 2' ] bipyrazinyl-4-yl) -methanone;

1- [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-carbonyl ] -pyrrolidine-2S-carboxylic acid amide;

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid tert-butoxyamide;

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid cyclopentylamide;

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (tetrahydro-furan-2-ylmethyl) -amide;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -thiomorpholin-4-yl-methanone;

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid isopropylamide;

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-carboxylic acid pyrrolidin-1-ylamide;

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid methoxy-methyl-amide;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (3R-hydroxy-pyrrolidin-1-yl) -methanone;

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid bis-cyclopropylmethyl-amide;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (4-fluoro-piperidin-1-yl) -methanone;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (1, 4-dioxa-8-aza-spiro [4.5] decan-8-yl) -methanone;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (4-hydroxymethyl-piperidin-1-yl) -methanone;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (4-hydroxy-4-methyl-piperidin-1-yl) -methanone;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -pyrrolidin-1-yl-methanone;

n- {1- [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-carbonyl ] -pyrrolidin-3S-yl } -acetamide;

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid cycloheptylamide;

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid N' -pyridin-2-yl-hydrazide;

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (2S-methoxymethyl-pyrrolidin-1-yl) -amide;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (1, 1-dioxothiomorpholin-4-yl) -methanone;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (3-hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) -methanone;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (2R-methoxymethyl-pyrrolidin-1-yl) -methanone;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (3S-hydroxy-pyrrolidin-1-yl) -methanone;

n- {1- [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-carbonyl ] -pyrrolidin-3R-yl } -acetamide;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (2S-hydroxymethyl-pyrrolidin-1-yl) -methanone;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methinone;

[2- (4-chloro-phenyl) -2- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

6- (morpholine-4-carbonyl) -2, 2-diphenyl-benzo [1, 3] dioxole-5-carbonitrile;

[2- (4-chloro-phenyl) -2- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] piperidin-1-yl-methanone;

[2- (4-chloro-phenyl) -2- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] pyrrolidin-1-yl-methanone;

[2, 2-bis- (2, 4-difluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[2, 2-bis- (2, 4-difluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -pyrrolidin-1-yl-methanone;

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

[2, 2-bis- (4-bromo-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

4- [2, 2-bis- (4-cyano-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-carbonyl ] -morpholine;

4- [2- (4-bromo-phenyl) -5-fluoro-6- (morpholine-4-carbonyl) -benzo [1, 3] dioxol-2-yl ] -benzonitrile;

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[2, 2-bis- (4-chloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[ 6-chloro-2, 2-bis- (2, 4-difluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[2- (2-chloro-4-fluoro-phenyl) -2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

[ 6-fluoro-2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[2, 2-bis- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

4- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -morpholine;

4- [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -morpholine;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (4, 4-difluoro-piperidin-1-yl) -methanone;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (4-trifluoromethyl-piperidin-1-yl) -methanone;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (3S-ethoxy-pyrrolidin-1-yl) -methanone;

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (1R-phenyl-ethyl) -amide;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (1-oxo-thiomorpholin-4-yl) -methanone;

[2, 2-bis- (2-chloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[ 6-fluoro-2, 2-bis- (4-trifluoromethyl-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[ 6-fluoro-2, 2-bis- (3-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[2- (2-chloro-4-fluoro-phenyl) -2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[2, 2-bis- (3, 4-difluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

[2, 2-bis- (3, 4-difluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[2, 2-bis- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] - (3-hydroxy-pyrrolidin-1-yl) -methanone;

[2, 2-bis- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] - (4-hydroxy-piperidin-1-yl) -methanone;

2, 2-bis- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid ethyl-methyl-amide;

2, 2-bis- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid bis- (2-hydroxy-ethyl) -amide;

[2, 2-bis- (4-chloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

[2, 2-bis- (4-chloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -pyrrolidin-1-yl-methanone;

[2, 2-bis- (2-chloro-4-fluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

[2, 2-bis- (3, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[2, 2-bis- (2, 5-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[2, 2-bis- (2-chloro-4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[2, 2-bis- (2-chloro-4-fluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[ 6-chloro-2, 2-bis- (2-chloro-4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid amide;

[2, 2-bis- (4-bromo-2-fluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (3, 4-cis-dihydroxy-pyrrolidin-1-yl) -methanone;

[2, 2-bis- (2, 3-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[ 6-fluoro-2, 2-bis- (4-trifluoromethoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[2, 2-bis- (2-chloro-4, 5-difluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

4- [2, 2-bis- (2-chloro-4-fluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -morpholine;

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] - (4-fluoro-piperidin-1-yl) -methanone;

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] - (4, 4-fluoro-piperidin-1-yl) -methanone;

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] - (4-trifluoromethyl-piperidin-1-yl) -methanone;

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] - (4-hydroxy-piperidin-1-yl) -methanone;

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -thiomorpholin-4-yl-methanone;

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -pyrrolidin-1-yl-methanone;

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] - (3S-hydroxy-pyrrolidin-1-yl) -methanone;

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] - (2S-hydroxymethyl-pyrrolidin-1-yl) -methanone;

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] - (2S-methoxymethyl-pyrrolidin-1-yl) -methanone;

(6-chloro-2, 2-di-p-tolyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone;

4- [ { 6-chloro-10 ', 11 ' -dihydro-spiro [1, 3-benzodioxole-2, 5 ' - [5H ] dibenzo [ a, d ] cyclohepten ] -5-yl } carbonyl ] -morpholine;

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (4-fluoro-piperidin-1-yl) -methanone;

(4, 4-difluoro-piperidin-1-yl) - [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -methanone;

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (4-trifluoromethyl-piperidin-1-yl) -methanone;

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -thiomorpholin-4-yl-methanone;

(3S-ethoxy-pyrrolidin-1-yl) - [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -methanone;

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - [ (S) - (2-methoxymethyl-pyrrolidin-1-yl) ] -methanone;

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - [ (S) -2-hydroxymethyl-pyrrolidin-1-yl ] -methanone;

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - [ (S) -3-hydroxy-pyrrolidin-1-yl ] -methanone;

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (4-hydroxy-piperidin-1-yl) -methanone;

4- [2, 2-bis- (2-chloro-4, 5-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -morpholine;

(2, 2-di-p-tolyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone;

(2, 2-di-p-tolyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone;

4- [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -morpholine;

4- (6-fluoro-2, 2-di-p-tolyl-benzo [1, 3] dioxol-5-sulfonyl) -morpholine;

1- { 6-fluoro-10 ', 11 ' -dihydrospiro [1, 3] -benzodioxole-2, 5 ' - [5H ] dibenzo [ a, d ] cycloheptene } -5-yl } sulfonyl ] -piperidine;

4- { 6-fluoro-10 ', 11 ' -dihydrospiro [1, 3-benzodioxole-2, 5 ' - [5H ] dibenzo [ a, d ] cycloheptene } -5-yl } sulfonyl ] -morpholine;

4- [ {10 ', 11 ' -dihydro-spiro [1, 3] -benzodioxole-2, 5 ' - [5H ] dibenzo [ a, d ] cyclohepten } -5-yl ] carbonyl ] -morpholine;

1- [ {10 ', 11 ' -dihydro-spiro [1, 3-benzodioxole-2, 5 ' - [5H ] dibenzo [ a, d ] cycloheptene } -5-yl ] carbonyl ] -piperidine;

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (3-methoxy-piperidin-1-yl) -methanone;

1- [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -pyrrolidine;

1- [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -piperidine;

4- [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -thiomorpholine;

1- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -piperidine;

1- [2, 2-bis- (2-chloro-4-fluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -piperidine;

1- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -pyrrolidine;

1- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -4-fluoro-piperidine;

1- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -4, 4-difluoro-piperidine;

1- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -4-trifluoromethyl-piperidine;

4- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -thiomorpholine;

1- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -2S-methoxymethyl-pyrrolidine;

2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonic acid (2S-methoxymethyl-pyrrolidin-1-yl) -amide;

{1- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -pyrrolidin-2S-yl } -methanol;

1- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -pyrrolidin-3S-ol;

1- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -piperidin-4-ol;

1- [2, 2-bis- (2-chloro-4, 5-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -piperidine;

4- { 6-fluoro-10 ', 11 ' -dihydro-spiro [1, 3-benzodioxole-2, 5 ' - [5H ] dibenzo [ a, d ] cycloheptene } -5-yl } -carbonyl ] -morpholine;

(6-fluoro-2, 2-di-p-tolyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone;

1- (6-fluoro-2, 2-di-p-tolyl-benzo [1, 3] dioxol-5-sulfonyl) -piperidine;

[ 6-fluoro-2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

[ 6-fluoro-2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (4-hydroxy-piperidin-1-yl) -methanone;

4-fluoro-1- [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -piperidine;

4, 4-difluoro-1- [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -piperidine;

1- [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -4-trifluoromethyl-piperidine;

1- [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -2-methoxymethyl-pyrrolidine;

1- [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -pyrrolidin-3S-ol;

1- [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -piperidin-4-ol;

[2, 2-bis- (3-chloro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

[2, 2-bis- (4-cyano-2-fluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[2, 2-bis- (3, 5-difluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

[2, 2-bis- (3, 5-difluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

6-fluoro- [2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - [ (S) -3-hydroxy-pyrrolidin-1-yl) ] -methanone;

6-fluoro-2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid ethyl-methyl-amide;

6-fluoro-2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (2-methoxy-ethyl) -methyl-amide;

[2, 2-bis- (3, 5-dichloro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

[2, 2-bis- (3, 5-dichloro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[2, 2-bis- (3-bromo-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[ 6-fluoro-2, 2-bis- (3-methoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[2, 2-bis- (3-methoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

[2, 2-bis- (3-chloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone.

Particularly preferred compounds of general formula (I) are selected from the following compounds and pharmaceutically acceptable salts thereof:

[2- (4-chloro-phenyl) -6-fluoro-2- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone;

[2- (4-chloro-phenyl) -6-fluoro-2- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

[2- (4-chloro-phenyl) -6-fluoro-2- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -pyrrolidin-1-yl-methanone;

[2, 2-bis- (4-chloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -piperidin-4-yl-methanone;

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] - (4, 4-difluoro-piperidin-1-yl) -methanone;

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] - (3S-hydroxy-pyrrolidin-1-yl) -methanone.

The invention also relates to a process for the preparation of the compounds of general formula (I) as defined above. The compounds of general formula (I) may be prepared by the methods given below, by the methods given in example 1 or by analogous methods. Suitable reaction conditions for each reaction step are well known to those skilled in the art. The starting materials are either commercially available or can be prepared by methods well known in the art or described in the following or in the examples.

The compounds of general formula (I) wherein R is as depicted in scheme 1, further described below, can be prepared using the general procedure ¹-R⁷And X is as defined above.

Scheme 1:

the catechol intermediate of formula A is ketalized according to scheme 1 with a bis-substituted dichloromethane derivative of formula B at elevated temperature (e.g., > 100 deg.C), in an inert solvent (e.g., toluene or pyridine) or neat, in the presence or absence of a base (e.g., pyridine) to provide product I. Alternatively, compounds of formula (I) may be prepared by reacting a compound of formula a with a ketone of formula C by methods well known in the art (see, for example, t. r. kelly, a. szabados, y. -j. lee, journal of organic chemistry (j. org. chem.)62(2) (1997)428) under elevated temperature (e.g., > 150 ℃) in an inert solvent (e.g., toluene) with or without removal of water, either by distillation, azeotropic distillation, or by addition of a drying agent (e.g., molecular sieves or 2, 2-dimethoxypropane).

On the other hand, the compounds of formula (I) can be prepared by methods well known in the art (see, for example, i.shibuya, e.katoh, y.gama, a.oishi, y.taguchi and t.tsuchiya, Heterocycles (Heterocycles), 43(1996)851), by reacting the catechol intermediate of formula a with a thione of formula (C') in an inert solvent (e.g. acetonitrile), either neat or in the presence or absence of a base (e.g. triethylamine) and a metal salt (e.g. CuI). The compounds of formula (I) can also be obtained by reduction of the corresponding compounds of formula (I) wherein X is-CH-with X being-CO-, in a manner known in the art ₂-。

Scheme 2:

the bis-substituted dichloromethane derivatives of formula B are readily prepared from the corresponding ketones by methods well known in the art by reaction with thionyl chloride in the presence of DMF or another N-formylating agent, by reaction with phosphorus pentachloride at elevated temperature (e.g., > 100 ℃) in the presence or absence of a suitable solvent (e.g., phosphorus oxychloride), by reaction with a Lewis acid (e.g., trichloro chloride)Electrophilic aromatic substitution of the trifluoromethyl derivative E with a benzene derivative of the formula D in an inert solvent, for example 1, 2-dichloroethane, in the presence of aluminium (for example R.K. Ramchandrani, R.D. Wakharkar, A.Sudalai, Tetrahedron letters 37(23) (1996)4063), by chlorination of bisaryl derivatives (for example U.S. Pat. No. 5578737 or W.Deuschel, Helv.Chim.acta 34 (1951)) or, in the case of symmetrical bis-substituted dichloromethane derivatives of the formula B, by reaction in the presence of a Lewis acid (for example AlCl)₃) Electrophilic aromatic substitution of benzene derivatives with tetrachloromethane in the presence of an inert solvent (e.g. 1, 2-dichloroethane) (see, for example, j.p. picard, c.kearns, canadian journal of research (can.j.res.)28(1950) 56).

Scheme 3:

the catechols of the general formula a are readily prepared from the corresponding diphenylmethylene protected ketals of the general formula (Ia) by treatment with an acid, for example trifluoroacetic acid, in a suitable inert solvent, for example dichloromethane, or by treatment with an acid, for example trifluoroacetic acid, neat or using an inert solvent, for example dichloromethane, in the presence of a suitable reducing agent, for example triethylsilane. On the other hand, the catechol of formula a is readily prepared from the corresponding bis-benzyl protected catechol of formula (a') (e.g. by hydrogenation in the presence of a suitable catalyst (e.g. palladium on carbon)) by reduction). Alternatively, the catechol derivative of formula F may be coupled with a suitable amine in a suitable inert solvent such as DMF, dichloromethane, pyridine or THF in the presence of a base such as triethylamine. After activation with a suitable coupling reagent (e.g. carbonyldiimidazole), the corresponding acid chlorides (X ═ CO, Z ═ Cl), the corresponding sulfonyl chlorides (X ═ SO), respectively, are reacted by methods well known in the art₂Z ═ Cl) or the corresponding carboxylic acids (X ═ CO, Z ═ OH) are used for the preparation of the catechols of the general formula a. The reaction of the general formula (A) with reduction of X to-CO-can be carried out in a manner known per se To give a compound of the general formula (A) in which X is-CH₂-。

Scheme 4:

the compounds of formula G can be coupled with suitable amines in the presence of a base such as triethylamine in a suitable inert solvent such as DMF, dichloromethane, pyridine or THF to give the benzodioxoles of formula (I). After activation with a suitable coupling reagent (e.g. carbonyldiimidazole), the corresponding acid chlorides (X ═ CO, Z ═ Cl), i.e. the corresponding sulfonyl chlorides (X ═ SO), respectively, are reacted by methods well known in the art₂Z ═ Cl) or the corresponding carboxylic acids (X ═ CO, Z ═ OH) are used for the preparation of benzodioxoles of the general formula (I).

Scheme 5:

benzodioxoles of general formula (I) wherein X is a single bond, can also be prepared by: the coupling of anilines of formula J with compounds of formula K in the presence of a base (e.g. triethylamine) in a suitable inert solvent (e.g. DMF, dichloromethane, pyridine or THF) as described in scheme 5 above gives benzodioxoles of formula (Ia). The benzodioxoles of formula (Ia) can then be further coupled with compounds of formula K' in a suitable inert solvent (e.g. DMF, dichloromethane, pyridine or THF) in the presence of a base (e.g. triethylamine) to give the benzodioxoles of formula (Ib). The compounds of formula K and K' may be R after activation with a suitable coupling reagent (e.g. carbonyldiimidazole) ⁵And R⁶The corresponding acid chlorides, the corresponding sulfonyl chlorides, the corresponding carbamoyl chlorides, the corresponding sulfamoyl chlorides, or the corresponding carboxylic acids, respectively, are formed.

The invention further relates to compounds of general formula (I) as defined above, prepared according to the process as defined above.

Certain compounds of formula (I) may bear asymmetric centers and thus may exist in more than one stereoisomeric form. The invention thus also relates to compounds and mixtures thereof, including racemic mixtures, in substantially pure isomeric form with one or more asymmetric centers. Such isomers may be prepared by asymmetric synthesis, e.g. using chiral intermediates, or the mixture may be resolved by conventional methods, e.g. chromatography (using chiral adsorbents or eluents) or using resolving agents.

It will be appreciated that the functional groups on the compounds of general formula (I) of the present invention may be derivatized to give derivatives which are capable of conversion back to the parent compound in vivo.

As described above, the compound of the general formula (I) or a pharmaceutically acceptable salt thereof can be used as a medicament for treating and/or preventing diseases associated with the modulation of CB1 receptor.

The invention thus also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant.

Furthermore, the present invention relates to the use of the compounds as defined above as therapeutically active substances, in particular as therapeutically active substances for the treatment and/or prevention of diseases which are associated with the modulation of the CB1 receptor.

In another embodiment the invention relates to a method for the treatment and/or prevention of diseases which are associated with the modulation of the CB1 receptor, which method comprises the step of administering a compound as defined above to a human being or animal.

The invention further relates to the use of compounds as defined above for the treatment and/or prevention of diseases which are associated with the modulation of the CB1 receptor.

Furthermore, the present invention relates to the use of a compound as defined above for the preparation of a medicament for the treatment and/or prevention of diseases which are associated with the modulation of the CB1 receptor. Such agents include compounds as defined above.

In the context of the present invention, expression 'diseases associated with modulation of the CB1 receptor' refers to diseases that can be treated and/or prevented by modulation of the CB1 receptor. Such diseases include, but are not limited to: psychiatric disorders, especially anxiety and anxiety disorders; psychosis; schizophrenia; depression; substance abuse disorders including psychotropic substance abuse, such as psychotropic substance abuse and/or dependence, including alcohol dependence and nicotine dependence; neuropathy; migraine headache; a state of tension; epilepsy; movement disorders; parkinson's disease; amnesia; memory and cognitive disorders; senile dementia; alzheimer's disease; eating disorders; obesity; type II diabetes or non-insulin dependent diabetes mellitus (NIDD); gastrointestinal diseases; vomiting; diarrhea; urinary disorders; cardiovascular diseases; reproductive diseases; inflammation; (ii) infection; cancer; diseases associated with demyelination, neuroinflammation, particularly in atherosclerosis or Guillain-Barre syndrome; viral encephalitis; cerebrovascular disease onset; and cranial wounds.

In a preferred aspect, the expression 'disease associated with modulation of the CB1 receptor' refers to eating disorders, type II diabetes or non-insulin dependent diabetes mellitus (NIDD), neuroinflammation, diarrhea, substance abuse and/or dependence including alcohol dependence and nicotine dependence. In a more preferred aspect, the term refers to eating disorders, obesity, type II diabetes or non-insulin dependent diabetes mellitus (NIDD), neuroinflammation, diarrhea, substance abuse and/or dependence, including alcohol dependence and nicotine dependence, with obesity being particularly preferred.

It is another preferred object to provide a method for the treatment or prophylaxis of type II diabetes (non-insulin dependent diabetes mellitus (NIDDM) in humans comprising the step of administering in combination or association a therapeutically effective amount of a compound of formula (I) with a therapeutically effective amount of a lipase inhibitor, in particular wherein said lipase inhibitor is orlistat.

Another preferred object is to provide a method for the treatment or prevention of obesity and obesity-related diseases comprising the step of administering a therapeutically effective amount of a compound of formula (I) in combination or association with a therapeutically effective amount of a further medicament for the treatment of obesity or eating disorders, such that together they give effective relief. Suitable additional agents include, but are not limited to, anorectics, lipase inhibitors and selective 5-hydroxytryptamine reuptake inhibitors (SSRIs). Combinations or combinations of the above active agents may include separate, sequential or simultaneous administration.

The preferred lipase inhibitor is tetrahydrotetrahydrochysene lipstatin.

Suitable anorectic agents for use in combination with the compounds of the present invention include, but are not limited to, amitriptan, amphetamine, benzphetamine, p-chlorphenbutamine, clobrex, clorfrex, loratadine, cletexamine, ciclexedrine, dexfenfluramine, amfepramone, diphemethodine, N-ethylphenylamine, fenbuterol, fenfluramine, fenirex, fenprix, fludorex, flutolrex, furfurylmethamphetamine, levoamphetamine, levofaxate, mazindol, mefenrex, methamphetamine, pseudoephedrine, pentorex, phenmetrazine, phentermine, phenylpropanolamine, pisipramine and sibutramine, and pharmaceutically acceptable salts thereof.

The most preferred anorectics are sibutramine and phentermine.

Suitable selective 5-hydroxytryptamine reuptake inhibitors for use in combination with the compounds of the present invention include fluoxetine, fluvoxamine, paroxetine and sertraline and pharmaceutically acceptable salts thereof.

Other biological activities of the compounds of the invention can be demonstrated by in vitro, ex vivo and in vivo assays well known in the art. For example, to demonstrate the efficacy of an agent in the treatment of obesity-related diseases such as diabetes, syndrome X or atherosclerotic diseases, and related diseases such as hypertriglyceridemia and hypercholesterolemia, the following tests may be used.

Method for measuring blood sugar level

Db/db mice (obtained from Jackson Laboratories, Bar Harbor, ME) were bled (via the eye or tail vein) and grouped according to equivalent mean blood glucose levels. They were given test compounds orally (by gavage in a pharmaceutically acceptable vehicle) once a day for 7-14 days. At this point the animals are again bled via the eye or tail vein and blood glucose levels are measured.

Method for measuring triglyceride level

hApoAl mice (obtained from Jackson Laboratories, Bar Harbor, ME) were bled (either through the eye or tail vein) and grouped according to equivalent mean serum triglyceride levels. They were given test compounds orally (by gavage in a pharmaceutically acceptable vehicle) once a day for 7-14 days. The animals were again bled by eye or tail vein and serum triglyceride levels were measured.

Method for determining HDL-cholesterol levels

To determine plasma HDL-cholesterol levels, hApoAl mice were bled and grouped according to equivalent mean plasma HDL-cholesterol levels. Mice were orally administered vehicle or test compound once daily for 7-14 days and then bled on day 2. Plasma HDL-cholesterol was analyzed.

Furthermore, to demonstrate the CNS activity of the compounds of the invention, the following in vivo assays may be used.

Method for testing work learning and space memory

Morris Water Maze is commonly used to evaluate working learning and spatial memory (Jasperss et al, neuroscience Commission 117: 149-. In this experiment, animals were placed in four-part pools. A platform is hidden in one of the four sections. The unit is placed in a pool and predicted to find a hidden platform within a predetermined time. During a number of training trials, animals learned to find the platform and escape the pool. Animals received multiple trials in this work. The total distance moved, the number of trials to find the platform, the potential time to find the platform and the path of swimming were recorded for each animal. The learning ability of the animals was determined by the length of time required to find the hidden platform and the number of trials. Memory loss or improvement is determined by the number of trials or potential times to find the platform at a predetermined delay time after data acquisition. Learning and memory was determined by the number of times the animal passed to find the quarter of the platform in the acquisition time period.

Method for testing drug dependence

Self-administration in animals is a predictor of the likelihood of compound abuse in humans. Improved methods of this approach may also be used to identify potentiated properties of drugs that prevent or block the potential for abuse. Suppression of self-administered compounds may prevent drug abuse or dependence thereof. (Ranaldi et al psychopharmacology (Psychopharmacol.) 161: 442-448, 2002; Campbell et al clinical psychopharmacology experiments (exp. Clin. Psychopharmacol.) 8: 312-25, 2000). In the self-administration test, animals are placed in an operating performance room containing active and inactive levers. Each response to the active lever results in an infusion of a test compound or drug known to be self-administered. Pressing on the inactive lever has no effect, but the recording is also performed. Animals were then trained to self-administer compounds/drugs over a set time period by finding drug entry during each dosing. The lighting of the room light is signaled from this time frame and the compound/drug utilization. When this period is over, the room light is turned off. The initiation of drug infusion occurs with each depression of the movable lever. Once the lever action is established, the number of lever presses to produce a drug infusion is increased. After stable compound/drug self-administration is achieved, the effect of the second compound on drug potentiation can be evaluated. Administration of this second compound before this period did not potentiate, decrease or produce a change in self-administration behavior.

The following tests were carried out to determine the activity of the compounds of general formula (I).

The affinity of the compounds of the invention for the cannabinoid CB1 receptor was determined using membrane preparations of Human Embryonic Kidney (HEK) cells, in which the human cannabinoid CB1 receptor was transiently transfected with [3H ] -CP-55,940, a system of zerniki forest viruses, and autoradioactive ligands. After incubation of freshly prepared cell membrane preparations with [3H ] -ligand with or without addition of the compounds according to the invention, bound and free ligand are separated by filtration through a glass fibre filter. Radioactivity on the filters was determined by liquid scintillation counting.

The affinity of the compounds of the invention for the cannabinoid CB2 receptor was determined using membrane preparations of Human Embryonic Kidney (HEK) cells, in which the human cannabinoid CB2 receptor was transiently transfected with [3H ] -CP-55,940, a system of zerniki forest viruses, and autoradioactive ligands. After incubation of freshly prepared cell membrane preparations with [3H ] -ligand with or without addition of the compounds according to the invention, bound and free ligand are separated by filtration through a glass fibre filter. Radioactivity on the filters was determined by liquid scintillation counting.

Cannabinoid CB1 antagonistic activity of the compounds of the invention was determined by functional studies using CHO cells stably expressing the human cannabinoid CB1 receptor (see m.linaldi-Carmona et al, journal of experimental drug therapy (j.pharmacol. exp. the.) 278(1996) 871). Stable expression of human cannabinoid receptors in cell systems was first described in Nature 1990, 346, 561-564(CB1) and Nature 1993, 365, 61-65(CB2), respectively. Forskolin was used to stimulate adenylate cyclase and was determined quantitatively by the amount of accumulated cyclic AMP. Concomitant activation of CB1 receptor agonists (e.g., CP-55,940 or (R) -WIN-55212-2) at the CB1 receptor attenuates forskolin-induced cAMP accumulation in a concentration-dependent manner. This CB1 receptor mediated response may be antagonized by CB1 receptor antagonists such as the compounds of the present invention.

Compounds of formula (I) have been shown to use Deven et al in molecular pharmacologyGood affinity to the CB1 receptor, determined under the experimental conditions described in mol. The compounds of the present invention, or pharmaceutically acceptable salts thereof, are and are selective for CB1 receptor antagonists with less affinity than IC₅₀2 μ M, preferably 1nM to 100 nM. They exhibit at least 10-fold selectivity for the CB2 receptor.

Compounds of the examples	IC₅₀[μM]
Compounds of the examples	IC₅₀[μM]	39	＜2μM
46	＜2μM	39	＜2μM
46	＜2μM	18	＜2μM
65	＜2μM	18	＜2μM
65	＜2μM	4	＜2μM
20	＜2μM	4	＜2μM
20	＜2μM	22	＜2μM
75	＜2μM	22	＜2μM
75	＜2μM	108	＜2μM

164	＜2μM
164	＜2μM	234	＜2μM
271	＜2μM	234	＜2μM

Effect of CB1 receptor antagonists/inverse agonists on CP 55,940-induced hypothermia in NMRI mice

Animal(s) production

Male NMRI mice were used in this study and they were obtained from research corporation Ltd (RCC) of flinsdorf (Switzerland). Mice weighing 30-31g were used in this study. The ambient temperature is about 20-21 deg.C and the relative humidity is 55-65%. The chamber was maintained on a 12 hour light-dark cycle in all experiments performed during the period of use of light. Tap water and food were available ad libitum.

Method

All measurements were performed between 12:00am and 5:00 pm. Mice were allowed to enter this environment and allowed to habituate for at least 2 hours before starting the experiment. They are always free to drink and drink. For each dose, 8 mice were used. Rectal temperature measurements were recorded by rectal bougie (RET 2 from physiotemp) and digital thermometer (Digi-sen 8528-20 from Cole Farmer, Chicago USA). Bougie was inserted approximately 3.5cm per mouse.

Body temperature was measured 15 minutes prior to administration of vehicle or CB1 receptor antagonist/inverse agonist. Body temperature was recorded 30 or 90 minutes after intraperitoneal or oral administration of the compound to assess any effect of the compound itself, respectively. The CB receptor agonist CP 55,940(0.3mg/kg) was administered immediately intravenously, followed by CP 55940 administration intravenously or re-thermometry at 20 minutes.

The in vivo activity of the compounds of formula (I) in their ability to modulate feeding behaviour was assessed by recording food consumption in animals deprived of food.

Rats were trained to feed for 2 hours/day and fasted for 22 hours. When they were trained according to this protocol, the food intake was consistent from day to day during the 2 hour feeding period.

