| Title of Invention | HETEROCYCLIC SUBSTITUTED PHENYL METHANONES AS INHIBITORS OF THE GLYCINE TRANSPORTER 1 |
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| Abstract | The present invention relates to compounds of general formula I wherein R is halogen. -OR , -SR , cycloalkyl, cyclic amide, heterocycloalkyl, aryl or 5-or 6-membered heteroaiyL, containing one, two or three heteroatoms, selected from the 4 group consisting of oxygen, sulphur or nitrogen; Rr/Rr are hydrogen, lower alkyl, lower alkyl substituted by halogen, -(CH2)x-cycloalkyl or -CCH2)x-aryl; R2 is -S(0)2-lower alkyl, -S(0)2NH-lower alkyl, N02 or CN; 4 k. x— is an aromatic or partially aromatic bicyclic amine, which may contain one or two additional N-atoms, selected from the group consisting of and wherein one of the additional N-ring atom may be available in form of its oxide |
| Full Text | The present invention relates to compounds of general formula I wherein R1 is halogen. -OR1 , -SR1 , cycloalkyl, cyclic amide, heterocycloalkyl. aryl or 5-or 6- membered heteroaryl, containing one, two or three heteroatoms. selected from the group consisting of oxygen, sulphur or nitrogen: are hydrogen, lower alkyl. lower alkyl substituted by halogen, —(CH2)x-cycIoalkyl or-(CH2)x-aryl; R2 is-S(0)2-lower alkyl,-S(0)2NH-lower alkyl, N02orCN; ^-^ is an aromatic or partially aromatic bicyclic amine, which may contain one or two additional N-atoms, selected from the group consisting of heterocycloalkyl lower alkoxy. CN. NCX NH2. aryl, 5-or 6-rnembered heteroaryi containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen. -NH-lower alky]. -N(lower alkyl)2- cyclic amide. -C(0)*cyclic amide, S-lower alkyl. -S(0)2-Iower alkyl, lower alky] substituted by halogen, lower alkoxy substituted by halogen. lower alkyl substituted by hydroxy, -CHCH2)y-Iower alkoxy, -0(CH2)yC(0)N(lower alkyl)2, -C(0)-lower alkyl, -0~iCU2)x-aryl -0-(CH2)x-cycloalkyL ^-(CH2)x-heterocycIoalkyL -C(0)01ower alkyl, ~C(0)-NH-lower alkyl, -C(0)-N(lower alkyl)2, 2-oxy-5-aza-bicyclo[2.2.1 ]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1 ]oct-8-yl; R and R in group e) may form together with ~{CH2)4- a six membered ring; or R, R\ R:? and R?" are independently from each other hydrogen or lower alkyl; and wherein all aryl-, cycloalkyK cyclic amide, heterocycloalkyl- or 5 or 6 membered heteroaryl groups as defined for R1, R , R1 and R to R1 may be unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, =0, halogen, lower alkyl, phenyl, lower alkyl substituted by halogen or lower alkoxy; n, m, 0, p, q, r, s and t are 1 or 2; x is 0, 1 or 2; y is 1 or 2; and to pharmaceutically acceptable acid addition salts thereof. Compounds encompassed by the present invention are those of the following structure: wherein the definitions are described above. The present invention relates also to processes for preparation of those compounds, t, to pharmaceutical compositions containing them and to their use in the treatment of neurological and neuropsychiatric disorders. It has surprisingly been found that the compounds of general formula I are good inhibitors of the glycine transporter 1 (GlyT-1), and that they have a good selectivity to glycine transporter 2 (GlyT-2) inhibitors. Schizophrenia is a progressive and devastating neurological disease characterized by episodic positive symptoms such as delusions, hallucinations, thought disorders and psychosis and persistent negative symptoms such as flattened affect, impaired attention and social withdrawal, and cognitive impairments (Lewis DA and Lieberman J A, NeurQn, 2000, 28:325-33). For decades research has focused on the "dopaminergic hyperactivity" hypothesis which has led to therapeutic interventions involving blockade of the dopaminergic system (Vandenberg RJ and Aubrey KR.. Exp. Opin. Ther. Targets, 2001, 5(4): 507-518: Nakazato A and Okuyama S, et al., 2000, Exp. Opin. Ther. Patents, 10(1): 75-98). This pharmacological approach poorly address negative and cognitive symptoms which are the best predictors of functional outcome (Sharma T., Br J. Psychiatry, 1999, 174(suppl. 28): 44-51). Glutamate neurotransmission, in particular NMDA receptor activity, plays a critical role in synaptic plasticity, learning and memory, such as the NMDA receptors appears to serve as a graded switch for gating the threshold of synaptic plasticity and memory formation (Hebb DO, 1949, The organization of behavior, Wiley, NY; Bliss TV and Collingridge GL, 1993, Nature, 361: 31-39). Transgenic mice overexpressing the NMDA NR2B subunit exhibit enhanced synaptic plasticity and superior ability in learning and memory (Tang JP et al., 1999, Nature: 401- 63-69). Thus, if a glutamate deficit is implicated in the pathophysiology of schizophrenia, enhancing glutamate transmission, in particular via NMDA receptor activation, would be predicted to produce both anti-psychotic and cognitive enhancing effects. The amino acid glycine is known to have at least two important functions in the CNS. It acts as an inhibitory amino acid, binding to strychnine sensitive glycine receptors, and it also influences excitatory activity, acting as an essential co-agonist with glutamate for N-methyl-D-aspartate (NMDA) receptor function. While glutamate is released in an activity-dependent manner from synaptic terminals, glycine is apparently present at a more constant level and seems to modulate/control the receptor for its response to glutamate. One of the most effective ways to control synaptic concentrations of neurotransmitter is to influence their re-uptake at the synapses. Neurotransmitter transporters by removing neurotransmitters from the extracellular space, can control their extracellular lifetime and thereby modulate the magnitude of the synaptic transmission (Gainetdinov RR et al. 2002. Trends in Pharm. ScL 23(8): 367-373). Two distinct glycine transporter genes have been cloned (GlyT-1 and GlyT-2) from mammalian brain, which give rise to two transporters with -50 % amino acid sequence homology. GIyT-1 presents four isoforms arising from alternative splicing and alternative promoter usage (la, lb. lc and Id). Only two of these isoforms have been found in rodent brain (GlyT-1 a and GlyT-lb). GlyT-2 also presents some degree of heterogeneity. Two GlyT-2 isoforms (2a and 2b) have been identified in rodent brains. GlyT-1 is known to be located in CNS and in peripheral tissues, whereas GlyT-2 is specific to the CNS. GlyT-1 has a predominantly glial distribution and is found not only in areas corresponding to strychnine sensitive glycine receptors but also outside these areas, where it has been postulated to be involved in modulation of NMDA receptor function (Lopez-Corcuera B et aL, 2001. Mol. Mem. Biol., 18: 13-20). Thus, one strategy to enhance NMDA receptor activity is to elevate the glycine concentration in the local microenvironment of synaptic NMDA receptors by inhibition of GlyT-1 transporter (Bergereon R. Et al., 1998, Proc. Natl Acad. Set. USA, 95: 15730-15734; Chen L et aL, 2003, J. NeurophysioL, 89 (2): 691-703). Glycine transporter inhibitors are suitable for the treatment of neurological and neuropsychiatric disorders.The majority of diseases states implicated are psychoses, schizophrenia (Armer RE and Miller DJ, 2001, Exp. Opin. Ther. Patents, 11 (4): 563-572), psychotic mood disorders such as severe major depressive disorder, mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorders and mood disorders associated with schizophrenia, (Pralong ET et al., 2002, Prog. NeurobioL, 67: 173-202), autistic disorders (Carlsson ML, 1998, J, Neural Transm. 105: 525-535), cognitive disorders such as dementias, including age related dementia and senile dementia of the Alzheimer type, memory disorders in a mammal, including a human, attention deficit disorders and pain (Armer RE and Miller DJ, 2001. Exp. Opin. Ther, Patents, 11 (4): 563-572).Objects of the present invention are the compounds of general formula I per se. the use of compounds of formula I and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment of diseases related to activation of NMDA receptors via Glyt-1 inhibition, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula I in the control or prevention of illnesses such as psychoses, disfunction in memory and learning, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer's disease. The preferred indications using the compounds of the present invention are schizophrenia, cognitive impairment and Alzheimer's disease. As used herein, the term "heterocycloalkyl" denotes a saturated carbon ring, containing from 3 to 6 carbon atoms as defined above, and wherein at least one of the carbon atoms is replaced by a heteroatom, selected from the group consisting of "N. O or S. Examples of such groups are tetrahydropyran-2. 3 or 4-yl, tetrahydrofuran-2 or 3-yL oxetan-3-yL [1,4]dioxin-2-yl and the like. The term "alkyl, substituted by halogen" denotes for example the following groups: CF3, CHF2. CH2F. CH2CF3: CH2CHF2; CH2CH2F, CH2CH2CF3r CH2CH2CH2CF3. CH(CF3)CH2CH3- C[(CH3)2j-CF3, CH2CH2CL CH2CF2CF3. CH2CF2CHF2s CF2CHFCF3. The term "lower alkoxy" denotes a saturated straight- or branched-chain group containing from 1 to 6 caFbon atoms as described above and which groups are connected via an oxygen atom. The term "aryl" denotes a one or two membered aromatic carbon ring, for example phenyl, benzyl or naphthyl. The term "cyclic amide" denotes a heterocycloalkyl group as defined above and wherein the N-atom is linked to the aromatic or partially aromatic bicyclic group or to the phenyl ring as defined in claim 1, for example piperidine, piperazine, morpholine, thiomorpholine, di-oxo-thiomorpholine, pyrrolidine, pyrazoline, imidazolidine, azetidine. and the like. Such groups can be substituted by one or more substituents, selected from the group consisting of halogen, hydroxy, phenyl, lower alkyl. lower alkoxy or =0. The term "5 or 6-membered heteroaryl" denotes for example fiiranyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyrimidinyl or the like. The term "pharmaceutical^ acceptable acid addition salts" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like. Most preferred compounds of formula I are those of formula I A. Especially preferred compounds of formula I A are those, wherein R is OR and R is as described above. [5-chloro-6-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-l53-dihydro-isoindol-2-yl]-[5-methanesulfonyl-2-(252?35353-pentafluoro-propoxy)-phenyl]-methaiione, rac-[5-methanesulfonyl-2-(2?253,3.3-pentafluoro-propoxy)-phenyl]-[5-(tetrahydro-pyran-3-yl)-l53"dihydro-isoindol-2-y]]-methanoTie, ((lS54S)-5-ch]oro-6-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-l,3-dihydro-isoindoI-2-yl)-[5-methanesulfonyl-2-((S)-2,2.2-trifluoro-l-rnethyl-ethoxy)-phenyl]-rnethanone, [5-fluoro-6-(tetrahydro-pyran-4-y])-l?3-dihydro-isoindol-2-yI]-[5-methanesulfonyl-2-((S)-2;252-trifIuoro-l-methy]-ethoxy)-pheny]]-methanone5 [5-rnethanesulfonyl-2-((S)-2;2,2-trifluoro-l-methyl-ethoxy)-phenyl]-[5-(tetrahydro-pyran-4-yloxy)-l53-dihydro~isoindol-2-y]]-methanone, [5-(3-fluoro-oxetan-3-yl)-l53-dihydro-isoindol-2-yl]-[5-methanesuIfonyl-2-((S)-2,2.2-trifluoro-l-methyl-ethoxy)-phenyl]-methanone, [5-methanesulfony]-2-((S)-2.2s2-frifluoro propoxy)-l,3-dihydro-isoindol-2-yl]-methanone, (5-nuoro-6-morpholin^-yi-13^ihydro-isoindol-2-y])-[5-methanesulfonyI-2-((S)-2;2,2-trifluoro-l-methyl-ethoxy)-phenyl]-methanone. (5-fluoro-6-morphoIin-4-yl-13-dihydro-isoindol-2-yl)-f5-methanesuIfonyl-2-(2.2.3,3.3-pentailuoro-propoxy)-phenyl]-methanone. (2-isopropoxy-5wTiethanesulfonyl-pheny])-[5-(tetrahydro-pyran-4-yloxy)-1.3-dih ydro- A specific compound of formula I H is the following: (5,6^imethyl-benzoimidazol-l-y^ ethoxy)-phenyl]-methanone. The present compounds of formula I and their pharmaceutical^ acceptable salts can be prepared by methods known in the art, for example, by a process described below, which process consists in Compounds of formula Hid can be prepared by reacting a halogen compound of formula IX with aryltributyltin. under Stille reaction conditions in the presence of a palladium catalyst like tris(dibenzylideneacetone)dipalladium(0) . to afford intermediate compounds of formula XT followed by hydrolysis in the presence of an aqueous base such as potassium hydroxide, sodium hydroxide or lithium hydroxide (Scheme 7). The haloeen-substituted and hvdroxvl-substituted starting materials of formula VI. VII and IX (as shown in Schemes 3-7) are either commercially available, are otherwise Alternatively, compounds of formulas IV A. IV Ek IV C and IV D can be prepared by reaction of an ortho-dihydroxymethylated compound of formula XII (XII A. XII B. XII C and XII D) with a chlorinating agent such as thionylchloride (Scheme 9). The ortho-dimethylated and -dihydroxymethylaied compound of formula XI (A. Br C and D) and XII (Ar B, C and D) as shown in Schemes 8 and 9 are either commercially For example, compounds of formula V can be prepared by reaction of acid compounds of formula III with an activating agent such as oxalylchloride followed by treatment with ammonium hydroxide (Scheme 10). Scheme 11 Preparation of compounds of formula II A, II B, II C and II D for R and R' being Alternatively, compounds of formula n A. II B; II C and II D can be prepared by reaction of bis-halogenated compounds of formula IV (A, B, C and D) in the presence of triphenylmethylamine and a base such as diisopropylethylamine to afford intermediate compounds of formula XIV (A. B, C and D) followed by deprotection in the presence of an acid such as trifluoroacetic acid (Scheme 12). In the case where compounds of general formula II contain reactive functionality (e.g. halogen substituents or thioether substituents) in R . R4 or R5, further reactions may be performed on either the compounds of formula II (A, B, C, D) or the compounds of formula II in which the nitrogen atom is protected (i.e. Boc or Trityl) or