To test the ability of the compounds of formula (I) to reduce food intake, 8 animals were used in a crossover study. Rats were each housed in a plexiglas box with a grid on the floor and paper was placed under the cage floor to collect any fecal material. The animals were provided food for 2 hours with a food dispenser (becher) filled with a pre-weighed amount of food. At the end of the feeding period, the rats were returned to their home cages. Each rat was weighed, after which the experiment was started and the amount of food consumed during the 2 hour feeding period was recorded. Different doses of test compound or vehicle were administered orally 60 minutes before the start of the 2 hour feeding period. A positive control rimonabant (SR141716) was included in this experiment. Anova analysis using replicate measurements was used, followed by Student Neumann-Keuls posthoc test. ^*P < 0.05 compared to saline treated rats.

Furthermore, the use of compounds of formula (I) in diseases or conditions can be demonstrated in animal disease models reported in the literature. The following are examples of such animal disease models: a) reduction in sweet monkey intake (behavior and drugs, 1998, 9, 179-181); b) reduction in sucrose and ethanol uptake in mice (psychotropic (Psychopharm) 1997, 132, 104-106); c) increase in rat locomotor activity and position regulation (psychopharmaceuticals 1998, 135, 324-332; psychopharmacology (psychromermacol) 2000, 151: 25-30); d) spontaneous locomotor activity in mice (J.Pharm.exp.Ther.)1996, 277, 586 + 594); e) reduction in self-administration of opiates in mice (science 1999, 283, 401-404).

The compounds of formula (I) and/or pharmaceutically acceptable salts thereof may be used as medicaments, for example in the form of pharmaceutical preparations for enteral, parenteral or topical administration. For example, they may be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft capsules, solutions, emulsions or suspensions; by rectal administration, for example in the form of suppositories; by parenteral administration, for example in the form of injection solutions or infusion solutions; or by topical administration, for example in the form of an ointment, cream or oil. Oral administration is preferred.

The pharmaceutical preparation may be produced in a manner well known to those skilled in the art by the following steps: the compounds of the general formula (I) and/or their pharmaceutically acceptable salts are mixed, optionally with other therapeutically valuable substances and suitable non-toxic inert therapeutically compatible solid or liquid carrier materials, into galenic administration forms and, if desired, with the usual pharmaceutical adjuvants.

Suitable support materials are not only inorganic support materials but also organic support materials. Thus, for example, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carrier materials for soft capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (although, depending on the nature of the active ingredient, no carriers may be required for soft capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier substances for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier substances for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

Conventional stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavoring agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.

The dosage of the compounds of the general formula (I) can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration and should of course be adapted to the individual requirements in each particular case. The daily dose contemplated for an adult patient is about 1-1000mg, especially about 1-100 mg. Depending on the severity of the disease and the precise pharmacokinetics, respectively, the compound may be administered in one or more daily dosage units, for example 1 to 3 dosage units.

The pharmaceutical preparations generally contain from about 1 to 500mg, preferably from 1 to 100mg, of a compound of formula (I).

The following examples serve to explain the invention in more detail. However, they are not intended to limit the scope of the present invention in any way.

Examples

MS ═ mass spectrum; ISP ═ ion spray (cationic); m.p. ═ melting point; aq. ═ water; DMSO ═ dimethyl sulfoxide; NMR ═ nuclear magnetic resonance spectroscopy; EDCI ═ N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride; HPLC ═ high performance liquid chromatography.

Example 1

Preparation of 1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -piperidine

2, 2-Diphenyl-benzo [1, 3] dioxol-5-sulfonyl chloride (3.36g, 9mmol) was dissolved in dichloromethane (135 ml). Piperidine (1.33ml, 13.5mmol) and ethyldiisopropylamine (2.3ml, 13.5mmol) were added at room temperature. The reaction was stirred at room temperature overnight and washed twice with 1N aqueous HCl, twice with 1N aqueous NaOH, and once with brine. The organic layer was dried over sodium sulfate and filtered. The solvent was evaporated and the residue was purified by column chromatography (4/1 hexane/ethyl acetate eluent). The product was suspended in diethyl ether and filtered to give a white crystalline solid (1.98g, 52%). m.p.: 163 ℃ and 164 ℃.

Preparation of 2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl chloride:

sulfonyl chloride derivatives were prepared according to literature procedures (WO9218490, EP 544166).

Method A

Process A is a general procedure for the preparation of 2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonamides starting from commercially available amines:

2, 2-Diphenyl-benzo [1, 3] dioxol-5-sulfonyl chloride (93mg, 0.25mmol) was dissolved in pyridine (1 ml). The appropriate amine (0.25mmol) was added and the reaction was heated to 60 ℃ overnight. Water was added and the oil was separated accordingly. The aqueous phase was decanted and the residue was stirred with acetonitrile. The solid precipitates, which are filtered off and washed with a little acetonitrile to give the product after drying under high vacuum.

The following examples above were prepared using general methods:

example 2

Process for preparation of 1- (4-chloro-phenyl) -4- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -piperazine

Preparation of

Using 4- (4-chlorophenyl) piperazine (49.2mg, 0.25mmol) as the amine gave the title compound as a white solid (27mg, 20%).

MS(ISP)：533.2(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.44-7.56(m，10H)，7.41(s，1H)，7.37(d，1H)，7.32(d，1H)，7.26(d，2H)，6.90(d，2H)，3.16-3.19(m，4H)，2.98-3.02(m，4H).

Example 3

1- (2, 3-dimethyl-phenyl) -4- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -piperazine

Preparation of oxazines

Using 4- (2, 3-dimethylphenyl) piperazine hydrochloride (56.7mg, 0.25mmol) as the amine, the title compound was obtained as a white solid (8mg, 6%).

MS(ISP)：527.2(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.45-7.60(m，5H)，7.47-7.55(m，5H)，7.46(s，1H)，7.38(d，1H)，7.31(d，1H)，7.01(t，1H)，6.89(m，2H)，3.00-3.12(m，4H)，2.82-2.88(m，4H)，2.17(s，3H)，2.02(s，3H).

Example 4

1- (2, 4-dichloro-phenyl) -4- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -piperazine

Preparation of

Using 4- (2, 4-dichlorophenyl) piperazine hydrochloride (66.9mg, 0.25mmol) as the amine, the title compound was obtained as a yellow solid (32mg, 23%).

MS(ISP)：567.1(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.45-7.60(m，10H)，7.42(s，1H)，7.34-7.39(m，4H)，7.31(d，1H)，7.16(d，1H)，3.00-3.08(m，8H).

Example 5

Process for preparing 1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4- (4-fluoro-phenyl) -piperazine

Preparation of

Using 4- (4-fluorophenyl) piperazine (45.1mg, 0.25mmol) as the amine, the title compound was obtained as a light yellow solid (66.4mg 51%).

MS(ISP)：517.2(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.51-7.56(m，4H)，7.45-7.49(m，6H)，7.41(s，1H)，7.37(d，1H)，7.29(d，1H)，7.02(t，1H)，6.90-6.94(m，1H)，3.11(m，4H)，3.01(m，4H).

Example 6

Process for preparing 1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4- (3-chloro-phenyl) -piperazine

Preparation of

Using 4- (3-chlorophenyl) piperazine (49.2mg, 0.25mmol) as the amine, the title compound was obtained as a light yellow solid (91.4mg, 68%).

MS(ISP)：533.2(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.48-7.56(m，4H)，7.44-7.48(m，6H)，7.41(s，1H)，7.36(d，1H)，7.29(d，1H)，7.19(t，1H)，6.91(s，1H)，6.82(d，1H)，6.79(d，1H)，3.23(m，4H)，3.00(m，4H).

Example 7

Preparation of 4- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -morpholine

Morpholine (21.8mg, 0.25mmol) was used as the amine to give the title compound as a white solid (51.1mg 48%).

MS(ISP)：424.4(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.52-7.57(m，4H)，7.46-7.49(m，6H)，7.37(s，1H)，7.33(d，1H)，7.29(d，1H)，3.61(m，4H)，2.86(m，4H).

Example 8

Preparation of 1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4-phenyl-piperazine

Using 4-phenylpiperazine (40.6mg, 0.25mmol) as the amine, the title compound was obtained as a light yellow solid (78.7mg, 63%).

MS(ISP)：499.3(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.52-7.56(m，4H)，7.44-7.48(m，6H)，7.41(s，1H)，7.35(d，1H)，7.30(d，1H)，7.19(t，2H)，6.89(d，2H)，6.77(t，1H)，3.17(m，4H)，3.02(m，4H).

Example 9

Preparation of 1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -pyrrolidine

Using pyrrolidine (17.8mg, 0.25mmol) as the amine, the title compound was obtained as a white solid (67.8mg, 67%).

MS(ISP)：408.3(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.53-7.57(m，4H)，7.43-7.49(m，7H)，7.39(d，1H)，7.25(d，1H)，3.12(m，4H)，1.64(m，4H).

Example 10

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4- (3-methoxy-phenyl) -piperazine

Preparation of oxazines

Using 4- (3-methoxyphenyl) piperazine dihydrochloride (66.3mg, 0.25mmol) as the amine, the title compound was obtained as a white solid (75.9mg, 58%).

MS(ISP)：529.3(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.52-7.56(m，4H)，7.44-7.48(m，6H)，7.41(s，1H)，7.37(d，1H)，7.29(d，1H)，7.08(t，1H)，6.48(d，1H)，6.42(s，1H)，6.38(d，1H)，3.68(s，3H)，3.17(m，4H)，3.01(m，4H).

Example 11

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4- (4-methoxy-phenyl) -piperazine

Preparation of oxazines

Using 4- (4-methoxyphenyl) piperazine dihydrochloride (66.3mg, 0.25mmol) as the amine, the title compound was obtained as a light brown solid (78.9mg, 60%).

MS(ISP)：529.2(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.52-7.57(m，4H)，7.45-7.48(m，6H)，7.38(s，1H)，7.36(d，1H)，7.31(d，1H)，6.85(d，2H)，6.78(d，2H)，3.66(s，3H)，3.03(m，8H).

Example 12

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4- (2-methoxy-phenyl) -piperazine

Preparation of oxazines

Using 4- (2-methoxyphenyl) piperazine (48.1mg, 0.25mmol) as the amine, the title compound was obtained as a light yellow solid (66.3mg, 50%).

MS(ISP)：529.2(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.54-7.58(m，4H)，7.45-7.49(m，6H)，7.41(s，1H)，7.38(d，1H)，7.31(d，1H)，6.85-6.94(m，4H)，3.70(s，3H)，3.01(m，8H).

Example 13

Process for preparing 1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4- (2-chloro-phenyl) -piperazine

Preparation of

Using 4- (2-chlorophenyl) piperazine hydrochloride (58.3mg, 0.25mmol) as the amine, the title compound was obtained as a light yellow solid (80.4mg, 60%).

MS(ISP)：533.2(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.54-7.58(m，4H)，7.45-7.49(m，7H)，7.43(s，1H)，7.38(d，1H)，7.32(d，1H)，7.30(t，1H)，7.15(d，1H)，7.06(t，1H)，3.04(m，8H).

Example 14

Process for preparing 1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4- (2-fluoro-phenyl) -piperazine

Preparation of

Using 4- (2-fluorophenyl) piperazine (45.1mg, 0.25mmol) as the amine, the title compound was obtained as a light yellow solid (92.8mg 72%).

MS(ISP)：517.2(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.54-7.57(m，4H)，7.45-7.49(m，6H)，7.42(s，1H)，7.37(d，1H)，7.31(d，1H)，6.96-7.17(m，4H)，3.05(m，8H).

Example 15

Preparation of 2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonic acid phenethyl-amide

Using phenylethylamine (30.3mg, 0.25mmol) as the amine, the title compound was obtained as a white solid (46.0mg, 40%).

MS(ISP)：458.4(M+H⁺，100)，475.3(M+NH₄ ⁺，45).NMR(300MHz，DMSO-d₆)ppm：7.44-7.56(m，11H)，7.33-7.21(m，2H)，7.10-7.21(m，6H)，2.95(q，2H)，2.64(t，2H).

Example 16

1-benzo [1, 3] dioxol-5-yl-4- (2, 2-diphenyl-benzo [1, 3] dioxol

Preparation of (E) -5-sulfonyl) -piperazine

Using 4- (3, 4-dioxomethylene phenyl) piperazine hydrochloride (64.7mg, 0.25mmol) as the amine, the title compound was obtained as a brown solid (46.6mg, 42%).

MS(ISP)：543.2(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.42-7.56(m，10H)，7.41(s，1H)，7.36(d，1H)，7.29(d，1H)，6.74(d，1H)，6.63(s，1H)，6.30(d，1H)，5.90(s，2H)，3.02(m，8H).

Example 17

Preparation of 4-benzyl-1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -piperidine

Using 4-benzylpiperidine (43.8mg, 0.25mmol) as the amine, the title compound was obtained as a white solid (37.6mg, 29%).

MS(ISP)：512.3(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.52-7.56(m，4H)，7.45-7.48(m，6H)，7.08-7.32(m，8H)，3.58(m，2H)，2.45(m，2H)，2.19(m，2H)，1.58(m，3H)，1.15(m，1H).

Method B

Process B is a general procedure for the preparation of 2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonamides starting from commercially available amines:

2, 2-Diphenyl-benzo [1, 3] dioxol-5-sulfonyl chloride (93mg, 0.25mmol) was dissolved in pyridine (1 ml). The appropriate amine (0.25mmol) was added and the reaction was heated to 60 ℃ overnight. Water was added and the oil was separated accordingly. The aqueous phase was decanted and the residue was stirred with acetonitrile. A solution was obtained which was subjected to preparative reverse phase chromatography (gradient acetonitrile/water containing 0.1% formic acid as eluent) to give the product after evaporation of the eluent and drying.

The following examples above were prepared using general methods:

example 18

Process for preparing 2- (2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonyl) -1, 2, 3, 4-tetrahydro-isoquinoline

Preparation of

Using 1, 2, 3, 4-tetrahydro-isoquinoline (33.3mg, 0.25mmol) as the amine, the title compound was obtained as a yellow solid (35mg, 30%).

MS(ISP)：470.3(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.40-7.54(m，12H)，7.24(d，1H)，7.05-7.13(m，4 H)，4.19(s，2H)，3.30(t，2H)，2.82(m，2H).

Example 19

Preparation of 2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonic acid benzyl-methyl-amide

Using N-methylbenzylamine (30.3mg, 0.25mmol) as the amine, the title compound was obtained as a yellow solid (48.3mg, 42%).

MS(ISP)：458.4(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.43-7.58(m，12H)，7.27-7.33(m，6H)，4.13(s，2H)，2.53(s，3H).

Example 20

Preparation of 2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonic acid benzylamide

Using benzylamine (26.8mg, 0.25mmol) as the amine, the title compound was obtained as a light yellow solid (25.1mg, 22%).

MS(ISN)：442.2(M-H⁺，100)，502.1(M+OAc^-，20).NMR(300MHz，DMSO-d₆)ppm：8.06(t，1H，NH)，7.46-7.56(m，11H)，7.36(d，1H)，7.32(s，1H)，7.14-7.18(m，5H)，3.97(d，2H).

Example 21

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4-methyl- [1, 4] diazacyclo

Preparation of heptane

Using N-methyl homopiperazine (28.5mg, 0.25mmol) as the amine, the title compound was obtained as a light brown solid (23.6mg, 21%).

MS(ISP)：451.4(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.45-7.56(m，10H)，7.41(s，1H)，7.36(d，1H)，7.23(s，1H)，3.22-3.39(m，4H)，2.50(m， 4H，under the DMSOpeak)，2.20(s，3H)，1.68-1.74(m，2H).

Example 22

1- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -4- (2, 2-diphenyl-benzo [1, 3] dioxol-5-

Preparation of sulfonyl) - [1, 4] diazepane

Using 1- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -homopiperazine (69.8mg, 0.25mmol) as the amine, the title compound was obtained as a yellow solid (76.9mg, 52%).

MS(ISP)：616.1(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：8.38(s，1H)，7.95(s，1H)，7.44-7.55(m，10H)，7.41(s，1H)，7.33(d，1H)，7.15(s，1H)，3.84(t，2H)，3.76(t，2H)，3.44(t，2H)，3.28(t，2H)，1.89(m，2H).

Example 23

Preparation of 2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonic acid phenylamide

Using aniline (23.3mg, 0.25mmol) as the amine, the title compound was obtained as a pale yellow solid (18.2mg, 17%).

MS(ISN)：428.3(M-H⁺，100).NMR(300MHz，DMSO-d₆)ppm：10.19(s，1H，NH)，7.43-7.52(m，10H)，7.32-7.35(m，2H)，7.14-7.21(m，3H)，6.98-7.09(m，3H).

Example 24

2, 2-Diphenyl-benzo [1, 3] dioxole-5-sulfonic acid [2- (4-methoxy-phenyl) -ethyl ] -acyl

Preparation of amines

Using 2- (4-methoxyphenyl) ethylamine (37.8mg, 0.25mmol) as the amine, the title compound was obtained as a pale yellow solid (67.1mg, 55%).

MS(ISN)：486.2(M-H⁺，100)，546.1(M+OAc^-，35).NMR(300MHz，DMSO-d₆)ppm：7.44-7.58(m，11H)，7.34-7.37(m，2H)，7.19(d，1H)，7.03(d，2H)，6.79(d，2H)，3.69(s，3H)，2.89(q，2H)，2.58(t，2H).

Example 25

1- (2, 2-diphenyl-benzo [1, 3]]Preparation of dioxole-5-sulfonyl) -4-methyl-piperazine

Using N-methylpiperazine (25.0mg, 0.25mmol) as the amine, the title compound was obtained as a white solid (11mg, 10%).

MS(ISP)：437.4(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.53-7.57(m，4H)，7.45-7.49(m，6H)，7.36(s，1H)，7.32(d，1H)，7.29(d，1H)，2.87(m，4H)，2.33(m，4H)，2.11(s，3H).

Example 26

1- (2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonyl) -4- (4-fluoro-phenyl) -1, 2, 3, 6-

Preparation of tetrahydro-pyridines

4- (4-fluorophenyl) -1, 2, 3, 4-tetrahydropyridine hydrochloride (2.56g, 12mmol) was suspended in dichloromethane (150 ml). Ethyldiisopropylamine (4.2ml, 25mmol) was added and the solution was stirred at room temperature for 10 min. 2, 2-Diphenyl-benzo [1, 3] dioxole-5-sulfonyl chloride (3.72g, 10mmol) was added and the reaction was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography (100g, eluent dichloromethane). The product was stirred with n-hexane, filtered and dried to give the sulfonamide as white crystals (3.86g, 75%).

MS(ISP)：514.3(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.50-7.54(m，4H)，7.44-7.48(m，7H)，7.36-7.40(m，3H)，7.26(d，1H)，7.09(t，2H)，6.03(m，1H)，3.68(m，2H)，3.23(t，2H)，2.50(s，2H，under DMSO peak).

Example 27

4- (4-chloro-phenyl) -1- (2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonyl) -1, 2, 3, 6-

Preparation of tetrahydro-pyridines

4- (4-chlorophenyl) -1, 2, 3, 4-tetrahydropyridine hydrochloride (19.37mg, 0.10mmol) was suspended in dichloromethane (2 ml). Ethyldiisopropylamine (0.035ml, 0.20mmol) was added and the solution was shaken at room temperature for 10 min. Adding 2, 2-diphenyl-benzo [1, 3]]Dioxol-5-sulfonyl chloride (37.28mg, 0.10mmol) and the reaction was shaken at room temperature for 12 h. Aqueous HCl (0.1N, 1.0ml) was added and the mixture was shaken for 30 min, the aqueous layer removed and the organic phase concentrated and purified by preparative reverse phase HPLC (YMC, ODS-AQ pad; 20% to 95% CH)₃CN/H₂O) to give the sulfonamide (2.6mg, 5%).

MS(ISP)：530.2(M+H⁺，100).NMR(500MHz，DMSO-d₆)ppm：7.31-7.56(m，16H)，7.26(d，1H)，6.10(m，1H)，3.70(m，2H)，3.24(m，2H)，2.50(m，2H，under DMSO peak).

Example 28

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4-phenyl-1, 2, 3, 6-tetrahydro-pyri-dine

Preparation of pyridines

4-phenyl-1, 2, 3, 4-tetrahydropyridine hydrochloride (15.92mg, 0.10mmol) was suspended in dichloromethane (2 ml). Ethyldiisopropylamine (0.035ml, 0.20mmol) was added and the solution was shaken at room temperature for 10 min. Adding 2, 2-diphenyl-benzo [1, 3] ]Dioxol-5-sulfonyl chloride (37.28mg, 0.10mmol), and the reaction was shaken at room temperature for 12 hours. Aqueous HCl (0.1N, 1.0ml) was added and the mixture was shaken for 30 min, the aqueous layer was removed and the organic phase was concentrated and purified by preparative reverse phase HPLC (YMC, ODS-AQ pad; 20% → 95% CH)₃CN/H₂O) to give the sulfonamide (23.6mg, 48%).

MS(ISP)：596.2(M+H⁺，100).NMR(500MHz，DMSO-d₆)ppm：7.22-7.55(m，17H)，6.06(m，1H)，3.70(m，2H)，3.24(m，2H)，2.50(m，2H，under DMSO peak).

Example 29

Racemic 1- [2- (2-chloro-phenyl) -2- (4-methoxy-phenyl) -benzo [1, 3] dioxole-

Preparation of 5-sulfonyl ] -piperidine

Method C

4- (piperidine-1-sulfonyl) -benzene-1, 2-diol (60mg, 0.2mmol) and (4-methoxyphenyl) - (2-chlorophenyl) -dichloromethane (51mg, 0.2mmol) were refluxed in toluene (2ml) overnight. After cooling, the reaction was cooled to room temperature and the solvent was evaporated. The residue was dissolved in dichloromethane and purified by silica gel column chromatography (eluent dichloromethane) to give the product as a colourless solid (42mg, 39%).

MS(ISP)：486.3(M+H⁺，100).NMR(300MHz，CDCll₃)ppm：7.80-7.90(m，1H)，7.30-7.43(m，8H)，6.97(d，1H)，6.89(d，1H)，3.82(s，3H)，2.98(m，4H)，1.60-1.70(m，4H)，1.40-1.50(m，2H).

The following examples were prepared according to procedure C:

example 30

Racemic 1- [2- (2-chloro-phenyl) -2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-sulfonyl

Preparation of phenyl-piperidine

Using 4-fluorophenyl-2-chlorophenyl-dichloromethane (57mg, 0.2mmol) as starting material, the title compound was obtained as a colorless foam (68mg, 71%). silica gel column chromatography was performed (25g, dichloromethane eluent).

MS(ISP)：474.2(M+H⁺，100).NMR(300MHz，CDCl₃)ppm：7.84(m，1H)，7.32-7.47(m，6H)，7.27(d，1H)，7.08(t，2H)，6.99(d，1H)，2.95-3.01(m，4H)，1.60-1.68(m，4H)，1.42-1.47(m，2H).

Example 31

Racemic 1- [2- (2-chloro-phenyl) -2-p-tolyl-benzo [1, 3] dioxole-5-sulfonyl ] -acetic acid

Preparation of piperidines

Using 4-methylphenyl-2-chlorophenyl-dichloromethane (57mg, 0.2mmol) as starting material, the title compound was obtained as a pale yellow foam (46mg, 44%). Silica gel column chromatography (25g, dichloromethane eluent) was performed.

MS(ISP)：470.2(M+H⁺，100).NMR(300MHz，CDCl₃)ppm：7.83(m，1H)，7.31-7.42(m，7H)，7.20(d，2H)，6.97(d，1H)，2.96-3.02(m，4H)，1.60-1.68(m，4H)，1.42-1.46(m，2H).

Example 32

Racemic 1- [2- (4-chloro-phenyl) -2- (4-methoxy-phenyl) -benzo [1, 3] dioxol-5-sulfonic acid

Preparation of acyl-piperidines

Using 4-methoxyphenyl-4-chlorophenyl-dichloromethane (60mg, 0.2mmol) as the starting material, the title compound was obtained as a pale red solid (35mg, 36%). Silica gel column chromatography (25g, dichloromethane eluent) was performed.

MS(EI)：485.2(M⁺，65)，374.2([M-PhCl]⁺，100).NMR(300MHz，CDCl₃)ppm：7.49(d，2H)，7.42(d，2H)，7.32(d，2H)，7.22(s，1H)，6.94(d，1H)，6.90(d，2H)，2.95-2.99(m，4H)，1.60-1.68(m，4H)，1.40-1.44(m，2H).

Example 33

Racemic 1- [2- (4-chloro-phenyl) -2-p-tolyl-benzo [1, 3] dioxole-5-sulfonyl ] -acetic acid

Preparation of piperidines

Using 4-methylphenyl-4-chlorophenyl-dichloromethane (85mg, 0.3mmol) as starting material, the title compound was obtained as a colorless foam (138mg, 97%). Column chromatography over silica gel (25g, 4/1 hexane/ethyl acetate eluent).

MS(ISP)：470.2(M⁺，100).NMR(300MHz，CDCl₃)ppm：7.49(d，2H)，7.40(d，2H)，7.36(d，2H)，7.31(d，1H)，7.23(d，1H)，6.94(d，2H)，2.95-2.99(m，4H)，1.60-1.68(m，4H)，1.39-1.46(m，2H).

Example 34

Preparation of 1- [2, 2-bis- (4-chloro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -piperidine

Using bis- (4-chlorophenyl) -dichloromethane (61mg, 0.2mmol) as the starting material, the title compound was obtained as a colorless solid (77mg, 78%). Silica gel column chromatography (25g, dichloromethane eluent) was performed.

MS(EI)：489.1(M⁺，30)，378.1([M-PhCl]⁺，30)，231.1(70)，84.3(100).NMR(300MHz，CDCl₃)ppm：7.47(d，4H)，7.37(d，4H)，7.33(d，1H)，7.25(s，1H)，6.96(d，1H)，2.95-3.00(m，4H)，1.60-1.68(m，4H)，1.40-1.46(m，2H).

Example 35

Racemic 1- [2- (4-fluoro-phenyl) -2-phenyl-benzo [1, 3] dioxol-5-sulfonyl ] -piperidine

Preparation of

Using 4-fluorophenyl-phenyl-dichloromethane (51mg, 0.2mmol) as starting material, the crude product was stirred in diethyl ether, filtered and dried to give the title compound as a white crystalline solid (66mg, 75%). m.p.: 125 ℃ and 126 ℃.

Example 36

Racemic 1- [2- (4-methoxy-phenyl) -2-phenyl-benzo [1, 3] dioxole-5-sulfonyl ] -

Preparation of piperidines

Using 4-methoxyphenyl-phenyl-dichloromethane (53mg, 0.2mmol) as starting material, the title compound was obtained as a white solid (56mg, 62%). Silica gel column chromatography (25g, 4/1 hexane/ethyl acetate) was performed.

MS(ISP)：452.4(M⁺，100).NMR(300MHz，CDCl₃)ppm：7.41-7.54(m，7H)，7.33(s，1H)，7.31(d，4H)，7.23(d，1H)，7.00(d，2H)，3.76(s，3H)，2.87(m，4H)，1.53(m，4H)，1.35(m，2H).

Example 37

Racemic 1- [2- (4-chloro-phenyl) -2-p-tolyl-benzo [1, 3] dioxol-5-sulfonyl

Preparation of yl ] -4- (4-fluoro-phenyl) -1, 2, 3, 6-tetrahydro-pyridine

Using 4-chlorophenyl-4-methylphenyl-dichloromethane (57mg, 0.2mmol) and 4- [4- (4-fluoro-phenyl) -3, 6-dihydro-2H-pyridine-1-sulfonyl ] -benzene-1, 2-diol (69mg, 0.2mmol) as starting materials, the title compound was obtained as a yellow-white crystalline solid (90mg, 80%) after dissolving the residue in hexane/ethyl acetate (4/1), stirring for 10 minutes, filtering the solid, and drying.

MS(EI)：561.2(M⁺，10)，176.2(100)，149.2(50).NMR(300MHz，CDCl₃)ppm：7.47(d，2H)，7.18-7.40(m，9H)，6.99(d，2H)，6.96(d，2H)，5.89(m，1H)，3.75(m，2H)，3.32(t，2H)，2.57(m，2H)，2.36(s，3H).

Preparation of 4- [4- (4-fluoro-phenyl) -3, 6-dihydro-2H-pyridine-1-sulfonyl ] -benzene-1, 2-diol

1- (2, 2-Diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4- (4-fluoro-phenyl) -1, 2, 3, 6-tetrahydro-pyridine (3.2g, 6.2mmol) was dissolved in dichloromethane (100 ml). Trifluoroacetic acid (50ml) was added dropwise and the reaction was stirred at room temperature for 5 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography (100g, dichloromethane then ethyl acetate as eluent). The product was crystallized from ether/hexane to give a white solid (2.1g, 96%).