the compounds of formula 1 so as to modify the substituent R°to R . Examples of such reactions include Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the preparations and examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used. Racemic mixtures of chiral compounds of formula I can be separated using chiral HPLC. The acid addition salts of the basic compounds of formula I may be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like. The compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention are good inhibitors of the glycine transporter I (GlyT-1). The compounds were investigated in accordance with the test given hereinafter; of the central nervous system, for example the treatment or prevention of schizophrenia, cognitive impairment and Alzheimer's disease. The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula 1 or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated. To 25.4 mmol 5-amino-6-chIoroisoindoline-l,3-dione (commercial, CAS: 5566-48-3) was added 127 mmol borane-THF complex and the resulting mixture was stirred at 80 C for 16 h. The reaction mixture was then cooled to room temperature and quenched by dropwise addition of 50 ml methanol. After stirring at room temperature for 30 min, 50 ml concentrated hydrochloric acid was added and the resulting mixture was stirred at 80 C for 30 min before being cooled to room temperature and concentrated in vacuo. The residue was made basic by addition of concentrated aqueous sodium hydroxide. The resulting crystals were collected by filtration, washed sequentially with water, a small amount of acetone, and a small amount of ether, and then dried in vacuo to yield the title compound as an off-white solid. MS (m/e): 171.1 ({37C1}M+H+, 40%), 169.2 ({35C1}M+H+, 100%). Example A2 3~Bromo~6,7-dihydro-5H-pyrrolo[3,4-b]pyridine a) 5-Bromo-2.3-bis-bromomethyl-pyridine hours. The mixture was then cooled 10 RT. filtered and the filtrate was concentrated in vacuo to provide the title compound as yellow oil which was used in the next reaction without further purification. b) 3-Bromo-6-trityl-6,7-dihvdro-5H-pvrrolor3.4-blpvridine A mixture of 0.87 mmol 5-Bromo-2,3-bis-bromomethyl-pyridine? 1.1 ramol tritylamine, and 2.61 mmol DIPEA in 3 ml DMF was stirred at 60°C for 2 h. The reaction mixture was evaporated in vacuo. The residue was taken in water and extracted with ethylacetate. The combined organic phases were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (Si02-heptane/dichloromethane) to yield the title compound as a light brown solid. MS (m/e): 243.4 (trityl ion, 100%) (c) 3-Bromo-6J-dihvdro-5H"pvrrolo["3,4-b]pvridine To a 0 °C solution of 0.18 mmol S-bromo^-trityl-ej-dihydro-SH-pyrrolo^^-blpyridine in 0.5 ml chloroform and 0.5 ml methanol was added dropwise 1 ml trifluoroacetic acid. After 5 minutes stirring at 0 °C and 30 minutes at RT, the reaction mixture was concentrated. The residue was taken in water/ether and 1ml IN HC1 was added. The aqueous phase was extracted with ether (2 times), then basified with 5N NaOH and extracted with dichloromethane (3 times). Combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a light yellow solid. MS (m/e): 199.0 (M*\ 100%) Lit. J. Am. Chem. Soc. 1996, 118 (30), 7215-7218. To a stirred suspension of 2.63 mmol 5-chloro-6-iodo-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester in 20 ml toluene were added 0.24 mmol 2-(dicyclohexylphosphino)biphenyl, 0.08 mmol tris(dibenzylideneacetone)dipalladium chloroform complex and 3.68 mmol sodium tert-butoxide and the mixture was stirred at 110 °C for 2 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and washed twice with brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiCb, heptane/ethyl acetate) to yield the title compound as a yellow oit. MS (m/e): 325.2 ({37C1}M+H+, 35%), 323.2 ({35C1}M+H+, 100%). (e) 5-ChlorO"6-pvTTolidin-l-vI-2.3-dilivdro-lH-'isoindole-hvdrochloride To a stirred suspension of 0,12 mmol 5-chloro-6-pyrrolidin-)-yl-1.3-dihydro-isoindole-2-carboxylic acid tert-butyl ester in 1 ml dioxane was added 1.86 mmol hydrogen chloride solution (4 M in dioxane) and the mixture was stirred at 90 °C for 2 h. The reaction mixture was then concentrated in vacuo to yield the title compound as a brown solid which was used in the next step without further purification. MS (m/e): 325.2 ({37Cl}M+H+, 35%)r 323.2 ({35C1}M+H"\ 100%). Example A4 5~ChIoro-6-methyI~23-dihydrolJH-isoindole hydrochloride Lit Org. Lett 2002, 4(20), 3517-3520. To a stirred suspension of 0.66 mmol 5-chloro-6-iodo-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) in 5 ml isopropanol were added 1.32 mmol ethylene glycol. 0.07 mmol copper(]) iodide. 1.32 mmol cesium carbonate. 0.13 mmol 1,20-phenanthroline and 3.29 mmol ethyl mercaptan and the reaction mixture was stirred at 120 °C for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography (S1O2, heptane/ethyl acetate) to yield the title compound as a white solid. MS (m/e): 260.0 ({37CI}[M-fH- Me^OCl^f, 42%), 258.1 ({35C1}[M+H-Me2OCH2]+, 100%). (b) 5-Chloro-6-ethvlsulfanYl-23-dihydro-lH-isoindole hydrochloride Prepared in analogy to Example A3 (e) from 5-Chloro-6-ethylsulfanyl-l,3~dihydro-isoindole-2-carboxylic acid tert-butyl ester and HC1. Off-white solid. MS (m/e): 216.2 ({37C1}M+H\ 42%), 214.2 ({35C1}M+H+, 100%). Example A6 5-Chloro-6-methoxy-2?3"dihydro-lH-isoindole hydrochloride (a) 5-Chloro-6-methoxv-K3-dihydro-isoindole-2-carboxylic acid tert-butyl ester acid. Light brown solid. Example A10 5-Pyrralidin-l-yl-2,3-dihydro-lH-isoindoIe (a) 5-Pvrrolidin-l-vl-L3-dihYdro-isoindole-2-carboxvlic acid tert-butyl ester To a stirred solution of 2.34 mmol l-fluoro-435-dimethyl-2-trifluoromethyl-benzene (CAS: 116850-000) in 14 ml glacial acetic acid was added dropwise 2.5 ml concentrated sulfuric acid. 16.4 mmol Chromium(VI) oxide was then added in small portions while the reaction mixture was cooled in an ice bath. The cooling bath was then removed and stirring continued at room temperature for 16 h. The reaction mixture was then poured onto water and the mixture extracted twice with tetrahydrofuran. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated in vacuo to yield the title compound as a grey solid which was used in the next step without further purification. MS (m/e): 250.9 ([M-H]\ 100%) (b) 5-Amino-6-trifluoromethyl-isoindole-l .3-dione To a room temperature suspension of 9.06 mmol 3-Trifluoromethyl-5H-furo[3?4-b]pyridin-7-onel (CAS: 765298-32-6) in 40 ml ethanol was added portionwise 19.9 mmol sodium borohydride. After 30 minutes, the reaction mixture was cooled to 0 °C5 2N HC1 was added to pHl and the solvent was removed in vacuo. The residue was taken in water, the mixture was neutralized with IN NaOH and then saturated with NaCl. The aqueous phase was extracted 6 times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a yellow oil (92% yield). MS (m/e): 230.1 (M+Na, 100%) Prepared in analogy to Example A2 (b) from 2,3-Bis-chloromethyl-5-trifluororaetiiyI-pyridine and triphenylmethylamine. White solid MS (m/e): 431.3 ([MH+5 100%)- (d) 3-Trifluorornethvl-6,7-dihvdro-5H-pvrrolo[3.4-b]pvridine Prepared in analogy to Example A2 (c) from 3-Trifluoromethyl-6-trityl-657-dihydro-5H-pyrrolo[3?4-b]pyridine and trifluoroacetic acid. Yellow oil. MS (m/e): 189.4 ([M+H+, 100%). Example A17 4-Fluoro-6-trifluoromethyl-2^3-dihydro-lH-isoindole The present invention relates to compounds of general formula I wherein R1 is halogen. -OR1 , -SR1 , cycloalkyl, cyclic amide, heterocycloalkyl. aryl or 5-or 6- membered heteroaryl, containing one, two or three heteroatoms. selected from the group consisting of oxygen, sulphur or nitrogen: are hydrogen, lower alkyl. lower alkyl substituted by halogen, —(CH2)x-cycIoalkyl or-(CH2)x-aryl; R2 is-S(0)2-lower alkyl,-S(0)2NH-lower alkyl, N02orCN; ^-^ is an aromatic or partially aromatic bicyclic amine, which may contain one or two additional N-atoms, selected from the group consisting of heterocycloalkyl lower alkoxy. CN. NCX NH2. aryl, 5-or 6-rnembered heteroaryi containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen. -NH-lower alky]. -N(lower alkyl)2- cyclic amide. -C(0)*cyclic amide, S-lower alkyl. -S(0)2-Iower alkyl, lower alky] substituted by halogen, lower alkoxy substituted by halogen. lower alkyl substituted by hydroxy, -CHCH2)y-Iower alkoxy, -0(CH2)yC(0)N(lower alkyl)2, -C(0)-lower alkyl, -0~iCU2)x-aryl -0-(CH2)x-cycloalkyL ^-(CH2)x-heterocycIoalkyL -C(0)01ower alkyl, ~C(0)-NH-lower alkyl, -C(0)-N(lower alkyl)2, 2-oxy-5-aza-bicyclo[2.2.1 ]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1 ]oct-8-yl; R and R in group e) may form together with ~{CH2)4- a six membered ring; or R, R\ R:? and R?" are independently from each other hydrogen or lower alkyl; and wherein all aryl-, cycloalkyK cyclic amide, heterocycloalkyl- or 5 or 6 membered heteroaryl groups as defined for R1, R , R1 and R to R1 may be unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, =0, halogen, lower alkyl, phenyl, lower alkyl substituted by halogen or lower alkoxy; n, m, 0, p, q, r, s and t are 1 or 2; x is 0, 1 or 2; y is 1 or 2; and to pharmaceutically acceptable acid addition salts thereof. Compounds encompassed by the present invention are those of the following structure: o enhance NMDA receptor activity is to elevate the glycine concentration in the local microenvironment of synaptic NMDA receptors by inhibition of GlyT-1 transporter (Bergereon R. Et al., 1998, Proc. Natl Acad. Set. USA, 95: 15730-15734; Chen L et aL, 2003, J. NeurophysioL, 89 (2): 691-703). Glycine transporter inhibitors are suitable for the treatment of neurological and neuropsychiatric disorders.The majority of diseases states implicated are psychoses, schizophrenia (Armer RE and Miller DJ, 2001, Exp. Opin. Ther. Patents, 11 (4): 563-572), psychotic mood disorders such as severe major depressive disorder, mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorders and mood disorders associated with schizophrenia, (Pralong ET et al., 2002, Prog. NeurobioL, 67: 173-202), autistic disorders (Carlsson ML, 1998, J, Neural Transm. 105: 525-535), cognitive disorders such as dementias, including age related dementia and senile dementia of the Alzheimer type, memory disorders in a mammal, including a human, attention deficit disorders and pain (Armer RE and Miller DJ, 2001. Exp. Opin. Ther, Patents, 11 (4): 563-572). maceutical^ acceptable acid addition salts" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like. Most preferred compounds of formula I are those of formula I A. Especially preferred compounds of [5-methanesulfonyI-2^(S)-2^?2-trifluorc>1-methyl^thoxy)-phenyl]-(2-methyl-3- trifluoromethyl-5jKiihydro-pyn'olo[3,4-b]pyridin-6-yl)-niethanone? [3^4-fluoro-phenyl)-5jKiihydr(>pyrrolo[3;4-b]pyridin^-yl]-[5-methanesulfo^ 2,2;2-trifluoro-l-methyI-ethoxy)-phenyl]-methanone, [5~methanesulfonyl-2-((S)-2,2,2-1rifluoro-l-methyl^ 5.7-dihydro-pyrrolo[3:,4-b]pyridin-6-y])-TTiethanone or [2-(4-fluoro-phenyl)-5,7^ihydro-pynx)lo[3,4^^ 2,2?2-trif]uoro-l-methyl-ethoxy)-phenyI]-methanone Preferred compounds of formula IC are the followings: (2-cyclobutylmethoxy-5-methanesulfonyl-phenyl)-(6-trifluoromethyl-l,3-dihydro-pyrrolo[3.4-c]pyridin-2-yl)-rnethanone, (4'-fluoro^-methanesulfonyI-biphenyl-2-yl)-(6-trifluoromethyl-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)-methanone? (3f,4,-difluoro-4-methanesulfonyl-biphenyl-2-yI)-(6-trifluoromethyl-133-dihydro-pyrrolo[3;4-c]pyridin-2-yl)-methanone. [5-metJianesu]fonyl-2-(2;23,3,3-pentafluoro-propoxy)-phenyl]-(6-trif!uoromethyl-1.3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)-methanone, [5-methanesu]fony]-2-(2.2334etrafluoro-propoxy)-pheny]]-(6-trifluoromethyl-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)-methanone, [6-(4-fluoro~pheny])-13-dihydro-pyrrolo[3,4-c]pyridin-2~y]]-[5-methariesulfonyl--2-((S)- Preferred compounds of formula I E are l-(4-methanesulfonyl-biphenyl-2K;arbonyl)-2r3-dihydro-lH-ijidole^H;arbonitri]e^ 1 -[5-methanesulfonyl-2-((S)-2.252-trifluoro~l -methyl-ethoxy)-benzoyl]-2,3-dihydro-l H-indole-4-carboxylic acid methyl ester, 1 -(2-isopropoxy-5-methanesulfonyl-benzoyl)-253-dihydro-lH!