MS(ISN)：348.2(M-H⁺，100).NMR(300MHz，，DMSO-d₆)ppm：10.0(br s，1H，OH)，9.80(br s，1H，OH)，7.44(d，1H)，7.42(d，1H)，7.08-7.19(m，4H)，6.92(d，1H)，6.07(brs，1H)，3.59(br s，2H)，3.13(m，2H)，2.51(m，2H，under DMSO peak).

Example 38

Racemic 1- [2- (4-chloro-phenyl) -2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-sulfonyl

Preparation of phenyl-piperidine

Using 4-chlorophenyl-4-fluorophenyl-dichloromethane (57mg, 0.2mmol) as starting material, the title compound was obtained as a colorless foam (77mg, 81%). Column chromatography over silica gel (25g, 4/1 hexane/ethyl acetate eluent).

MS(EI)：473.2(M⁺，30)，215.2(40)，84.3(100).NMR(300MHz，CDCl₃)ppm：7.46-7.53(m，4H)，732-7.39(m，3H)，7.24(s，1H)，7.09(t，2H)，6.96(d，1H)，2.96-3.00(m，4H)，1.60-1.68(m，4H)，1.40-1.46(m，2H).

Example 39

Racemic 1- [2- (2, 4-dichloro-phenyl) -2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonic acid

Preparation of acyl-piperidines

Using 2, 4-dichlorophenyl-4-fluorophenyl-dichloromethane (65mg, 0.2mmol) as starting material, the title compound was obtained as a colorless foam (81mg, 80%). Column chromatography over silica gel (25g, 4/1 hexane/ethyl acetate eluent).

MS(ISP)：508.2(M+H⁺，100).NMR(300MHz，CDCl₃)ppm：7.78(d，1H)，7.32-7.47(m，3H)，7.32-7.37(m，2H)，7.28(s，1H)，7.08(t，2H)，6.99(d，1H)，2.97-3.00(m，4H)，1.61-1.68(m，4H)，1.40-1.47(m，2H).

Example 40

Preparation of 1- [2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -piperidine

Using bis- (4-fluorophenyl) -dichloromethane (55mg, 0.2mmol) as starting material, the title compound was obtained as a colorless foam (75mg, 82%). Column chromatography over silica gel (25g, 4/1 hexane/ethyl acetate eluent). m.p.: 148 ℃ and 149 ℃.

EXAMPLE 41

Racemic 1- [2- (3-chloro-phenyl) -2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-sulfonyl

Preparation of phenyl-piperidine

Using 3-chlorophenyl-4-fluorophenyl-dichloromethane (58mg, 0.2mmol) as starting material, the different compounds were obtained as colorless viscous oils (82mg, 86%). Column chromatography over silica gel (25g, 4/1 hexane/ethyl acetate eluent).

MS(ISP)：474.2(M+H⁺，100).NMR(300MHz，CDCl₃)ppm：7.49-7.55(m，3H)，7.33-7.44(m，4H)，7.26(s，1H)，7.09(t，2H)，6.97(d，1H)，2.96-3.00(m，4H)，1.60-1.68(m，4H)，1.40-1.46(m，2H).

Example 42

Racemic 1- [2- (4-chloro-phenyl) -2- (2-chloro-phenyl) -benzo [1, 3] dioxole-5-sulfonyl

Preparation of phenyl-piperidine

Using 2-chlorophenyl-4-chlorophenyl-dichloromethane (61mg, 0.2mmol) as the starting material, the title compound was obtained as a colorless solid (40mg, 41%). Silica gel column chromatography (25g, dichloromethane eluent) was performed.

MS(EI)：489.1(M⁺，30)，378.1(35)，231.1(60)，84.2(100).NMR(300MHz，CDCl₃)ppm：7.42-7.86(m，1H)，7.33-7.44(m，8H)，7.27(d，1H)，6.99(d，1H)，2.96-3.00(m，4H)，1.60-1.68(m，4H)，1.42-1.47(m，2H).

Method D

The bisaryl-dichloromethane derivatives required for the preparation of the above examples were prepared according to method D according to literature procedures (R K. Ramchandrani, R D. Wakharkar, A. Sudalai, Tetrahedron Lett.) (37) (23) (1996) 4063-4064).

Preparation of (4-methoxyphenyl) (2-chlorophenyl) -dichloromethane:

aluminum trichloride (400mg, 3mmol) was suspended in 1, 2-dichloroethane (1.4 ml). 2-chlorobenzotrifluoride (180mg, 1mmol) was added at 0 ℃ under argon. A dark red solution was obtained to which anisole (108mg, 1mmol) was added. The reaction was stirred at 0 ℃ for 3 hours. It was poured onto ice, stirred for 5 minutes and extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated to give the product as a dark red viscous oil (416mg 138%) which was used in the next step without purification.

The known bisaryl-dichloromethane is prepared by this method:

4-methylphenyl-4-chlorophenyl-dichloromethane

Bis- (4-chlorophenyl) -dichloromethane

2-chlorophenyl-4-chlorophenyl-dichloromethane

(4-methoxyphenyl) (2-chlorophenyl) -dichloromethane

The following bisaryl-dichloromethane derivatives are known in the literature and can be prepared according to method D from commercially available starting materials. These compounds were not purified because some of them were unstable in column chromatography and were used as crude product in the next step without purification:

from 2-chlorotrifluorotoluene (180mg, 1mmol), AlCl₃(400mg, 3mmol) and fluorobenzene (96mg, 1mmol) to prepare 4-fluorophenyl-2-chlorophenyl-dichloromethane: pale yellow oil (380mg, 131% crude).

From 2-chlorotrifluorotoluene (180mg, 1mmol), AlCl₃(400mg, 3mmol) and toluene (92mg, 1mmol) to prepare 4-methylphenyl-2-chlorophenyl-dichloromethane: pale yellow oil (380mg, 131% crude).

From 4-chlorotrifluoromethylene (180mg, 1mmol), AlCl₃(400mg, 3mmol) and anisole (108mg, 1mmol) 4-methoxyphenyl-4-chlorophenyl-dichloromethane was prepared: red solid (345mg, 120% crude) containing benzophenone (about 30%).

From 4-chlorotrifluoromethylene (180mg, 1mmol), AlCl ₃(400mg, 3mmol) and fluorobenzene (96mg, 1mmol) to prepare 4-chlorophenyl-4-fluorophenyl-dichloromethane: a light yellow oil (382mg, 131% crude).

From 2, 4-dichlorotrifluorotoluene (215mg, 1mmol), AlCl₃(400mg, 3mmol) and fluorobenzene (96mg, 1mmol) to prepare 2, 4-dichlorophenyl-4-fluorophenyl-dichloromethane: a light yellow oil (382mg, 118% crude).

From 3-chlorotrifluorotoluene (180mg, 1mmol), AlCl₃(400mg, 3mmol) and fluorobenzene (96mg, 1mmol) to prepare 3-chlorophenyl-4-fluorophenyl-dichloromethane: pale yellow oil (384mg, 132% crude).

From trifluorotoluene (146mg, 1mmol), AlCl₃(400mg, 3mmol) and fluorobenzene (96mg, 1mmol) to give 4-fluorobenzenePhenyl-dichloromethane base: pale yellow oil (335mg, 131% crude).

The following bisaryl-dichlormethane are known in the literature, but the synthesis thereof is not described. These compounds were prepared using method D:

from 4-fluorotrifluorotoluene (164mg, 1mmol), AlCl₃(400mg, 3mmol) and fluorobenzene (96mg, 1mmol) to prepare bis- (4-fluorophenyl) -dichloromethane (EP 96008): pale yellow oil (377mg, 138% crude).

From trifluorotoluene (146mg, 1mmol), AlCl₃(400mg, 3mmol) and anisole (108mg, 1mmol) 4-methoxyphenyl-phenyl-dichloromethane (R.Laatikainen, V.Kral, J.chem.Soc., Perkin Trans.2(8) (1985) 1091-1100; U.S. 3824310): dark red viscous oil (352mg, 132% crude).

Preparation of 4- (piperidine-1-sulfonyl) -benzene-1, 2-diol:

1- (2, 2-Diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -piperidine (1.92g, 4.5mmol) was dissolved in dichloromethane (69 ml). Trifluoroacetic acid (20.7ml) and water (8 drops) were added at room temperature. The reaction was stirred at room temperature for 24 hours. The solvent was evaporated and the residue was dissolved in 3 times n-pentane and evaporated again to remove trifluoroacetic acid. The residue was purified by column chromatography on silica gel (100g, eluent: dichloromethane then 1/19 methanol/dichloromethane). The product was precipitated from ether/n-pentane. The solvent was evaporated and the residue was stirred with n-pentane. The solid was filtered and dried to give the product as a white crystalline solid (1.13g, 97%).

MS(ISN)：256.0(M-H⁺，100).NMR(300MHz，DMSO-D₆)ppm：9.98(s，1H，OH)，9.69(s，1H，OH)，7.05(dd，1H)，7.01(dd，1H)，6.90(d，1H)，2.78-2.83(m，4H)，1.50-1.68(m，4H)，1.30-1.40(m，2H).

method-E

Benzotriazol-1-yl 2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylate (87mg, 0.2mmol), the appropriate amine (22mg, 0.25mmol) and ethyldiisopropylamine (32mg, 0.25mmol) were dissolved in acetonitrile (2ml) and stirred at room temperature for 3 hours. Water (20ml) was added and the reaction was stirred at room temperature for 1 hour. The precipitate was filtered off, washed with water and dried in high vacuum to give the product as a white crystalline solid.

The preparation of the activated ester, i.e. benzotriazol-1-yl 2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylate, is described in the literature (EP544166),

The following examples were prepared according to procedure E:

example 43

Racemic (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (3-hydroxy-pyrrolidin-1-yl) -

Preparation of ketones

From 2, 2-diphenyl-benzo [1, 3] dioxol-5-carboxylic acid benzotriazol-1-yl ester (87mg, 0.2mmol) and 3-pyrrolidinol (22mg, 0.25mmol) the title compound was obtained as a white crystalline solid (73mg, 94%). m.p.: 106-107 ℃.

Example 44

Preparation of 4- (2, 2-diphenyl-benzo [1, 3] dioxol-5-carbonyl) -piperazine-1-carbaldehyde

From 2, 2-diphenyl-benzo [1, 3] dioxol-5-carboxylic acid benzotriazol-1-yl ester (87mg, 0.2mmol) and formyl-piperazine (32mg, 90% pure, 0.25mmol), the title compound was obtained as a white crystalline solid (73mg, 88%). m.p.176-177 ℃.

Example 45

Process for preparing (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (4-hydroxymethyl-piperidin-1-yl) -methanone

Preparation of

From 2, 2-diphenyl-benzo [1, 3] dioxol-5-carboxylic acid benzotriazol-1-yl ester (87mg, 0.2mmol) and 4- (hydroxymethyl) -piperidine (29mg, 0.25mmol), the title compound was obtained as a white crystalline solid (76mg, 91%). m.p.197-198 ℃.

Example 46

(1, 4-dioxa-8-aza-spiro [4.5] dec-8-yl) - (2, 2-diphenyl-benzo [1, 3] dioxol

Preparation of (E) -5-yl-methanones

From 2, 2-diphenyl-benzo [1, 3] dioxol-5-carboxylic acid benzotriazol-1-yl ester (87mg, 0.2mmol) and 1, 4-dioxa-8-azaspiro (4, 5) decane (36mg, 0.25mmol) the title compound was obtained as a white crystalline solid (74mg, 83%). m.p.150-151 ℃.

Example 47

Preparation of (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone

From 2, 2-diphenyl-benzo [1, 3] dioxol-5-carboxylic acid benzotriazol-1-yl ester (87mg, 0.2mmol) and morpholine (22mg, 0.25mmol) the title compound was obtained as a white crystalline solid (64mg, 82%). m.p.149-150 ℃.

Example 48

Preparation of (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (4-methyl-piperazin-1-yl) -methanone

Prepare for

From 2, 2-diphenyl-benzo [1, 3] dioxol-5-carboxylic acid benzotriazol-1-yl ester (87mg, 0.2mmol) and 1-methylpiperazine (25mg, 0.25mmol) the title compound was obtained as a white crystalline solid (72mg, 90%). m.p.115-116 ℃.

Example 49

Process for preparing (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (4-isopropyl-piperazin-1-yl) -methanone

Preparation of

From 2, 2-diphenyl-benzo [1, 3] dioxol-5-carboxylic acid benzotriazol-1-yl ester (87mg, 0.2mmol) and 1- (2-propyl) -piperazine (32mg, 0.25mmol) the title compound was obtained as a colorless foam (84mg, 98%). The operation is as follows: after addition of water (20ml), the reaction was stirred at room temperature for 1 hour. Dichloromethane was added and the mixture was stirred for 10 minutes. The organic layer was separated, washed with water and dried over sodium sulfate. The solvent was evaporated to give the product after drying in high vacuum.

MS(ISP)：429.6(M+H⁺，100).NMR(300MHz，DMSO-D₆)ppm：7.51-7.56(m，4H)，7.43-7.47(m，6H)，7.08(d，1H)，7.07(s，1H)，6.92(d，1H)，3.3-3.6(br m，4H)，2.65(sept，1H)，2.38-2.42(br m，4H)，0.95(d，6H).

Example 50

Preparation of 1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-carbonyl) -piperidin-4-one

From 2, 2-diphenyl-benzo [1, 3] dioxol-5-carboxylic acid benzotriazol-1-yl ester (87mg, 0.2mmol), 4-piperidone monohydrate hydrochloride (39mg, 0.25mmol) and ethyldiisopropylamine (58mg, 0.45mmol) the title compound was obtained as a light yellow foam (75mg, 94%). After addition of water (20ml), the reaction was stirred at room temperature for 1 hour. Dichloromethane was added and the mixture was stirred for 10 minutes. The organic layer was separated, washed with water and dried over sodium sulfate. The solvent was evaporated to give the product after drying in high vacuum.

MS(ISP)：400.5(M+H⁺，100)，417.3(M+NH₄ ⁺，40)，799.3(2M+H⁺，20).NMR(300MHz，DMSO-D₆)ppm：7.47-7.57(m，4H)，7.44-7.47(m，6H)，7.17(s，1H)，7.11(d，1H)，7.05(d，1H)，3.62-3.82(br m，4H)，2.39-2.44(br m，4H).

Example 51

Preparation of (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (4-hydroxy-piperidin-1-yl) -methanone

Prepare for

From 2, 2-diphenyl-benzo [1, 3] dioxol-5-carboxylic acid benzotriazol-1-yl ester (87mg, 0.2mmol), 4-hydroxypiperidine hydrochloride (34mg, 0.25mmol) and ethyl-diisopropylamine (58mg, 0.45mmol) the title compound was obtained as a colorless foam (73mg, 91%). The operation is as follows: after addition of water (20ml), the reaction was stirred at room temperature for 1 hour. Dichloromethane was added and the mixture was stirred for 10 minutes. The organic layer was separated, washed with water and dried over sodium sulfate. The solvent was evaporated to give the product after drying in high vacuum.

MS(ISP)：402.5(M+H⁺，100).NMR(300MHz，DMSO-D₆)ppm：7.51-7.56(m，4H)，7.43-7.49(m，6H)，7.07(d，1H)，7.05(s，1H)，6.91(d，1H)，4,76(d，1H，OH)，3.70(m，1H)，3.11-3.18(m，2H)，2.51(m，2H under the DMSO peak)，1.63-1.79(m，2H)，1.25-1.39(m，2H).

Example 52

Preparation of (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -pyrrolidin-1-yl-methanone

From 2, 2-diphenyl-benzo [1, 3] dioxol-5-carboxylic acid benzotriazol-1-yl ester (87mg, 0.2mmol), pyrrolidine (18mg, 0.25mmol) and ethyl-diisopropylamine (32mg, 0.25mmol) the title compound was obtained as a light yellow foam (75mg, 91%). The operation is as follows: after addition of water (20ml), the reaction was stirred at room temperature for 1 hour. Dichloromethane was added and the mixture was stirred for 10 minutes. The organic layer was separated, washed with water and dried over sodium sulfate. The solvent was evaporated to give the product after drying in high vacuum.

MS(ISP)：372.3(M+H⁺，100)，743.3(2M+H⁺，80).NMR(300MHz，DMSO-D₆)ppm：7.48-7.56(m，4H)，7.43-7.48(m，6H)，7.18(s，1H)，7.09(d，1H)，7.05(d，1H)，3.35-3.42(m，4H)，1.77-1.84(m，4H).

Example 53

Racemic 1- (2, 2-Diphenyl-benzo [1, 3] dioxol-5-carbonyl) -piperidine-3-carboxylic acid ethyl ester

Preparation of

Method F

Benzotriazol-1-yl 2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylate (87mg, 0.2mmol), (rac) -ethyl 3-piperidinecarboxylate (36mg, 0.25mmol), and ethyl-diisopropylamine (32mg, 0.25mmol) were dissolved in acetonitrile (1ml) and stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC (acetonitrile/water 0.1% formic acid as gradient) to give the product as a white solid (24.8mg, 27%).

MS(ISP)：458.4(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.52-7.56(m，4H)，7.43-7.46(m，6H)，7.08(d，1H)，7.07(s，1H)，6.92(d，1H)，4.03(m，2H)，3.12(m，2H)，2.50(m，2H，under DMSO peak)，1.92(m，1H)，1.63(m，2H)，1.43(m，2H)，1.12(m，3H).

The following examples were prepared according to procedure F above:

example 54

[4- (5-chloro-2-methoxy-phenyl) -piperazin-1-yl ] - (2, 2-diphenyl-benzo [1, 3] dioxole

Preparation of (E) -5-yl-methanones

From 2, 2-diphenyl-benzo [1, 3] dioxol-5-carboxylic acid benzotriazol-1-yl ester (87mg, 0.2mmol), 1- (5-chloro-2-methoxy-phenyl) piperazine hydrochloride (66mg, 0.25mmol), and ethyl-diisopropylamine (64mg, 0.50mmol), the title compound was obtained as a white solid (42.7mg, 41%).

MS(ISP)：527.1(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.44-7.60(m，10H)，6.87-7.01(m，6H)，3.78(s，3H)，3.06(br m，4H)，2.97(br m，4H).

Example 55

(2, 2-Diphenyl-benzo [1, 3] dioxol-5-yl) - (4-m-tolyl-piperazin-1-yl) -methanone

Preparation of

From 2, 2-diphenyl-benzo [1, 3] dioxol-5-carboxylic acid benzotriazol-1-yl ester (87mg, 0.2mmol), 1- (3-tolyl) piperazine dihydrochloride (62mg, 0.25mmol) and ethyl-diisopropylamine (96mg, 0.75mmol), the title compound was obtained as a light yellow solid (14.0mg, 15%).

MS(ISP)：477.3(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.53-7.57(m，4H)，7.44-7.48(m，6H)，7.09-7.13(m，3H)，6.99(d，1H)，6.75(m，2H)，6.62(d，1H)，3.60(br m，4H)，3.12(br m，4H)，2.24(s，3H).

Example 56

Preparation of (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-methanone

Method G

Benzotriazol-1-yl 2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylate (217mg, 0.5mmol), piperidine (46mg, 0.55mmol) and ethyl-diisopropylamine (0.1ml, 0.6mmol) were dissolved in dichloromethane (10 ml). The solution was stirred at room temperature for 4 hours and the solvent was evaporated. The residue was purified by silica gel column chromatography (20g, eluent ethyl acetate) to give the product as a white solid (135mg, 70%).

MS(ISP)：386.4(M+H⁺，100)，771.3(2M+H⁺，25).NMR(300MHz，DMSO-d₆)ppm：7.52-7.56(m，4H)，7.43-7.48(m，6H)，7.07(d，1H)，7.04(s，1H)，6.90(d，1H)，3.40(br m，2H)，1.58(br m，2H)，1.48(br m，6H).

The following examples were prepared according to method G:

example 57

(2, 2-Diphenyl-benzo [1, 3] dioxol-5-yl) - (4-o-tolyl-piperazin-1-yl) -methanone

Preparation of

From 2, 2-diphenyl-benzo [1, 3] dioxol-5-carboxylic acid benzotriazol-1-yl ester (87mg, 0.2mmol), 1- (2-tolyl) piperazine dihydrochloride (62mg, 0.25mmol), and ethyl-diisopropylamine (96mg, 0.75mmol), the title compound was obtained as a light yellow solid (1.1mg, 1%).

MS(ISP)：477.3(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.53-7.57(m，4H)，7.44-7.47(m，6H)，7.09-7.14(m，4H)，6.91-7.03(m，3H)，3.61(br m，4H)，2.82(br m，4H)，2.26(s，3H).

Example 58

Racemic 1- (2, 2-Diphenyl-benzo [1, 3] dioxol-5-carbonyl) -piperidine-2-carboxylic acid ethyl ester

Preparation of

From 2, 2-diphenyl-benzo [1, 3] dioxol-5-carboxylic acid benzotriazol-1-yl ester (87mg, 0.2mmol), racemic ethyl 2-piperidinoate (39mg, 0.25mmol), and ethyl-diisopropylamine (32mg, 0.25mmol), the title compound was obtained as a white solid (22.6mg, 24%).

MS(ISP)：458.4(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.53-7.56(m，4H)，7.43-7.49(m，6H)，7.09(d，1H)，7.02(s，1H)，6.92(d，1H)，5.14(br m，1H)，4.16(br q，2H)，3.58(br m，1H)，3.12(br m，1H)，2.11(br m，1h)，1.18-1.63(m，9H).

Example 59

Preparation of [4- (2, 3-dichloro-phenyl) -piperazin-1-yl ] - (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -methanone

From 2, 2-diphenyl-benzo [1, 3] dioxol-5-carboxylic acid benzotriazol-1-yl ester (87mg, 0.2mmol), 1- (2, 3-dichlorophenyl) piperazine hydrochloride (66.9mg, 0.25mmol), and ethyldiisopropylamine (64mg, 0.50mmol), the title compound was obtained as a light yellow solid (58.3mg, 55%).

MS(ISP)：531.1(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.53-7.57(m，4H)，7.44-7.48(m，6H)，7.31-7.33(m，2H)，7.11-7.14(m，2H)，7.09(d，1H)，7.02(d，1H)，3.63(br m，4H)，2.98(br m，4H).

Example 60

[4- (4-chloro-3-trifluoromethyl-phenyl) -piperazin-1-yl ] - (2, 2-diphenyl-benzo [1, 3] dioxole

Preparation of en-5-yl-methanones

From 2, 2-diphenyl-benzo [1, 3] dioxol-5-carboxylic acid benzotriazol-1-yl ester (87mg, 0.2mmol), 1- (4-chloro-3-trifluoromethyl-phenyl) piperazine (66.2mg, 0.25mmol) and ethyl-diisopropylamine (32mg, 0.25mmol) the title compound was obtained as a white solid (35.8mg, 30%).

MS(ISP)：565.2(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.52-7.58(m，4H)，7.44-7.49(m，7H)，7.27(s，1H)，7.23(d，1H)，7.13(s，1H)，7.10(d，1H)，7.00(d，1H)，3.60(brm，4H)，3.28(br m，4H).

Example 61

Racemic (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (3-hydroxymethyl-piperidin-1-yl) -

Preparation of ketones

From 2, 2-diphenyl-benzo [1, 3] dioxol-5-carboxylic acid benzotriazol-1-yl ester (87mg, 0.2mmol), racemic 3-hydroxymethylpiperidine (28.8mg, 0.25mmol) and ethyl-diisopropylamine (32mg, 0.25mmol) the title compound was obtained as a white solid (6.0mg, 7%).

MS(ISP)：416.4(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：7.52-7.58(m，4H)，7.43-7.46(m，6H)，7.06(d，1H)，7.05(s，1H)，6.91(d，1H)，4.50(br s，1H，OH)，3.32(m，2H)，2.45(m，2H)，1.10-1.78(m，7H).

Example 62

(2, 2-Diphenyl-benzo [1, 3] dioxol-5-yl) - (2, 3, 5, 6-tetrahydro- [1, 2' ] bipyrazinyl

Preparation of (E) -4-yl-methanones

From 2, 2-diphenyl-benzo [1, 3] dioxol-5-carboxylic acid benzotriazol-1-yl ester (87mg, 0.2mmol), 1- (2-pyrazinyl) piperazine (41.1mg, 0.25mmol) and ethyl-diisopropylamine (32mg, 0.25mmol) the title compound was obtained as a white solid (19.0mg, 20%).

MS(ISP)：465.3(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：8.31(s，1H)，8.13(s，1H)，7.86(s，1H)，7.53-7.57(m，4H)，7.44-7.48(m，6H)，7.14(s，1H)，7.11(d，1H)，7.01(d，1H)，3.61(br m，8H).

Example 63

(2, 2-Diphenyl-benzo [1, 3] dioxol-5-yl) - (4-pyridin-2-yl-piperazin-1-yl) -methanone

Preparation of

From 2, 2-diphenyl-benzo [1, 3] dioxol-5-carboxylic acid benzotriazol-1-yl ester (87mg, 0.2mmol), 1- (2-pyridyl) piperazine (40.8mg, 0.25mmol) and ethyl-diisopropylamine (32mg, 0.25mmol) the title compound was obtained as a white solid (53.2mg, 57%).

MS(ISP)：464.3(M+H⁺，100).NMR(300MHz，DMSO-d₆)ppm：8.11(m，1H)，7.52-7.57(m，4H)，7.44-7.48(m，7H)，7.13(s，1H)，7.10(d，1H)，7.00(d，1H)，6.82(d，1H)，6.64(dd，1H)，3.53(br m，8H).

Example 64

(4-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (4-methyl-piperazin-1-yl) -methanone

Preparation of

Method H

4-fluoro-2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylic acid (336mg, 1mmol) was dissolved in dichloromethane (15 ml). EDCI (210mg, 1.1.mmol) and 1-methyl-piperazine (220mg, 2.2mmol) were added and the solution was stirred at room temperature for 5 hours. The reaction was concentrated and the residue was purified by silica gel column chromatography (20g, 5% methanol in dichloromethane as eluent) to give the product as white crystals (150mg, 37%).

MS(ISP)：419.4(M+H⁺，100)，460.5(M+MeCN+H⁺，70)，837.4(2M+H⁺，50).NMR(300MHz，DMSO-D₆)ppm：7.52-7.58(m，4H)，7.46-7.50(m，6H)，7.01(d，1H)，6.92(d，1H)，3.60(m，2H)，3.22(m，2H)，2.32(m，2H)，2.22(m，2H)，2.18(s，3H).

Preparation of 4-fluoro-2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylic acid:

4-fluoro-2, 2-diphenyl-benzo [1, 3] dioxole (5.8g, 20mmol) was dissolved in THF (40 ml). The reaction system was cooled to-78 ℃ under an argon atmosphere. TMEDA (2.9ml, 20mmol) was added followed by dropwise addition of N-butyllithium (12.5ml, 1.6N in hexanes). The reaction was stirred at-78 ℃ for 2 hours. Carbon dioxide (20g) was added at this temperature. The reaction was warmed to 0 ℃ and poured into water (80 ml). The reaction was extracted with ethyl acetate. The aqueous layer was neutralized with 1N aqueous HCl and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtered, the solvent was evaporated and the residue was suspended in n-hexane, stirred for 10 min and the product was filtered off to give the acid as a white solid (4.0g, 60%). m.p.: 189 and 191 ℃.

Preparation of 4-fluoro-2, 2-diphenyl-benzo [1, 3] dioxole:

3-Fluorocatechol (12.81g, 100mmol) and dichlorodiphenylmethane (23.71g, 100mol) were dissolved in toluene (250ml) and heated under reflux overnight. The solvent was evaporated and the residue was chromatographed on silica gel (200g, 1/1 dichloromethane/hexanes as eluent) to give the ketal as a white crystalline solid (26.74g, 91%). m.p.: 65-67 ℃.

The following examples were prepared using method H:

example 65

Preparation of (4-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone

From 4-fluoro-2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylic acid (336mg, 1mmol), EDCI (210mg, 1.1.mmol) and morpholine (190mg, 2.2mmol) the title compound was obtained as a white solid (183mg, 46%). Silica gel chromatography (20g, 5% methanol in dichloromethane as eluent) was performed.

MS(ISP)：406.4(M+H⁺，100)，811.2(2M+H⁺，25).NMR(300MHz，DMSO-D₆)ppm：7.54-7.58(m，4H)，7.46-7.50(m，6H)，7.01(d，1H)，6.96(d，1H)，3.63(m，4H)，3.52(m，2H)，3.27(m，2H).

Example 66

Preparation of (4-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone

From 4-fluoro-2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylic acid (336mg, 1mmol), EDCI (210mg, 1.1.mmol) and piperidine (187mg, 2.2mmol) the title compound was obtained as a white solid (103mg, 26%). Silica gel chromatography (20g, 5% methanol in dichloromethane as eluent) was performed.

MS(ISP)：404.5(M+H⁺，100)，807.4(2M+H⁺，30).NMR(300MHz，DMSO-D₆)ppm：7.48-7.56(m，4H)，7.42-7.48(m，6H)，6.98(d，1H)，6.89(d，1H)，3.58(m，2H)，3.20(m，2H)，1.46-1.62(m，4H)，1.38-1.46(m，2H).

Example 67

Preparation of (4, 7-dichloro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone

Prepare for

From 4, 7-dichloro-2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylic acid (154mg, 0.4mmol), EDCI (84mg, 0.44mmol) and piperidine (75mg, 0.88mmol) the title compound was obtained as a white solid (27mg, 15%). Silica gel chromatography (20g, ethyl acetate as eluent) was performed.

MS(ISP)：454.4(M+H⁺，100).NMR(300MHz，DMSO-D₆)ppm：7.48-7.55(m，10H)，7.09(s，1H)，3.58(m，2H)，3.14(m，2H)，1.48-1.60(m，4H)，1.38-1.48(m，2H).

Preparation of 4, 7-dichloro-2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylic acid:

2, 5-dichloro-3, 4-dihydroxybenzoic acid (1g, 4.48mmol) and dichlorodiphenylmethane (2.12g, 9.96mmol) were dissolved in toluene (40ml) and heated to reflux for 24 hours. After cooling, the solvent was evaporated and the residue was purified by silica gel column chromatography (100g, dichloromethane followed by 5% methanol in dichloromethane as eluent) to give the acid as white crystals (490mg, 28%).

MS(ISN)：385.0(M-H⁺，100).NMR(300MHz，DMSO-D₆)ppm：13.47(br s，1H，OH)，7.59(s，1H)，7.54(br m，10H).

The preparation of 2, 5-dichloro-3, 4-dihydroxybenzoic acid is described in the literature (EP 416410).

Example 68

Preparation of (4, 7-dichloro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone

Prepare for

From 4, 7-dichloro-2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylic acid (154mg, 0.4mmol), EDCI (84mg, 0.44mmol) and morpholine (77mg, 0.88mmol) the title compound was obtained as a white solid (88mg, 49%). Silica gel chromatography (20g, ethyl acetate as eluent) was performed.

MS(ISP)：456.4(M+H⁺，100).NMR(300MHz，DMSO-D₆)ppm：7.52(m，10H)，7.15(s，1H)，3.45-3.72(m，6H)，3.20(m，2H).

Example 69

(4, 7-dichloro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (4-methyl-piperazin-1-yl) -

Preparation of ketones

From 4, 7-dichloro-2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylic acid (115mg, 0.3mmol), EDCI (63mg, 0.33mmol) and N-methylpiperazine (66mg, 0.66mmol) the title compound was obtained as a white solid (28mg, 20%). Silica gel chromatography (20g, 5% methanol in dichloromethane as eluent) was performed.

MS(ISP)：469.1(M+H⁺，100).NMR(300MHz，DMSO-D₆)ppm：7.52(m，10H)，7.10(s，1H)，3.44-3.68(m，2H)，3.18(m，2H)，2.20-2.40(m，4H)，2.18(s，3H).

Example 70

(7-bromo-4-chloro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (4-methyl-piperazine-1-

Preparation of phenyl-methanones

From 7-bromo-4-chloro-2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylic acid (100mg, 0.23mmol), EDCI (49mg, 0.25mmol) and N-methylpiperazine (50mg, 0.50mmol) the title compound was obtained as a white solid (9mg, 8%). Silica gel chromatography (20g, 5% methanol in dichloromethane as eluent) was performed.

MS(ISP)：513.1(M+H⁺，100).NMR(300MHz，DMSO-D₆)ppm：7.52(m，10H)，7.18(s，1H)，3.44-3.68(m，2H)，3.17(m，2H)，2.20-2.40(m，4H)，2.09(s，3H).

Preparation of 7-bromo-4-chloro-2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylic acid:

methyl 7-bromo-4-chloro-2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylate (520mg, 1.16mmol) was dissolved in THF (6 ml). Lithium hydroxide hydrate (190mg, 4.64mmol) in water (6ml) was added. After addition of methanol (2ml), the reaction was heated to reflux for 5 hours. After cooling, the organic solvent was evaporated and diluted with water, acidified with 1N aqueous HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated in vacuo. The residue was stirred with n-hexane. The product precipitated as a white solid (350mg, 70%), filtered and dried.

MS(ISP)：429.1(M+H⁺，100).NMR(300MHz，DMSO-D₆)ppm：13.45(br s，1H，OH)，7.68(s，1H)，7.52(m，10H).

The preparation of methyl 7-bromo-4-chloro-2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylate is described in the literature (EP 0544166).

Example 71

Process for preparing (7-bromo-4-chloro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone

Preparation of

From 7-bromo-4-chloro-2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylic acid (100mg, 0.23mmol), EDCI (49mg, 0.25mmol) and piperidine (50mg, 0.50mmol) the title compound was obtained as a white solid (7mg, 7%). Silica gel chromatography (20g, ethyl acetate as eluent) was performed.

MS(ISP)：498.1(M+H⁺，100).NMR(300MHz，DMSO-D₆)ppm：7.52(m，10H)，7.17(s，1H)，3.56(m，2H)，3.12(m，2H)，1.48-1.60(m，4H)，1.40-1.482.09(m，2H).

Example 72

Process for preparing (7-bromo-4-chloro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone

Preparation of

From 7-bromo-4-chloro-2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylic acid (1100mg, 0.23mmol), EDCI (49mg, 0.25mmol) and morpholine (44mg, 0.50mmol) the title compound was obtained as a white solid (47mg, 39%). Silica gel chromatography (20g, ethyl acetate as eluent) was performed.

MS(ISP)：500.1(M+H⁺，100).NMR(300MHz，DMSO-D₆)ppm：7.52(m，10H)，7.23(s，1H)，3.42-3.70(m，6H)，3.19(m，2H).

Example 73

Preparation of (7-hydroxy-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanones

Prepare for

Piperidine (0.3ml, 2mmol) and ethyldiisopropylamine (0.5ml, 3mmol) were dissolved in dichloromethane (10 ml). 7-hydroxy-2, 2-diphenyl-benzo [1, 3] dioxol-5-carbonyl chloride (353mg, 1mmol) in dichloromethane (3ml) was added dropwise at room temperature. The reaction was stirred at room temperature for 24 hours. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic layer was extracted with 1n hcl aqueous solution, brine, dried over sodium sulfate and filtered. The solvent was evaporated and the residue was purified by silica gel column chromatography (20g, 5% methanol in dichloromethane as eluent) to give phenol as a white solid (180mg, 45%).

MS(ISP)：400.3(M+H⁺，100).NMR(300MHz，DMSO-D₆)ppm：10.08(s，1H，OH)，7.52-7.55(m，4H)，7.41-7.48(m，6H)，6.52(s，1H)，6.46(s，1H)，3.38(br m，4H)，1.59(br m，2H)，1.09(br m，4H).

Preparation of 7-hydroxy-2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylic acid is described in the literature (K.S. Feldman, S.M.Ensel, J.Am.chem.Soc.) (115 (3) (1993) 1162-3.)

Preparation of 7-hydroxy-2, 2-diphenyl-benzo [1, 3] dioxol-5-carbonyl chloride:

7-hydroxy-2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylic acid (334mg, 1mmol) was dissolved in chloroform (5 ml). One drop of triethylamine was added. Thionyl chloride (0.33ml, 4.5mmol) was added at 45-50 ℃ over 30 minutes. The solution was then stirred at 70 ℃ for 6 hours. Excess thionyl chloride was removed by evaporation. The crude 7-hydroxy-2, 2-diphenyl-benzo [1, 3] dioxol-5-carbonyl chloride was used in the next step without further purification.

Example 74

Preparation of 1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -carbonyl-4- (4-fluoro-phenyl) -1, 2, 3, 6-tetrahydro-pyridine

4- (4-fluorophenyl) -1, 2, 3, 4-tetrahydropyridine hydrochloride (106mg, 0.5mmol) was suspended in dichloromethane (10 ml). Ethyldiisopropylamine (150mg, 1.2mmol) was added followed by 2-diphenyl-benzo [1, 3] dioxol-5-carboxylic acid benzotriazol-1-yl ester (150mg, 0.5 mmol). The reaction was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography (20g, ethyl acetate as eluent). The amide was obtained as white crystals (177mg, 75%).

MS(ISP)：478.4(M+H⁺，100).NMR(300MHz，DMSO-D₆)ppm：7.53-7.57(m，4H)，7.44-7.50(m，8H)，7.17(t，2H)，7.15(s，1H)，7.10(d，1H)，7.01(d，1H)，6.15(br s，1H)，4.15(brs，CH₂)，3.62(m，2H)，2.52(m，2H under DMSO peak).

Example 75

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl-methyl) -4- (4-fluoro-phenyl) -1, 2, 3, 6-

Preparation of tetrahydro-pyridines

Lithium aluminum hydride (13mg, 0.36mmol) was suspended in THF (10 ml). (2, 2-Diphenyl-benzo [1, 3] dioxol-5-yl) - [4- (4-fluoro-phenyl) -3, 6-dihydro-2H-pyridin-1-yl ] -methanone (104mg, 0.22mmol) dissolved in THF (1.5ml) was added dropwise at room temperature under an argon atmosphere. The reaction was heated to reflux for 2 hours. Lithium aluminium hydride (50mg) was added and the reaction was heated to reflux under argon overnight. Lithium aluminium hydride solution (0.3ml, 1M solution in THF) was added and the reaction was heated to reflux for 4 hours. The reaction was cooled (ice bath) and a mixture of water (0.4ml) and THF (1.5ml) was added slowly under an argon atmosphere. The reaction was stirred for 10 minutes and potassium carbonate solid (2g) was added. The reaction was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate. The organic solution was dried over sodium sulfate, filtered and the solvent was evaporated to give the product as a white colorless viscous oil (85mg, 85%).

MS(ISP)：464.4(M+H⁺，100).NMR(300MHz，DMSO-D₆)ppm：7.52-7.56(m，4H)，7.42-7.53(m，7H)，7.14(t，2H)，6.98(m，2H)，6.87(s，1H)，6.83(d，1H)，6.09 (br s，1H)，3.48(s，CH₂)，3.01(m，2H)，2.59(m，2H)，2.52(m，2H).

Example 78

Preparation of N- (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -benzenesulfonamide

2, 2-Diphenyl-1, 3-benzodioxol-5-amine was dissolved in methylene chloride (5 ml). N-ethyldiisopropylamine (0.1ml.0.6mmol) and benzenesulfonyl chloride (88mg, 0.5mmol) were added. The reaction was stirred at room temperature for 5 hours. The reaction system was washed with cold aqueous 1N HCl, aqueous 1N NaOH and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated in vacuo. The residue was purified by column chromatography using dichloromethane as eluent. The product was crystallized from hexane to give the product as white crystals (12mg, 6%).

MS：428.3([M-H]^-).

NMR(300MHz，DMSO-d₆)ppm：10.05(br，1H，NH)，7.69(d，2H)，7.59(d，1H)，7.55(d，2H)，7.50-7.38(m，10H)，6.87(d，1H)，6.73(s，1H)，6.50(d，1H).

The following examples 79-86 (excluding example 82) were prepared using the procedure for preparing example 78:

example 79

Preparation of N, N-bis (methylsulfonyl) -2, 2-diphenyl-1, 3-benzodioxol-5-amine

The title compound was produced from 2, 2-diphenyl-1, 3-benzodioxol-5-amine and methanesulfonyl chloride following the general method of example 78.

A yellow-white solid.

MS：m/e＝446.4([M+H]⁺)

NMR(300MHz，DMSO-d₆)ppm：7.44-7.58(m，10H)，7.28(s，1H)，7.13(d，1H)，7.06(d，1H)，3.49(s，6H).

Example 80

Preparation of N, N-bis (butylsulfonyl) -2, 2-diphenyl-1, 3-benzodioxol-5-amine

The title compound was produced from 2, 2-diphenyl-1, 3-benzodioxol-5-amine and butanesulfonyl chloride following the general method of example 78.

MS：m/e＝530.4([M+H]⁺).

NMR(300MHz，DMSO-d₆)ppm：7.44-7.58(m，10H)，7.22(s，1H)，7.12(d，1H)，7.03(d，1H)，3.62(br，4H)，1.71(m，4H)，1.40(m，4H)，0.88(t，6H).

Example 81

Preparation of cyclohexanecarboxylic acid (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -amide

The title compound was produced by the general method of example 78 from 2, 2-diphenyl-1, 3-benzodioxol-5-amine and cyclohexanecarbonyl chloride.

MS：m/e＝400.5([M+H]⁺).

NMR(300MHz，DMSO-d₆)ppm：9.71(br，1H，NH)，7.41-7.56(m，11H)，6.97(d，1H)，6.92(d，1H)，2.23(br，1H)，1.60-1.80(m，10H)，1.18-1.42(m，10H).

Example 82

Preparation of butane-1-sulfonic acid (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -amide

N, N-bis (butylsulfonyl) -2, 2-diphenyl-1, 3-benzodioxol-5-amine (example 80, 79mg, 0.15mmol) was dissolved in tetrahydrofuran (4 ml). A solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 0.16mL, 0.16mmol) was added dropwise at room temperature and the solution was stirred at room temperature overnight. The reaction was heated to reflux for 30 minutes, poured into water, and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated in vacuo. The residue was purified by column chromatography using dichloromethane as eluent. Crystallization from hexanes gave the product as white crystals (45mg, 74%).

ISN-MS：m/e＝408.2([M+H]^-，100).

NMR(300MHz，DMSO-d₆)ppm：9.53(br，1H，NH)，7.55-7.42(m，10H)，6.98(d，1H)，6.90(s，1H)，6.69(d，1H)，3.00(m，2H)，1.59(m，2H)，0.804(t，3H).

Example 83

Preparation of N- (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -butanamide

The title compound was produced from 2, 2-diphenyl-1, 3-benzodioxol-5-amine and butyryl chloride following the general procedure of example 78.

MS：m/e＝360.3([M+H]⁺.

MR(300MHz，DMSO-d₆)ppm：9.78(br，1H，NH)，7.41-7.55(m，11H)，6.94(m，2H)，2.22(t，2H)，1.59(m，2H)，0.89(t，3H).

Example 84

Preparation of morpholine-4-carboxylic acid (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -amide

The title compound was produced by the general method of example 78 from 2, 2-diphenyl-1, 3-benzodioxol-5-amine and 4-morpholinylcarbonyl chloride.

MS：m/e＝403.4([M+H]⁺).

NMR(300MHz，DMSO-d₆)ppm：8.41(br，1H，NH)，7.40-7.55(m，10H)，7.21(s，1H)，6.89(d，1H)，6.83(d，1H)，3.58(m，4H)，3.37(m，4H).

Example 85

Preparation of piperidine-1-sulfonic acid (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -amide

The title compound was produced from 2, 2-diphenyl-1, 3-benzodioxol-5-amine and piperidine-1-sulfonyl chloride following the general method of example 78.

MS：m/e＝435.3([M+H]⁺).

NMR(300MHz，DMSO-d₆)ppm：9.62(br，1H，NH)，7.41-7.55(m，10H)，6.97(d，1H)，6.87(s，1H)，6.68(d，1H)，3.04(m，4H)，1.37(m，6H).

Example 86

Preparation of piperidine-1-carboxylic acid (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -amide

The title compound was produced from 2, 2-diphenyl-1, 3-benzodioxol-5-amine and piperidinecarbonyl chloride following the general procedure of example 78.

MS：m/e＝401.4([M+H]⁺).

NMR(300MHz，DMSO-d₆)ppm：8.30(br，1H，NH)，7.40-7.55(m，10H)，7.22(d，1H)，6.84(m，2H)，3.36(m，2H)，1.45-1.56(m，6H).

Example 87

[2- (4-chloro-phenyl) -2- (2-fluoro-4-methoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] -morphoie

Preparation of lin-4-yl-methanones

a) Preparation of (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone

To a mixture of 1H-benzotriazol-1-yl 2, 2-diphenyl-1, 3-benzodioxole-5-carboxylate (300mg, 0.689mmol) in acetonitrile (2.0mL) at 0 deg.C was added morpholine (100mg, 1.15mmol, 1.67 eq.). After 10 minutes, the ice bath was removed and the reaction was stirred at 20 ℃ for 3 hours. The reaction was partitioned between water and dichloromethane. The combined organic layers were washed with brine and dried in vacuo to give the title compound (267mg, quantitative) as a white solid.

MS：m/e＝388.4([M+H]⁺)。

1H-benzotriazol-1-yl 2, 2-diphenyl-1, 3-benzodioxole-5-carboxylate was prepared according to literature procedures (EP 544166).

b) Preparation of (3, 4-dihydroxy-phenyl) -morpholin-4-yl-methanones

To a cooled (0 ℃) solution of (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone (270mg, 0.7mmol) in trifluoroacetic acid (4mL) was added triethylsilane (160mg, 1.38mmol, 1.96 eq.). The reaction mixture was stirred at 0 ℃ for 20 minutes. The ice bath was removed and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated. Purification by flash chromatography gave the title compound (147mg, 95%) as a white solid.

MS：m/e＝220.3([M-H]^-)。

c) Preparation of (4-chloro-phenyl) - (2-fluoro-4-methoxy-phenyl) -methanone

Aluminum trichloride (144g, 1.08mol) was added to a cooled (0 ℃ C.) nitrobenzene solution (450 mL). A solution of 4-chlorobenzoyl chloride (128.5mL, 1mol) in nitrobenzene (200mL) was added slowly. 3-Fluoroanisole (108.5mL, 0.95mol) was added slowly. The reaction mixture was stirred at 20 ℃ overnight and partitioned between ice water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic phases were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The warm solution was poured onto cyclohexane. The solid was filtered, washed with cyclohexane and dried in vacuo to give the title compound (104.5g, 41%) as an off-white solid.

MS：m/e＝264([M]⁺)

d) Preparation of 4-chloro-2 '-fluoro-4' -methoxy-dichlorodiphenylmethane

N, N-dimethylformamide (0.03ImL, 0.4mmol, 1eq.) was added to a solution of (4-chloro-phenyl) - (2-fluoro-4-methoxy-phenyl) -methanone (106mg, 0.4mmol, 1eq.) in thionyl chloride (0.6 mL). The reaction mixture was stirred at reflux for 18 h and the volatiles were removed in vacuo to give the title compound as an orange oil (135mg, 87%).

NMR(300MHz，CDCl₃)ppm：7.82(dd，1H)，7.56(d，2H)，7.32(dd，2H)，6.73(dd，1H)，6.63(dd，1H)，3.83(s，3H).

e) Preparation of [2- (4-chloro-phenyl) -2- (2-fluoro-4-methoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

A solution of (3, 4-dihydroxy-phenyl) -piperidin-1-yl-methanone (37.7mg, 0.169mmol) and 2-fluoro-4-methoxy-4' -chlorodiphenyldichloromethane (67.5mg, 0.175mmol) in toluene (1.7mL) was heated under reflux over 42 hours. The reaction mixture was cooled and adsorbed on silica. Purification by flash chromatography gave the title compound (46mg, 58%) as a yellow semisolid.

MS：m/e＝470.2([M+H]⁺)。

Example 88

4- [2- (4-chloro-phenyl) -2- (2-fluoro-4-methoxy-phenyl) -benzo [1, 3] dioxole-5-sulfonyl

Preparation of phenyl morpholine

a) Preparation of 4- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -morpholine

To [3, 4- [ (diphenylmethylene) dioxy group]Phenyl radical]To a solution of sulfonyl chloride (202mg, 0.54mmol) in tetrahydrofuran (2mL) was added morpholine (52mg, 0.596mmol, 1.1eq.) and potassium tert-butoxide (73mg, 0.65mmol, 1.2 eq.). The reaction mixture was stirred at 20 ℃ for 48 hours and partitioned between aqueous hydrochloric acid (1N) and dichloromethane. The aqueous phase was extracted with dichloromethane. The organic layer was washed with aqueous sodium bicarbonate and brine. Purification by flash chromatography gave the title compound (179mg, 78%) as an off-white solid. MS: 424.5([ M + H) }/e ]⁺)。

[3, 4- [ (diphenylmethylene) dioxy ] phenyl ] sulfonyl chloride was prepared according to literature procedures (EP 544166 and WO 9218490).

b) Preparation of 4- (morpholine-4-sulfonyl) -benzene-1, 2-diol

The title compound was produced by the general method of example 87b from 4- (2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonyl) -morpholine (example 88 a). A yellow-white solid.

MS：m/e＝257.9([M-H])。

c) Preparation of 4- [2- (4-chloro-phenyl) -2- (2-fluoro-4-methoxy-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -morpholine

The title compound was produced by the general method of example 87e from 4- (morpholine-4-sulfonyl) -benzene-1, 2-diol (example 88b) and 2-fluoro-4-methoxy-4' -chlorodiphenyl dichloromethane (example 87 d). A white solid.

MS：m/e＝506.9([M+H]⁺)。

Example 89

[2- (4-methoxy-phenyl) -2- (3-nitro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholine

Preparation of (E) -4-yl-methanones

a) Preparation of (4-methoxyphenyl) - (3-nitrophenyl) -methanone

To a mixture of cold (0 ℃) anisole (17.7mL, 0.162mol, 1.0eq.) and aluminum trichloride (26.9g, 0.202mol, 1.25eq.) in 1, 2-dichloroethane (140mL) was slowly added 3-nitrobenzoyl chloride (30g, 0.162 mol). The cooling bath was removed and the reaction mixture was stirred at 20 ℃ for 2 hours. The reaction mixture was poured into ice water. Concentrated hydrochloric acid (5mL) was added. The aqueous layer was extracted with dichloromethane (2 fold). The combined organic layers were dried over sodium sulfate, filtered and the volatiles removed in vacuo. Purification by flash chromatography gave the title compound (35.1g, 84%) as an orange solid, m.p.: 88-89 deg.C

b) Preparation of 4-methoxy-3' -nitro-dichlorodiphenylmethane

The title compound was produced from (4-methoxyphenyl) - (3-nitrophenyl) -methanone (example 89a) according to the general method of example 87 d. A yellow oil.

NMR(300MHz，CDCl₃)ppm：8.53-8.52(m，1H)，8.23(dd，1H)，7.95(dd，1H)，7.59-7.50(m，3H)，6.89(d，2H)，3.85(s，3H).

c) Preparation of [2- (4-methoxy-phenyl) -2- (3-nitro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

The title compound was produced by the general method of example 87e from (3, 4-dihydroxy-phenyl) -morpholin-1-yl-methanone (example 87b) and 4-methoxy-3' -nitro-dichlorodiphenylmethane (example 89 b). White foam.

MS：m/e＝463.3([M+H]⁺)。

Example 90

[4- [2- (4-methoxy-phenyl) -2- (3-nitro-phenyl) -benzo [1, 3] dioxole-5-sulfonyl

Preparation of phenyl morpholine

The title compound was produced by the general method of example 108c from 4- (morpholine-4-sulfonyl) -benzene-1, 2-diol (example 88b) and 4-methoxy-3' -nitro-dichlorodiphenylmethane (example 89 b). A light yellow oil.

MS：m/e＝499([M+H]⁺)。

Example 91

[4- [2- (4-methoxy-phenyl) -5- (morpholine-4-carbonyl) -benzo [1, 3] dioxol-2-yl ] -benzyl

Preparation of nitriles

a) Preparation of 4- (4-methoxy-benzoyl) -benzonitrile

The title compound was produced from 4- (4-methoxy-benzoyl) -benzonitrile according to the general method of example 87 d. A yellow oil.

NMR(300MHz，CDCl₃)ppm：7.70-7.60(m，4H)，7.43(d，2H)，6.82(d，2H)，3.77(s，3H).

b) Preparation of 4-cyano-4-methoxy-dichlorodiphenylmethane

The title compound was produced from 4- (4-methoxy-benzoyl) -benzonitrile (example 91a) according to the general method of example 87 d. A yellow oil.

MS：m/e＝443.4([M+H]⁺)。

c) Preparation of 4- [2- (4-methoxy-phenyl) -5- (morpholine-4-carbonyl) -benzo [1, 3] dioxol-2-yl ] -benzonitrile

The title compound was produced by the general method of example 87e from (3, 4-dihydroxy-phenyl) -morpholin-1-yl-methanone (example 87b) and 4-cyano-4-methoxy-dichlorodiphenylmethane (example 91 b). A yellow oil.

MS：m/e＝443.4([M+H]⁺)。

Example 92

4- [2- (4-methoxy-phenyl) -5- (morpholine-4-sulfonyl) -benzo [1, 3] dioxol-2-yl ] -propionic acid

Preparation of benzonitrile

The title compound was produced by the general method of example 88c from 4- (morpholine-4-sulfonyl) -benzene-1, 2-diol example 88b) and 4-cyano-4-methoxy-dichlorodiphenylmethane (example 91 b). A yellow-white foam.

MS：m/e＝479.3([M+H]⁺)。

Example 93

[2- (2-fluoro-4-methoxy-phenyl) -2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morphoie

Preparation of lin-4-yl-methanones

a) Preparation of (2-fluoro-4-methoxy-phenyl) - (4-fluoro-phenyl) -methanone

To a cold (5 ℃) mixture of aluminum trichloride (144g, 1.08mol, 1.13eq.) in nitrobenzene (450mL) was slowly added a solution of 4-fluorobenzoyl chloride (120mL, 1mol, 1.05eq.) in nitrobenzene (200 mL). To the reaction mixture was added slowly 3-fluoroanisole (108.5mL, 0.95 mol). The cooling bath was removed and the reaction mixture was stirred at 20 ℃ for 3 hours and poured into ice water. The aqueous layer was extracted with dichloromethane (2 fold). The combined organic layers were dried over sodium sulfate, filtered and the volatiles removed in vacuo. The crude mixture was crystallized from cyclohexane, filtered and the solid washed with cyclohexane. The solid was dried in vacuo to give the title compound (57.78g, 25%) as a white solid, m.p.: 89.7-90.1 ℃.

b) Preparation of 2-fluoro-4-methoxy-4' -fluoro-dichlorodiphenylmethane

The title compound was produced from (2-fluoro-4-methoxy-phenyl) - (4-fluoro-phenyl) -methanone (example 93a) according to the general method of example 87 d. Yellow semi-solid.

MS：m/e＝304.2([M+H]⁺)。

c) Preparation of [2- (2-fluoro-4-methoxy-phenyl) -2- (4-fluoro-phenyl) ═ benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

The title compound was produced by the general method of example 87e from (3, 4-dihydroxy-phenyl) -morpholin-1-yl-methanone (example 87b) and 2-fluoro-4-methoxy-4' -fluoro-dichlorodiphenylmethane (example 93 b). Brown oil.

MS：m/e＝454.5([M+H⁺]。

Practice ofExample 94

4- [2- (2-fluoro-4-methoxy-phenyl) -2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-sulfonyl

Preparation of phenyl morpholine

The title compound was produced by the general method of example 88c from 4- (morpholine-4-sulfonyl) -benzene-1, 2-diol (example 88b) and 2-fluoro-4-methoxy-4' -fluoro-dichlorodiphenylmethane (example 93 b). White foam.

MS：m/e＝490.3([M+H]⁺)。

Example 95

Preparation of (6-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone

a) Preparation of 2-fluoro-4, 5-dihydroxy-benzaldehyde

To a cooled (-78 ℃) solution of 6-fluoro veratraldehyde (2g, 10.9mmol) in dichloromethane (40mL) was added a solution of boron tribromide in dichloromethane (1M, 44mL, 44mmol, 4.0 eq.). The reaction was allowed to reach room temperature and stirred overnight. The reaction mixture was partitioned between ice-water bath diethyl ether. The aqueous layer was extracted with ether. The combined organic layers were washed with water, dried over sodium sulfate and filtered. The volatiles were removed in vacuo. Purification by flash chromatography gave the title compound (1.71mg, quant.) as a dark solid.

MS：m/e＝156.0([M]⁺)。

b) Preparation of 4, 5-bis-benzyloxy-2-fluoro-benzaldehyde

To a solution of 2-fluoro-4, 5-dihydroxy-benzaldehyde (44.0g, 282mmol) in acetone (1L) was added potassium carbonate (39.0g, 0.282mmol, 1.0eq.) and benzyl bromide (33.5mL, 0.282mmol, 1.0 eq.). The reaction mixture was stirred at 20 ℃ overnight. The mixture was filtered through a dicalite pad. After evaporation, purification by flash chromatography gave the title compound (5.34g, 6%) as a white solid.

MS：m/e＝336.1([M])。

c) Preparation of 4, 5-bis-benzyloxy-2-fluoro-benzoic acid

To a cold (0 ℃) solution of 4, 5-bis-benzyloxy-2-fluoro-benzaldehyde (2.15g, 6.39mmol) in acetone (86.0mL) was slowly added Jones' reagent (4.3 mL). The reaction mixture was stirred at 0 ℃ for 19 hours. Propanol (0.43mL) was added and the reaction mixture was stirred at 20 ℃ for 40 minutes. The crude mixture was filtered, washed with acetone and poured into water (50 mL). The solid was filtered, washed with water and dried in vacuo to give the title compound (1.82g, 81%) as a white solid.