-indole-4-carboxylic acid methyl ester or (4-bromo-2,3-dihydro-indol-l-yl)-[5-methanesu]fonyl-2-((S)-2,2?2-trifluoro-l-methyl-ethoxy)-pheny]]-methanone. Specific compounds of formula I F are the followings: (5-bromo-indol-l-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-methanone, l-[5-methanesulfonyl-2-((S)-2?2,2-trifluoro-l-methyl-ethoxy)-benzoyl]-lH-indole-6-carbonitrile. (6-chloro-indol-l-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-methanone or (4-bromo-indol-l-yl)-[5-methanesulfonyl-2-(2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-methanone. ing agent such as oxalylchloride followed by treatment with ammonium hydroxide (Scheme 10). Scheme 11 Preparation of compounds of formula II A, II B, II C and II D for R and R' being hydrogen. Alternatively, compounds of formula n A. II B; II C and II D can be prepared by reaction of bis-halogenated compounds of formula IV (A, B, C and D) in the presence of triphenylmethylamine and a base such as diisopropylethylamine to afford intermediate compounds of formula XIV (A. B, C and D) followed by deprotection in the presence of an acid such as trifluoroacetic acid (Scheme 12). In the case where compounds of general formula II contain reactive functionality (e.g. halogen substituents or thioether substituents) in R . R4 or R5, further reactions may be performed on either the compounds of formula II (A, B, C, D) or the compounds of formula II in which the nitrogen atom is protected (i.e. Boc or Trityl) or the compounds of formula 1 so as to modify the substituent R°to R . Examples of such reactions include Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the preparations and examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used. Racemic mixtures of chiral compounds of formula I can be separated using chiral HPLC. The acid addition salts of the basic compounds of formula I may be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like. The compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention are good inhibitors of the glycine transporter I (GlyT-1). The compounds were investigated in accordance with the test given hereinafter; Solutions and materials Uptake buffer (UB): 150 mM NaCL 10 mM Hepes-Tris, pH 7.4, 1 mM CaCl2, 2.5 mM KCL 2.5 mM MgSO^ 10 mM (+) D-glucose, Flp~in™-CHO (Invitrogen Cat n° R758-07)cells stably transfected with mGlyTlb cDNA. Glycine uptake inhibition assay (mGlyT-lb) On day 1 mammalian cells, (Flp-in™-CHO), transfected with mGlyT-lb cDNA , were plated at the density of 40,000 cells/well in complete F-12 medium, without hygromycin in 96-well culture plates. On day 2, the medium was aspirated and the cells were washed twice with uptake buffer (UB). The cells were then incubated for 20 min at 22°C with either (i) no potential competitor, (ii) 10 mM non-radioactive glycine , (iii) a concentration of a potential inhibitor. A range of concentrations of the potential inhibitor was used to generate data for calculating the concentration of inhibitor resulting in 50 % of the effect (e.g. ICso, the concentration of the competitor inhibiting glycine uptake of 50 %), A solution was then immediately added containing [3H]-glycine 60 nM (11-16 Ci/mmol) and 25 [iM non-radioactive glycine. The plates were incubated with gentle shaking and the reaction was stopped by aspiration of the mixture and washing (three times) with ice-cold UB. The cells were lysed with scintillation liquid, shaken 3 hours and the radioactivity in the cells was counted using a scintillation counter. The pharmaceutical preparations can. moreover, contain preservatives, solubilizers. stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants. salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers. The most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of schizophrenia, cognitive impairment and Alzheimer's disease. The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula 1 or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated. To 25.4 mmol 5-amino-6-chIoroisoindoline-l,3-dione (commercial, CAS: 5566-48-3) was added 127 mmol borane-THF complex and the resulting mixture was stirred at 80 C for 16 h. The reaction mixture was then cooled to room temperature and quenched by dropwise addition of 50 ml methanol. After stirring at room temperature for 30 min, 50 ml concentrated hydrochloric acid was added and the resulting mixture was stirred at 80 C for 30 min before being cooled to room temperature and concentrated in vacuo. The residue was made basic by addition of concentrated aqueous sodium hydroxide. The resulting crystals were collected by filtration, washed sequentially with water, a small amount of acetone, and a small amount of ether, and then dried in vacuo to yield the title compound as an off-white solid. MS (m/e): 171.1 ({37C1}M+H+, 40%), 169.2 ({35C1}M+H+, 100%). Example A2 3~Bromo~6,7-dihydro-5H-pyrrolo[3,4-b]pyridine atography (Si02-heptane/dichloromethane) to yield the title compound as a light brown solid. MS (m/e): 243.4 (trityl ion, 100%) (c) 3-Bromo-6J-dihvdro-5H"pvrrolo["3,4-b]pvridine To a 0 °C solution of 0.18 mmol S-bromo^-trityl-ej-dihydro-SH-pyrrolo^^-blpyridine in 0.5 ml chloroform and 0.5 ml methanol was added dropwise 1 ml trifluoroacetic acid. After 5 minutes stirring at 0 °C and 30 minutes at RT, the reaction mixture was concentrated. The residue was taken in water/ether and 1ml IN HC1 was added. The aqueous phase was extracted with ether (2 times), then basified with 5N NaOH and extracted with dichloromethane (3 times). Combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a light yellow solid. MS (m/e): 199.0 (M*\ 100%) Example A3 5-ChIoro-6"pyrrolidiri-l-vl-23-dihydro-lH-isoindole-hydrochloride (d) 5^hloro^pyrrolidm-l-Yl-13-d^^ acid tert-butyl ester Lit. J. Am. Chem. Soc. 1996, 118 (30), 7215-7218. To a stirred suspension of 2.63 mmol 5-chloro-6-iodo-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester in 20 ml toluene were added 0.24 mmol 2-(dicyclohexylphosphino)biphenyl, 0.08 mmol tris(dibenzylideneacetone)dipalladium chloroform complex and 3.68 mmol sodium tert-butoxide and the mixture was stirred at 110 °C for 2 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and washed twice with brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiCb, heptane/ethyl acetate) to yield the title compound as a yellow oit. MS (m/e): 325.2 ({37C1}M+H+, 35%), 323.2 ({35C1}M+H+, 100%). (e) 5-ChlorO"6-pvTTolidin-l-vI-2.3-dilivdro-lH-'isoindole-hvdrochloride To a stirred suspension of 0,12 mmol 5-chloro-6-pyrrolidin-)-yl-1.3-dihydro-isoindole-2-carboxylic acid tert-butyl ester in 1 ml dioxane was added 1.86 mmol hydrogen chloride solution (4 M in dioxane) and the mixture was stirred at 90 °C for 2 h. The reaction mixture was then concentrated in vacuo to yield the title compound as a brown solid which was used in the next step without further purification. MS (m/e): 325.2 ({37Cl}M+H+, 35%)r 323.2 ({35C1}M+H"\ 100%). Example A4 5~ChIoro-6-methyI~23-dihydrolJH-isoindole hydrochloride (a) 5-Chloro-6-methvl-1.3-dihvdro-isoindole-2-carboxvlic acid tert-butvl ester Lit Org. Lett 2002, 4(20), 3517-3520. To a stirred suspension of 0.66 mmol 5-chloro-6-iodo-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) in 5 ml isopropanol were added 1.32 mmol ethylene glycol. 0.07 mmol copper(]) iodide. 1.32 mmol cesium carbonate. 0.13 mmol 1,20-phenanthroline and 3.29 mmol ethyl mercaptan and the reaction mixture was stirred at 120 °C for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography (S1O2, heptane/ethyl acetate) to yield the title compound as a white solid. MS (m/e): 260.0 ({37CI}[M-fH- Me^OCl^f, 42%), 258.1 ({35C1}[M+H-Me2OCH2]+, 100%). (b) 5-Chloro-6-ethvlsulfanYl-23-dihydro-lH-isoindole hydrochloride Prepared in analogy to Example A3 (e) from 5-Chloro-6-ethylsulfanyl-l,3~dihydro-isoindole-2-carboxylic acid tert-butyl ester and HC1. Off-white solid. MS (m/e): 216.2 ({37C1}M+H\ 42%), 214.2 ({35C1}M+H+, 100%). Example A6 5-Chloro-6-methoxy-2?3"dihydro-lH-isoindole hydrochloride (a) 5-Chloro-6-methoxv-K3-dihydro-isoindole-2-carboxylic acid tert-butyl ester hloro-6-ethanesulfonYl-K3-dihvdro-isoindole-2-carboxylic acid tert-butyl ester Prepared in analogy to Example A3 (e) from 5-chloro-6-ethanesulfonyl-1.3-dihydro-isoindole~2-carboxylic acid tert-butyl ester and HC1. Grey solid, MS (m/e): 248.1 ({37C1}M+H\ 30%), 246.2 ({35C1}M+H\ 100%). Example A8 2^hloro-6,7-dihydro-5H-pyrroio[3,4-b]pyridiiie (a)2^hloro^tritvl^jKiihYdro-5H-pvrrolo[3.4-b1pyridine Prepared in analogy to Example A2 (b) from 6-chloro~2?3-bis-chloromethy]-pyridine (CAS: 220001-94-5) and triphenylmethylamine. Light yellow foam. MS (m/e): 397.0 ([MH+, 100%). (b) 2-Chloro-6,7-dihvdro-5H-pVTTolor3.4-b1pvridine Prepared in analogy to Example A2 (c) from 2-chloro-6-trityl-6.7-dihydro-5H-pyrrolo[3.4-b]pyridine and trifluoroacetic acid. Light brown solid. MS (m/e): 154.9 ([M"? 100%). Example A9 2r5-Dihydro-lH-isoindoIe-4-carbonitrile (a) 2-Trityl-2.3-dihvdro-l H-isoindoie-4-carbonitrile Prepared in analogy to Example A3 (e) from 5-PyTTolidin-l-yl-1.3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and HCI. Brown oil. MS (m/e): 189.6 (M-H--T 100%). 43 Example Al 1 5-EthylsulfanyL2,3-dihvdro-lH-isoindole hydrochloride (a) 5-Ethvlsulf3Lnvl-1.3-dihydro-isoindole-2-carboxviic acid tert-butyl ester Lit. Tetrahedron 2004. 60, 7397-7403. To a stirred suspension of 1.34 mrnol 5-bromo-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (CAS: 201940-08-1) in 2 ml dioxane were added 0.03 mmol l?l'-bis(diisopropylphosphino)ferrocene, 0.03 mmol palladium acetate, 1.61 mmol sodium tert-butoxide and 2.68 mmol ethanethiol and the mixture was stirred at 100 °C for 16 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate/tetrahydrofuran and washed with brine. The organic phase was dried over sodium sulfate and concentrated in vacuo to yield the title compound as a brown oil which was used in the next step without further purification. (b) 5-Ethylsulfanvl-23-dihvdro-lH-isoindole hydrochloride oacetic acid. Light brown solid. Example A13 6-Trifluoromethyl-23-dihydro-lH-pyrroIo[3,4-c]pyridine (a) 4,5-Bis-chloromethvl-2-trif1uoromethyl-pyridine To a room temperature suspension of 2.5 mmol (5-Hydroxymethyl-2-trifluoromethyl-pyridin-4-yl)-methanol (CAS: 765298-25-7) in 3 ml dichloromethane was added dropwise 12.5 mmol thionylchloride. After 1 hour, the reaction mixture was evaporated in vacuo. The residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SiCh, heptane/ethyl acetate) to yield the title compound as a light yellow oil (66% yield). MS (m/e): 243.0 (M-H. 100%) A solution of 7 mmol (3-hydroxymethyl-6-trifluoromethyl-pyridin-2-yl)-methanol in 20 ml dichloromethane was cooled to 0° C. 0.15 mmol 4-(N.N-dimethylamino)-pyridine and 15 mmol of mesyl chloride was added, followed by careful addition of 28 mmol triethyl amine. After stirring for 1 hour at 0° C the reaction mixture was extracted with dichloromethane. dried and concentrated. The crude mesylate was dissolved in 10 ml N.N-dimethyl formamide, treated with 21 mmol DIPEA and 9 mmol triphenyl Prepared in analogy to Example A2 (c) from 3-Trifluoromethyl-6-trityl-657-dihydro-5H-pyrrolo[3?4-b]pyridine and trifluoroacetic acid. Yellow oil. MS (m/e): 189.4 ([M+H+, 100%). Example A17 4-Fluoro-6-trifluoromethyl-2^3-dihydro-lH-isoindole (a) 3-Fluoro-N,N-diisopropyl-5-trifluoromethvl-benzamide A dried 200ml round-bottomed flask containing 20 ml diethylether was cooled to ~75°C then 22.15 mmol diisopropylamine, 22.15 mmol 1.6M n-butyllithium in hexane, and a solution of 14.77 mmol 3-fluoro-N,N-diisopropyl-5-trifluoromethyl-benzamide in 20 ml diethylether were added sequentially. The mixture was stirred at -75°C for 2 hours. 2.9 ml DMF was added dropwise. After the reaction was stirred for another hour, the mixture was warmed and stirred at room temperature for 30 minutes. The mixture was quenched with 100 ml 10% citric acid and extracted 3 times with ether. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (S1O2, heptane/ethyl acetate) to yield the title compound as a light yellow solid (90% yield). MS (m/e): 320.1 (M+rf", 100%) (f) 5-Trifluoromethoxy-2.3-dihydro-l H-isoindole Prepared in analogy to Example A2(c) from 5-Trifluoromethoxy-2-trityl-2,3-dihydro-1 H-isoindole. Dark brown oil. Example A19 S-difluoromethoxy-l^-dihydro-lH-isoindoline trifluoroacetic acid (a) 5-DifluoromethoxY-K3-dihvdro-isoindole-2-carboxylic acid tert-butyl ester A mixture containing 0.68 mmol 5-Hydroxy-lT3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (CAS: 226070-47-9), 0.68 mmol potassium carbonate and 0.68 mmol ethvl chlorodifluoroacetate in 1.5 ml DMF was stirred overniaht at 65 °C. The mixture was then partitioned between ethyl acetate and water and the organic phase was then separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified Prepared in analogy to Example A17(a) from 6-Methyl-5-trifluoromethyl-pyridine-2-carboxylic acid (CAS: Prepared in analogy to Example A13(a) from (3-Hydroxymethyl-6-methyl-5-trifluoromethyl-pyridin-2-yl)-methanol. Colorless oil. MS (m/e): 257.0 ([M+H]+: 100%) Prepared in analogy to Example A 16(a) from rac-5-Methyl-3-trifluoromethyl-5H-furo[3r4~b]pyridin-7-one. Colorless oil. MS"(m/e): 222.2 ([M+Hf, 100%) (d) rac-5-Methyl-3-trifluoromethyl-6-trit\,l-6.7-dihvdro-5H-pviTolol3.4-blpvridine Prepared in analogy to Example A 14(c) from rac-l-(2-Hydroxymethyl-5-trifluoromethyl-pyridin-3-yl)-ethanol. Yellow oil. (e) rac-5-Metfayl-3-trifluorometfayl^,7^ihvdrcH5H-pvrrolor3.4-b]pvridin^ Prepared in analogy to Example A2(c) from rac-5-Methyl-3-trifluoromethyl-6-trityl-6,7-dihydro-5H-pyTTolo[354-b]pyridine. Yellow oil. MS (m/e): 203.3 ([M+H]+, 100%) Example A22 6-Chloro-2r3-dihydro-lH-pyrrolo[3,4-c]pyridine (a) 6-Chloro-N.N-diisopropvl-nicotinamide Prepared in analogy to Example A17(a) from 2-chlorpyridine-5-carboxylic acid. Yellow oil. MS (m/e): 241.3 ([M+Hf, 100%) (b) 6-Chloro-4-formyl-N,N-diisopropvl-nicotinamide Prepared in analogy to Example A 17(c) from 6-Cbloro-4-formyl-N.N-diisopropyl-nicotinamide. White solid. (d) (6^hloro^hvdroxvmetfavl-pvridin-3-yl)-metfaanol Prepared in analogy to Example A16(a) from 6-Chloro-lH-furo[3,4-c]pyridin-3-one. White solid. MS (m/e): 172.0 ([M-H], 100%) (e) 6-Chloro-2-tritvl-23-dihydro-lH-pvrrolo[3.4-c]pyridine Prepared in analogy to Example A 14(c) from (6-Chloro~4-hydroxymethyl-pyridin-3-yl)-methanol. White foam. (f) 6-Chloro-2.3-dihvdro-lH-pyrrolo[3,4-clpyridine Example A23 5-(4-Methyl-thiazoI-2-yi)-23-dihydro-lH-isoindole (a) 5-(4A5.5-Tetramethy]-["].3.2]dioxaborolan-2-vl)-1.3-dihvdro-isoindo]e-2-carboxv]ic acid tert-butyl ester A mixture containing 5.03 mmol 5-Bromo-13Kiihydro-isoindole-2-carboxylic acid tert-butyl ester (CAS: 201940-08-1), 16.6 mmol potassium carbonate. 5.5 mmol bis(pinacolato)diboron and 0.15 mmol Ll-bis(diphenylphosphino)feiTOCene dichloro palladium (II) dichloromethane adduct in 15 ml degazed DMF was stirred at 70°C for 6 hours. The solvent was removed in vacuo. The residue was stirred in 30 ml dichloromethane. The mixture was filtered and the filtrate concentrated in vacuo. The crude oil was purified on a 50 g Flashpack cartridge (Eluent: Heptane/AcOEt) to afford the title compound as a white solid (63 % yield). MS (m7e): 346.1 ([M+H]+, 100%) (b) 5-(4-Methvl-thiazol-2-yl)-L3-dihvdro-isoindole-2-carboxvlic acid tert-butyl ester A mixture containing 3.2 mmol 5-(4A555-Tetramethyl-[13,2]dioxaboroIan-2-yl)-1.3-dihydro-isoindole-2-carboxylic acid tert-butyl ester, 15.9 mmol potassium carbonate. 3.8 mmol 2-Iodo~4-methyl-thiazole (CAS: 34203-25-3) and 0.1 mmol Prepared in analogy to Example A3(e) from 5-(2-Methyl-pyridin-4-yl)-L3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and using trifluoacetic acid instead of hydrochloride acid. Brown solid. MS (m/e): 211.0 ([M+Hf, 100%) Example A25 S^S-Metbyl-thiophen-^yiyiyS-dihydro-lH-isoindole (a) 545-Methvl-thiophen-3-Yl)-13^ihvdro-isoindole-2- Prepared in analogy to Example A23(b) from 5-(4.455?5-Tetramethyl-[1 ?3,2]dioxaborolan-2-yl)-l 53-dihydro-isoindole-2-carboxylic acid tert-butyl ester and 4-bromo-2-methykhiophene (commercial). Light yellow solid. MS (m/e): 315.2 ([M]+, 100%) (b) 5-(5-Methyl-thiophen-3-vl)-2.3-dihvdro-l H-isoindole Prepared in analogy to Example A3(e) from 5-(5-Methyl-thiophen-3-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and using trifluoacetic acid instead of hydrochloride acid. Light yellow solid. MS (m/e): 216.1 ([M+H]+s 100%) Example A26 5-(5-Methy!-thiazoL2-yl)-23-dihydro-l H-isoindole 3-n-DimethYlammo-meth^Z>Ylidene]-4^ acid tert-butyl ester A solution of 13.5 mmol N-BOC-3-pyrrolidone and 13.5 mmol N,N-dimethylfonnamide-dirnethylacetal in 50 ml N,N-dimethylformamide was hold overnight at 60° C. The reaction mixture was quenched by addition of 50 ml water and extracted 3 times with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give the crude title compound as a yellowish oil. Yield = 90%. MS (m/e): 241.4 ([M+H]+, 100%). b) 2-Trifluoromethvl-5.7-dihvdro-pvrrolo[3.4-dlpyrirnidine-6-carboxvlic acid tert-butyl ester 4.4 mmol of 4-trifluoromethyl-lH-indole were dissolved in 8 ml acetic acid. 8.8 mmol of sodium cyanoborohydride were added at once and the reaction mixture stirred at room temperature for 3.5 hours. 20 ml of water were added. The reaction mixture is treated with acqueous sodium hydroxide 40% until basic. Extraction with ethyl acetate yields the crude title compound as a yellowish waxy solid. Yield = 76 %. MS (m/e): 188.4 ([M+H]+, 97 %). Example A30 2r5-Dihydro-lH-indoIe-4-carbonitrile This compound was prepared in analogy to example A29c), starting from 4-cyanoindole. Yield - 15 %. MS (m/e): 144.1 ([M]+, 53 %). Example A31 rac-5-Chloro-3-methyl-2^-dihydro-lH-indole This compound was prepared in analogy to example A29c), starting from 4-methylindole. Yield = 49 %. MS (m/e): 133.1 ([M]+, 80 %). Example A32 2-(2^5-Dihydro-lH-indol-4-yloxy)-N?N-dimethyl-acetamide 4-Iodo-5-trifluoromethyl-phthalic acid Prepared in analogy to Example A 15(b) from 4-iodo-5-trifluoromethyl-phthalic acid and urea. Brown solid. MS (m/e): 339.9 ([M-H]\ 100%) (c) 5-Iodo-6-trifluoromethvl-23-dihydro-l//-isoindole Prepared in analogy to Example Al from 5-iodo-6-trifluoromethyl-isoindole-l ,3-dione and borane tetrahydrofuran complex. Brown solid. MS (m/e): 314.0 ([M+H*5 100%). (d) 5-Iodo-6-trifluoromethvl-K3-dihvdro-isoindole-2-carboxylic acid tert-butyl ester Prepared in analogy to Example A3(c) from 5-iodo-6-trifluoromethyl-2.3-dihydro-lH-isoindole and di-tert-butyl dicarbonate. White solid. MS (m/e): 358.0 ([M+H-Me2C=CH2]+, 100%). Prepared in analogy to Example A5(a) from 5-iodo-6-lrinuoromethy]-l,3-dihvdro-isoindole-2-carboxylic acid tert-butyl ester and ethyl mercaptan. White solid. MS (m/e); 292.1 ([M+H-Me20=CH2f. 100%). Prepared in analogy to Example A3(e) from 5-ethylsulfanyl-6-trifluoromethyl-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Yellow solid. MS (m/e): 284.3 ([M+H]+, 100%). Example A36 5-Fluoro-6-trifluoromethyl-2^-dihydro-lH-isoindoIe trifluoroacetate To 7.93 mmol 4-fluoro-5-trifluoromethyl-phthalic acid (Example A15(a)) in 20 ml methanol was added 1.19 mmol cone, sulphuric acid and the mixture was heated at reflux for 2 days. The mixture was then cooled to room temperature, diluted with ethyl acetate, and washed sequentially with 0.5 M aq. sodium hydroxide solution and brine. The organic phase was then separated, dried over sodium sulfate, and concentrated in vacuo to afford the title compound as a yellow solid (54% yield). EI-MS (m/e): 280.1 (M+, 5%). 249.1 ([M-MeOf, 100%). further 15 min at 50 °C. then cooled to room temperature and acidified to pH 1 by dropwise addition of 5 M aq HC1. The mixture was then partitioned between ethyl acetate and brine and the organic phase was then separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: methanol/dichloromethane) to afford the title compound as a colourless oil (57% yield). MS (m/e): 283.1 ([M-K)Ac)]\ 100%), 223.1 ([M-H]\ 20%). (c) 5-Fluoro-6-trifluoromethvl-2-trityl-2.3-dihvdro-l H-isoindole To a mixture of 1.56 mmol (4-fluoro-2-hydroxymethyl-5-trifluoromethyl-phenyl)-methanol and 0.08 mmol DMAP in 5 ml dichloromethane at 0 °C were added dropwise 3.28 mmol methanesulfonyl chloride and 6.25 mmol triethylamtne. The mixture was stirred at 0 °C for 1 h, and then heated quenched with water. The mixture was extracted with dichloromethane and the organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in DMF and then 4.68 mmol N,N-diisopropylethylamine and 2.03 mmol triphenylrhethylamine were added sequentially. The mixture was heated at 60 °C for 1 day and then at 80 °C for a further day. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: ethyl acetate/heptane) to afford the title compound as a white amorphous solid (23% yield). El-MS (m/e): 370.1 ([M-Ph]". 100%). (d) 5-Fluoro-6-trifluoromethvl-2.3-dihydro-l H-isoindole trifluoroacetate To a mixture of 0.33 mmol 5-fluoro-6-trifluoromethyl-2-trityl-2.3-dihydro-l H-isoindole in 1.5 methanol and 1.5 ml chloroform at 0 °C was added dropwise 1.63 mmol trifluoroacetic acid and the mixture was then stirred at RT for 3 h before being concentrated in vacuo to afford the title compound as a yellow solid (100% yield). EI-MS (m/e): 206.1 ([M+H]+? 100%). Example A37 5^hloro^piperidin-l-yl-23^hydro-lH-iso«idole hydrochloride (a) 5oxvlic acid tert-butyl ester Prepared in analogy to Example A3(d) from 5~chloro-6-iodo-l-3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) and piperidine. Yellow solid. MS (m/e): 339.1 ({37C1}M+H\ 29%), 337.1 ({35C1}M+H+, 100%). (b) 5-ChlorO"6-piperidin-l-vl-2,3-dihydro-lH-isoindole hydrochloride Prepared in analogy to Example A3(e) from 5-chloro-6-piperidin-l-yl-1.3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Brown solid. MS (m/e): 239.2 ({37C1}M+H+. 35%)r 237.1 ({35C1}M+H\ 100%). Prepared in analogy to Example Al from 5-iodo-isoindole-l?3-dione (CAS: 98556-60-6) and borane tetrahydrofuran complex. Brown solid. MS (m/e): 246.1 ([M+H\ 100%). (b) 5-Iodo-13HJihvdro-isoindole-2-carboxvlic acid tert-butyl ester Prepared in analogy to Example A3(c) from 5-iodo-2,3-dihydro-lH-isoindole and di-tert-butyl dicarbonate. White solid. MS (m/e): 290.0 ([M+H-Me2C<:h2> (c) 5-(2-MethoxV"ethoxv)-L3~dihydro-isoindole-2-carboxvlic acid tert-butyl ester V Prepared in analogy to Example A6(a) from 5-iodo-1.3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and 2-methoxyethanol. White solid. MS (m/e): 237.9 ([M+H-Me2C<:h2f> (d) 5-(2-Methoxy-ethoxy)-2.3-dihydro-lH-isoindole hydrochloride Prepared in analog}' to Example A3(e) from 5-(2-methoxy-ethoxy)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. White solid. MS (m/e): ■194.3 ([M+H]+, 100%). Example A39 l-(2.3-Dihydro-lH-isoindoI-5-yl)-pyrro!idin-2-one hydrochloride Lit. J. Am. Chem. Soc. 2001. 123, 7727-7729. To a stirred suspension of 0.58 mmol 5-iodo-1.3-dihydro-isoindole-2-carboxylic acid tert-buty] ester (Example A38(b)) in 4 ml dioxane were added 0.12 mmol coppexfl) iodide. 1.74 mmol potassium carbonate. 0.17 mmol trans-L2-diaminocyclohexane and 2.90 mmol 2-pyrrolidone and the reaction mixture was stirred at 140 °C for 16 h. The mixture was then cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography (S1O2, heptane/ethyl acetate) to yield the title compound as a white solid. MS (m/e): 247.3 ([M+H-Me2C=CH2]+, 100%). (b) l-(2.3-Dihvdro-lH-isoindol-5-vl)-pvrrolidin-2-one hydrochloride Prepared in analogy to Example A3(e) from 5-(2-oxo-pyrrolidin-l-yl)-1.3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Off-white solid. MS (m/e): 203.4 ([M+H]+, 100%). Prepared in analogy to Example A3(e) from 5-isopropoxy-L3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Brown solid. MS (m/e): 178.3 ([M+H]+, 100%). Example A41 5-Ethoxy-2^-dihydro-lH-isoindoIe hydrochloride Prepared in analogy to Example A6(a) from 5-iodo~l,3-dihydro-isomdole-2-carboxylic acid tert-butyl ester (Example A38(b)) and ethanol. Light brown solid. MS (m/e): 208.1 ([M+H-Me2C=CH2]+, 100%). Prepared in analogy to Example A3(e) from 5-ethoxy-1,3-dihydro-isoindole-2-carboxylicacid tert-butyl ester and hydrochloric acid. Brown solid. MS (m/e): 164.4 ([M+H]"\ ! 00%). Prepared in analogy to Example A3(d) from 5-iodo-1.3-dihydxo-isoindole-2-carboxylic acid tert-butyl ester (Example A3 8(b)) and 4,4-difluoropiperidine hydrochloride. Yellow solid. MS (m/e): 339.1 ([M+H]+, 100%). (b) 5-(4.4-Difluoro-piperidin-l-vl)-2.3-dihvdro-lH-isoindole hydrochloride Prepared in analogy to Example A3(e) from 5-(4,4-difluoro-piperidin-l-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Light yellow solid. MS (m/e): 239.3 ([M+H}+, 100%). Example A43 5-Ethoxy-6-trifluoromethyl-2^-dihydro-lH-isoindole hydrochloride (a) 5-Ethoxv-6-trifluoromethyl-K3-dihydro-isoindole-2-carboxvlic acid tert-butyl ester Prepared in analogy to Example A3(e) from 5-ethoxy-6-trifluoromethyl-13- To a stirred solution 0.54 mmol 5-trifluoromethy]-6-vinyl-1.3-dihydro-isoindole-2-carboxylic acid tert-butyl ester in 50 ml methanol was added 50 mg 10% palladium on charcoal and the mixture was stirred under an atmosphere of hydrogen (0.6 bar positive pressure) for 72 h. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (SiC^, heptane/ethyl acetate) to yield the title compound as a white solid (20% yield). MS (m/e): 260.0 ([M+H-Me2OCH2]+, 100%). Example A46 5-Morpholin^yl-^triflnoromethyl-2^3-dihydro-lH-isoindoIe hydrochloride (b) S^TetrahydrcHpvran^vlVI3KiihvdrQ-isoindole-2H^arboxvlic acid tert-butvl Ester (a) 5-(3,6-Dihvdro-2H-pvran-4-ylV6-trifluoromethvl-l .3-dihvdroisoindole-2-carboxvlic acid tert-butyl ester Prepared in analogy to Example A49(a) from 5-iodo^trifluoromethyl-13-dihydro-isoindole-2-carboxyIic acid tert-butyl ester (Example 35(d)) and tributyl-(3?6-dihydro-2H-pyran-4-yI)-stannane. Yellow solid. MS (m/e): 314.0 ([M+H-Me2C=CH2]+; 100%). fb) 5-(Tetrahydro-pvran^1-yl)-6-trifluoromethvl-l ,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester Prepared in analogy to Example A49(b) from 5-(3,6-dihydro-2H-pyran^~yl)-6-trifluoromethyl-l?3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and ammonium formate. Off-white solid. MS (m/e): 316.1 ([M+H-Me2(>CH2f, 100%). (c) 5-(Tetrahydro-pyran-4-yn-6-trifluoromethyl-2.3-dihydro-l H-isoindole hydrochloride Prepared in analogy to Example A3(e) from 5-(4-hydroxy-4-phenyl-piperidin-l-yl)-1.3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Off-white solid. MS (m/e): 295.4 ([M+H]+. 100%). Example A54 5-Methyl-6-morpholin-4-yl-2.3-dihydro-lH-isoindole hydrochloride Prepared in analogy to Example A3(e) from 5-(2,2,2-1xifluoro-ethy])-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl Ester and hydrochloric acid. Off-white solid. MS (m/e): 202.4 ([M+Hf, 100%). Example A56 S^S-Methoxy-azetidin-l-yl^Z^-dihydro-lH-isoindoIe trifluoro-acetate (a) 5-(3-Methoxy-azetidin-l-ylV13-dihydro-isoindole-2-carboxYlic acid tert-butyl Ester Prepared in analogy to Example A3(d) from 5-iodo-13-dihydro-isoindole~2-carboxylic acid tert-butyl ester (Example A38(b)) and 3-methoxy-azetidine hydrochloride. Orange oil. MS (m/e): 305.4 ([M+Hf, 100%). (b) 5-Cvclopropvl-6-morpholin-4~vl-23-dihydro-l H-isoindole trifluoroacetate Prepared in analogy to Example A2(c) from 5-cyclopropyl-6-morpholin-4-yl-13-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Brown solid. MS (m/e): 245.4 ([M+H]+, 100%). Prepared in analogy to Example A49(a) from 5~chloro-6-iodo-13-dihydro-isoindoIe~2-carboxylic acid tert-butyl ester (Example A3(c)) and tributyl-(3,6-dibydro-2H-pyran-4-yl)-stannaiie. Yellow solid. MS (m/e): 2823 ({37Cl}[M+H-Me2C-CH2]+; 49%)? 2803 ({35Cl}[M+H-Me2C=CH2f, 100%). (b) 5-Cvclopropvl-6-(3.6-dibvdro-2H-pvran-4-vn-l3-dihvdro-isoiDdole-2-ca3i>oxvlic acid tert-butyl ester Prepared in analogy to Example A54(a) from 5-chIoro-6-(3y6-dihydro-2H-pyran-4-yl)- 1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and tributylcyclopropylstannane. Yellow oil. MS (m/e): 286.1 ([M+H-Me2C-CH2f5 100%). (c) 5-Cvclopropyl-6-(tetrahvdro-pvran-4-vl)-l3-dihydro-isoindole-2-carboxylic acid tert-butyl Ester Prepared in analogy to Example A49(b) from 5-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-\i)-13-dihydro-isoindole-2-carboxylic acid tert-butyl ester and ammonium formate. Colourless oil. MS (m/e): 288.0 ([M+H-Me2OCH2]\ 100%). (d) 5clopropyl-6~ftetxahydro~pyran^-yQ-23~dihydro-l H-isoindole trifluoro-acetate Prepared in analogy to Example A3(b) from 2-benzyl-5-bromo~isoindole-L3-dione (CAS: 82104-06-1) and borane tetrahydrofiiran complex. White solid. MS (m/e): 290.0 ({81Br}[M+H]+, 100%), 288.1 ({79Br}[M+H]\ 100%). (b) 4-(2-Benzyl-23-dihydro-l H-isouidol-5-YlVtetrahydro-pvran^l-ol To a stirred suspension of 1.54 mmol 2-ben2yl-5-bromo-2.3-dihydro-lH-isoindole in 3 ml THF at -78 °C was added dropwise 3.85 mmol butyllithium solution (1.6 M in hexane) and stirring continued at -78 °C for 1 h. To the resulting yellow solution was added dropwise a solution of 3.08 mmol tetrahydro-4H-pyran-4-one in 0.7 ml THF and the mixture was stirred at -78 °C for 30 min and then allowed to warm to room temperature. The reaction was quenched by addition of 1 M aq HCK diluted with ethyl acetate, and then made basic by addition of 2 M aq NaOH. The phases were separated and the organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO?, heptane/ethyl acetate) to yield the title compound as a yellow solid (25% yield). MS (m/e): 310.3 ([M+Hf, 100%). (c) 4-(2.3-Dihydro-lH-isoindol-5-yn-tetrahvdro-pvran-4-ol To a stirred solution 0.39 mmol 4-(2-benzyl-2,3-dihydro-lH-isoindol-5-yI)-tetrahydro-pyran-4-ol in 20 ml methanol was added 40 mg 10% palladium on charcoal and the mixture was stirred under an atmosphere of hydrogen for 3 h. The reaction mixture was then filtered and the filtrate was concentrated in vacuo to yield the title compound as a yellow solid (100% yield). MS (m/e): 220.3 ([M+H]+, 100%,). Example A63 5-Methyl-6^tetrahydro-pyran-4-yI)-2^-dihydro-lB[-isoindole triflooro-acetate Example A75 5-(Tetrahydro-pyran-2-yl)-23-dihydro-lH-isoindole (a) 2-Benzyl-5-(5,6-dihvdro^H-pvran-2-vl)-2,3-dihvdro-l H-isoindole Prepared in analogy to Example A49(a) from 2-benzyl-5-bromo-2;3-dihydro-l H-isoindole (Example A62(a)) and tributyl-(556-dihydro-4H-pyran-2-yl)-stannane. Orange oil. MS (m/e): 292.1 ([M+H]+, 100%). (b) 5-(Tetrahydro-ovran-2-vl)-2.3-dihvdro-lH-isoindole Prepared in analogy to Example A49(b) from 2-benzyl-5-(5,6-dihydro-4H-pyran-2-yl)-2,3-dihydro-lH-isoindole and ammonium formate. Light brown solid. MS (m/e): 204.4 ([M+H"]". 