MS：m/e＝351.1([M-H]^-) Jones reagent: to a cold (0 ℃) solution of chromium oxide (826mg, 8.3mmol) in water (1.3mL) was slowly added concentrated sulfuric acid (0.86 mL). The solution was diluted with water (2.15 mL).

d) Preparation of (4, 5-bis-benzyloxy-2-fluoro-phenyl) -piperidin-1-yl-methanone

The title compound was produced from 4, 5-bis-benzyloxy-2-fluoro-benzoic acid (example 95c) and piperidine according to the general method for example 108 e. A white solid.

MS：m/e＝420.5([M+H]⁺)。

e) Preparation of (2-fluoro-4, 5-dihydroxy-phenyl) -piperidin-1-yl-methanone

The title compound was produced from (4, 5-bis-benzyloxy-2-fluoro-phenyl) -piperidin-1-yl-methanone (example 95d) according to the general method of example 87 b.

A colorless semisolid.

MS：m/e＝240.2([M+H]⁺)。

f) Preparation of (6-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone

The title compound was produced by the general method of example 108c from (2-fluoro-4, 5-dihydroxy-phenyl) -piperidin-1-yl-methanone (example 95e) and dichlorodiphenylmethane. A colorless semisolid.

MS：m/e＝404.3([M+H]⁺)。

Example 96

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperazine

Preparation of pyridin-1-yl-methanones

The title compound was produced by the general method of example 108c from (2-fluoro-4, 5-dihydroxy-phenyl) -piperidin-1-yl-methanone (example 95e) and 2, 4-dichloro-4' -fluoro-chlorodiphenyldichloromethane (example 108 b). A white solid.

MS：m/e＝404.3([M-C₅H₁₀N^*]⁺)

Example 97

[ 6-fluoro-2- (4-fluoro-phenyl) -2-phenyl-benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methyl

Preparation of ketones

a) Preparation of 4-fluorodiphenyl dichloromethane

The title compound was produced from trifluorotoluene and fluorobenzene following the general procedure for example 108 b. A yellow oil.

NMR(300MHz，CDCl₃)ppm：7.63-7.57(m，4H)，7.38-7.35(m，3H)，7.06-7.00(m，2H).

b) Preparation of [ 6-fluoro-2- (4-fluoro-phenyl) -2-phenyl-benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone

The title compound was produced by the general method of example 108c from (2-fluoro-4, 5-dihydroxy-phenyl) -piperidin-1-yl-methanone (example 95e) and 4-fluorodiphenyldichloromethane (example 97 a). A white solid.

MS：m/e＝422.2([M+H]⁺)。

Example 98

[2- (2-chloro-phenyl) -6-fluoro-2- (4-methoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperazine

Preparation of pyridin-1-yl-methanones

a) Preparation of 2-chloro-4' -methoxy-diphenyl dichloromethane

The title compound was produced from 2-chlorotrifluoromethylene and anisole following the general method of example 108 b. Brown oil.

NMR(300MHz，CDCl₃)ppm：7.46-7.35(m，6H)，6.85(d，2H)，3.83(s，3H).

b) Preparation of [2- (2-chloro-phenyl) -6-fluoro-2- (4-methoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone

The title compound was produced according to the general method for example 108c from [2- (2-chloro-phenyl) -6-fluoro-2- (4-methoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone (example 95e) and 2-chloro-4' -methoxy-diphenyl dichloromethane (example 98 a). A white solid.

MS：m/e＝468.1([M+H]⁺)。

Example 99

Preparation of (6-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone

a) Preparation of (4, 5-bis-benzyloxy-2-fluoro-phenyl) -morpholin-4-yl-methanone

The title compound was produced by the general method of example 108e from 4, 5-bis-benzyloxy-2-fluoro-benzoic acid (example 95c) and morpholine. A white solid.

MS：m/e＝421.1([M+H]⁺)。

b) Preparation of (2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanones

The title compound was produced from (4, 5-bis-benzyloxy-2-fluoro-phenyl) -morpholin-4-yl-methanone (example 99a) according to the general method of example 87 b.

A white solid.

MS：m/e＝242.2([M+H]⁺)。

c) Preparation of (6-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone

The title compound was produced by the general method of example 108c from (2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 99b) and dichlorodiphenylmethane. A white solid.

MS：m/e＝406.2([M+H]⁺)。

Example 100

[ 6-fluoro-2- (4-fluoro-phenyl) -2-phenyl-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methyl

Preparation of ketones

The title compound was produced by the general method of example 108c from (2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 99b) and 4-fluorodiphenyldichloromethane (example 97 a). A white solid.

MS：m/e＝424.3([M+H]⁺)。

Example 101

[2- (2-chloro-phenyl) -6-fluoro-2- (4-methoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] -morphoie

Preparation of lin-4-yl-methanones

The title compound was produced by the general method of example 108c from (2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 99b) and 2-chloro-4' -methoxy-diphenyl dichloromethane (example 98 a). A white solid.

MS：m/e＝424.3([M+H]⁺)。

Example 102

(6-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - [4- (4-fluoro-phenyl) -piperazine-1-

Preparation of phenyl-methanones

a) Preparation of (4, 5-bis-benzyloxy-2-fluoro-phenyl) - [4- (4-fluoro-phenyl) -piperazin-1-yl ] -methanone

The title compound was produced by the general method of example 108e from 4, 5-bis-benzyloxy-2-fluoro-benzoic acid (example 95c) and 1- (4-fluorophenyl) piperazine. A pale yellow solid.

MS：m/e＝514.6([M+H]⁺)。

b) Preparation of (2-fluoro-4, 5-dihydroxy-phenyl) - [4- (4-fluoro-phenyl) -piperazin-1-yl ] -methanone

The title compound was produced according to the general method for example 87b from (4, 5-bis-benzyloxy-2-fluoro-phenyl) - [4- (4-fluoro-phenyl) -piperazin-1-yl ] -methanone (example 102 a). A white solid.

MS：m/e＝335.2([M+H]⁺)。

c) Preparation of (6-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - [4- (4-fluoro-phenyl) -piperazin-1-yl ] -methanone

The title compound was produced according to the general method for example 108c from (2-fluoro-4, 5-dihydroxy-phenyl) - [4- (4-fluoro-phenyl) -piperazin-1-yl ] -methanone (example 102b) and dichlorodiphenylmethane. Light brown solid.

MS：m/e＝499.2([M+H]⁺)。

Example 103

[ 6-fluoro-2- (4-fluoro-phenyl) -2-phenyl-benzo [1, 3] dioxol-5-yl ] - [4- (4-fluoro-benzene

Preparation of yl) -piperazin-1-yl ] -methanone

The title compound was produced according to the general method for example 108c from (2-fluoro-4, 5-dihydroxy-phenyl) - [4- (4-fluoro-phenyl) -piperazin-1-yl ] -methanone (example 102b) and 4-fluorodiphenyldichloromethane (example 97 a). Grey solid.

MS：m/e＝517.2([M+H]⁺)。

Example 104

[2- (2-chloro-phenyl) -6-fluoro-2- (4-methoxy-phenyl) -benzo [1, 3] dioxol-5-yl ]

Preparation of [4- (4-fluoro-phenyl) -piperazin-1-yl ] -methanone

The title compound was produced according to the general method for example 108c from (2-fluoro-4, 5-dihydroxy-phenyl) - [4- (4-fluoro-phenyl) -piperazin-1-yl ] -methanone (example 102b) and 2-chloro-4' -methoxy-diphenyl dichloromethane (example 98 a).

An orange solid.

MS：m/e＝563.2([M]⁺)。

Example 105

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-methoxy-phenyl) -benzo [1, 3] dioxole-5-

Preparation of a base-piperidin-1-yl-methanone

a) Preparation of 2, 4-dichloro-4' -methoxy-diphenyl-dichloromethane

The title compound was produced by the general method of example 108b from 2, 4-dichlorotrifluorotoluene and anisole. A red oil.

(insert spectral data)

b) Preparation of [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-methoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone

The title compound was produced by the general method of example 108c from (2-fluoro-4, 5-dihydroxy-phenyl) -piperidin-1-yl-methanone (example 95e) and 2, 4-dichloro-4' -methoxy-diphenyl dichloromethane (example 105 a). An orange oil.

MS：m/e＝502.3([M+H]⁺)。

Example 106

Preparation of yl-morpholin-4-yl-methanones

The title compound was produced by the general method of example 108c from (2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 99b) and 2, 4-dichloro-4' -methoxy-diphenyl dichloromethane (example 105 a). A yellow oil.

MS：m/e＝504.3([M+H]⁺)。

Example 107

Preparation of yl ] - [4- (4-fluoro-phenyl) -piperazin-1-yl ] -methanone

The title compound was produced according to the general method for example 108c from (2-fluoro-4, 5-dihydroxy-phenyl) - [4- (4-fluoro-phenyl) -piperazin-1-yl ] -methanone (example 102b) and 2, 4-dichloro-4' -methoxy-diphenyl dichloromethane (example 105 a).

Brown oil.

MS：m/e＝597.2([M]⁺)。

Example 108

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morphoie

Preparation of lin-4-yl-methanones

a) Preparation of 4-bromo-5-fluoro-benzene-1, 2-diol

To a cooled (-78 deg.C) solution of 4-fluoroveratrole (5.0g, 32mmol) in dichloromethane (106mL) was slowly added a solution of tribromoborane in dichloromethane(1M, 96mL, 96mmol, 3.0 eq.). The reaction mixture was warmed to 20 ℃ and stirred overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate (3 times). The combined organic layers were washed with aqueous sodium bicarbonate, dried over sodium sulfate and filtered. The volatiles were removed in vacuo. The brown solid was diluted with chloroform (50mL) and dichloromethane (10 mL). A solution of bromine in carbon tetrachloride (5ml) was added slowly. After 3 hours, the volatiles were removed in vacuo. Purification by flash chromatography gave the title compound (6.51g, 98%) as a brown solid. MS: m/e is 207.9([ M + H ] ]⁺。

b) Preparation of 2, 4-dichloro-4' -fluoro-diphenyl-dichloromethane

To a cooled (0 ℃) suspension of aluminium trichloride (2.02g, 15mmol, 3.0eq.) in 1, 2-dichloroethane (7mL) was slowly added 2, 4-dichlorotrifluorotoluene (1.1g, 5mmol) followed by fluorobenzene (0.483g, 5mmol, 1.0 eq.). The reaction mixture was stirred at 0-5 ℃ for 5 hours, then poured onto ice and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The volatiles were removed in vacuo to give the title compound (1.63g, quantitative) as a yellow oil.

MS：m/e＝325.0([M+H]⁺)。

c) Preparation of 5-bromo-2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole

A mixture of 4-bromo-5-fluoro-benzene-1, 2-diol (6.43g, 31.1mmol) and 2, 4-dichloro-4' -fluoro-chlorodiphenyl dichloromethane (10.07g, 31.1mmol, 1.0eq.) was heated at 180 ℃ with stirring for 20 minutes. The reaction mixture was cooled to 20 ℃, diluted with dichloromethane and adsorbed on silica. Purification by flash chromatography gave the title compound (9.98g, 70%) as a light yellow solid.

MS：m/e＝457.9([M+H]⁺)。

d) Preparation of [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid

To a cooled (-78 ℃) solution of 5-bromo-2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol (16.5g, 36.0mmol) in diethyl ether (250mL) was slowly added a solution of n-butyllithium in hexane (1.6M, 23mL, 36.0mmol, 1.0 eq.). After 1 hour at-78 ℃, solid carbon dioxide (about 50g) was added to the solution and the reaction was warmed to 20 ℃. After 16 h at 20 ℃, the reaction mixture was partitioned between water (150mL), ethyl acetate (1.5L) and hydrochloric acid (1N, 150 mL). The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water. The volatiles were removed in vacuo. Purification by flash chromatography gave the title compound (10.73g, 69%) as a light yellow solid.

MS：m/e＝422.3([M-H]^-)。

e) Preparation of [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

To a solution of [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (380mg, 0.898mmol) in N, N-dimethylformamide (7mL) was added carbonyldiimidazole (189mg, 1.17mmol, 1.3 eq.). The reaction mixture was stirred at 20 ℃ for 16 hours.

Morpholine (196mg, 2.24mmol, 2.5eq.) was added and the reaction was stirred at 90 ℃ for 8 hours. The reaction mixture was partitioned between hydrochloric acid (1N) bath ethyl acetate. The organic layer was washed with brine and water and the volatiles were removed in vacuo. Purification by flash chromatography gave the title compound (367mg, 83%) as a white solid.

MS：m/e＝493.43([M+H]⁺)。

Example 110

Preparation of (6-methyl-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone

Prepare for

a) Preparation of 4-bromo-5-methyl pyrocatechol

To a solution of homoveratrole (136.4g, 1.1mol) in chloroform (1.2L) and dichloromethane (300mL) was slowly added a solution of bromine (66mL, 1.28mol, 1.2eq.) in carbon tetrachloride (250 mL). After 5 hours, the reaction mixture was neutralized to pH7 with aqueous sodium hydroxide solution and the aqueous layer was extracted with chloroform. The combined organic layers were dried over sodium sulfate, filtered and the volatiles removed in vacuo to give the title compound as a light brown solid, m.p.: 92-98 ℃.

b) Preparation of 5-bromo-6-methyl-2, 2-diphenyl-benzo [1, 3] dioxole

The title compound was produced from 4-bromo-5-methyl pyrocatechol and diphenyl dichloromethane following the general method of example 108 c. A white solid.

MS：m/e＝368.0([M+H⁺])。

c) Preparation of lithium 6-methyl-2, 2-diphenyl-1, 3-benzodioxole-5-carboxylate

To a cold (-70 ℃) solution of 5-bromo-6-methyl-2, 2-diphenyl-benzo [1, 3] dioxol (example 110b, 91.8g, 250mmol) in tetrahydrofuran (140mL) was slowly added a solution of n-butyllithium in hexane (170mL, 1.6M, 1.1eq.) and tetrahydrofuran (100 mL). After 15 minutes, excess solid carbon dioxide was added. The reaction was warmed to room temperature. The solid was filtered and dried in vacuo to give the title compound (79.4g, 77%) as a white solid.

MS：m/e＝345.2([M+2Li])。

d) Preparation of (6-methyl-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone

To a solution of 6-methyl-2, 2-diphenyl-1, 3-benzodioxole-5-carboxylic acid lithium salt (101.5mg, 0.3mmol) in N, N-dimethylformamide (3mL) was added N, N' -tetramethyl-O- (1H-benzotriazol-1-yl) -uronium-hexafluorophosphate (114mg, 0.3mmol, 1.0 eq.). The reaction mixture was stirred at 20 ℃ for 1 hour. Piperidine (26mg, 0.3mmol, 1.0eq.) was added and the reaction mixture was stirred at 20 ℃ for 20 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and then dried over sodium sulfate, filtered and evaporated. Purification by flash chromatography gave the title compound (73mg, 61%) as a light yellow solid.

MS：m/e＝400.2

Example 111

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

Preparation of

a) Preparation of 4, 4' -difluoro-diphenyldichloromethane

The title compound was produced from 4, 4' -difluorobenzophenone by the general method of example 88 d. A yellow oil.

MS：m/e＝272([M-H]⁺)。

b) Preparation of [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

The title compound was produced by the general method of example 108c from (3, 4-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 87b) and 4, 4' -difluoro-diphenyl dichloromethane (example 111 a). White foam.

MS：m/e＝442.3([M+H]⁺)。

Example 112

Preparation of (6-bromo-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone

a) Preparation of 6-bromo-2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylic acid

To a solution of 5-bromo-6-methyl-2, 2-diphenyl-benzo [1, 3] dioxole (5.20g, 14.1mmol, example 110b) in pyridine (52mL) and water (26mL) was added potassium permanganate (6.71g, 42.5mmol, 3.0eq.) at room temperature. After 3 hours, the reaction mixture was partitioned between ethyl acetate and hydrochloric acid (1N). The aqueous layer was extracted with ethyl acetate. After evaporation, the residue was adsorbed on silica. Purification by flash chromatography gave the title compound (4.656g, 83%) as an off-white solid.

MS：m/e＝395.0([M-H]^-)。

b) Preparation of (6-bromo-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone

The title compound was produced by the general method of example 108e from 6-bromo-2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylic acid (example 112a) and piperidine. A white solid.

MS：m/e＝464.1([M+H]⁺)

Example 113

(+) - [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -carboxylic acid

Preparation of morpholin-4-yl-methanones

The title compound was produced from racemic [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone (example 108e) by preparative chiral hplc (chiralpak ad). A white solid.

MS：m/e＝493.3([M+H]⁺)。

Example 114

(-) - [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -propanoic acid

Preparation of morpholin-4-yl-methanones

MS：m/e＝493.3([M+H]⁺)。

Example 115

[2- (2, 4-dichloro-phenyl) -2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholine-4-

Preparation of a base-methanone

The title compound was produced by the general method of example 108c from 2, 4-dichloro-4, -fluoro-diphenyldichloromethane (example 108b) and (3, 4-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 87 b). Gum arabic.

MS：m/e＝474.1([M+H]⁺)。

Example 116

[2- (2, 4-dichloro-phenyl) -2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidine-1-carboxylic acid

Preparation of a base-methanone

The title compound was produced according to the general method for example 108c from 2, 4-dichloro-4' -fluoro-diphenyldichloromethane (example 108b) and (3, 4-dihydroxy-phenyl) -piperidin-4-yl-methanone. Gum arabic.

MS：m/e＝472.2([M+H]⁺)。

Example 117

Preparation of (6-chloro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone

a) Preparation of (6-chloro-benzo [1, 3] dioxol-5-yl) -piperidin-4-yl-methanone

The title compound was produced from 6-chloro-1, 3-benzodioxole-5-carboxylic acid and piperidine according to the general method for example 218 c. Colorless solid, m.p.: 138 ℃ and 139 ℃.

MS：m/e＝267.9([M+H]⁺)。

b) Preparation of (2-chloro-4, 5-dihydroxy-phenyl) -piperidin-4-yl-methanone

The title compound was produced by the general method of example 218b from (6-chloro-benzo [1, 3] dioxol-5-yl) -piperidin-4-yl-methanone (example 117 a).

Light grey solid.

MS：m/e＝256.1([M+H]⁺)。

c) Preparation of (6-chloro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone

The title compound was produced by the general method of example 108c from α, α -diphenyldichloromethane and (2-chloro-4, 5-dihydroxy-phenyl) -piperidin-4-yl-methanone (example 117 b). A colorless solid.

MS：m/e＝418.1([M]⁺)。

Example 118

Preparation of (6-chloro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone

The title compound was produced by the general method of example 108c from α, α -diphenyl dichloromethane and (2-chloro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 218 b). A white solid.

MS：m/e＝422.0([M+H]⁺)。

Example 119

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid ethyl ester

Preparation of methyl-amides

To a solution of [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d, 220 mg; 0.52 mmol; 1eq.) in N, N-dimethylformamide (5mL) was added carbonyldiimidazole (110 mg; 0.68 mmol; 1.3eq.) and the mixture was stirred at 20 ℃ for 2 h. A solution of ethyl-methylamine in N, N-dimethylformamide (1M, 1 mL; 1.3 mmol; 2.5eq.) was added and the reaction mixture was stirred at 20 ℃ for 4 days. Purification by preparative HPLC (YMC pro C18) gave the title compound as a stock solution in 10mM DMSO.

MS：m/e＝464.2([M]⁺)。

Example 120

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid methyl ester

Preparation of mesityl-propyl-amides

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and methyl-propylamine following the general method of example 119.

MS：m/e＝478.2([M]⁺)。

Example 121

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (2-

Preparation of methyl-pyrrolidin-1-yl) -methanones

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 2-methyl-pyrrolidine following the general method of example 119.

MS：m/e＝490.2([M]⁺)

Example 122

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid nitrogen

Preparation of heterocyclic Heptane-1-ylamides

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 1-aminopiperidine following the general method of example 119.

MS：m/e＝519.3([M]⁺)。

Example 123

Azetidin-1-yl- [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxido

Preparation of heterocyclopenen-5-yl-methanones

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and azetidine following the general method of example 119.

MS：m/e＝462.2([M]⁺)。

Example 124

Azepan-1-yl- [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole

Preparation of heterocyclopenen-5-yl-methanones

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and azepane according to the general method for example 119.

MS：m/e＝504.2([M]⁺)。

Example 125

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid

Preparation of (2, 2-dimethyl-1-methylcarbamoyl-propyl) -amide

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and L-tert-leucine-N-methylamide following the general method of example 119.

MS：m/e＝549.4([M]⁺)。

Example 126

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ]

Preparation of (2S-methoxymethyl-pyrrolidin-1-yl) -methanone

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 2S-methoxymethyl-pyrrolidine following the general method of example 119.

MS：m/e＝520.4([M]⁺)。

Example 127

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-

Preparation of alkyl- (2R-hydroxymethyl-pyrrolidin-1-yl) -methanone

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 2R-hydroxymethyl-pyrrolidine following the general method of example 119.

MS：m/e＝506.2([M]⁺)。

Example 128

1- [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carbonyl

Preparation of yl ] -pyrrolidine-2R-carboxylic acid dimethylamide

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 2R-carboxylic acid dimethylamine pyrrolidine according to the general method of example 119.

MS：m/e＝547.3([M]⁺)。

Example 129

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid ring

Preparation of butylamides

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and cyclobutylamine following the general method of example 119.

MS：m/e＝476.3([M]⁺)。

Example 130

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid morpholine

Preparation of lin-4-ylamides

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and N-aminomorpholine according to the general method for example 119.

MS：m/e＝507.2([M]⁺)。

Example 131

Preparation of 1, 2, 3, 5, 6-tetrahydro-pyrazin-4-yl methanone

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 1- (2-pyrazinyl) -piperazine following the general method of example 119.

MS：m/e＝569.3([M]⁺)

Example 132

Preparation of yl ] -pyrrolidine-2S-carboxylic acid amide

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and pyrrolidine-2S-carboxylic acid amide following the general method of example 119.

MS：m/e＝519.3([M]⁺)

Example 133

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid tert-butyl ester

Preparation of butoxy-amides

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and tert-butoxy-amine following the general procedure of example 119.

MS：m/e＝494.2([M]⁺)

Example 134

Preparation of pentylamides

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and cyclopentylamine following the general procedure of example 119.

MS：m/e＝490.3([M]⁺)

Example 135

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (tetrakis)

Preparation of hydro-furan-2-ylmethyl) -amide

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and (tetrahydro-furan-2-ylmethyl) -amine following the general method of example 119.

MS：m/e＝506.2([M]⁺)

Example 136

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -thio

Preparation of morpho-4-yl-methanones

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and thiomorpholine following the general method of example 119.

MS：m/e＝508.2([M]⁺)

Example 137

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid iso-forms

Preparation of propylamides

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and isopropylamine according to the general procedure of example 119.

MS：m/e＝464.2([M]⁺)

Example 138

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid pyri-dine

Preparation of pyrrolidin-1-ylamides

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and pyrrolidinamine following the general method of example 119.

MS：m/e＝491.3([M]⁺)

Example 139

Preparation of oxy-methyl-amides

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and methoxy-methyl-amine following the general method of example 119.

MS：m/e＝466.2([M]⁺)

Example 140

Preparation of (3R-hydroxy-pyrrolidin-1-yl) -methanones

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 3R-hydroxy-pyrrolidine following the general method of example 119.

MS：m/e＝492.2([M]⁺)

Example 141

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid bis-

Preparation of cyclopropylmethyl-amides

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and bis-cyclopropylmethyl-amine following the general method of example 119.

MS：m/e＝530.2([M]⁺)

Example 142

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (4-

Preparation of fluoro-piperidin-1-yl) -methanones

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 4-fluoro-piperidine following the general procedure of example 119.

MS：m/e＝530.2([M]⁺)

Example 143

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -propanoic acid

Preparation of (1, 4-dioxa-8-aza-spiro [4.5] decan-8-yl) -methanones

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 1, 4-dioxa-8-azaspiro (4.5) decane following the general method of example 119.

MS：m/e＝548.3([M]⁺)

Example 144

Preparation of hydroxymethyl-piperidin-1-yl) -methanones

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 4-hydroxymethyl-piperidine following the general procedure of example 119.

MS：m/e＝520.3([M]⁺)

Example 145

Preparation of hydroxy-4-methyl-piperidin-1-yl) -methanones

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 4-hydroxy-4-methyl-piperidine following the general procedure of example 119.

MS：m/e＝520.3([M]⁺)

Example 146

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -pyri-dine

Preparation of pyrrolidin-1-yl-methanones

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and pyrrolidine following the general method of example 119.

MS：m/e＝476.1([M]⁺)

Example 147

N- {1- [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-

Preparation of carbonyl-pyrrolidin-3S-yl-acetamide

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 3S-acetamidopyrrolidine following the general method of example 119.

MS：m/e＝533.2([M]⁺)

Example 148

Preparation of heptylamides

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and cycloheptylamine following the general procedure of example 119.

MS：m/e＝518.3([M]⁺)

Example 149

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid N-

Preparation of pyridin-2-yl-hydrazides

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 2-hydrazinopyridine following the general procedure of example 119.

MS：m/e＝514.3([M]⁺)

Example 150

Preparation of (2S-methoxymethyl-pyrrolidin-1-yl) -amide

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 2S-methoxymethyl-pyrrolidin-1-amine according to the general method of example 119.

MS：m/e＝534.2([M]⁺)

Example 151

Preparation of 1, 1-dioxothiomorpholin-4-yl methanones

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 1, 1-dioxo-1-thiomorpholine following the general method of example 119.

MS：m/e＝540.4([M]⁺)

Example 152

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (3-)

Preparation of hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) -methanones

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and nortropine (nortropine) following the general method of example 119.

MS：m/e＝532.2([M]⁺)

Example 153

Preparation of yl ] - (2R-methoxymethyl-pyrrolidin-1-yl) -methanone

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 2R-methoxymethyl-pyrrolidine following the general method of example 119.

MS：m/e＝520.2([M]⁺)

Example 154

Preparation of yl ] - (3S-hydroxy-pyrrolidin-1-yl) -methanone

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5 carboxylic acid (example 108d) and 3S-hydroxy-pyrrolidine following the general method of example 119.

MS：m/e＝492.2([M]⁺)

Example 155

Preparation of carbonyl-pyrrolidin-3R-yl-acetamide

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 3R-acetamido-pyrrolidine following the general method of example 119.

MS：m/e＝533.3([M]⁺)

Example 156

Preparation of alkyl- (2S-hydroxymethyl-pyrrolidin-1-yl) -methanone

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 2S-hydroxymethyl-pyrrolidine following the general method of example 119.

MS：m/e＝506.2([M]⁺)

Example 157

Preparation of lin-4-yl-thiones

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone (example 108e, 79mg, 0.16mmol) and Lawesson's reagent (33mg, 0.08mmol) in benzene (1mL) were heated to reflux for 4 h. The reaction mixture was evaporated in vacuo. Purification by flash chromatography gave the title compound (75mg, 92%) as a yellow oil.

MS：m/e＝508.0([M]⁺)。

Example 158

[2- (4-chloro-phenyl) -2- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morphoie

Preparation of lin-4-yl-methanones

a) Preparation of 2, 4, 4' -trichlorodiphenyl dichloromethane

The title compound was produced from 2, 4-dichloro-trifluorotoluene and chlorobenzene according to the general procedure for example 108 b. Brown oil.

MS：m/e＝339.9([M]⁺)。

b) Preparation of 5-bromo-2- (4-chloro-phenyl) -2- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxole

The title compound was produced by the general method of example 108c from 4-bromo-5-fluoro-benzene-1, 2-diol (example 108a) and 2, 4, 4' -trichlorodiphenyl dichloromethane (example 158 a). A white solid.

MS：m/e＝473.9([M]⁺)。

c) Preparation of 2- (4-chloro-phenyl) -2- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid

The title compound was produced by the general method of example 108d from 5-bromo-2- (4-chloro-phenyl) -2- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxole (example 158 b). An orange solid.

MS：m/e＝437.0([M-H]^-)。

d) Preparation of [2- (4-chloro-phenyl) -2- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

The title compound was produced by the general method of example 108e from 2- (4-chloro-phenyl) -2- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid (example 158c) and morpholine. An orange solid.

MS：m/e＝508.3([M+H]⁺)。

Example 159

Preparation of 6- (morpholine-4-carbonyl) -2, 2-diphenyl-benzo [1, 3] dioxole-5-carbonitrile

a) Preparation of (6-bromo-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone

The title compound was produced by the general method of example 108e from 6-bromo-2, 2-diphenyl-benzo [1, 3] dioxole-5-carboxylic acid (example 110c) and morpholine. A white solid.

MS：m/e＝466.2([M+H]⁺)。

b) Preparation of 6- (morpholine-4-carbonyl) -2, 2-diphenyl-benzo [1, 3] dioxole-5-carbonitrile

A mixture of (6-bromo-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone, (204mg, 0.437mmol) and copper cyanide (102mg, 1.139mmol, 2.6eq.) in N-methylpyrrolidine (3mL) was heated at 190 ℃ and over the course of 16 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine and evaporated in vacuo. Purification by flash chromatography gave the title compound (4.656g, 83%) as an off-white solid.

MS：m/e＝413.1([M+H]⁺)。

Example 160

[2- (4-chloro-phenyl) -2- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -piperazine

Preparation of pyridin-1-yl-methanones

The title compound was produced from 2- (4-chloro-phenyl) -2- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid (example 158c) and piperidine according to the general procedure for example 108 e. A white solid.

MS：m/e＝506.0([M+H]⁺)。

Example 161

[2- (4-chloro-phenyl) -2- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -pyri-dine

Preparation of pyrrolidin-1-yl-methanones

The title compound was produced from 2- (4-chloro-phenyl) -2- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid (example 158c) and pyrrolidine following the general method of example 108 e.

A yellow-white solid.

MS：m/e＝491.9([M+H]⁺)。

Example 162

Process for preparing [2, 2-bis- (2, 4-difluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanones

Preparation of

a) Preparation of 2, 2 ', 4, 4' -tetrafluorodiphenyl dichloromethane

Aluminum trichloride (5.32g, 39.9mmol) was added to 1, 3-difluorobenzene (8g, 70.12mmol) while stirring. The mixture was cooled to about 10 ℃ and carbon tetrachloride (14.5mL) was added dropwise over a 1 hour period. The mixture was stirred at 30 ℃ for 3.5 hours, diluted with dichloromethane and poured onto ice. The phases were separated, the organic phase was dried over magnesium sulfate and evaporated to give the title compound as a light brown solid which was used without further purification.

MS：m/e 273.0([M-Cl]^-)。

b) Preparation of [2, 2-bis- (2, 4-difluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl methanone

The title compound was produced by the general method of example 108c from 2, 2 ', 4, 4' -tetrafluorodiphenyldichloromethane and (3, 4-dihydroxy-phenyl) morpholin-4-yl-methanone (example 87 b). Light brown solid.

MS：m/e＝460.1([M+H]⁺)。

Example 163

Process for preparing [2, 2-bis- (2, 4-difluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanones

Preparation of

The title compound was produced by the general method of example 108c from 2, 2 ', 4, 4' -tetrafluorodiphenyldichloromethane (example 162a) and (3, 4-dihydroxy-phenyl) -piperidin-4-yl-methanone. Yellow foam.

MS：m/e＝458.3([M+H]⁺)。

Example 164

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -pyrrolidin-1-yl-methyl

Preparation of ketones

a) Preparation of 5-bromo-6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxole

The title compound was produced by the general method of example 108c from 4-bromo-5-fluoro-benzene-1, 2-diol (example 108a) and 4, 4' -difluorodiphenyl dichloromethane (example 111 a). A colorless oil.

MS：m/e＝407.9([M]⁺)。

b) Preparation of [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -pyrrolidin-1-yl-methanone

The title compound was produced according to the general method for example 166b from 5-bromo-6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxole (example 164a) and 1-pyrrolidine-carbonyl chloride. A light yellow oil.

MS：m/e＝426.3([M+H]⁺)。

Example 165

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone

Preparation of

The title compound was produced according to the general method for example 166b from 5-bromo-6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxole (example 164a) and 1-piperidine-carbonyl chloride. A yellow oil.

MS：m/e＝440.3([M+H]⁺)。

Example 166

[2, 2-bis- (4-bromo-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

Preparation of

a) Preparation of 5-bromo-6-fluoro-2, 2-diphenyl-benzo [1, 3] dioxoles

The title compound was produced by the general method of example 108c from 4-bromo-5-fluoro-benzene-1, 2-diol (example 108a) and diphenyl dichloromethane.

A yellow-white solid.

MS：m/e＝370.0([M+H⁺])。

b) Preparation of (6-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone

To a cooled (-78 ℃) solution of 5-bromo-6-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol (17.59g, 47.4mmol) in diethyl ether (300mL) was slowly added a solution of n-butyllithium in hexane (1.6M, 30mL, 48mmol, 1.0 eq.). The reaction mixture was stirred at-78 ℃ after which 4-morpholinecarbonyl chloride (8.5g, 56.9mmol, 1.2eq.) was added. The reaction mixture was warmed to 20 ℃ and poured into aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine. The volatiles were removed in vacuo. Purification by flash chromatography gave the title compound (13.0g, 68%) as a light yellow solid.

MS：m/e＝406.2([M+H]⁺)。

c) Preparation of (2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanones

The title compound was produced from (6-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone following the general method of example 87 b. Light brown solid.

MS：m/e＝442.2([M+H]⁺)。

d) Preparation of 4, 4' -dibromodiphenyl dichloromethane

The title compound was produced from 4-bromotrifluorotoluene and bromobenzene by the general method of example 108 b. A pale yellow semi-solid.

MS：m/e＝392.0([M+H]⁺)。

e) Preparation of [2, 2' -bis- (4-bromo-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

The title compound was produced by the general method of example 108c from (2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 166c) and 4, 4' -dibromodiphenyl dichloromethane (example 166 d). A pale yellow solid.

MS：m/e＝364.1([M+H]⁺)。

Example 167

Preparation of 4- [2, 2-bis- (4-cyano-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-carbonyl ] -morpholine

Prepare for

A mixture of [2, 2 '-bis- (4-bromo-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone (example 166e, 400mg, 0.71mmol, 1.0eq.), copper cyanide (381mg, 4.26mmol, 6.0eq.), tris (dibenzylideneacetone) dipalladium (32.5mg, 0.035mmol, 0.05eq.), tetraethylammonium cyanide (111mg, 0.71mmol, 1.0eq.), and 1, 1' -bis (diphenylphosphinyl) ferrocene (78.7mg, 0.142mmol, 0.2eq.) was flushed with nitrogen. Degassed dioxane (10mL) was added and the reaction mixture was heated to reflux over the course of 4 hours. The reaction mixture was diluted with ethyl acetate, filtered and washed with aqueous sodium bicarbonate, brine and water. The volatiles were removed in vacuo. Purification by flash chromatography gave the title compound (141mg, 44%) as a pale yellow semi-solid.

MS：m/e＝456.1([M+H⁺])。

Example 168

4- [2- (4-bromo-phenyl) -5-fluoro-6- (morpholine-4-carbonyl) -benzo [1, 3] dioxol-2-yl ] -benzyl

Nitrile

The title compound was produced as a by-product following the general procedure for example 167. A pale yellow solid.

MS：m/e＝509.0([M+H⁺])。

Example 169

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methyl

Preparation of ketones

The title compound was produced by the general method of example 108c from 2, 2 ', 4, 4' -tetrafluorodiphenyldichloromethane (example 162a) and (2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 99 b). Light brown gum.

MS：m/e＝478.1([M+H]⁺)。

Example 170

[2, 2-bis- (4-chloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

Preparation of

a) Preparation of dichlorobis (4-chlorophenyl) dichloromethane

The title compound was produced from 4, 4' -dichlorobenzophenone following the general method of example 87d and was used without further purification. Yellow solid.

MS：m/e＝304.0，306.0([M]⁺)。

b) Preparation of [2, 2-bis- (4-chloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

The title compound was produced by the general method of example 108c from dichlorobis (4-chlorophenyl) methane and 2-fluoro-4, 5-dihydroxy-phenyl) morpholin-4-yl-methanone (example 166 c). Light brown foam.

MS：m/e＝474.0，476.0([M]⁺)。

Example 171

[ 6-chloro-2, 2-bis- (2, 4-difluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methyl

Preparation of ketones

The title compound was produced by the general method of example 108c from 2, 2 ', 4, 4' -tetrafluorodiphenyldichloromethane (example 162a) and (2-chloro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 218 b). Gum arabic.

MS：m/e＝494.1([M+H]⁺)。

Example 172

[2- (2-chloro-4-fluoro-phenyl) -2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-one

Preparation of a base-methanone

a) 2-chloro-1- [ dichloro- (4-fluoro-phenyl) -methyl ] -4-fluoro-benzene

(2-chloro-4-fluoro-phenyl) - (4-fluoro-phenyl) -methanone (0.25g, 0.99mmol) and phosphorus pentachloride (0.21g, 1.01mmol) were mixed under argon and heated at 150 ℃ for 2 hours. The mixture was cooled to room temperature, diluted with dichloromethane and poured onto ice. The phases were separated, the organic phase was dried over magnesium sulphate and evaporated to give the title compound as a pale yellow oil (0.2g) which was found by NMR to contain about 50% of the desired product together with starting material (35%) and monochlorinated compound (15%). The mixture was used without further purification.

b) Preparation of [2- (2-chloro-4-fluoro-phenyl) -2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone

The title compound was produced by the general method of example 108c from 2-chloro-1- [ dichloro- (4-fluoro-phenyl) -methyl ] -4-fluoro-benzene (example 172a) and (3, 4-dihydroxy-phenyl) -piperidin-4-yl-methanone. Light brown gum.

MS：m/e＝456.1([M+H]⁺)。

Example 173

[ 6-fluoro-2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

Preparation of

a) Preparation of bis- (2-fluoro-phenyl) -methanones

To a stirred solution of 2-fluorobenzeneboronic acid (280mg, 2mmol), Cs under nitrogen₂CO₃To a suspension of (1.63g, 5mmol) and tetrakis (triphenylphosphine) palladium (O) (40mg, 0.02mmol) in toluene (35ml) was added 2-fluorobenzoyl chloride (634mg, 4mmol) dropwise. The suspension was heated at 100 ℃ for 16 hours, cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with aqueous potassium bicarbonate, brine, dried over sodium sulfate, filtered and evaporated. Purification by flash chromatography gave the title compound (210mg, 46%).

A colorless liquid.

MS：m/e＝218.1([M⁺]。

b) Preparation of bis- (2-fluorophenyl) dichloromethane

The title compound was produced from bis- (2-fluoro-phenyl) -methanone (example 173a) following the general method of example 182 and was used without further purification. Brown solid.

c) Preparation of [ 6-fluoro-2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

The title compound was produced by the general method of example 108c from (2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-1-yl-methanone (example 99b) and bis- (2-fluorophenyl) dichloromethane (example 173 b). Light brown amorphous solid.

MS：m/e＝442.3([M+H]⁺)。

Example 174

[2, 2-bis- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methyl

Preparation of ketones

a) Preparation of 2, 2 ', 4, 4' -tetrachloro-dichlorodiphenylmethane

The title compound was produced from 2, 4-dichlorobenzene by the general method of example 207 a. White crystals.

m.p.：139-142℃；MS：m/e＝373.9，375.9([M]⁺)。

b) Preparation of [2, 2-bis- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

The title compound was produced by the general method of example 108c from 2, 2 ', 4, 4' -tetrachloro-dichlorodiphenylmethane and 2-fluoro-4, 5-dihydroxy-phenyl) morpholin-4-yl-methanone (example 166 c). White foam.

MS：m/e＝541.9，543.9([M]⁺)。

Example 175

4- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -morpholine

Preparation of

The title compound was produced by the general method of example 108c from 2, 2 ', 4, 4' -tetrafluorodiphenyldichloromethane (example 162a) and 4-fluoro-5- (morpholine-1-sulfonyl) -benzene-1, 2-diol (example 234 b). A yellow-white foam.

MS：m/e＝514.2([M+H]⁺)。

Example 176

4- [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-sulfonyl

Preparation of phenyl morpholine

The title compound was produced by the general method of example 108c from 2, 4-dichloro-4' -fluoro-diphenyl dichloromethane and 4-fluoro-5- (morpholine-1-sulfonyl) -benzene-1, 2-diol (example 234 b). A yellow-white foam.

MS：m/e＝528.1([M+H]⁺)。

Example 177

Preparation of yl ] - (4, 4-difluoro-piperidin-1-yl) -methanone

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 4, 4' -difluoropiperidine following the general procedure for example 108 e. Yellow gum.

MS：m/e＝526.1([M]⁺)。

Example 178

Preparation of trifluoromethyl-piperidin-1-yl) -methanones

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 4- (trifluoromethyl) piperidine hydrochloride following the general method of example 108 e. A white gum.

MS：m/e＝558.0([M]⁺)。

Example 179

Preparation of (3S-ethoxy-pyrrolidin-1-yl) -methanones

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 3S-ethoxy-pyrrolidine following the general method of example 108 e. A colorless oil.

MS：m/e＝520.1([M]⁺)。

Example 180

Preparation of (1R-phenyl-ethyl) -amide

The title compound was produced according to the general method for example 108e from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and (1R-phenyl-ethyl) -amine. A colorless oil.

MS：m/e＝526.1([M]⁺)。

Example 181

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (1-

Preparation of oxo-thiomorpholin-4-yl) -methanones

A solution of m-chloroperbenzoic acid (74mg, 0.3mmol) in dichloromethane (1.2mL) was added to a cooled (-20 ℃ C.) solution of [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -thiomorpholin-4-yl-methanone (example 136) (153mg, 0.3mmol) in dichloromethane (1.7 mL). The reaction mixture was stirred at-20 ℃ for 3 hours and quenched with 5% aqueous sodium thiosulfate. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with 10% sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and the volatiles removed in vacuo. Purification by flash chromatography gave the title compound as a white foam (141mg, 89%).

MS：m/e＝524.1([M]⁺)。

Example 182

[2, 2-bis- (2-chloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

Preparation of

a) Preparation of bis- (2-chlorophenyl) dichloromethane

A mixture of 2, 2' -dichlorobenzophenone (502mg, 2mmol) and phosphorus pentachloride (833mg, 4mmol, 2.0eq.) was stirred at 170 ℃ for 28 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane and washed with cold water. The organic layer was dried over sodium sulfate, filtered and the volatiles removed in vacuo to give the title compound (629mg, quantitative) as an orange oil.

MS：m/e＝306.0([M]⁺)。

b) Preparation of [2, 2-bis- (2-chloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

A mixture of bis- (2-chlorophenyl) dichloromethane (example 182, 258mg, 0.84mmol, 2.6eq.) and (2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 87b, 72mg, 0.32mmol) was heated at 150 ℃ for 5 hours in a sealed glass tube. Purification by flash chromatography gave the title compound (6.8mg, 4.5%) as an off-white solid, m.p.: at 98 deg.c.

MS：m/e＝474.0([M+H]⁺)。

Example 183

[ 6-fluoro-2, 2-bis- (4-trifluoromethyl-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl

Preparation of methanones

a) Preparation of bis- (4-trifluoromethyl-phenyl) -methanone

The title compound was produced from 4-trifluoromethyl-phenylboronic acid and 4-trifluoromethyl-benzoyl chloride according to the general method of example 173 a. White crystalline solid.

MS：m/e＝318.1([M]⁺)。

b) Preparation of bis- (4-trifluoromethyl-phenyl) dichloromethane

The title compound was produced from bis- (4-trifluoromethyl-phenyl) -methanone (example 183a) according to the general method of example 87d and used without further purification. Brown solid.

c) Preparation of [ 6-fluoro-2, 2-bis- (4-trifluoromethyl-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

The title compound was produced by the general method of example 108c from (2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-1-yl-methanone (example 99b) and bis- (4-trifluoromethyl-phenyl) dichloromethane (example 183 b). Light brown amorphous solid.

MS：m/e＝542.1([M+H]⁺)

Example 184

[ 6-fluoro-2, 2-bis- (3-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

Preparation of

a) Preparation of bis- (3-fluorophenyl) dichloromethane

The title compound was produced from bis- (3-fluoro-phenyl) -methanone following the general method of example 87d and was used without further purification.

b) Preparation of [ [ 6-fluoro-2, 2-bis- (3-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

The title compound was produced by the general method of example 108c from (2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-1-yl-methanone (example 99b) and bis- (3-fluorophenyl) dichloromethane (example 184 a). A yellow-white amorphous solid.

MS：m/e＝442.1([M+H]⁺)。

Example 185

[2- (2-chloro-4-fluoro-phenyl) -2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholine-4-

Preparation of a base-methanone

The title compound was produced by the general method of example 108c from 2-chloro-1- [ dichloro- (4-fluoro-phenyl) -methyl ] -4-fluoro-benzene (example 172a) and (3, 4-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 87 b). Light brown gum.

MS：m/e＝458.3([M+H]⁺)。

Example 186

Process for preparing [2, 2-bis- (3, 4-difluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanones

Preparation of

The title compound was produced by the general method of example 108c from 1, 1' - (dichloromethylene) bis [3, 4-difluoro-benzene and (3, 4-dihydroxy-phenyl) -piperidin-4-yl-methanone. Light brown gum.

MS：m/e＝458.2([M+H]⁺)。

Example 187

Process for preparing [2, 2-bis- (3, 4-difluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanones

Preparation of

The title compound was produced by the general method of example 108c from 1, 1' - (dichloromethylene) bis [3, 4-difluoro-benzene and (3, 4-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 87 b). A colorless gum.

MS：m/e＝460.2([M+H]⁺)。

Example 188

[2, 2-bis- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] - (3-hydroxy-pyrrole)

Preparation of alk-1-yl-methanones

a) Preparation of 5-bromo-2, 2-bis- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxole

The title compound was produced by the general method of example 108c from 2, 2 ', 4, 4' -tetrachloro-dichlorodiphenylmethane (example 174a) and 4-bromo-5-fluoro-benzene-1, 2-diol (example 108 a). A colorless solid.

MS：m/e＝507.9，509.9([M]⁺)。

b) Preparation of 2, 2-bis- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid

The title compound was produced from 5-bromo-2, 2-bis- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxol according to the general method of example 108 d. White foam.

MS：m/e＝471.0，473.0([M-H]^-)。

c) Preparation of [2, 2-bis- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] - (3-hydroxy-pyrrolidin-1-yl) -methanone

The title compound was produced from 2, 2-bis- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid and 3-pyrrolidinol according to the general method of example 108 e. A light yellow foam.

MS：m/e＝541.9，543.9([M]⁺)。

Example 189

[2, 2-bis- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] - (4-hydroxy-piperidine)

Preparation of (E) -1-yl-methanones

The title compound was produced from 2, 2-bis- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid and 4-hydroxy-piperidine following the general procedure of example 108 e. A light yellow foam.

MS：m/e＝556.0，558.0([M]⁺)。

Example 190

2, 2-bis- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid ethyl-methyl-

Preparation of amides

The title compound was produced from 2, 2-bis- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid and N-ethylmethylamine following the general method of example 108 e. White foam.

MS：m/e＝514.0，516.0([M]⁺)。

Example 191

2, 2-bis- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid bis- (2-hydroxy-

Preparation of ethyl) -amides

The title compound was produced by the general method of example 108e from 2, 2-bis- (2, 4-dichloro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid and diethanolamine. A light yellow foam.

MS：m/e＝560.0，562.0([M]⁺)。

Example 192

[2, 2-bis- (4-chloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone

Preparation of

a) Preparation of 5-bromo-2, 2-bis- (4-chloro-phenyl) -6-fluoro-benzo [1, 3] dioxole

The title compound was produced by the general method of example 108c from dichlorobis (4-chlorophenyl) dichloromethane (example 170a) and 4-bromo-5-fluoro-benzene-1, 2-diol (example 108 a). A colorless foam.

MS：m/e＝437.9，439.9，441.9([M]⁺)。

b) Preparation of 2, 2-bis- (4-chloro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid

The title compound was produced from 5-bromo-2, 2-bis- (4-chloro-phenyl) -6-fluoro-benzo [1, 3] dioxol according to the general method of example 108 d. Yellow solid.

MS：m/e＝403.1，405.1([M-H]^-)。

c) Preparation of [2, 2-bis- (4-chloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone

The title compound was produced from 2, 2-bis- (4-chloro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid and piperidine according to the general procedure for example 108 e. White foam.

MS：m/e＝437.9，439.9，441.9([M]⁺)。

Example 193

[2, 2-bis- (4-chloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -pyrrolidin-1-yl-methyl

Preparation of ketones

The title compound was produced from 2, 2-bis- (4-chloro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid and pyrrolidine according to the general method for example 108 e. White foam.

MS：m/e＝458.1，460.1([M]⁺)。

Example 194

[2, 2-bis- (2-chloro-4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone

Preparation of

a) Preparation of 2, 2 '-dichloro-4, 4' -difluorodiphenyl dichloromethane

Bis (2-chloro-4-fluorophenyl) -methanone (1.6g, 5.57mmol) and phosphorus pentachloride (1.4g, 6.72mmol) were heated at 165 ℃ for 5 hours in a sealed tube. The mixture was cooled to room temperature, diluted with dichloromethane and poured onto ice. The phases were separated, the organic phase was dried over magnesium sulfate and evaporated to give the title compound as a light brown oil (1.46g) consisting of a mixture of the desired product and the starting ketone (NMR) about 4: 1, which was used without further purification.

NMR(300MHz，CDCl₃) ppm: 8.39(dd, 2H, J ═ 4.5, 6.6Hz, product), 7.55(dd, o.5h, benzophenone), 7.17(dd, o.5h, J ═ 4.5, 6.3Hz, benzophenone), 7.10(in, 4.5H, product and benzophenone), 3.14(in, 4H), 1.70-1.40(in, 6H).

b) Preparation of [2, 2-bis- (2-chloro-4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone

The title compound was produced from 2, 2 '-dichloro-4, 4' -difluorodiphenyl dichloromethane and (3, 4-dihydroxy-phenyl) -piperidin-4-yl-methanone following the general method of example 108 c. Light brown gum.

MS：m/e＝490.1([M+H]⁺)。

Example 195

[2, 2-bis- (3, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methyl

Preparation of ketones

The title compound was produced by the general method of example 108c from 1, 1' - (dichloromethylene) bis [3, 4-difluoro-benzene ] and (2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 99 b). A yellow-white foam.

MS：m/e＝478.3([M+H]⁺)。

Example 196

[2, 2-bis- (2, 5-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methyl

Preparation of ketones

a) Preparation of bis- (2, 5-difluorophenyl) dichloromethane

The title compound was produced from 2, 5-difluorobenzene following the general method of example 207 a. A viscous light brown oil.

MS：m/e＝308.1([M]⁺)。

b) Preparation of [2, 2-bis- (2, 5-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

The title compound was produced by the general method of example 108c from (2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-1-yl-methanone (example 99b) and bis- (2, 5-difluorophenyl) dichloromethane (example 196 a). Light brown amorphous solid.

MS：m/e＝477.1([M]⁺)。

Example 197

[2, 2-bis- (2-chloro-4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

Preparation of

The title compound was produced by the general method of example 108c from 2, 2 '-dichloro-4, 4' -difluorodiphenyl dichloromethane (example 194a) and (3, 4-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 87 b). Gum arabic.

MS：m/e＝492.2([M+H]⁺)。

Example 198

[2, 2-bis- (2-chloro-4-fluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-

Preparation of ketones

The title compound was produced by the general method of example 108c from 2, 2 '-dichloro-4, 4' -difluorodiphenyl dichloromethane (example 194a) and (2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 99 b). A yellow-white foam.

MS：m/e＝510.1([M+H]⁺)。

Example 199

[ 6-chloro-2, 2-bis- (2-chloro-4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-

Preparation of ketones

The title compound was produced by the general method of example 108c from 2, 2 '-dichloro-4, 4' -difluorodiphenyl dichloromethane (example 194a) and (2-chloro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 218 b). Light brown foam.

MS：m/e＝526.1([M+H]⁺)。

Example 200

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid acyl

Preparation of amines

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and ammonium hydroxide following the general procedure of example 108 c. White foam.

MS：m/e＝422([M]⁺)。

Example 201

[2, 2-bis- (4-bromo-2-fluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-

Preparation of ketones

a) Preparation of 4, 4 '-dibromo-2, 2' -difluoro-benzophenone

Tetrakis (triphenylphosphine) palladium (0.15g, 0.13mmol) was dissolved in anisole (15 mL). 1-bromo-3-fluoro-4-iodobenzene (2.0g, 6.6mmol), 4-bromo-2-fluorobenzeneboronic acid (1.45g, 6.6mmol) and potassium carbonate (2.7g, 19.9mmol) were added along with 15mL anisole. The mixture was stirred at 80 ℃ and 10 bar carbon monoxide pressure for 16 hours. The reaction mixture was cooled, added to a toluene/water mixture (120mL, 1: 1), the phases separated and the aqueous phase extracted twice with toluene. The organic phase was collected, washed with brine and the solvent was evaporated. Crystallization from hexane afforded the title compound as white crystals (1.17g, 47%).

MS：m/e＝375.9，377.9([M+H]⁺)。

b) Preparation of 4, 4 '-dibromo-2, 2' -difluoro-dichlorodiphenylmethane

A mixture of 4, 4 '-dibromo-2, 2' -difluoro-benzophenone (1.3g, 3.5mmol), phosphorus oxychloride (26mL), and phosphorus pentachloride (4.4g, 21mmol) was stirred at boiling temperature for 72 hours. The mixture was cooled and poured into ice/water (200 mL). The product was extracted into dichloromethane. The organic phase was collected, dried over sodium sulfate and the solvent was removed in vacuo to give the product, which was used without further purification as a light brown oil.

MS：m/e＝429.8，431.8([M]⁺)。

c) Preparation of [2, 2-bis- (4-bromo-2-fluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

The title compound was produced by the general method of example 108c from 4, 4 '-dibromo-2, 2' -difluoro-dichlorodiphenylmethane and 2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 166 c). A colorless oil.

MS：m/e＝598.0，600.0，602.0([M]⁺)。

Example 202

Preparation of yl ] - (3, 4-cis-dihydroxy-pyrrolidin-1-yl) -methanone

a) Preparation of [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (2, 5-dihydro-pyrrol-1-yl) -methanone

The title compound was produced from [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 108d) and 3-pyrroline following the general method of example 108 e. A yellow oil.

MS：m/e＝474([M]⁺)。

b) Preparation of [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (3, 4-cis-dihydroxy-pyrrolidin-1-yl) -methanone

To a solution of [2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (2, 5-dihydro-pyrrol-1-yl) -methanone (70mg, 0.15mmol) in acetone (3.7mL) and water (1.5mL) was added 4-methylmorpholine-4-oxide monohydrate (23mg, 0.16mmol), osmium tetroxide (0.02mL, 0.0015mmol) and potassium osmate (VI) dihydrate (2.4mg, 0.0065mmol) and the reaction was stirred at 20 ℃ for 24 h. Sodium thiosulfate pentahydrate was added and the reaction mixture was stirred for 30 minutes and poured onto crushed ice. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with brine, dried over sodium sulfate, filtered and the volatiles were removed in vacuo. Purification by flash chromatography gave the title compound as a black oil (56mg, 74%).

MS：m/e＝508.1([M]⁺)。

Example 203

[2, 2-bis- (2, 3-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methyl

Preparation of ketones

a) Preparation of bis- (2, 3-difluoro-phenyl) -methanones

The title compound was produced by the general method of example 173a from 2, 3-difluorophenylboronic acid and 2, 3-difluoro-benzoyl chloride. An off-white crystalline solid.

MS：m/e＝254.1([M]⁺)。

b) Preparation of bis- (2, 3-difluorophenyl) dichloromethane

The title compound was produced from bis- (2, 3-difluoro-phenyl) -methanone (example 203a) according to the general method of example 87d and used without further purification. Brown solid.

c) Preparation of [2, 2-bis- (2, 3-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

The title compound was produced according to the general method of 108c from (2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-1-yl-methanone (example 99b) and bis- (2, 3-difluorophenyl) dichloromethane (example 203 b). A yellow-white amorphous solid.

MS：m/e＝478.1([M+H]⁺)。

Example 204

[ 6-fluoro-2, 2-bis- (4-trifluoromethoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholine-4-

Preparation of a base-methanone

a) Preparation of bis- (4-trifluoromethoxy-phenyl) -methanone

The title compound was produced from 4-trifluoromethoxy-phenylboronic acid and 4-trifluoromethoxy-benzoyl chloride following the general procedure of example 173 a.

Light brown solid.

MS：m/e＝350([M]⁺)。

b) Preparation of bis- (4-trifluoromethoxy-phenyl) dichloromethane

The title compound was produced from bis- (4-trifluoromethoxy-phenyl) -methanone in phosphorus oxychloride (example 203a) following the general procedure of example 182a and was used without further purification. Brown solid.

c) Preparation of [ 6-fluoro-2, 2-bis- (4-trifluoromethoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

The title compound was produced by the general method of example 108c from (2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-1-yl-methanone (example 99b) and bis- (4-trifluoromethyl-phenyl) dichloromethane (example 204 b). A yellow-white amorphous solid.

MS：m/e＝574.2([M+H]⁺)。

Example 205

[2, 2-bis- (2-chloro-4, 5-difluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methyl

Preparation of ketones

The title compound was produced by the general method of example 108c from 1, 1' - (dichloromethylene) bis [ 2-chloro-4, 5-difluorobenzene and (3, 4-dihydroxy-phenyl) -piperidin-4-yl-methanone. A yellow-white foam.