100%). Example A76 5-Chloro-6-(tetrahydro-furan-3~y!)-23-dihydro-lH-isoindo!e trifluoroacetatc To a stirred suspension of 50.8 mmol 2-fluoro-4,5-dimethyl-phenylamine (commercial, CAS: 117832-17-4) in 70 ml water was added dropwise at 0 °C a solution of 5 ml concentrated sulfuric acid in 15 ml water. A solution of 66.0 mmol sodium nitrite in 15 ml water was then added dropwise and stirring continued at 0 °C for 60 min. A solution of 1 73 mmol potassium iodide in 50 ml water was then added dropwise over 30 min while maintaining the reaction temperature between 0 and 5 CC. The reaction mixture was then wanned to room temperature and stirred for 3 h before being quenched with aqueous sodium thiosulphite solution and diluted with ethyl acetate. The phases were To 9.38 mmol 4-fluoro-5-iodo-phthalic acid dimethyl ester in 25 ml absolute ethanol was added 9.38 mmol calcium chloride. 18.8 mmol sodium borohydride was then added in small portions and the reaction mixture was stirred for 4 h at room temperature, then at reflux for 2 h and then at room temperature overnight The mixture was quenched by addition of 20 mil M aq. hydrochloric acid and diluted with water and ethyl acetate. The phases were separated and the organic phase was extracted four times with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a yellow oil (98% yield). MS (m/e): 283.1 ([M+ H]+, 100%). To 0.58 mmol 3-(23-dihydro-lH-isoindol-5-yl)-oxetan-3-ol in 2 ml acetonitrile and 2 ml nitromethane at -60 °C was added 1.15 mmol diethylaminosulfur trifluoride and the mixture was allowed to warm to 0 °C over 30 min. The reaction mixture was re-cooled to -60 °C and quenched by addition of 5 ml saturated aq. sodium carbonate solution. The mixture was warmed to RT and diluted with THF and ethyl acetate, then washed sequentially with water and with brine. The organic phase was separated, dried over sodium sulfate, and concentrated in vacuo to afford the title compound as a brown oil (67% yield). MS (m/e): 194.3 ([M+H]+5 100%). Example A&2 5-CycIopropyImethoxy-2^-dihydro-lH-isoindoIe trifluoroacetate (a) 5-Cvclopropylmethoxv-L3-dihvdro-isoindole-2-carboxvlic acid tert-butyl ester Prepared in analogy to Example A6(a) from 5-iodo-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and cyclopropylmethanol. Off-white solid. MS (m/e): 234.1 ([M+H-Me2C=CH2]+, 100%) (b) 5-Cyclopropylmethoxy-2.3-dihvdro-l H-isoindole trifluoroacetate Prepared in analogy to Example A2(c) from 5-cyclopropy!methoxy-1.3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. MS (m/e): 190.4 ([M+H]+. 100%). Example A83 5^3^^TriflBor€Hpropoxy)-2,3-dihydro-l H-isoindole trifluoroacetate (a) 5^333-Trifluoro-propoxvV13KiihvdTO-isoindole-2K^rboxviic acid tert-butyl ester To 753 nnnol fuming nitric acid at 0 °C was added dropwise 150 ml 20% oleum. 150.6 mmol 5-fluoro-isoindole-l ;3-dione was then added portionwise and the resulting suspension was allowed to warm to room temperature over 4 hours and then stirred for a further 16 h at room temperature and finally was heated at 50 °C for 3 h. The reaction mixture was poured onto ice and the resulting mixture was filtered and the filter cake dried in vacuo to afford the title compound as a yellow solid (68% yield). MS (m/e): 209.1 ([M-H]\ 100%). (c) 5-Amino-6-fluoro-isoindo1e-1.3-dione To a suspension of 99.9 mmol 5-fluoro-6~nitro-isoindole-L3-dione in 400 ml tr concentrated hydrochloric acid was added 350 mmol tin(II) chloride dehydrate and the resulting mixture was heated at 60 °C for 2 h. The reaction mixture was then poured onto ice-water and then 28% aq sodium hydroxide was added with stirring until a suspension was formed. The crystals were collected by filtration and dried in vacuo to afford the title compound as a yellow solid (80% yield). MS concentrated under reduced pressure. The residue was treated with water and extracted 3 times with 400 ml dichloromethane. The combined organic phases were dried over sodium sulfate. Evaporation under reduced pressure yielded the title compound as a white crystalline solid (yield 79%). MS (m/e): 217.2 (M-H+, 100%). Example B5 5-MethanesuIfonyl-2-((R)-2JZ,2-tnfluoro-l-methvI-ethoxy)-beR2oic acid fa) 5-Methanesulfonvl-2-((rR)-2.2.2-trifluoro-l-methvl-ethoxv)-ben2oic acid methyl ester The title compound was obtained by separation of rac-5-methanesulfonyl-2-(2,2,2-trifluoro-1 -methyl-ethoxy)-benzoic acid methyl ester (Example B3(a)) by chiral HPLC (Chiralcel OD, 15 % ethanol/ Heptane, flow 35 ml min1, 220 nm, retention time: 74 min.)- (b) 5-Methanesulfonyl"2-(rR)-2.2.2--trifluoro-l-methyl-ethoxv)-benzoic acid Prepared in analogy to Example B3(c) from 5-methanesulfonyl-2-((R)-2,2,2-trifluoro-l-methyl-ethoxy)-benzoic acid methyl ester. MS (m/e): 311.0 ([M-H]\ 100%) Example B6 2-EthylsiilfanyI-5-methanesulfonyI-benzoic acid To a solution of 4.58 mmol 2-fluoro-5-methanesulfonyl-benzoic acid (Example B4{b)) in 6 ml N,N-dimethylformamide were added 13.8 mol cesium carbonate and 9.16 mmol 2.2,2-trifluoro-ethanethiol and the mixture was stirred at 90 °C for 30 min. The reaction mixture was then cooled to room temperature and acidified to pHl by addition of hydrochloric acid before being extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a red-brown solid which was used in the next step without further purification (yield 99%). MS (m/e): 312.9 ([M-H]\ 100%). Example B8 2-Isobutylsulfanyl-5-methanesulfonyl-benzoic acid Prepared in analogy to Example A6(a) from (4-Iodo-l53-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((S)-2,2?2-trifluoro-l-methyl-ethoxy)-phenyl]-methanone (Example C1). Light brown solid. MS (m/e): 444.4 [M+H+], 100%). Example 99 [[5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(5-methyi~6- trifluoromethyi-l^-dihydro-isoindol^-yl^methanone 100 [[5-Methanesuifonyl-2^(S)-2^,2-trifluor{>-l-methyl^thoxy)-phenyl]-(5-methoxy-6- trifluoromethyI-l!3^ihydro-isoindol-2-yI)-nietiiaiione Prepared in analogy to Example A6(a) from (5-Iodo-6-trifluoromethyl-L3-dihydrcH isoindol-2-yl)-[5-methanesulfonyl-2-^(S)-2,252-trifluoro-l-methyl-ethoxy)-phenyl]-methanone (Example C2). White solid. MS (m/e): 512.0 [M+H]\ 100%). In analogy to Example 1, compounds 101 to 312 of the following table were prepared from the acid derivatives and amine derivatives To a solution of 0.19 mmol (5-Iodo-l J-dihydro-isoindol^-yl^S-methanesulfonyl-^-^S^^^^rifluoro-l-methyl-ethoxy^phenylj-methanone (Example C3) in 1ml DMF under argon was added successively 0.018 mmol tetrakistriphenylphosphine. 0.28 mmol phenyl boronic acid and 0.56 mmol potassium carbonate. The reaction mixture was 61) in 2 ml dichloromethane was added 0.31 mmol 3-chloroperbenzoic acid. The mixture was stirred at room temperature for 72 hours. The mixture was diluted with dichloromethane. The solution was washed twice with a sat bicarbonate solution and once with a 10% sodium carbonate solution to destroy any residual peroxides, dried over sodium sulfate, filtered and the solvent was removed in vacuo. The crude solid was purified on a 5g Flashpack cartridge. Eluent: Heptane/ethylacetate to provide the title compound (92%). White foam. MS (m/e): 516.1 [M+NILJ^ 100%). Example 354 6-Chloro-2-(2-isopropoxy-5-methanesulfonyl-beiizoyl)-2^-dihydro-isoindoH-one 0.4 mmol 6-chloro-l-isoindolinone (CAS : 58083-59-3) was dissolved in 3 ml of pyridine. 0.05 mmol of 4-dimethylaminopyridine was added, followed by slow addition of a solution of 0.5 mmol 2-isopropoxy-5-methanesulfonyl-benzoyl chloride (prepared from example Bl and oxalyl chloride in dichloromethane) in 2 ml dichloromethane at room temperature. The reaction mixture is stirred for 10 minutes at room temperature-then the dichloromethane is stripped off in the rotatory evaporator. The remaining solution was then refluxed for 3 hours. The dark red solution was quenched with water, acidified by addition of diluted hydrochloric acid and extracted 3 times with ethyl acetate. The organic phase is dried and concentrated- Chromatography (silica gel; ethyl acetate / heptane) gave the title compound as a slightly yellowish solid. Yield - 55 %. MS (m/e): 408.2 [M+H]+, 100%). Example 355 [5-MethanesuIfonyl-2-((S)-2,2^-trifluoro-l~methyl-ethoxy)-phenyl]^4-morphoIin-4- yl^^-dihydro-indol-l-yl^methanone The amino acid glycine is known to have at least two important functions in the CNS. It acts as an inhibitory amino acid, binding to strychnine sensitive glycine receptors, and it also influences excitatory activity, acting as an essential co-agonist with glutamate for N-methyl-D-aspartate (NMDA) receptor function. While glutamate is released in an activity-dependent manner from synaptic terminals, glycine is apparently present at a more constant level and seems to modulate/control the receptor for its response to glutamate. One of the most effective ways to control synaptic concentrations of neurotransmitter is to influence their re-uptake at the synapses. Neurotransmitter transporters by removing neurotransmitters from the extracellular space, can control their extracellular lifetime and thereby modulate the magnitude of the synaptic transmission (Gainetdinov RR et al. 2002. Trends in Pharm. ScL 23(8): 367-373). Two distinct glycine transporter genes have been cloned (GlyT-1 and GlyT-2) from mammalian brain, which give rise to two transporters with -50 % amino acid sequence homology. GIyT-1 presents four isoforms arising from alternative splicing and alternative promoter usage (la, lb. lc and Id). Only two of these isoforms have been found in rodent brain (GlyT-1 a and GlyT-lb). GlyT-2 also presents some degree of heterogeneity. Two GlyT-2 isoforms (2a and 2b) have been identified in rodent brains. GlyT-1 is known to be located in CNS and in peripheral tissues, whereas GlyT-2 is specific to the CNS. GlyT-1 has a predominantly glial distribution and is found not only in areas corresponding to strychnine sensitive glycine receptors but also outside these areas, where it has been postulated to be involved in modulation of NMDA receptor function (Lopez-Corcuera B et aL, 2001. Mol. Mem. Biol., 18: 13-20). Thus, one strategy to enhance NMDA receptor activity is to elevate the glycine concentration in the local microenvironment of synaptic NMDA receptors by inhibition of GlyT-1 transporter (Bergereon R. Et al., 1998, Proc. Natl Acad. Set. USA, 95: 15730-15734; Chen L et aL, 2003, J. NeurophysioL, 89 (2): 691-703). Glycine transporter inhibitors are suitable for the treatment of neurological and neuropsychiatric disorders.The majority of diseases states implicated are psychoses, schizophrenia (Armer RE and Miller DJ, 2001, Exp. Opin. Ther. Patents, 11 (4): 563-572), psychotic mood disorders such as severe major depressive disorder, mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorders and mood disorders associated with schizophrenia, (Pralong ET et al., 2002, Prog. NeurobioL, 67: 173-202), autistic disorders (Carlsson ML, 1998, J, Neural Transm. 105: 525-535), cognitive disorders such as dementias, including age related dementia and senile dementia of the Alzheimer type, memory disorders in a mammal, including a human, attention deficit disorders and pain (Armer RE and Miller DJ, 2001. Exp. Opin. Ther, Patents, 11 (4): 563-572). Objects of the present invention are the compounds of general formula I per se. the use of compounds of formula I and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment of diseases related to activation of NMDA receptors via Glyt-1 inhibition, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula I in the control or prevention of illnesses such as psychoses, disfunction in memory and learning, schizophrenia, dementia and other diseases in which cognitive Alternatively, compounds of formula Ilia, where R1 is lower alkyl, lower alkyl, substituted by halogen or -{CFbVcycloalkyl can be prepared by reacting a hydroxy compound of formula VII with an alcohol of formula R1 OH, under Mitsunobu reaction conditions in the presence of a phosphine like triphenylphosphine or diphenyl-2-pyridylphosphine, and a dialkylazadicarboxylate like diethylazadicarboxylate or di-tert-butyl azodicarboxylate, to afford intermediate compounds of formula VIII, followed by hydrolysis in the presence of an aqueous base such as potassium hydroxide, sodium hydroxide or lithium hydroxide (Scheme 4). Compounds of formula 111b where R' is lower alkyl. lower alkyl. substituted by halogen or --{CHiK-cycloalkyL can be prepared by reaction of a halogen compound of formula VI with a thiol of formula R SHr optionally in the presence of a base, such as Alternatively, compounds of formulas IV A. IV Ek IV C and IV D can be prepared by reaction of an ortho-dihydroxymethylated compound of formula XII (XII A. XII B. XII C and XII D) with a chlorinating agent such as thionylchloride (Scheme 9). The ortho-dimethylated and -dihydroxymethylaied compound of formula XI (A. Br C and D) and XII (Ar B, C and D) as shown in Schemes 8 and 9 are either commercially For example, compounds of formula V can be prepared by reaction of acid compounds of formula III with an activating agent such as oxalylchloride followed by