MS：m/e＝526.1([M+H]⁺)。

Example 206

4- [2, 2-bis- (2-chloro-4-fluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -morpholine

Preparation of

The title compound was produced by the general method of example 108c from 2, 2 '-dichloro-4, 4' -difluorodiphenyl dichloromethane (example 194a) and 4-fluoro-5- (morpholine-1-sulfonyl) -benzene-1, 2-diol (example 234 b). Light brown solid.

MS：m/e＝546.0([M+H]⁺)。

Example 207

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methyl

Preparation of ketones

a) Preparation of 2, 2 ', 4, 4' -tetrafluorodiphenyl dichloromethane

To a cooled (10 ℃) mixture of 1, 3-difluorobenzene (50g, 0.438mol) and aluminum trichloride (33.3g, 250mmol, 0.57eq.) was slowly added carbon tetrachloride (91 mL). The reaction mixture was warmed to 30 ℃ over the course of 4 hours. Ice water was added. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and the volatiles removed in vacuo to give the title compound 60.3g, 89%) as a dark brown oil.

MS：m/e＝273.2([M-Cl^*]⁺)。

b) Preparation of 5-bromo-2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole

The title compound was produced according to the general method for example 108c from 4-bromo-5-fluoro-benzene-1, 2-diol (example 108a) and [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone (example 207 a). A pale yellow solid.

MS：m/e＝444.0([M+H]⁺)。

c) Preparation of 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid

The title compound was produced by the general method of example 108d from 5-bromo-2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol (example 207 b). Yellow solid.

MS：m/e＝407.0([M-H]^-)。

d) Preparation of [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone

The title compound was produced from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid (example 207c) and piperidine according to the general procedure for example 108 e. A yellow oil.

MS：m/e＝476.1([M+H]⁺)。

Example 208

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] - (4-fluoro-piperidine)

Preparation of (E) -1-yl-methanones

The title compound was produced by the general method of example 108e from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid (example 207c) and 4-fluoropiperidine. A white solid.

MS：m/e＝494.1([M+H]⁺)。

Example 209

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] - (4, 4-difluoro-piperazines

Preparation of pyridin-1-yl-methanones

The title compound was produced from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid (example 207c) and 4, 4-difluoropiperidine following the general procedure for example 108 e. A white solid.

MS：m/e＝512.2([M+H⁺)。

Example 210

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] - (4-trifluoromethyl-

Preparation of piperidin-1-yl) -methanones

The title compound was produced from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid (example 207c) and 4- (trifluoromethyl) piperidine following the general method of example 108 e. A yellow oil.

MS：m/e＝544.2([M+H]⁺)。

Example 211

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] - (4-hydroxy-piperidine)

Preparation of (E) -1-yl-methanones

The title compound was produced by the general method of example 108e from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid (example 207c) and 4-hydroxypiperidine. A white solid.

MS：m/e＝491.1([M+H]⁺)。

Example 212

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -thiomorpholine-4-

Preparation of a base-methanone

MS：m/e＝494.1([M+H]⁺)。

Example 213

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -pyrrolidin-1-yl-

Preparation of ketones

The title compound was produced by the general method of example 108e from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid (example 207c) and pyrrolidine. A white solid.

MS：m/e＝462.1([M+H]⁺)。

Example 214

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] - (3S-hydroxy-pir-inyl ]

Preparation of pyrrolidin-1-yl) -methanones

The title compound was produced from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid (example 207c) and 3S-hydroxypyrrolidine following the general method of example 108 e. A white solid.

MS：m/e＝478.1([M+H]⁺)。

Example 215

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] - (2S-hydroxymethyl-

Preparation of pyrrolidin-1-yl) -methanones

The title compound was produced according to the general method for example 108e from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid (example 207c) and L-prolinol. A white solid.

MS：m/e＝492.2([M+H]⁺)。

Example 216

[2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] - (2S-methoxy-phenyl)

Preparation of methyl-pyrrolidin-1-yl) -methanones

The title compound was produced from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-carboxylic acid (example 207c) and 2S- (methoxymethyl) pyrrolidine following the general method of example 108 e. A light yellow oil.

MS：m/e＝506.1([M+H]⁺)。

Example 217

Process for preparing (6-chloro-2, 2-di-p-tolyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone

Preparation of

The title compound was produced according to the general method of example 233d from bis (4-methylphenyl) -thione and (2-chloro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 218 b). Light brown gum.

MS：m/e＝450.2([M+H]⁺)。

Example 218

4- [ { 6-chloro-10 ', 11 ' -dihydro-spiro [1, 3-benzodioxole-2, 5 ' - [5H ] dibenzo [ a, d ] ring

Preparation of heptene-5-yl carbonyl morpholine

a) Preparation of (6-chloro-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone

To a mixture of 6-chloro-1, 3-benzodioxole-5-carboxylic acid (0.49g, 2.44mmol) and hydroxybenzotriazole (66mg, 0.49mmol) in acetonitrile (20mL) was added morpholine (0.53mL, 6.1mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (0.52g, 2.7 mmol). The orange solution was stirred at room temperature for 72 hours, diluted with ethyl acetate and poured into water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a white solid (0.53g, 80%), mp155 ℃.

MS：m/e.270.2([M+H]⁺)。

b) Preparation of 2-chloro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanones

A solution of 1M boron trifluoride in dichloromethane (11mL) was added dropwise to a cooled (ice-bath) solution of (6-chloro-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone (example 218a) (1.98g, 7.34mmol) in dichloromethane (20 mL). The mixture was stirred at room temperature overnight and diluted with 1M potassium dihydrogen phosphate (10 mL). After stirring for 1 hour, the phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and evaporated to give the title compound as a brown foam (1.82g, 96%), which was used without further purification.

MS：m/e 494.1([M+H]⁺)。

c) Preparation of 4- [ { 6-chloro-10 ', 11 ' -dihydro-spiro [1, 3] -benzodioxole-2, 5 ' - [5H ] dibenzo [ a, d ] cycloheptene } -5-yl ] carbonyl ] -morpholine

The title compound was produced according to the general method of example 233d from 2, 3, 6, 7-dibenzocycloheptane-1-thione and (2-chloro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 218 b). Light brown solid.

MS：m/e＝448.1([M+H]⁺)。

Example 219

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (4-fluoro-piperidin-1-

Preparation of phenyl-methanones

a) Preparation of 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid

The title compound was produced by the general method of example 108d from 5-bromo-6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol (example 164 a). A light yellow foam.

MS：m/e＝371.2([M-H]⁺)。

b) Preparation of [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (4-fluoro-piperidin-1-yl) -methanone

The title compound was produced by the general method of example 108e from 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 219a) and 4-fluoropiperidine hydrochloride. A yellow oil.

MS：m/e＝458.2([M+H]⁺)。

Example 220

(4, 4-difluoro-piperidin-1-yl) - [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxole

Preparation of (E) -5-yl-methanones

The title compound was produced from 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 219a) and 4, 4' -difluoropiperidine following the general procedure for example 108 e. A yellow oil.

MS：m/e＝476.1([M+H]⁺)。

Example 221

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (4-trifluoromethyl-piper-ine

Preparation of pyridin-1-yl-methanones

The title compound was produced by the general method of example 108e from 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 219a) and 4- (trifluoromethyl) piperidine hydrochloride. A yellow oil.

MS：m/e＝508.2([M+H]⁺)。

Example 222

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -thiomorpholin-4-yl-

Preparation of ketones

The title compound was produced by the general method of example 108e from 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 219a) and thiomorpholine. A yellow-white foam.

MS：m/e＝458.2([M+H]⁺)。

Example 223

(3S-ethoxy-pyrrolidin-1-yl) - [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxole

Preparation of en-5-yl-methanones

The title compound was produced by the general method of example 108e from 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 219a) and 3S-ethoxypyrrolidine. A yellow oil.

MS：m/e＝470.2([M+H]⁺)。

Example 224

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - [ (S) - (2-methoxymethyl)

Preparation of yl-pyrrolidin-1-yl) ] -methanones

The title compound was produced by the general method of example 108e from 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 219a) and 2S-methoxymethylpyrrolidine. A yellow oil.

MS：m/e＝470.2([M+H]⁺)。

Example 225

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - [ (S) -2-hydroxymethyl-pyri-dine

Preparation of pyrrolidine-1-yl-methanones

The title compound was produced according to the general method for example 108e from 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 219a) and L-prolinol. A yellow oil.

MS：m/e＝456.1([M+H]⁺)。

Example 226

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - [ (S) -3-hydroxy-pyrrole

Preparation of alk-1-yl-methanones

The title compound was produced by the general method of example 108e from 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 219a) and 3S-hydroxypyrrolidine. Yellow foam.

MS：m/e＝442.1([M+H]⁺)。

Example 227

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (4-hydroxy-piperidin-1-

Preparation of phenyl-methanones

The title compound was produced from 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 219a) 4-hydroxypiperidine according to the general method of example 108 e. A yellow oil.

MS：m/e＝456.1([M+H]⁺)。

Example 228

4- [2, 2-bis- (2-chloro-4, 5-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl ] -

Preparation of morpholine

The title compound was produced by the general method of example 108c from 1, 1' - (dichloromethylene) bis [ 2-chloro-4, 5-difluorobenzene and 4-fluoro-5- (morpholine-1-sulfonyl) -benzene-1, 2-diol (example 234 b). A yellow-white foam.

MS：m/e＝582.0([M+H]⁺)。

Example 229

Preparation of (2, 2-di-p-tolyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone

The title compound was produced according to the general method of example 233d from bis (4-methylphenyl) -thione and (3, 4-dihydroxy-phenyl) -piperidin-4-yl-methanone. A yellow-white foam.

MS：m/e＝414.2([M+H]⁺)。

Example 230

Preparation of (2, 2-di-p-tolyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone

The title compound was produced according to the general method of example 233d from bis (4-methylphenyl) -thione and (3, 4-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 87 b). A yellow-white foam.

MS：m/e＝416.2([M+H]⁺)。

Example 231

Preparation of 4- [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -morpholine

Prepare for

The title compound was produced according to the general method of example 245d from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl chloride (example 261b) and morpholine. Yellow gum.

MS：m/e＝478.1([M+H]⁺)。

Example 232

Preparation of 4- (6-fluoro-2, 2-di-p-tolyl-benzo [1, 3] dioxol-5-sulfonyl) -morpholine

The title compound was produced according to the general method for example 233d from bis (4-methylphenyl) -thione and 4-fluoro-5- (morpholine-1-sulfonyl) -benzene-1, 2-diol (example 234 b). Light brown gum.

MS：m/e＝470.1([M+H]⁺)。

Example 233

1- { 6-fluoro-10 ', 11 ' -dihydrospiro [1, 3] -benzodioxole-2, 5 ' - [5H ] dibenzo [ a, d ] ring

Preparation of heptene } -5-yl) sulfonyl ] -piperidine

a) Preparation of 2-fluoro-4, 5-dimethoxy-benzenesulfonyl chloride

To a suspension of sulfur trioxide N, N-dimethylformamide complex (4.108g, 27mmol) in 1, 2-dichloroethane was added dropwise 4-fluoroveratrole (3.49g, 22 mmol). The mixture was slowly heated to 85 ℃ in an oil bath. After 2.5 hours, the solid had dissolved to give a golden yellow solution. Traces of starting material were still present and heating was continued for an additional 4.5 hours. The oil bath was removed and thionyl chloride (1.95mL, 27mmol) was added dropwise. The mixture was heated at 85 ℃ for 4 hours and cooled to room temperature. The solution was poured into water and extracted with dichloromethane (3 × 50mL), the combined organic layers were washed with water, dried over magnesium sulfate and evaporated. The remaining traces of N, N-dimethylformamide were azeotropically removed by bath toluene to give the product as a yellow-white solid, which was used without further purification.

MS：m/e 254.0([M]⁺)。

b) Preparation of 1- (2-fluoro-4, 5-dimethoxy-benzenesulfonyl) -piperidine

Piperidine (4.15mL, 42.02mmol) was slowly added to a cooled (ice bath) solution of 2-fluoro-4, 5-dimethoxy-benzenesulfonyl chloride (5g, 19.63mmol) in dichloromethane (110 mL). The mixture was stirred at room temperature overnight, diluted with dichloromethane and poured into water. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with brine, dried over magnesium sulfate and evaporated. The crude product was used without further purification.

NMR(300MHz，CDCl₃)ppm：7.23(d，1H，J＝6Hz)，6.71(d，1H，J＝11Hz)，3.93(s，3H)，3.90(s，3H)，3.14(m，4H)，1.70-1.40(m，6H).

c) Preparation of 4-fluoro-5- (piperidine-1-sulfonyl) -benzene-1, 2-diol

A solution of 1M boron tribromide in dichloromethane (58mL) was added dropwise to a cooled solution of 1- (2-fluoro-4, 5-dimethoxy-benzenesulfonyl) -piperidine (5.89g, 19.42mmol) in dichloromethane (100mL) maintaining the temperature at 10-20 ℃. The mixture was stirred at room temperature overnight and poured into 1M aqueous potassium dihydrogen phosphate solution and ice. After stirring for 1 hour, the phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (10: 1 dichloromethane/methanol as eluent) to give the title compound as brown gum (4.17g, 78%) MS: m/e 274.1([ M-H ]]⁺)。

d) Preparation of 1- { 6-fluoro-10 ', 11 ' -dihydrospiro [1, 3] -benzodioxole-2, 5 ' - [5H ] dibenzo [ a, d ] cycloheptene } -5-yl } sulfonyl ] -piperidine

A mixture of 2, 3, 6, 7-dibenzocycloheptane-1-thione (0.281g, 1.25mmol), 4-fluoro-5- (piperidine-1-sulfonyl) -benzene-1, 2-diol (0.230g, 0.84mmol), copper (I) chloride (0.207g, 2.09mmol) and triethylamine (0.46mL, 3.34mmol) was heated under reflux in acetonitrile (5mL) for 4 hours. The mixture was cooled to room temperature and filtered through a small pad of silica gel eluting with 1: 1 ethyl acetate/heptane. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (15: 1 heptane/ethyl acetate as eluent) to give the product as a light yellow foam (0.215g, 55%).

MS：m/e 465.2([M]⁺)。

Example 234

4- { 6-fluoro-10 ', 11 ' -dihydrospiro [1, 3] -benzodioxole-2, 5 ' - [5H ] dibenzo [ a, d ] ring

Preparation of heptene-5-ylsulfonyl morpholine

a) Preparation of 1- (2-fluoro-4, 5-dimethoxy-benzenesulfonyl) -piperidine

The title compound was produced by the general method of example 233c) from 2-fluoro-4, 5-dimethoxy-benzenesulfonyl chloride (example 233a) and morpholine. Colorless solid, mp107-108 ℃ MS: m/e 305.1([ M ]]⁺)。

b) Preparation of 4-fluoro-5- (morpholine-1-sulfonyl) -benzene-1, 2-diol

The title compound was produced by the general method of example 233c from 1- (2-fluoro-4, 5-dimethoxy-benzenesulfonyl) -piperidine (example 234 a). Light brown solid, MS: m/e 276.0([ M-H ]]⁺)。

c) Preparation of 4- { 6-fluoro-10 ', 11 ' -dihydrospiro [1, 3-benzodioxole-2, 5 ' - [5H ] dibenzo [ a, d ] cyclohepten ] -5-yl } sulfonyl ] -morpholine

The title compound was produced according to the general method for example 233d from 2, 3, 6, 7-dibenzocycloheptane-1-thione and 4-fluoro-5- (morpholine-1-sulfonyl) -benzene-1, 2-diol (example 234 b). Light yellow solid, MS: m/e 467.2([ M ]]⁺)。

Example 235

4- [ {10 ', 11 ' -dihydro-spiro [1, 3-benzodioxole-2, 5 ' - [5H ] dibenzo [ a, d ] cyclohepta

Preparation of en-5-yl-carbonyl-morpholine

The title compound was produced according to the general method of example 233d from 2, 3, 6, 7-dibenzocycloheptane-1-thione and (3, 4-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 87 b). Gum arabic.

MS：m/e 414.2([M+H]⁺)。

Example 236

1- [ {10 ', 11 ' -dihydro-spiro [1, 3-benzodioxole-2, 5 ' - [5H ] dibenzo [ a, d ] cyclohepta

Preparation of alkyl } -5-yl ] carbonyl ] -piperidine

The title compound was produced according to the general method of example 233d from 2, 3, 6, 7-dibenzocycloheptane-1-thione and (3, 4-dihydroxy-phenyl) -piperidin-4-yl-methanone. Gum arabic.

MS：m/e 414.2([M+H]⁺)。

Example 237

[ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (3-methoxy-piperidine)

Preparation of (E) -1-yl-methanones

The title compound was produced by the general method of example 108e from 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (example 219a) and 3-methoxypiperidine. A colorless oil.

MS：m/e 470.1([M+H]⁺)。

Example 240

Process for preparing 1- [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -pyrrolidine

Preparation of

The title compound was produced according to the general method of example 245d from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl chloride (example 261b) and pyrrolidine. A yellow-white solid.

MS：m/e 462.1([M+H]⁺)。

Example 241

Preparation of 1- [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -piperidine

Prepare for

The title compound was produced according to the general method of example 245d from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl chloride (example 261b) and piperidine. Yellow solid.

MS：m/e 476.1([M+H]⁺)。

Example 242

4- [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -thiomorpholine

Preparation of

The title compound was produced by the general method of example 245d from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl chloride (example 261b) and thiomorpholine. A white solid.

MS：m/e 494.1([M+H]⁺)。

Example 243

1- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -piperidine

Preparation of

The title compound was produced by the general method of example 108c from 2, 2 ', 4, 4' -tetrafluorodiphenyldichloromethane (example 162a) and 4-fluoro-5- (piperidine-1-sulfonyl) -benzene-1, 2-diol (example 233 c). Gum arabic.

MS：m/e 512.3([M+H]⁺)。

Example 244

1- [2, 2-bis- (2-chloro-4-fluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -piperidine

Preparation of

The title compound was produced by the general method of example 108c from 2, 2 '-dichloro-4, 4' -difluorodiphenyl dichloromethane (example 194a) and 4-fluoro-5- (piperidine-1-sulfonyl) -benzene-1, 2-diol (example 233 c). A colorless gum.

MS：m/e 544.1([M+H]⁺)。

Example 245

1- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -pyrrole

Preparation of alkanes

a) Preparation of 5-bromo-2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole

The title compound was produced by the general method of example 108c from 2, 2 ', 4, 4' -tetrafluorodiphenyldichloromethane (example 207a) and 4-bromo-5-fluoro-benzene-1, 2-diol (example 108 a). A light yellow oil.

MS：m/e 444.0([M+H]⁺)。

b) Preparation of 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfinic acid

To a cooled (-78 ℃) solution of 5-bromo-2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol (7.3g, 16mmol) in diethyl ether (48mL) was added a solution of n-butyllithium in hexane (1.6M, 10.3mL, 16mmol, 1.0 eq.). After 1 hour at-78 ℃, sulfur dioxide was bubbled through the solution for 45 minutes. The reaction mixture was flushed with nitrogen and warmed to 0 ℃. The reaction was neutralized with aqueous hydrochloric acid (0.5N), diluted with dichloromethane and the organic layer washed with water, dried over sodium sulfate and the volatiles removed in vacuo. Purification by flash chromatography gave the title compound (4.2g, 60%) as a white solid.

MS：m/e＝427.0([M-H]^-)。

c) Preparation of 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl chloride

To a solution of 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfinic acid (3.2g, 7mmol) in chloroform (25mL) was added N-chlorosuccinimide (1.0g, 7mmol, 1.0eq.) at 20 ℃. After 40 minutes, the reaction mixture was filtered and the filtrate was evaporated. The residue was suspended in dichloromethane, dried over sodium sulfate and the solvent removed in vacuo to give the title product as pale yellow gum.

MS：m/e＝462.0([M+H]⁺)。

d) Preparation of 1- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -pyrrolidine

To a solution of 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl chloride (250mg, 0.54mmol) in diethyl ether (3mL) was added pyrrolidine (0.11mL, 1.35mmol, 2.5 eq.). The reaction mixture was diluted with ethyl acetate (50mL), washed with aqueous hydrochloric acid (1N), brine and water. The organic layer was dried over sodium sulfate and the volatiles were removed in vacuo. Purification by flash chromatography gave the title compound (198mg, 74%) as a white foam.

MS：m/e＝498.2([M+H]⁺)。

Example 246

1- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl ] -4-fluoro-

Preparation of piperidines

The title compound was produced by the general method of example 245d from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl chloride (example 245c) and 4-fluoropiperidine. White foam.

MS：m/e＝530.1([M+H]⁺)。

Example 247

1- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -4, 4-di

Preparation of fluoro-piperidines

The title compound was produced from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl chloride (example 245c) and 4, 4-difluoropiperidine following the general method of example 245 d. White foam.

MS：m/e＝548.1([M+H]⁺)。

Example 248

1- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -4-tris

Preparation of fluoromethyl-piperidines

The title compound was produced from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl chloride (example 245c) and 4-trifluoromethylpiperidine hydrochloride following the general method of example 245 d. White foam.

MS：m/e＝580.2([M+H]⁺)。

Example 249

4- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -thio

Preparation of morpholine

The title compound was produced by the general method of example 245d from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl chloride (example 245c) and thiomorpholine. White foam.

MS：m/e＝530.0([M+H]⁺)。

Example 250

1- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -2S-methyl

Preparation of oxymethyl-pyrrolidines

The title compound was produced from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl chloride (example 245c) and (2S) -methoxymethylpyrrolidine following the general method of example 245 d. White foam.

MS：m/e＝542.2([M+H]⁺)。

Example 251

2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonic acid (2S-methoxy-phenyl)

Preparation of methyl-pyrrolidin-1-yl) -amides

The title compound was produced according to the general method of example 245d from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl chloride (example 245c) and 1-amino- (2S) -methoxymethylpyrrolidine. Yellow viscous oil.

MS：m/e＝556.1([M-H]^-)。

Example 252

{1- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] -pyrrole

Preparation of alk-2S-yl } -methanol

The title compound was produced according to the general method of example 245d from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl chloride (example 245c) and L-prolinol. White foam.

MS：m/e＝528.2([M-H]^-)。

Example 253

Preparation of alk-3S-ols

The title compound was produced from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl chloride (example 245c) and 3S-hydroxypyrrolidine following the general method of example 245 d. White foam.

MS：m/e＝514.2([M-H^-])。

Example 254

Preparation of (E) -4-alcohols

The title compound was produced according to the general method of example 245d from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl chloride (example 245c) and 4-hydroxypiperidine. White foam.

MS：m/e＝528.2([M-H]^-)。

Example 255

1- [2, 2-bis- (2-chloro-4, 5-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl ] -substituted benzene

Preparation of piperidines

The title compound was produced by the general method of example 108c from 1, 1' - (dichloromethylene) bis [ 2-chloro-4, 5-difluorobenzene and 4-fluoro-5- (piperidine-1-sulfonyl) -benzene-1, 2-diol (example 233 c). A yellow-white foam.

MS：m/e＝580.1([M+H]⁺)。

Example 256

4- [ { 6-fluoro-10 ', 11 ' -dihydro-spiro [1, 3-benzodioxole-2, 5 ' - [5H ] dibenzo [ a, d ] ring

Preparation of heptene } -5-yl) -carbonyl ] -morpholine

The title compound was produced according to the general method of example 233d from 2, 3, 6, 7-dibenzocycloheptane-1-thione and (2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 99 b). Light brown solid.

MS：m/e＝432.3([M+H]⁺)。

Example 257

Process for preparing (6-fluoro-2, 2-di-p-tolyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone

Preparation of

The title compound was produced according to the general method of example 233d from bis (4-methylphenyl) -thione and (2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanone (example 99 b). Light brown gum.

MS：m/e＝434.3([M+H]⁺)。

Example 258

Preparation of 1- (6-fluoro-2, 2-di-p-tolyl-benzo [1, 3] dioxol-5-sulfonyl) -piperidine

The title compound was produced according to the general method of example 233d from bis (4-methylphenyl) -thione and 4-fluoro-5- (piperidine-1-sulfonyl) -benzene-1, 2-diol (example 233 c). Gum arabic.

MS：m/e＝470.2([M+H]⁺)。

Example 259

Process for preparing [ 6-fluoro-2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] piperidin-1-yl-methanones

Preparation of

a) Preparation of 5-bromo-6-fluoro-2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxole

The title compound was produced by the general method of example 108c from 4-bromo-5-fluoro-benzene-1, 2-diol (example 108a) and bis- (2-fluoro-phenyl) methanone (example 173 a). A colorless solid.

MS：m/e＝407.9([M]⁺)。

b) Preparation of 6-fluoro-2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid

The title compound was produced from 5-bromo-6-fluoro-2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxole and carbon dioxide according to the general method for example 108 d. Light brown solid.

MS：m/e＝371.2([M-H]⁺)。

c) Preparation of [ 6-fluoro-2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone

The title compound was produced according to the general procedure for example 108e from 6-fluoro-2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid and piperidine with (benzotriazol-1-yl-oxy-tris-dimethylamino) -phosphonium hexafluorophosphate (BOP) as coupling reagent (instead of carbonyldiimidazole) in acetonitrile as solvent at room temperature (reaction time 20 h). A yellow-white solid.

MS：m/e＝440.3([M+H]⁺)。

Example 260

[ 6-fluoro-2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (4-hydroxy-piperidin-1-

Preparation of phenyl-methanones

The title compound was produced according to the general procedure for example 108e from 6-fluoro-2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid and 4-hydroxy-piperidine with (benzotriazol-1-yl-oxy-tris-dimethylamino) -phosphonium hexafluorophosphate (BOP) as coupling reagent (instead of carbonyldiimidazole) in acetonitrile as solvent at room temperature (reaction time 20 h). A yellow-white solid.

MS：m/e＝456.2([M+H]⁺)。

Example 261

4-fluoro-1- [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -piperidine

Preparation of

a) Preparation of 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfinic acid

The title compound was produced by the general method of example 245b from 5-bromo-6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol (example 164 a). A yellow-white foam.

MS：m/e＝391.1([M-H]^-)。

b) Preparation of 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl chloride

The title compound was produced from 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-sulfinic acid (example 261a) following the general method of example 245 c. A yellow oil.

MS：m/e＝426.0([M+H]⁺)。

c) Preparation of 4-fluoro-1- [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -piperidine

The title compound was produced according to the general method of example 245d from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl chloride (example 261b) and 4-fluoropiperidine. White foam.

MS：m/e＝494.4([M+H]⁺)。

Example 262

4, 4-difluoro-1- [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-sulfonyl ] -

Preparation of piperidines

The title compound was produced from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl chloride (example 261b) and 4, 4-difluoropiperidine following the general method of example 245 d. White foam.

MS：m/e＝512.4([M+H]⁺)。

Example 263

1- [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-sulfonyl ] -4-trifluoromethyl

Preparation of a phenyl-piperidine

The title compound was produced from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl chloride (example 261b) and 4- (trifluoromethyl) -piperidine hydrochloride following the general method of example 245 d. White foam.

MS：m/e＝544.4([M+H]⁺)。

Example 264

1- [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -2S-methoxy

Preparation of methyl-pyrrolidine

The title compound was produced from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl chloride (example 261b) and 2S-methoxymethylpyrrolidine following the general method of example 245 d. White foam.

MS：m/e＝506.3([M+H]⁺)。

Example 265

1- [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -pyrrolidine

Preparation of (E) -3S-alcohols

The title compound was produced according to the general method of example 245d from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl chloride (example 261b) and 3S-hydroxypyrrolidine. White foam.

MS：m/e＝478.2([M+H]⁺)。

Example 266

1- [ 6-fluoro-2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -piperidin-4-ol

Preparation of

The title compound was produced according to the general method of example 245d from 2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxole-5-sulfonyl chloride (example 261b) and 4-hydroxypyrrolidine. A white solid.

MS：m/e＝491.1([M+H]⁺)。

Example 267

Preparation of [2, 2-bis- (3-chloro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone

Prepare for

a) Preparation of bis- (3-chloro-phenyl) -methanol

This compound was prepared from 3-chloro-iodobenzene as in example 269 a; light yellow oil, MS: 252([ M ]) M/e]⁺)。

b) Preparation of bis- (3-chloro-phenyl) -methanones

This compound was prepared from bis- (3-chloro-phenyl) -methanol as in example 269 b; white solid

MS：m/e＝250([M]⁺)。

c) Preparation of bis- (3-chloro-phenyl) -dichloromethane

Preparation of bis- (3-chloro-phenyl) -methanone and PCl according to example 269c₅Preparing the compound; white solid MS: 306([ M ]) M/e]⁺)。

d) Preparation of ethyl 2, 2-bis- (3-chloro-phenyl) -benzo [1, 3] dioxole-5-carboxylate

This compound was prepared from bis- (3-chloro-phenyl) -dichloromethane and ethyl 3, 4-dihydroxybenzoate according to example 269 d; yellow viscous oil, MS: 415([ M + H) }/e]⁺)。

e) Preparation of 2, 2-bis- (3-chloro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid

Preparation of 2, 2-bis- (3-chloro-phenyl) -benzo [1, 3] carbonyl [ sic ] amide according to example 269e]Dioxole-5-carboxylic acid ethyl ester to prepare the compound; white solid, m.p.: 166 ℃, MS: 386([ M-H) ]^-)。

f) Preparation of [2, 2-bis- (3-chloro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone

From 2, 2-bis- (3-chloro-phenyl) -benzo [1, 3] e according to example 269f]Dioxole-5-carboxylic acid and piperidine to prepare the compound; light yellow solid, m.p.: 54 ℃, MS: m/e is 454([ M + H)]⁺)。

Example 268

[2, 2-bis- (4-cyano-2-fluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholine-4-

Preparation of a base-methanone

A mixture of [2, 2-bis- (4-bromo-2-fluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone (0.3g, 0.5mmol), copper (I) cyanide (0.81g), tris (dibenzylideneacetone) dipalladium (O) chloroform complex (78mg), tetraethylammonium cyanide (226mg), and 1, 1' -bis- (diphenylphosphino) -ferrocene (165mg) was boiled in dioxane (8mL) for 3 days. To the cooled mixture were added ethyl acetate (60mL) and sodium bicarbonate (60mL), the phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phase was collected, washed with brine and dried over sodium sulfate. The volatiles were removed and the residue was purified by silica gel chromatography (ethyl acetate/heptane) to give the title product as a light yellow foam (0.17 g; 71%).

MS：m/e＝491.1([M]⁺)。

Example 269

[2, 2-bis- (3, 5-difluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone

Preparation of

a) Preparation of bis- (3, 5-difluoro-phenyl) -methanol

A mixture of 486mg magnesium, 8mL dry ether, a small amount of 3, 5-difluoro-bromobenzene and an amount of iodine was warmed to initiate the Grignard reaction. 2.38mL of 3, 5-difluoro-bromobenzene in 40mL of dry ether was added dropwise and the mixture refluxed for 1 hour. 0.81mL of ethyl formate was added and the mixture was stirred at room temperature for 21 hours. The reaction was quenched with 7mL of 1N hydrochloric acid, diluted with ethyl acetate and washed with water and brine. The solvent was evaporated and the residue was chromatographed to give 1.56g of a pale yellow solid,

m.p.：62℃；MS：315([M+AcO]^-)。

b) preparation of bis- (3, 5-difluoro-phenyl) -methanones

1.56g of bis- (3, 5-difluoro-phenyl) -methanol, 1.06g of MnO₂And 36mL of 1, 2-dichloroethane were refluxed for 4 hours. The mixture was cooled, filtered and evaporated. The residue was chromatographed to give 1.47g of a white solid, m.p.: 79 ℃; MS: 254([ M ]⁺]。

c) Preparation of bis- (3, 5-difluoro-phenyl) -dichloromethane

508mg of bis- (3, 5-difluoro-phenyl) -methanone and 833mg of PCl₅Placed in a sealed glass tube and heated to 170 ℃ for 7 hours. The reaction mixture was diluted with dichloromethane and washed twice with water and ice. Evaporation of the solvent gave 333mg of a pale yellow oil without further purification.

d) Preparation of ethyl 2, 2-bis- (3, 5-difluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylate

239mg of dichloro-bis (3, 5-difluorophenyl) methane and 141mg of ethyl 3, 4-dihydroxybenzoate were heated to 180 ℃ for 2 hours and 15 minutes. The brown mixture was diluted with dichloromethane and saturated NaHCO₃The solution and water were washed. The dried solution was evaporated and the residue was purified on silica gel to give 284mg of resin oil, MS: 419([ M + H)]⁺)。

e) Preparation of 2, 2-bis- (3, 5-difluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid

267mg of 2, 2-bis- (3, 5-difluoro-phenyl) -benzo [1, 3]]Dioxole-5-carboxylic acid ethyl ester, 3.8mL of ethanol, and 0.96mL of 1N NaOH were stirred at room temperature for 6 hours. The solvent was evaporated and the residue was treated with ethyl acetate, diluted with brine and water. Purification on silica gel gave 204mg of white crystals, m.p.: at 96 ℃; MS: 389([ M-H)]^-)。

f) Preparation of [2, 2-bis- (3, 5-difluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone

96mg of 2, 2-bis- (3, 5-difluoro-phenyl) -benzo [1, 3]]Dioxole-5-carboxylic acid, 93mg HBTU, 1mL DMF and 50mg N-methylmorpholine were stirred at room temperature. After 5 minutes, 21mg of piperidine were added and the mixture was stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate and washed twice with water. Evaporation of the solvent and purification on silica gel gave 111mg of white foam, MS: 457([ M ] ]⁺)。

Example 270

[2, 2-bis- (3, 5-difluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

Preparation of

Prepared according to example 269f from 2, 2-bis- (3, 5-difluoro-phenyl) -benzo [1, 3-]Dioxole-5-carboxylic acid and morpholine; white foam, MS 459([ M)]⁺)。

Example 271

6-fluoro- [2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - [ (S) -3-hydroxy-pyrrole

Preparation of alk-1-yl ] -methanones

The title compound was produced according to the general method of example 108e from 6-fluoro-2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid and (S) -3-hydroxy-pyrrolidine with (benzotriazol-1-yl-oxy-tris-dimethylamino) -phosphonium hexafluorophosphate (BOP) as coupling reagent (instead of carbonyldiimidazole) in acetonitrile as solvent at room temperature. A yellow-white solid.

MS：m/e＝442.3([M+H]⁺)。

Example 272

6-fluoro-2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid ethyl-methyl-amide

Preparation of

The title compound was produced according to the general method of example 108e from 6-fluoro-2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid and ethyl-methyl-amine with (benzotriazol-1-yl-oxy-tris-dimethylamino) -phosphonium hexafluorophosphate (BOP) as coupling reagent (instead of carbonyldiimidazole) in acetonitrile as solvent at room temperature. A yellow-white solid.

MS：m/e＝414.3([M+H]⁺)。

Example 273

6-fluoro-2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid (2-methoxy-ethyl) -

Preparation of methyl-amides

The title compound was produced according to the general method of example 108e from 6-fluoro-2, 2-bis- (2-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid and (2-methoxy-ethyl) -methyl-amine with (benzotriazol-1-yl-oxy-tri-dimethylamino) -phosphonium hexafluorophosphate (BOP) as coupling reagent (instead of carbonyldiimidazole) in acetonitrile as solvent at room temperature. A yellow-white solid.

MS：m/e＝444.3([M+H]⁺)。

Example 274

[2, 2-bis- (3, 5-dichloro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone

Preparation of

a) Preparation of bis- (3, 5-dichloro-phenyl) -methanol

This compound was prepared from 3, 5-dichloro-iodobenzene as in example 269 a; yellow-white solid, m.p.: 126 ℃; MS: m/e is 322([ M ]]⁺)。

b) Preparation of bis- (3, 5-dichloro-phenyl) -methanone

This compound was prepared from bis- (3, 5-dichloro-phenyl) -methanol as in example 269 b; yellow-white solid, m.p.: 157 ℃; MS: 320([ M ]) M/e ]⁺)。

c) Preparation of bis- (3, 5-dichlorophenyl) dichloromethane

Bis- (3, 5-dichloro-phenyl) -methanone and PCl according to example 269c₅Preparing the compound; a pale red solid.

d) Preparation of ethyl 2, 2-bis- (3, 5-dichloro-phenyl) -benzo [1, 3] dioxole-5-carboxylate

This compound is prepared from bis- (3, 5-dichlorophenyl) dichloromethane and ethyl 3, 4-dihydroxybenzoate according to example 269 d; light red solid, m.p.: 89 ℃; MS: m/e is 484([ M ]]⁺)。

e) Preparation of 2, 2-bis- (3, 5-dichloro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid

Preparation of 2, 2-bis- (3, 5-dichloro-phenyl) -benzo [1, 3] carbonyl [ phenyl ] amide from (meth) acrylic acid according to example 269e]Dioxole-5-carboxylic acid ethyl ester to prepare the compound; white foam, MS: 455([ M-H ]) in M/e]^-)。

f) Preparation of [2, 2-bis- (3, 5-dichloro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone

Prepared according to example 269f from 2, 2-bis- (3, 5-dichloro-phenyl) -benzo [1, 3-]Dioxole-5-carboxylic acid and piperidine to prepare the compound; waxy solid, MS: 455([ M + H) } M/e]⁺)。

Example 275

[2, 2-bis- (3, 5-dichloro-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

Preparation of

Prepared according to example 269f from 2, 2-bis- (3, 5-dichloro-phenyl) -benzo [1, 3-]Dioxole-5-carboxylic acid and morpholine; waxy solid, MS: 526 parts of M/e ([ M + H ]]⁺)。

Example 276

[2, 2-bis- (3-bromo-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

Preparation of

a) Preparation of bis- (3-bromophenyl) -dichloromethane

340mg of bis- (3-bromo-phenyl) -methanone, 0.08mL of DMF and 5mL of thionyl chloride are refluxed for 24 hours. The solvent was evaporated in vacuo to give a yellow-white waxy solid, MS: 394([ M ]) of M/e]⁺)。

b) Preparation of [2, 2-bis- (3-bromo-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

79mg of bis- (3-bromophenyl) -dichloromethane and 48mg of (2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanone are heated to 180 ℃ for 1 hour. Chromatography of the dark residue gave a yellow-white waxy solid, MS: 564([ M + H) for M/e])⁺。

Example 277

[ 6-fluoro-2, 2-bis- (3-methoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-

Preparation of ketones

a) Preparation of dichloro-bis- (3-methoxyphenyl) -dichloromethane

The compound was prepared according to example 276 a; a brown liquid.

b) Preparation of [ 6-fluoro-2, 2-bis- (3-methoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

The compound was prepared according to example 276 b; pale brown waxy solid, MS: 466([ M + H)]⁺)。

Example 278

[2, 2-bis- (3-methoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone

Preparation of

a) Preparation of ethyl 2, 2-bis- (3-methoxy-phenyl) -benzo [1, 3] dioxole-5-carboxylate

This compound was prepared from dichloro-bis- (3-methoxyphenyl) -methane and ethyl 3, 4-dihydroxybenzoate according to example 269 d; the crude product was used in the next step.

b) Preparation of 2, 2-bis- (3-methoxy-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid

Preparation of 2, 2-bis- (3-methoxy-phenyl) -benzo [1, 3] carbonyl]Dioxole-5-carboxylic acid ethyl ester to prepare the compound; waxy solid, MS: m/e 377([ M-H)]^-)。

c) Preparation of [2, 2-bis- (3-methoxy-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone

Preparation of 2, 2-bis- (3-methoxy-phenyl) -benzo [1, 3] carbonyl compound according to example 269f]Dioxole-5-carboxylic acid and piperidine to prepare the compound; waxy solid, MS: 446([ M + H) }/e]⁺)。

Example 279

[2, 2-bis- (3-chloro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-yl ] -morpholin-4-yl-methanone

Preparation of

This compound was prepared from bis- (3-chloro-phenyl) -dichloromethane and (2-fluoro-4, 5-dihydroxy-phenyl) -morpholin-4-yl-methanone as in example 276 b; viscous brown oil, MS: 474([ M + H) }/e]⁺)。

Galenic preparation examples

Example A

Film-coated tablets containing the following components may be prepared in a conventional manner:

components Each sheet is

Tablet core:

10.0mg 200.0mg of a compound of formula (I)

Microcrystalline cellulose 23.5mg 43.5mg

60.0mg 70.0mg of hydrous lactose

Povidone K3012.5mg 15.0mg

Sodium starch glycolate 12.5mg 17.0mg

Magnesium stearate 1.5mg 4.5mg

(tablet core weight) 120.0mg 350.0mg

Film coating:

hydroxypropyl methylcellulose 3.5mg 7.0mg

Polyethylene glycol 60000.8 mg 1.6mg

Talc 1.3mg 2.6mg

0.8mg of iron (yellow) oxide 1.6mg

Titanium dioxide 0.8mg 1.6mg

The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granules were mixed with sodium starch glycolate and magnesium stearate and compressed into tablet cores of 120 or 350mg, respectively. The cores are coated with the above film-coated aqueous solution/suspension.

Example B

Capsules containing the following components may be prepared in a conventional manner:

components Each granule

25.0mg of a compound of formula (I)

Lactose 150.0mg

Corn starch 20.0mg

Talc 5.0mg

The ingredients were sieved and mixed and filled into size 2 capsules.

Example C

The injection solution may contain the following composition:

3.0mg of a Compound of formula (I)

Polyethylene glycol 400150.0 mg

Sufficient acetic acid to pH5.0

Water for injection solution is added to 1.0ml

The active ingredient is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH was adjusted to 5.0 with acetic acid. The volume was adjusted to 1.0ml by adding the balance water. The solution was filtered, filled into vials with the appropriate excess and sterilized.

Claims

1. A compound of the general formula (I):

wherein:

R¹and R²Independently unsubstituted phenyl, or phenyl which is independently mono-, di-or trisubstituted with hydroxy, lower alkyl, lower alkoxy, perfluoro-lower alkyl, perfluoro-lower alkoxy, alkanoyl, cyano, nitro or halogen; orR¹And R²Together with the carbon atom to which they are attached form 10 ', 11 ' -dihydro-2, 5 ' - [5H ]]Dibenzo- [ a, d]A cycloheptene residue;

When X is-C (O) -or-SO₂When is, R⁶Is hydrogen; or

R⁵And R⁶Together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered monocyclic or 8-, 9-, 10-or 12-membered bicyclic saturated or unsaturated heterocyclic ring which may optionally contain one or two further heteroatoms independently selected from O, N and S, said heterocyclic ring being optionally mono-, di-or tri-substituted independently by lower alkyl, lower alkoxycarbonyl, hydroxy lower alkyl, lower alkoxy-lower alkyl, di-lower alkylcarbamoyl, carbamoyl, lower alkylcarbonylamino, oxo, dioxo, alkanoyl, amino lower alkyl, hydroxy, lower alkoxy, halogen, perfluoro-lower alkyl, cyano, heteroaryl or by phenyl or phenyl lower alkyl, wherein said phenyl moiety may optionally be mono-, di-or tri-substituted independently by lower alkyl, lower alkoxy, lower alkylcarbonylamino, oxo, dioxo, alkanoyl, amino lower alkyl, hydroxy, lower alkoxy, halogen, perfluoro-lower alkyl, cyano, heteroaryl or by phenyl or phenyl lower alkyl, Lower alkoxy, halogen, perfluoro-lower alkyl, hydroxy, alkanoyl or cyano mono-, di-or tri-substituted;

R⁷is hydrogen, halogen, lower alkyl or cyano;

R⁸is phenyl, cycloalkyl, heterocyclyl or heteroaryl;

x is a single bond, -CH₂-、-C(O)-、-SO₂-or-SO₂NH-；

Y is-CH₂-, -C (O) -, -NH-or-SO₂-。

2. The compound of claim 1 wherein R is¹And R²Independently is phenyl, which is optionally mono-, di-or tri-substituted independently by hydroxy, lower alkyl, lower alkoxy, perfluoro-lower alkyl, alkanoyl, cyano or halogen; r ³And R⁴Independently hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, perfluoro-lower alkyl, alkanoyl or cyano; r⁵Is hydrogen or lower alkyl; r⁶Is phenyl or phenyl lower alkyl, wherein the phenyl moiety may be optionally mono-, di-or tri-substituted independently by lower alkyl, lower alkoxy, halogen, perfluoro-lower alkyl, hydroxy, alkanoyl or cyano; r⁵And R⁶Together with the nitrogen atom to which they are attached form a 5-, 6-or 7-membered monocyclic or 9-or 10-membered bicyclic saturated or unsaturated heterocyclic ring which may optionally contain one or two other heteroatoms independently selected from O, N and S, said heterocyclic ring being optionally mono-, di-or tri-substituted independently by lower alkyl, lower alkoxycarbonyl, hydroxy lower alkyl, alkanoyl, amino lower alkyl, hydroxy, lower alkoxy, halogen, perfluoro-lower alkyl, cyano, heteroaryl or by phenyl or phenyl lower alkyl, wherein said phenyl moiety may be optionally mono-, di-or tri-substituted by lower alkyl, lower alkoxy, halogen, perfluoro-lower alkyl, hydroxy, alkanoyl or cyano; r⁷Is hydrogen; x is-CH₂-, -C (O) -or-SO₂-。

3. The compound of any one of claims 1 or 2, wherein R ¹And R²Independently unsubstituted phenyl or phenyl which is mono-, di-or trisubstituted independently by lower alkyl, lower alkoxy, perfluoro-lower alkyl, perfluoro-lower alkoxy, cyano, nitro or halogen.

4. A compound according to any one of claims 1 to 3, wherein R is¹And R²Independently phenyl, which is independently mono-or di-substituted by halogen or by lower alkoxy.

5. The compound of any one of claims 1-4, wherein R¹And R²Together with the carbon atom to which they are attached form 10 ', 11 ' -dihydro-2, 5 ' - [5H ]]Dibenzo- [ a, d]A cycloheptene residue.

6. The compound of any one of claims 1-5, wherein R³And R⁴Independently hydrogen, hydroxy or halogen.

7. The compound of any one of claims 1-6, wherein R³And R⁴Is hydrogen.

8. The compound of any one of claims 1-7, wherein R⁵And R⁶Together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered monocyclic or 8-, 9-, 10-or 12-membered bicyclic saturated or unsaturated heterocyclic ring which may optionally contain one or two additional heteroatoms independently selected from O, N and S, said heterocyclic ring being optionally mono-, di-or tri-substituted independently by lower alkyl, lower alkoxycarbonyl, hydroxy lower alkyl, lower alkoxy-lower alkyl, di-lower alkylcarbamoyl, carbamoyl, lower alkylcarbonylamino, oxo, alkanoyl, amino lower alkyl, hydroxy, lower alkoxy, halogen, perfluoro-lower alkyl, cyano, heteroaryl, or by phenyl or phenyl lower alkyl, wherein said phenyl moiety may optionally be mono-, di-or tri-substituted independently by lower alkyl, lower alkoxy, lower alkylcarbonylamino, oxo, alkanoyl, amino lower alkyl, hydroxy, lower alkoxy, halo, Lower alkoxy, halogen, perfluoro-lower alkyl, hydroxy, alkanoyl or cyano is mono-, di-or tri-substituted.

9. The compound of any one of claims 1-8, wherein R⁵And R⁶Together with the nitrogen atom to which they are attached form piperazinyl, morpholino, piperidinyl, piperidin-4-one, pyrrolidinyl, thiomorpholino, azepanyl, 1, 2, 3, 4-tetrahydro-isoquinolinyl, 1, 2, 3, 6-tetrahydro-pyridinyl, [1, 4 ] y]-diazepanyl, 1, 4-dioxa-8-aza-spiro [4.5 ]]Dec-8-yl, 2, 3, 5, 6-tetrahydro- [1, 2']Bipyrazinyl-4-yl and 3-hydroxy-8-aza-bicyclo [3.2.1 ].]Oct-8-yl, which is optionally mono-, di-or tri-substituted independently by lower alkyl, lower alkoxycarbonyl, hydroxy lower alkyl, lower alkoxy-lower alkyl, di-lower alkylcarbamoyl, carbamoyl, lower alkylcarbonylamino, oxo, dioxo, alkanoyl, hydroxy, lower alkoxy, halogen, perfluoro-lower alkyl, heteroaryl, or by phenyl or phenyl lower alkyl, wherein said phenyl moiety may be optionally mono-, di-or tri-substituted by lower alkyl, lower alkoxy, halogen or perfluoro-lower alkyl.

10. The compound of any one of claims 1-9, wherein R⁵And R⁶Together with the nitrogen atom to which they are attached form piperidinyl, morpholino, thiomorpholino or pyrrolidinyl, optionally mono-or di-substituted independently by hydroxy or by halogen.

11. The compound of any one of claims 1-7, wherein R⁵Is hydrogen, lower alkyl, lower alkylsulfonyl, cycloalkyl lower alkyl or hydroxy-lower alkyl.

12. The compound of any one of claims 1-7, wherein R⁶Is Y-R⁸Lower alkyl, lower alkoxy, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkylcarbamoyl-lower alkyl, heterocyclyl, cycloalkyl, phenyl or phenyl lower alkyl, whereinThe phenyl moiety may be optionally mono-, di-or tri-substituted independently by lower alkyl, lower alkoxy, halogen, perfluoro-lower alkyl, hydroxy, alkanoyl or cyano.

13. The compound of any one of claims 1-12, wherein R⁷Is hydrogen.

14. The compound of any one of claims 1-12, wherein R⁷Is cyano, halogen or lower alkyl.

15. The compound of any one of claims 1-14, wherein R⁸Is morpholino, piperidinyl or azepanyl.

16. The compound of any one of claims 1-15, wherein X is-c (o) -or-SO₂-。

17. The compound of any one of claims 1-16, wherein Y is-CH₂-or-NH-.

18. A compound according to any one of claims 1 to 17, selected from the following compounds:

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -piperidine;

4- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -morpholine;

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4-phenyl-piperazine;

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -pyrrolidine;

2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonic acid phenethyl-amide;

4-benzyl-1- (2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonyl) -piperidine;

2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonic acid benzyl-methyl-amide;

2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonic acid benzylamide;

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4-methyl- [1, 4] diazepane;

2, 2-diphenyl-benzo [1, 3] dioxole-5-sulfonic acid phenylamide;

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-sulfonyl) -4-methyl-piperazine;

1- [2, 2-bis- (4-chloro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -piperidine;

racemic 1- [2- (4-fluoro-phenyl) -2-phenyl-benzo [1, 3] dioxol-5-sulfonyl ] piperidine;

1- [2, 2-bis- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-sulfonyl ] -piperidine;

racemic 1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (3-hydroxy-pyrrolidin-1-yl) -methanone;

4- (2, 2-diphenyl-benzo [1, 3] dioxol-5-carbonyl) -piperazine-1-carbaldehyde;

(2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone;

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-carbonyl) -piperidin-4-one;

(2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -pyrrolidin-1-yl-methanone;

(2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone;

(2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) - (2, 3, 5, 6- [1, 2' ] bipyrazinyl-4-yl) -methanone;

(4-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone;

(4-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone;

(7-hydroxy-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone;

1- (2, 2-diphenyl-benzo [1, 3] dioxol-5-ylmethyl) - (4-fluoro-phenyl) -1, 2, 3, 6-tetrahydro-pyridine.

19. A compound according to any one of claims 1 to 17, selected from the following compounds:

N- (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -benzenesulfonamide;

n, N-bis (methylsulfonyl) -2, 2-diphenyl-1, 3-benzodioxol-5-amine;

n, N-bis (butylsulfonyl) -2, 2-diphenyl-1, 3-benzodioxol-5-amine;

cyclohexanecarboxylic acid (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -amide;

butane-1-sulfonic acid (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -amide;

n- (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -butyramide;

morpholine-4-carboxylic acid (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -amide;

piperidine-1-sulfonic acid (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -amide;

piperidine-1-carboxylic acid (2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -amide;

(6-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

(6-fluoro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone;

(6-methyl-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone;

(6-bromo-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone;

[2- (2, 4-dichloro-phenyl) -2- (4-fluoro-phenyl) -benzo 1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

(6-chloro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone;

(6-chloro-2, 2-diphenyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] - (2-methyl-pyrrolidin-1-yl) -methanone;

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid azepan-1-ylamide;

[2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] morpholin-4-yl-methinone;

6- (morpholine-4-carbonyl) -2, 2-diphenyl-benzo [1, 3] dioxole-5-carbonitrile;

4- [2- (4-bromo-phenyl) -5-fluoro- (morpholine-4-carbonyl) -benzo [1, 3] dioxol-2-yl ] -benzonitrile;

[2, 2-bis- (2-chloro-4-fluoro-phenyl) -benzo [1, 3] dioxol-5-yl ] -piperidin-1-yl-methanone;

2- (2, 4-dichloro-phenyl) -6-fluoro-2- (4-fluoro-phenyl) -benzo [1, 3] dioxole-5-carboxylic acid-amide;

(6-chloro-2, 2-di-p-tolyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone;

(2, 2-di-p-tolyl-benzo [1, 3] dioxol-5-yl) -piperidin-1-yl-methanone;

(2, 2-di-p-tolyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone;

4- (6-fluoro-2, 2-di-p-tolyl-benzo [1, 3] dioxol-5-sulfonyl) -morpholine;

1- { 6-fluoro-10 ', 11 ' -dihydrospiro [1, 3-benzodioxole-2, 5 ' - [5H ] dibenzo [ a, d ] cyclohepten ] -5-yl } sulfonyl ] -piperidine;

4- { 6-fluoro-10 ', 11 ' -dihydrospiro [1, 3-benzodioxole-2, 5 ' - [5H ] dibenzo [ a, d ] cyclohepten ] -5-yl } sulfonyl ] -morpholine;

4- [ {10 ', 11 ' -dihydro-spiro [1, 3-benzodioxole-2, 5 ' - [5H ] dibenzo [ a, d ] cyclohepten ] -5-yl } carbonyl ] -morpholine;

4- [2, 2-bis- (2, 4-difluoro-phenyl) -6-fluoro-benzo [1, 3] dioxol-5-sulfonyl ] thiomorpholine;

4- [ { 6-fluoro-10 ', 11 ' -dihydro-spiro [1, 3-benzodioxole-2, 5 ' - [5H ] dibenzo [ a, d ] cycloheptene ] -5-yl } -carbonyl ] -morpholine;

(6-fluoro-2, 2-di-p-tolyl-benzo [1, 3] dioxol-5-yl) -morpholin-4-yl-methanone;

1- (6-fluoro-2, 2-di-p-tolyl-benzo [1, 3] dioxol-5-yl) -piperidine;

20. A compound according to any one of claims 1 to 18, selected from the following compounds:

21. A process for the preparation of a compound of formula (I) as claimed in any one of claims 1 to 20, which process comprises the steps of:

a) ketalizing the catechol intermediate of general formula (A) with a disubstituted dichloromethane derivative of general formula (B) under elevated temperature conditions, in an inert solvent or neat conditions, in the presence or absence of a base,

wherein the formula of the general formula (A) is as follows:

wherein R is³、R⁴、R⁵、R⁶、R⁷And X is as defined in claim 1;

wherein the structural formula of the general formula (B) is as follows:

wherein R is¹And R²As defined in claim 1;

to obtain a compound of general formula (I):

wherein R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷And X is as defined in claim 1;

b) reacting the catechol intermediate of formula (A) with a ketone of formula (C),

Wherein the formula of formula (A) is as follows:

wherein R is³、R⁴、R⁵、R⁶、R⁷And X is as defined in claim 1;

wherein the formula of formula (C) is as follows:

wherein R is¹And R²As defined in claim 1;

the reaction is carried out at elevated temperature, neat or in an inert solvent with or without removal of water by distillation, azeotropic distillation or addition of a drying agent to give the compound of formula (I):

c) reacting the catechol intermediate of formula (A) with a thioketone of formula (C'),

wherein the formula of formula (A) is as follows:

wherein R is³、R⁴、R⁵、R⁶、R⁷And X is as defined in claim 1;

wherein the formula of formula (C') is as follows:

wherein R is¹And R²As defined in claim 1;

the reaction is carried out in pure or inert solvent, in the presence or absence of a base and a metal salt, to give a compound of the general formula (I):

d) coupling a compound of formula (G) with a suitable amine of formula (H),

wherein the formula of formula (G) is as follows:

wherein R is¹、R²、R³、R⁴And R⁷As defined in claim 1, and when X is CO, Z is Cl or OH or when X is SO₂When Z is Cl;

wherein the formula of formula (H) is as follows:

Wherein R is⁵And R⁶As defined in claim 1;

when X is CO and Y is OH, the reaction is carried out in an inert solvent in the presence of a base and/or a coupling reagent to give a compound of general formula (I):

wherein R is¹、R²、R³、R⁴、R⁵、R⁶And R⁷As defined in claim 1 and when X is CO or SO₂。

22. A compound according to any one of claims 1 to 20, whenever prepared by a process as claimed in claim 21.

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 and a pharmaceutically acceptable carrier and/or adjuvant.

24. Compounds according to any of claims 1 to 20 for use as therapeutically active substances.

25. Compounds according to any of claims 1 to 20 for use as therapeutically active substances for the treatment and/or prevention of diseases which are associated with the modulation of the CB1 receptor.

26. A method for the treatment and/or prophylaxis of diseases which are associated with the modulation of the CB1 receptor, which method comprises the step of administering a compound according to any of claims 1 to 20 to a human being or animal.

27. The use of compounds according to any of claims 1 to 20 for the treatment and/or prevention of diseases which are associated with the modulation of the CB1 receptor.

28. The use of compounds according to any of claims 1 to 20 for the preparation of medicaments for the treatment and/or prevention of diseases which are associated with the modulation of the CB1 receptor.

29. The novel compounds, processes for their preparation and methods of use as claimed and claimed substantially as hereinbefore described.