treatment with ammonium hydroxide (Scheme 10). Scheme 11 Preparation of compounds of formula II A, II B, II C and II D for R and R' being Alternatively, compounds of formula n A. II B; II C and II D can be prepared by reaction of bis-halogenated compounds of formula IV (A, B, C and D) in the presence of triphenylmethylamine and a base such as diisopropylethylamine to afford intermediate compounds of formula XIV (A. B, C and D) followed by deprotection in the presence of an acid such as trifluoroacetic acid (Scheme 12). The acid addition salts of the basic compounds of formula I may be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like. The compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention are good inhibitors of the glycine transporter I (GlyT-1). The compounds were investigated in accordance with the test given hereinafter; The compounds of formula I and the pharmaceutical^ acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally. e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions. The pharmaceutical preparations can. moreover, contain preservatives, solubilizers. stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants. salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers. To 25.4 mmol 5-amino-6-chIoroisoindoline-l,3-dione (commercial, CAS: 5566-48-3) was added 127 mmol borane-THF complex and the resulting mixture was stirred at 80 C for 16 h. The reaction mixture was then cooled to room temperature and quenched by dropwise addition of 50 ml methanol. After stirring at room temperature for 30 min, 50 ml concentrated hydrochloric acid was added and the resulting mixture was stirred at 80 To a stirred suspension of 96.1 mmol 5-amino-6-chloroisoindoline-L3-dione (commercial, CAS: 5566-48^3) in 170 ml water was added dropwise at 10 °C a solution of 11 ml concentrated sulfuric acid in 50 ml water. After cooling the mixture to 5 °C, a solution of 120 mmol sodium nitrite in 40 ml water was added dropwise and stirring continued at 0 °C for 90 min. A solution of 327 mmol potassium iodide in 80 ml water was then added dropwise over 40 min while maintaining the reaction temperature between 0 and 5 °C. The reaction mixture was then warmed to room temperature and subsequently heated at 35 °C for 45 min and then 60 °C for 30 min before being recooled to room temperature and diluted with tetrahydrofuran/ethyl acetate (1/2). The phases were separated and the organic phase washed sequentially with aqueous sodium thiosulphite and brine and then dried over sodium sulfate and concentrated in vacuo. The residue was resuspended in 300 ml dichloromethane, stirred for 10 min at room temperature, and the resulting crystals collected by filtration to yield the title compound as a light brown solid. MS (m/e): 308.9 ({37C1}M+, 35%), 306.9 ({35C1}M+, 100%). (b) 5-Chloro-6-iodo-2.3-dihydro-lH-isoindole Prepared in analogy to Example Al from 5-chloro-6-iodo-isoindole-K3-dione and borane-THF complex. Off-white solid. MS (m/e): MS (m/e): 282.0 ({37CI}M+H\ 35%), 279.9 ({35C1}M+H\ 100%). Lit. J. Am. Chem. Soc. 1996, 118 (30), 7215-7218. To a stirred suspension of 2.63 mmol 5-chloro-6-iodo-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester in 20 ml toluene were added 0.24 mmol 2-(dicyclohexylphosphino)biphenyl, 0.08 mmol tris(dibenzylideneacetone)dipalladium chloroform complex and 3.68 mmol sodium tert-butoxide and the mixture was stirred at 110 °C for 2 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and washed twice with brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiCb, heptane/ethyl acetate) to yield the title compound as a yellow oit. MS (m/e): 325.2 ({37C1}M+H+, 35%), 323.2 ({35C1}M+H+, 100%). (e) 5-ChlorO"6-pvTTolidin-l-vI-2.3-dilivdro-lH-'isoindole-hvdrochloride To a stirred suspension of 0,12 mmol 5-chloro-6-pyrrolidin-)-yl-1.3-dihydro-isoindole-2-carboxylic acid tert-butyl ester in 1 ml dioxane was added 1.86 mmol hydrogen chloride solution (4 M in dioxane) and the mixture was stirred at 90 °C for 2 h. The reaction mixture was then concentrated in vacuo to yield the title compound as a brown solid which was used in the next step without further purification. MS (m/e): 325.2 ({37Cl}M+H+, 35%)r 323.2 ({35C1}M+H"\ 100%). 38 Example A4 5~ChIoro-6-methyI~23-dihydrolJH-isoindole hydrochloride (a) 5-Chloro-6-methvl-1.3-dihvdro-isoindole-2-carboxvlic acid tert-butvl ester Lit. Tetrahedron Lett. 1999. ¥0, 2719-2722. To a stirred suspension of 1.58 mrnol 5-chloiXH6-irxio-13-dihydro-isoindole-2- Prepared in analogy to Example A3 (e) from 5-chloro-6-methyl-1.3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and HC1. Grey solid. MS (m/e): 170.1 ({ CI}M+rf", 35%), 168.3 ({35C1}M+H+, 100%). Example A5 5-ChIoro-6-ethylsulfanyl-2r5-dihydro-lH-isoindole hydrochloride (a) 5-Chloro-6-ethvlsulfany]-L3-dihydro-isoindole-2-carboxvlic acid tert-butyl ester Prepared in analogy to Example A2 (b) from 6-chloro~2?3-bis-chloromethy]-pyridine (CAS: 220001-94-5) and triphenylmethylamine. Light yellow foam. MS (m/e): 397.0 ([MH+, 100%). (b) 2-Chloro-6,7-dihvdro-5H-pVTTolor3.4-b1pvridine Prepared in analogy to Example A2 (c) from 2-chloro-6-trityl-6.7-dihydro-5H-pyrrolo[3.4-b]pyridine and trifluoroacetic acid. Light brown solid. MS (m/e): 154.9 ([M"? 100%). Example A9 2r5-Dihydro-lH-isoindoIe-4-carbonitrile Prepared in analogy to Example A3 (e) from 5-PyTTolidin-l-yl-1.3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and HCI. Brown oil. MS (m/e): 189.6 (M-H--T 100%). 43 Example Al 1 5-EthylsulfanyL2,3-dihvdro-lH-isoindole hydrochloride (a) 5-Ethvlsulf3Lnvl-1.3-dihydro-isoindole-2-carboxviic acid tert-butyl ester Prepared in analogy to Example A3 (e) from 5-Ethylsulfanyl-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and HC1. Light Brown solid. MS (m/e): 216.3 ([M+H+, 100%). Example Al 2 5-Chloro-6~fluoro-273-dihydro-lH-isoindole (a) 1.2-Bis-bromomethyl-4-chloro-5-fluoro-benzene Prepared in analogy to Example A2 (a) from l-ChIoro-2-fluoro-4.5-dimethyl-benzene (CAS: 1 16850-30-7) and NBS. Brown oil. To a room temperature suspension of 2.5 mmol (5-Hydroxymethyl-2-trifluoromethyl-pyridin-4-yl)-methanol (CAS: 765298-25-7) in 3 ml dichloromethane was added dropwise 12.5 mmol thionylchloride. After 1 hour, the reaction mixture was evaporated in vacuo. The residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SiCh, heptane/ethyl acetate) to yield the title compound as a light yellow oil (66% yield). MS (m/e): 243.0 (M-H. 100%) (b) 6-Trif1uoromethvl-2-tritvl-2.3-dihvdro-nn[-pyrrolo!'3.4-clpvridine Prepared in analogy to Example A2 (b) from 4,5-Bis-chloromethyl-2-trifluoromethyl-pyridine and triphenylmethylamine. White solid. (c) 6~Trifluoromethyl-2.3-dihydro-l H-pvrrolo[3.4-c]pyridine Prepared in analogy to Example A2 (c) from 6-Trifluoromethyl-2-trityl-2,3-dihydro-lH-pyrrolo[3,4-c]pyridineand trifluoroacetic acid. Off white solid. Example A14 2-Trifluoromethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine A solution of 6 mmol 6-trifluoromethy]-pyridine-2,3-dicarboxylic acid dimethyl ester in 10 ml methanol was cooled to 0° C. 12 mmol of sodium borohydride and 6 mmol of calcium chloride were added and the resulting mixture stirred overnight at room temperature. After cooling again to 0° the reaction mixture was neutralized by addition of 5 ml 3M aqueous hydrochloric acid. The mixture is concentrated, diluted with water and extracted 3 times with ethyl acetate. The crude compound is purified by chromatography (SiC>2; ethyl acetate / n-heptane 1:1) to give the title compound as a yellow oil. Yield: 72%. MS (m/e): 208.1 (MH+, 100%). To a room temperature suspension of 9.06 mmol 3-Trifluoromethyl-5H-furo[3?4-b]pyridin-7-onel (CAS: 765298-32-6) in 40 ml ethanol was added portionwise 19.9 mmol sodium borohydride. After 30 minutes, the reaction mixture was cooled to 0 °C5 2N HC1 was added to pHl and the solvent was removed in vacuo. The residue was taken in water, the mixture was neutralized with IN NaOH and then saturated with NaCl. The aqueous phase was extracted 6 times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a yellow oil (92% yield). MS (m/e): 230.1 (M+Na, 100%) Prepared in analogy to Example A2 (c) from 4-Fluoro-6-trifluoromethyl-2~trityI-2.3-dihydro-1 H-isoindole and trifluoroacetic acid. Yellow oil. MS (m/e): 206.1 ([M+H^ 100%). Example A18 5~TrifIuoromethoxy-2?3-dihydro-l H-isoindole Prepared in analogy to Example A 17(a) from 4-(trifuoromethoxy)-benzoic acid. Yellow oil. MS (m/e): 290.2 ([M+H]+, 100%) fb) 2-Formyl-N,N"diisopropvl-4-trifluorometfaoxv-benzamide Prepared in analogy to Example A17(b) from N,N-Diisopropyl-4-trifluoromethoxy-benzamide. Yellow oil MS (m/e): 318.1 ([M+H]+, 100%) (c) 5-Trifluoromethoxy-3H-isobenzofuran-l-one Prepared in analogy to Example A17(c) from 2-Foimyl-N,N-diisopropyl-4-trifluoromethoxy-benzamide. White needle. MS (m/e): 219.1 ([M+H]+, 100%) (d) (2-HYdroxvmethyl-5-trifluoromethoxv-phenYl)-methanol Prepared in analogy to Example A 14(c) from (2~Hydrc>xymethyl-5~trifluoromethoxy-phenyl)-methanol- Light red oil. (f) 5-Trifluoromethoxy-2.3-dihydro-l H-isoindole Prepared in analogy to Example A2(c) from 5-Trifluoromethoxy-2-trityl-2,3-dihydro-1 H-isoindole. Dark brown oil. Example A19 S-difluoromethoxy-l^-dihydro-lH-isoindoline trifluoroacetic acid (a) 5-DifluoromethoxY-K3-dihvdro-isoindole-2-carboxylic acid tert-butyl ester A mixture containing 0.68 mmol 5-Hydroxy-lT3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (CAS: 226070-47-9), 0.68 mmol potassium carbonate and 0.68 mmol ethvl chlorodifluoroacetate in 1.5 ml DMF was stirred overniaht at 65 °C. The mixture was then partitioned between ethyl acetate and water and the organic phase was then separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified Prepared in analogy to Example A17(a) from 2-chlorpyridine-5-carboxylic acid. Yellow oil. MS (m/e): 241.3 ([M+Hf, 100%) (b) 6-Chloro-4-formyl-N,N-diisopropvl-nicotinamide Prepared in analogy to Example A 17(c) from 6-Cbloro-4-formyl-N.N-diisopropyl-nicotinamide. White solid. (d) (6^hloro^hvdroxvmetfavl-pvridin-3-yl)-metfaanol Prepared in analogy to Example A16(a) from 6-Chloro-lH-furo[3,4-c]pyridin-3-one. White solid. MS (m/e): 172.0 ([M-H], 100%) (e) 6-Chloro-2-tritvl-23-dihydro-lH-pvrrolo[3.4-c]pyridine Prepared in analogy to Example A 14(c) from (6-Chloro~4-hydroxymethyl-pyridin-3-yl)-methanol. White foam. (f) 6-Chloro-2.3-dihvdro-lH-pyrrolo[3,4-clpyridine ogy to Example A3(e) from 5-(2-Methyl-pyridin-4-yl)-L3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and using trifluoacetic acid instead of hydrochloride acid. Brown solid. MS (m/e): 211.0 ([M+Hf, 100%) Example A25 S^S-Metbyl-thiophen-^yiyiyS-dihydro-lH-isoindole (a) 545-Methvl-thiophen-3-Yl)-13^ihvdro-isoindole-2- Prepared in analogy to Example A23(b) from 5-(4.455?5-Tetramethyl-[1 ?3,2]dioxaborolan-2-yl)-l 53-dihydro-isoindole-2-carboxylic acid tert-butyl ester and 4-bromo-2-methykhiophene (commercial). Light yellow solid. MS (m/e): 315.2 ([M]+, 100%) (b) 5-(5-Methyl-thiophen-3-vl)-2.3-dihvdro-l H-isoindole Prepared in analogy to Example A3(e) from 5-(5-Methyl-thiophen-3-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and using trifluoacetic acid instead of hydrochloride acid. Light yellow solid. MS (m/e): 216.1 ([M+H]+s 100%) Example A26 5-(5-Methy!-thiazoL2-yl)-23-dihydro-l H-isoindole Prepared in analogy to Example A23(b) from 5-(4A5.5-Tetramethyl-f 1,3.2]dioxaborolan-2-yl)-13-dihydro-isoindole-2-carboxylic acid tert-butyl ester and 2-Iodo-5-methyl-thiazole (CAS: 847547-16-4). Yellow solid. MS (m/e): 317.0 ([M]\ 100%) Prepared in analogy to Example A3(e) from 5-(5-Methyl-thiazol-2-yl)-l,3-dihydro-isoindole-2-carboxyIic acid tert-butyl ester and using trifluoacetic acid instead of hydrochloride acid. Brown gum. MS (m/e): 217.0 ([M+H]+, 100%) Example A27 S-Thiazol-2-yI-2^-dihydro-lH-isoindoIe (a) 5-Thiazol-2-yl-L3H3ihvdro-isoindole-2-carbox\'lic acid tert-butyl ester Prepared in analogy to Example A3(e) from 5-Thiazol-2-yl-1.3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and using trifluoacetic acid instead of hydrochloride acid. Yellow gum. MS (m/e); 202.8 ([M+H]+, 100%) Example A28 2-TrifluoromethyW,7Hiihydro-5H-pyiTt>to^ a) 3-n-DimethYlammo-meth^Z>Ylidene]-4^ acid tert-butyl ester A solution of 13.5 mmol N-BOC-3-pyrrolidone and 13.5 mmol N,N-dimethylfonnamide-dirnethylacetal in 50 ml N,N-dimethylformamide was hold overnight at 60° C. The reaction mixture was quenched by addition of 50 ml water and extracted 3 times with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give the crude title compound as a yellowish oil. Yield = 90%. MS (m/e): 241.4 ([M+H]+, 100%). b) 2-Trifluoromethvl-5.7-dihvdro-pvrrolo[3.4-dlpyrirnidine-6-carboxvlic acid tert-butyl ester 3.4 mmol of 2-Trifluoromethyl-5.7Hdihydro^^ acid tert-butyl ester was dissolved in a mixture of 20 ml dichloromethane and 3 g trifluoroacetic acid. The mixture was hold at 45° C for 3 hours and concentrated to give the title compound as a waxy solid. Yield = 100%. MS (m/e): 190.3 ([M+H]+5 100 %). Example A29 4-Trifluoromethyl-2r3-dihydro-lH-indole a) Dimethyl-[(E)-2--(2-nitro-6-trifluoromethvl-phenYl)-vinvl]-amine A solution of 17 mmol 2-methyl-3-nitrobenzotrifluoride and 43 mmol N;N-dimethylformamide-dimethylacetal in 30 ml N,N-dimethylformamide was hold at 120° C overnight. The reaction mixture is concentrated in vacuo to give the crude title compound. Yield - 83%. MS (m/e): 261.1 ([M+H]+, 90 %). 4.4 mmol of 4-trifluoromethyl-lH-indole were dissolved in 8 ml acetic acid. 8.8 mmol of sodium cyanoborohydride were added at once and the reaction mixture stirred at room temperature for 3.5 hours. 20 ml of water were added. The reaction mixture is treated with acqueous sodium hydroxide 40% until basic. Extraction with ethyl acetate yields the crude title compound as a yellowish waxy solid. Yield = 76 %. MS (m/e): 188.4 ([M+H]+, 97 %). Example A30 2r5-Dihydro-lH-indoIe-4-carbonitrile This compound was prepared in analogy to example A29c), starting from 4-cyanoindole. Yield - 15 %. MS Prepared in analogy to Example A5(a) from 5-iodo-6-lrinuoromethy]-l,3-dihvdro-isoindole-2-carboxylic acid tert-butyl ester and ethyl mercaptan. White solid. MS (m/e); 292.1 ([M+H-Me20=CH2f. 100%). further 15 min at 50 °C. then cooled to room temperature and acidified to pH 1 by dropwise addition of 5 M aq HC1. The mixture was then partitioned between ethyl acetate and brine and the organic phase was then separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: methanol/dichloromethane) to afford the title compound as a colourless oil (57% yield). MS (m/e): 283.1 ([M-K)Ac)]\ 100%), 223.1 ([M-H]\ 20%). (c) 5-Fluoro-6-trifluoromethvl-2-trityl-2.3-dihvdro-l H-isoindole To a mixture of 1.56 mmol (4-fluoro-2-hydroxymethyl-5-trifluoromethyl-phenyl)-methanol and 0.08 mmol DMAP in 5 ml dichloromethane at 0 °C were added dropwise 3.28 mmol methanesulfonyl chloride and 6.25 mmol triethylamtne. The mixture was stirred at 0 °C for 1 h, and then heated quenched with water. The mixture was extracted with dichloromethane and the organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in DMF and then 4.68 mmol N,N-diisopropylethylamine and 2.03 mmol triphenylrhethylamine were added sequentially. The mixture was heated at 60 °C for 1 day and then at 80 °C for a further day. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: ethyl acetate/heptane) to afford the title compound as a white amorphous solid (23% yield). El-MS (m/e): 370.1 ([M-Ph]". 100%). (d) 5-Fluoro-6-trifluoromethvl-2.3-dihydro-l H-isoindole trifluoroacetate Example A37 5^hloro^piperidin-l-yl-23^hydro-lH-iso«idole hydrochloride (a) 5oxvlic acid tert-butyl ester Prepared in analogy to Example A3(d) from 5~chloro-6-iodo-l-3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) and piperidine. Yellow solid. MS (m/e): 339.1 ({37C1}M+H\ 29%), 337.1 ({35C1}M+H+, 100%). (b) 5-ChlorO"6-piperidin-l-vl-2,3-dihydro-lH-isoindole hydrochloride Prepared in analogy to Example A3(e) from 5-ethoxy-6-trifluoromethyl-13- (a) 5^hloro-6-morpholin-4-yl-13-dihydro-isoindole-2-carfaoxylic acid tert-butyl ester Prepared in analogy to Example A3(d) from 5-chloro-6-iodo-l53-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) and morpholine. Yellow solid. MS (m/e): 341.3 ({37C1}M+H+, 20%), 339.1 ({35CI}M+H+, 100%). (b) 5-Chloro-6-morpholin-4-Yl-2.3-dihydro-lH-isoindole hydrochloride Prepared in analogy to Example A3(e) from 5-chloro-6-morpholin-4-yl-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Off-white solid. MS (m/e): 241.4 ({37C1}M+H+, 52%)T 239.3 ({35C1}M+H\ 100%). Example A45 5-Ethyl-6-trifluoromethyI-23-dihydro-lH-isoindole hydrochloride (a) 5-Trifluoromethyl-6-vinvl-L3-dihvdro-isoindole-2-carboxylic acid tert-butyl ester (c) 5-rretrahvdro-pyran-4-yl)-2.3-dihvdro-lH-isoindole hydrochloride Example A50 5~(Tetrahydro-pYraD-4-yl)-6-trifluoromethyI-2r3-dihydro-lH-isoindoIe hydrochloride (a) 5-(3,6-Dihvdro-2H-pvran-4-ylV6-trifluoromethvl-l .3-dihvdroisoindole-2-carboxvlic acid tert-butyl ester Prepared in analogy to Example A49(a) from 5-iodo^trifluoromethyl-13-dihydro-isoindole-2-carboxyIic acid tert-butyl ester (Example 35(d)) and tributyl-(3?6-dihydro-2H-pyran-4-yI)-stannane. Yellow solid. MS (m/e): 314.0 ([M+H-Me2C=CH2]+; 100%). fb) 5-(Tetrahydro-pvran^1-yl)-6-trifluoromethvl-l ,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester Prepared in analogy to Example A49(b) from 5-(3,6-dihydro-2H-pyran^~yl)-6-trifluoromethyl-l?3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and ammonium formate. Off-white solid. MS (m/e): 316.1 ([M+H-Me2(>CH2f, 100%). (c) 5-(Tetrahydro-pyran-4-yn-6-trifluoromethyl-2.3-dihydro-l H-isoindole hydrochloride Example A51 5-(l,l-Dioxo-l-thiomorpholin-4-\i)-2r3-dihydrolH-isoindole hydrochloride (a) 5-(l.I- Dioxo-1-thiomorpholin -4-yl)-13-dihydro-isoindoIe-2-carboxvlic acid tert-butyl ester Prepared in analogy to Example A3(d) from 5-iodo-l,3- Prepared in analogy to Example A3(e) from 5-(4-methoxy-piperidin-l-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Brown solid. MS (m/e): 233.3 ([M+H]+, 100%). nalogy to Example A54(a) from 5~chloro-6-(3,6-dihydro-2H-pyran-4-yl)-l?3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A61(a)) and tetramethystannane. White solid. MS (m/e): 260.3 ([M+H-Me2CH2]+, 100%). (b) 5-Methvl-6-(tetrahvdrO"pvran-4-yn-13-dihvdro-isoindole-2-carboxylic acid tert- butvl ester Prepared in analog}' to Example A49(b) from 5-(3.6-dihydro-2H-pyran-4-yl)-6-methyl-1.3-dihvdro-isoindole-2-carboxvlic acid tert-butvl ester and ammonium formate. Yellow solid. MS (m/e): 262.1 ([M+H-Me2C=CH2l+? 100%). (c) 5-Methyl-6-(tetrahvdro-pvran-4-vl)-2.3-dihydro-lH-isoindole trifluoro-acetate Prepared in analogy to Example A2(c) from 5-methyl-6-(tetrahydro-pyran-4-yl)-l_3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. MS (m/c): 218.4 ([M+H]+, 100%). Example A64 3^2^Dihydro-lH-isoindol-5-yI)-2-methyl-tetrahydro-fai^ (a) 3-(2-Benzyl-2,3-dihydro-l H-isoindol-5-vl)-2-methyl4etrahvdro-fiiran-3-ol Prepared in analogy to Example A62(b) from 2-benzyl-5-bromo-2;3-dihydro-lH-isoindole (Example A62(a)) and 2-methyltetrahydrofuran-3-one. Brown oil. MS (m/e): 310.4 ([M+Hf, 100%). (b) 3-f23-Dihvdro-lH-isoindol-5-vl)-2-methvl-tetrahydro-furan-3-ol Prepared in analogy to Example A2(c) from 5-cyclopropy!methoxy-1.3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. MS (m/e): 190.4 ([M+H]+. 100%). Example A83 5^3^^TriflBor€Hpropoxy)-2,3-dihydro-l H-isoindole trifluoroacetate (a) 5^333-Trifluoro-propoxvV13KiihvdTO-isoindole-2K^rboxviic acid tert-butyl ester Prepared in analogy to Example A6(a) from 5-iodo-L3-dihydro-isomdole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 3,3,3-trifluoropropanoL Off-white solid. MS (m/e): 276.3 ([M+H-Me2C-CH2]+? 100%) (b) 5-(33,3-Trifluoro-propoxv)-2.3-dihydro-lH-isoindole trifluoroacetate Prepared in analogy to Example A2(c) from 5-(33,3-trifluoro-propoxy)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Brown oil. MS (m/e): 232.1 ([M+Hf, 100%). Example A84 5-Fluoro-6-morpholin-4-yI-23-dihydro-lH-isoindole trifluoroacetate Example B8 2-Isobutylsulfanyl-5-methanesulfonyl-benzoic acid Example B9 5-Methanesulfonyl-2-methylsuIfanyl-benzoic acid Example B10 5-MethanesulfonyI-2-(2^^-trifluoro-ethoxy)-ben2oicacid Prepared in analogy to Example Bl (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example Bl(a)) and 2,2,2-trifluoro-ethanol. The crude material was purified by preparative HPLC to yield the title compound as a white solid. MS (m/e): 297.0 ([M-H]"9 100%). Example Bll 2-Isobutoxy-5-methanesuIfonyI-benzoic acid Example B12 5-Methanesulfonyl-2-morpholin-4-yl-benzoic acid A mixture of 4.26 mmol 2-chloro-5-methanesulfonyl-benzoic acid (Example Bl(a)) in 8 ml morpholine was heated at 110 °C for 15 h. After evaporation of all volatiles the residue was acidified by addition of 1 N HC1 and extracted three times with ethyl acetate. The combined organic extracts were washed sequentially with 1 N HC1 and saturated brine, dried over sodium sulphate, and concentrated in vacuo to afford the title compound as a light yellow amorphous solid (58%). MS (m/e): 284.1 ([M-H]", 100%). Example B13 2-Methoxy-5-methylsulfanioyl-benzoicacid (a) 5-ChlorosulfonyI-2-hydroxy-benzoic acid To 3.26 mol chlorosulfonic acid at 0 °C was added 652 mmol salicylic acid in small portions and the mixture was then allowed to stir at RT for 1 h, then at 50 °C for 1 h, and finally at 70 °C for 1 h. The mixture was then added dropwise to 1000 ml ice-water with stirring and stirring continued for an additional 30 min. The ensuing white crystals were collected by filtration, washed three times with water, and then dried in vacuo at 45 °C for 16 h to yield the title compound. MS (m/e): 236.8 ([{37C1}M-H]"; 33%), 235.0 ([{37C1}M-H]\ 100%) Example 323 [5-Methanesulfonyl--2-((S)-2^^2-trifluoro-l-niethyl-ethoxy)-phenyl]-(5-phenyl-lr3- . dihydro-isoindol-2-yl)-methanone To a solution of 0.19 mmol (5-Iodo-l J-dihydro-isoindol^-yl^S-methanesulfonyl-^-^S^^^^rifluoro-l-methyl-ethoxy^phenylj-methanone (Example C3) in 1ml DMF under argon was added successively 0.018 mmol tetrakistriphenylphosphine. 0.28 mmol phenyl boronic acid and 0.56 mmol potassium carbonate. The reaction mixture was R4 is hydrogen, hydroxy, halogen, =0, Cj^-alkyl, cycloalkyl, heterocycloalkyl, Ci-e-alkoxy, CN, N02, NH2> aryl, 5-or 6-membered heteroaryl containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen, -NH-Cj^-alkyl, -N(Ci_6-alkyl)2, cyclic amide, -C(0)-cyclic amide, S-Cj^-alkyl, -S(0)2- Ci-6-alkyl, Q-6-alkyl substituted by halogen, Q-e-alkoxy substituted by halogen* Ct^-alky! substituted by hydroxy, -0-(CH2)y- CK6-alkoxy, -0(CH2)vC(0)N(Ci^-alkyl)2, -C(O)- Ci.6-alkyl, ~0-(CH2)x-aryl, -0-(CH2)x-cycloalkyl, -0-(CH2)x-heterocycloalkyl, -C(0)0- C^-alkyl, -C(0)-NH- C,.6-alkyl, -C(0)-N(CU6-alkyl)2, 2-oxy-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8~aza-bicycIo[3.2.1]oct-8-yl; heterocycloalkyl,> Ci.6-aIkoxy, CN, N02, NH2, aryl, 5-or 6-membered heteroaryl containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen, -NH~, Q^-alkyl, -N(, Ci_6-alkyl)2, cyclic amide, -C(0)-cyclic amide, S-, Ci^-alkyl, -S(0)2-, d-6-alkyl,, Q^-alkyi substituted by halogen,, Q_6-alkoxy substituted by halogen, Ci-g-alkyl substituted by hydroxy, -0-(CH2)r, d-e-alkoxy, -0(CH2)yC(0)N(> CM- alkyi)2, -C(O)-, C^-alkyl, -0-(CH2)x-aryi, -0(CH2)x-cycloalkyl, -0-(CH2)x-heterocycloaIkyl, -C(0)0-, d^alkyl, -C(0)-NH-, C^-alkyi, -C(0)-N(, C^-alkyl)2> 2-oxy-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct~8-yl; and wherein all aryi-, cycloalkyl-, cyclic amide, heterocycloalkyl- or 5 or 6 membered heteroaryl groups as defined for R , R , R and R may be unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, =0, halogen,, Q^-alkyl, phenyl,, Ci.6-alkyl substituted by halogen or , Ci_6-alkoxy; is 1 or 2; x is 0,1 or 2; y is 1 or 2; and pharmaceutical^ acceptable acid addition salts thereof. 8. Compounds of formula I G according to claim 1 wherein R1 is halogen, -OR1, -SR1 , cycloalkyl, cyclic amide, heterocycloalkyl, aryl or 5-or 6-membered heteroaryl, containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen; R /R are hydrogen, Q.6-alkyl, Q.e-alkyl substituted by halogen, ~(CH2)x-cycloalky! or -(CH2)x-aryl; tetrahydro-pyran-4-yloxy)-l,3-dihydro- isoindol-2-yl] -rnethanone, [5-methanesulfonyl-2-(2J2>3>3,3-pentafluoro-propoxy)-phenyl]-[5-(tetrahydro-pyran-4~ yloxy)-l>3-dihydro-isoindol-2-yl]-methanone, [5-ch]oro-6-(tetrahydro-pyran-4-yloxy)-l?3-dihydro-isoindol-2-yl]-[5-methanesulfony]-2- ((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl] -rnethanone, [5-chloro*6-(tetrahydro-p)Tan-4-yloxy)-l)3-dihydro-isoindol-2-yl]-(2-isopropoxy-5- methanesulfonyl-phenylVmethanone, wherein the substituents are as defined in claim 1, and, if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts. 21. A medicament containing one or more compounds as claimed in any one of claims 1 to 19 and pharmaceutically suitable excipients. 22. A medicament according to claim 21, wherein the illnesses are psychoses, pain, dysfunction in memory and learning, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer's disease. 23. The use of a compound as claimed in any one of claims 1 to 19 for the manufacture of medicaments for the treatment of psychoses, pain, neurodegenerative dysfunction in memory and learning, schizophrenia, dementia and other diseases in which cognitivePrepared in analog}' 10 Example 1 from 2-chioro-6.7-dihydro-5H-p\TroKo[3.4-b]p>ridine (Example A8(b)) and 5-methanesu!fonyl-2-((S)-2,2.2-irif]uoro-l-meth)l-ethoxy)-benzoie acid (example B3). Yellow foam. MS (m/e): 451.0 ({37C1}[M+H]+, 41%)? 449.2 ({35C]}[Nf+H]\ 100%). A mixture of 0.387 mmol 2-isopropoxy-5-methanesulfonyl-benzoic acid (example Bl)r 0.464 mmol 2,3-Dihydro-lH-isoindole (commercial), 0.426 mmol TBTU and 1.935 mmol DIPEA in 1.4 ml DMF was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo. The residue was taken in water and extracted with ethylacetate. The combined organic phases were washed with saturated sodium bicarbonate solution, dried " •' over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (Si(>25 heptane/ethyl acetate) to yield the title compound as a light brown solid (88% yield). MS (m/e): 360.2 [M+H]+, 100%) The amino acid glycine is known to have at least two important functions in the CNS. It acts as an inhibitory amino acid, binding to strychnine sensitive glycine receptors, and it also influences excitatory activity, acting as an essential co-agonist with glutamate for N-methyl-D-aspartate (NMDA) receptor function. While glutamate is released in an activity-dependent manner from synaptic terminals, glycine is apparently present at a more constant level and seems to modulate/control the receptor for its response to glutamate. One of the most effective ways to control synaptic concentrations of neurotransmitter is to influence their re-uptake at the synapses. Neurotransmitter transporters by removing neurotransmitters from the extracellular space, can control their extracellular lifetime and thereby modulate the magnitude of the rac-[5-methanesulfonyI-2^2.23533-pentafluor^ 3-y])-l,3-dihydro-isoindol-2-y]]-inetharjone? rac-(2-isopropoxy-5-methanesulfonyl-phenyl)-[5^te1rahydro-pyrari-3-yl)-l53-dihydro-isoindol-2-yl]-methanone, [5-chloro-6-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-l53-dihydro-isoindol-2-yl]-[5-methanesulfonyl-2-(252?35353-pentafluoro-propoxy)-phenyl]-methaiione, rac-[5-methanesulfonyl-2-(2?253,3.3-pentafluoro-propoxy)-phenyl]-[5-(tetrahydro-pyran-3-yl)-l53"dihydro-isoindol-2-y]]-methanoTie, ((lS54S)-5-ch]oro-6-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-l,3-dihydro-isoindoI-2-yl)-[5-methanesulfonyl-2-((S)-2,2.2-trifluoro-l-rnethyl-ethoxy)-phenyl]-rnethanone, [5-fluoro-6-(tetrahydro-pyran-4-y])-l?3-dihydro-isoindol-2-yI]-[5-methanesulfonyl-2-((S)-2;252-trifIuoro-l-methy]-ethoxy)-pheny]]-methanone5 [5-rnethanesulfonyl-2-((S)-2;2,2-trifluoro-l-methyl-ethoxy)-phenyl]-[5-(tetrahydro-pyran-4-yloxy)-l53-dihydro~isoindol-2-y]]-methanone, [5-(3-fluoro-oxetan-3-yl)-l53-dihydro-isoindol-2-yl]-[5-methanesuIfonyl-2-((S)-2,2.2-trifluoro-l-methyl-ethoxy)-phenyl]-methanone, [5-methanesulfony]-2-((S)-2.2s2-frifluoro propoxy)-l,3-dihydro-isoindol-2-yl]-methanone, (5-nuoro-6-morpholin^-yi-13^ihydro-isoindol-2-y])-[5-methanesulfonyI-2-((S)-2;2,2-trifluoro-l-methyl- known in the chemical literature, or may be prepared using a variety of methods well known in the art. The bis-halogenated compounds of formula IVa, where RJ and FT are H can be prepared by methods well known in the art. Alternatively, compounds of formula n A. II B; II C and II D can be prepared by reaction of bis-halogenated compounds of formula IV (A, B, C and D) in the presence of triphenylmethylamine and a base such as diisopropylethylamine to afford intermediate compounds of formula XIV (A. B, C and D) followed by deprotection in the presence of an acid such as trifluoroacetic acid (Scheme 12). In the case where compounds of general formula II contain reactive functionality (e.g. halogen substituents or thioether substituents) in R . R4 or R5, further reactions may be performed on either the compounds of formula II (A, B, C, D) or the compounds of formula II in which the nitrogen atom is protected (i.e. Boc or Trityl) or the compounds of formula 1 so as to modify the substituent R°to R . Prepared in analogy to Example A2 (c) from 4-Fluoro-6-trifluoromethyl-2~trityI-2.3-dihydro-1 H-isoindole and trifluoroacetic acid. Yellow oil. MS (m/e): 206.1 ([M+H^ 100%). Example A18 5~TrifIuoromethoxy-2?3-dihydro-l H-isoindole A mixture containing 0.68 mmol 5-Hydroxy-lT3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (CAS: 226070-47-9), 0.68 mmol potassium carbonate and 0.68 mmol ethvl chlorodifluoroacetate in 1.5 ml DMF was stirred overniaht at 65 °C. The mixture was then partitioned between ethyl acetate and water and the organic phase was then separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified Prepared in analogy to Example A16(a) from 2-Methyl-3-trifluoromethyl-5H-furo[3?4-b]pyridin-7-one. White solid. MS (m/e): 222.1 ([M+H]+, 100%) (e) 23-BisKrhlorometbvl^-methvl-5-trifluoronaethyl-pvridine Prepared in analogy to Example A13(a) from (3-Hydroxymethyl-6-methyl-5-trifluoromethyl-pyridin-2-yl)-methanol. Colorless oil. MS (m/e): 257.0 ([M+H]+: 100%) (f) 2-Methyl-3-1rifluoromethvl-6-tTi1?/l-6.7-dihYdro-5H-pvTTolor3.4-b1pvridine Example A21 Rac-5-Methyl-3-trif1uoromethyl^,7^ihydro-5H-pyrroIo[3,4-b]pyridine (a) 3-Acet^l-5-trifluoromethvl-pvridine-2-carbQxylic acid diisopropylamide Prepared in analogy to Example A17(b) from 5-Trifluoromethy]~pyridine-2-carboxylic acid Prepared in analogy to Example A 14(c) from rac-l-(2-Hydroxymethyl-5-trifluoromethyl-pyridin-3-yl)-ethanol. Yellow oil. (e) rac-5-Metfayl-3-trifluorometfayl^,7^ihvdrcH5H-pvrrolor3.4-b]pvridin^ Prepared in analogy to Example A2(c) from rac-5-Methyl-3-trifluoromethyl-6-trityl-6,7-dihydro-5H-pyTTolo[354-b]pyridine. Yellow oil. MS (m/e): 203.3 ([M+H]+, 100%) Example A22 6-Chloro-2r3-dihydro-lH-pyrrolo[3,4-c]pyridine (a) 6-Chloro-N.N-diisopropvl-nicotinamide A mixture containing 5.03 mmol 5-Bromo-13Kiihydro-isoindole-2-carboxylic acid tert-butyl ester (CAS: 201940-08-1), 16.6 mmol potassium carbonate. 5.5 mmol bis(pinacolato)diboron and 0.15 mmol Ll-bis(diphenylphosphino)feiTOCene dichloro palladium (II) dichloromethane adduct in 15 ml degazed DMF was stirred at 70°C for 6 hours. The solvent was removed in vacuo. The residue was stirred in 30 ml dichloromethane. The mixture was filtered and the filtrate concentrated in vacuo. The crude oil was purified on a 50 g Flashpack cartridge (Eluent: Heptane/AcOEt) to afford the title compound as a white solid (63 % yield). MS (m7e): 346.1 ([M+H]+, 100%) (b) 5-(4-Methvl-thiazol-2-yl)-L3-dihvdro-isoindole-2-carboxvlic acid tert-butyl ester Prepared in analogy to Example A3(e) from 5^4-Methyl4hia^l-2-yl)~13^ihydro-isoindole-2-carboxylic acid tert-butyl ester and using trifluoacetic acid instead of hydrochloride acid. Brown solid. MS (m/e): 217.1 ([M+H]+s 100%) Example A24 5-(2-MethyI-pyridiii-4-yl)-2^-dihydro-lH-isoindoIe fa) 5-(2-Methvl-pvridin-4"vl)-K3-dihvdro-isoindole-2-carboxYlic acid tert-butyl ester Prepared in analogy to Example A3(e) from 5-(2-Methyl-pyridin-4-yl)-L3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and using trifluoacetic acid instead of hydrochloride acid. Brown solid. MS (m/e): 211.0 ([M+Hf, 100%) Example A25 S^S-Metbyl-thiophen-^yiyiyS-dihydro-lH-isoindole (a) 545-Methvl-thiophen-3-Yl)-13^ihvdro-isoindole-2- Prepared in analogy to Example A23(b) from 5-(4.455?5-Tetramethyl-[1 ?3,2]dioxaborolan-2-yl)-l 53-dihydro-isoindole-2-carboxylic acid tert-butyl ester and 4-bromo-2-methykhiophene (commercial). Light yellow solid. MS (m/e): 315.2 ([M]+, 100%) (b) 5-(5-Methyl-thiophen-3-vl)-2.3-dihvdro-l H-isoindole Prepared in analogy to Example A3(e) from 5-(5-Methyl-thiophen-3-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and using trifluoacetic acid instead of hydrochloride acid. Light yellow solid. MS (m/e): 216.1 ([M+H]+s 100%) Example A26 5-(5-Methy!-thiazoL2-yl)-23-dihydro-l H-isoindole Prepared in analogy to Example A23(b) from 5-(4A5.5-Tetramethyl-f 1,3.2]dioxaborolan-2-yl)-13-dihydro-isoindole-2-carboxylic acid tert-butyl ester and 2-Iodo-5-methyl-thiazole (CAS: 847547-16-4). Yellow solid. MS (m/e): 317.0 ([M]\ 100%) Prepared in analogy to Example A3(e) from 5-isopropoxy-L3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Brown solid. MS (m/e): 178.3 ([M+H]+, 100%). Example A41 5-Ethoxy-2^-dihydro-lH-isoindoIe hydrochloride Prepared in analogy to Example A6(a) from 5-iodo~l,3-dihydro-isomdole-2-carboxylic acid tert-butyl ester (Example A38(b)) and ethanol. Light brown solid. MS (m/e): 208.1 ([M+H-Me2C=CH2]+, 100%). Prepared in analogy to Example A3(e) from 5-ethoxy-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Brown solid. MS (m/e): 164.4 ([M+H]"\ ! 00%). Prepared in analogy to Example A3(d) from 5-iodo-1.3-dihydxo-isoindole-2-carboxylic acid tert-butyl ester (Example A3 8(b)) and 4,4-difluoropiperidine hydrochloride. Yellow solid. MS (m/e): 339.1 Prepared in analogy to Example A3(d) from 5-chloro-6-iodo-l53-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) and morpholine. Yellow solid. MS (m/e): 341.3 ({37C1}M+H+, 20%), 339.1 ({35CI}M+H+, 100%). (b) 5-Chloro-6-morpholin-4-Yl-2.3-dihydro-lH-isoindole hydrochloride Prepared in analogy to Example A3(e) from 5-chloro-6-morpholin-4-yl-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Off-white solid. MS (m/e): 241.4 ({37C1}M+H+, 52%)T 239.3 ({35C1}M+H\ 100%). Example A45 5-Ethyl-6-trifluoromethyI-23-dihydro-lH-isoindole hydrochloride (a) 5-Trifluoromethyl-6-vinvl-L3-dihvdro-isoindole-2-carboxylic acid tert-butyl ester To a stirred solution 0.61 mmol 5-iodo-6-trifluoromethyI-1.3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A35(d)) in 3 ml dioxane were added 0.04 mmol palladium(II) acetate and 0.18 mmol triphenylarsine and the mixture was stirred at RT for 10 min. 0.91 mmol vinyltributylstannane was then added and the mixture was heated at 100 °C for 16 h. The reaction mixture was then cooled to room temperature, filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (S1O2- heptane/ethyl acetate) to yield the title compound as a yellow solid (93% yield). MS (m/e): 258.0 ({M+H-Me2C=€H2f ? 100%). Example A46 5-Morpholin^yl-^triflnoromethyl-2^3-dihydro-lH-isoindoIe hydrochloride Prepared in analogy to Example A3(d) from 5-iodo-6-trifluoromethyl-l73-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A35(d)) and morpholine. White solid. MS (m/e): 373.0 ([M+H]+? 100%). (b) 5-Morpholm-4-Yl-6-trifluoromethyl-2.3-dihvdro-lH-isoindole hydrochloride Prepared in analogy to Example A3(e) from 5-morpholin^-yl-6-trifluoromethyl-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Off-white solid. MS (m/e): 273.0 ([M+H]+, 100%). h. The reaction mixture was then cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was resuspended in THF, 25% aqueous hydrochloric acid was added, and the mixture was stirred at RT for 3 h. The mixture was then partitioned between ethyl acetate and water and the phases were separated. The aqueous phase was made alkaline to pH 14 by addition of 30% aqueous NaOH solution and then extracted with ethyl acetate. The organic phase was then washed with brine, dried over sodium sulfate, and concentrated in vacuo to yield the title compound as a brown solid (95% yield). MS (m/e): 162.6 ([M+H]+, 100%). Example A48 l-(6-Trifluoromethyl-23-dihydro-lH-isoindoI-5-yI)-ethanone Prepared in analogy to Example A47 from 5-iodo-6-trifluoromethyI-1.3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A35(d)) and 1-ethoxyvmyltributylstaimane. White solid. MS (m/e): 230.3 ([M+H]+, 100%). Example A49 S-CTetrahydro-pyran^-Yi^l^-dihydro*!H-isoindole hydrochloride (b) S^TetrahydrcHpvran^vlVI3KiihvdrQ-isoindole-2H^arboxvlic acid tert-butvl Ester To a stirred solution 7.27 mmol 5-(3,6-dihydro-2H-pyran^~yl)-],3-dihydro-isoindoIe-2-carboxylic acid tert-butyl ester in 60 ml methanol were added 1.60 g 10% palladium on charcoal and 72.7 mmol ammonium formate and the mixture was heated at reflux for 30 min. The reaction mixture was then cooled to room temperature, filtered, and the filtrate concentrated in vacuo. The residue was taken up in THF and washed with brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiC>2, heptane/ethyl acetate) to yield the title Prepared in analog}' to Example A49(b) from 5-(3.6-dihydro-2H-pyran-4-yl)-6-methyl-1.3-dihvdro-isoindole-2-carboxvlic acid tert-butvl ester and ammonium formate. Yellow solid. MS (m/e): 262.1 ([M+H-Me2C=CH2l+? 100%). (c) 5-Methyl-6-(tetrahvdro-pvran-4-vl)-2.3-dihydro-lH-isoindole trifluoro-acetate Prepared in analogy to Example A2(c) from 5-methyl-6-(tetrahydro-pyran-4-yl)-l_3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. MS (m/c): 218.4 ([M+H]+, 100%). Example A64 3^2^Dihydro-lH-isoindol-5-yI)-2-methyl-tetrahydro-fai^ (a) 3-(2-Benzyl-2,3-dihydro-l H-isoindol-5-vl)-2-methyl4etrahvdro-fiiran-3-ol Prepared in analogy to Example A62(b) from 2-benzyl-5-bromo-2;3-dihydro-lH-isoindole (Example A62(a)) and 2-methyltetrahydrofuran-3-one. Brown oil. MS (m/e): 310.4 ([M+Hf, 100%). (b) 3-f23-Dihvdro-lH-isoindol-5-vl)-2-methvl-tetrahydro-furan-3-ol Prepared in analogy to Example A62(c) from 3-(2-benzyl-2.3-dihydro-1H-isoindol-5-yl)-2-methyl-tetrahydro-furan-3-ol and hydrogen. Yellow oil. MS (m/e): 220.3 ([M+H]"\ 100%). Example A65 S^Z-Methyl-tetrahydro-furan-S-yl^Z^-dihydro-lH-isoindole (a) 2-Benzyl-5-f2-methyl-2.5"dihydro-furan-3-yn-2,3-dihydro-lH-i$oindole temperature overnight The reaction mixture was then concentrated in vacuo and the residue was purified by chromatography (S1O2. heptane/ethyl acetate) to yield the title compound as a colourless oil (33% yield). MS (m/e): 292.1 ([M+H]+, 100%). (b) 5^2-Methyl-tetrahvdro-fijran-3-YlV2.3Kiihvdro-lH"isoindole Prepared in analogy to Example A62(c) from 2-benzyl-5-(2-methyl-2.5-dihydro-furan-3-yl)-23-dihydro-lH-isoindole and hydrogen. Yellow oil. MS (m/e): 20*4.1 ([M+H]+, 100%). Example A66 3-(2r3-Dihydro-lH-isoindol-5-yl)-tetrahydro-furan-3-ol (a) 3-(2-Benzyl-2 J-dihvdro-1 H-isoindol-5-vl)-tetrahydro-furan-3-oI Prepared in analogy to Example A62(b) from 2-benzyl-5-bromo-2.3-dihydro-l H-isoindole (Example A62(a)) and tetrahydrofuran-3-one. Brown oil. MS (m/e): 296.4 ([M+Hf5 100%). (b) 3-(2.3-Dihydro-l H-isoindol-5-ylVtetrahydro-furan-3-ol Prepared in analogy to Example A65(a) from 3-(2-benzyl-2;3-dihydro-lH-isoindol-5-yl)-tetrahydro-fiiran-3-ol (Example A66(a)) and methanesulfonyl chloride, triethylamine, and DBU. Brown solid. MS (m/e): 278.0 ([M+H]*5 100%). (b) 5- Prepared in analogy to Example A62(c) from 2-benzyl-5-(2?5-dihydro-furan-3-yl)-2,3-dihydro-lH-isoindole and hydrogen. Brown oil. MS (m/e): 190.4 ([M+H]+; 100%). Example A68 5-Chloro-6-(tetrahydro-pyran-4-yI)-2r3-dihydro-lH-isoindole trifluoro-acetate (a) 5-Chloro-6-(tetrahvdro-pYran-4-Yl)-K3-dihydro-isoindole-2-carboxvlic acid tert-butyl ester To a stirred solution 0.81 mmol 5-chloro-6-(3.6-dihydro-2H-p>Tan-4-yl)-L3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A61(a)) in 40 ml methanol was added 0.41 mmol platinum(IV) oxide and the mixture was stirred under an atmosphere of hydrogen for 1 6 h. The reaction mixture was then filtered and the filtrate was 95 concentrated in vacuo. The residue was purified by chromatography (SiCK heptane/ethyl acetate) to yield the title compound as a white solid (38% yield). MS (rn/e): 284.3 ({37Cl}[M+H-Me2C=CH2]+, 49%)5 282.3 ({35Cl}[M+H-Me2C=CH2]\ 100%). (b) 5-Chloro-6-(tetrahvdro-pYran-4-vl)-2.3-dihvdro-l H-isoindole trifluoro-acetate Prepared in analogy to Example A2(c) from 5-chloro-6-(tetrahydro-pyran-4-yl)-13-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. MS (m/e): 240.2 ({37C1}[M4-H]+, 39%), 238.1 ({35C1}[M+H]+, 100%). Example A69 5-Ethyl-6-(tetrahydro-pyran-4-yl)-23-d>hydro-lH-isoindole trifluoro-acetate (a) 5-(3,6-Dihvdro-2H-pvmn^-vlV6-vinvl-K3-dihvdro-isoindole-2-c^rboxvlic acid tert- butyl ester Prepared in analogy to Example A54(a) from 5-chloro-6-(3,6-dihydro~2H-pyran-4-yl)-L3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A61(a)) and vinyltributylstannane. White solid. MS (m/e): 272.4 ([M+H-Me2C==CH2]+, 100%). (b) 5-Ethvl-6-(tetrahvdro-pyran-4-vn-13-dihydro-isoindole-2-carboxylic acid tert-butyl ester Prepared in analogy to Example A2(c) from 5-e1hyl-6-(tetrahydro-p)aan-4-yl)-L3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. MS (m/e): 232.1 ([M+H]\ 100%). Example A70 (2S,6R)-4^2^-Dihydro-lH-isoindoI-5-yI}-2,6^imethyl-teti^hydro-pyi^n-4-oI (a) (2S.6RM-(2-Benzvl-23KJihydro-lH^^ ol Prepared in analogy to Example A62(b) from 2~benzyl-5-bromo-2.3-dihydro-l H-isoindole (Example A62(a)) and (2R.6S)-2,6-dimethyl4etrahydro-pyran~4-one. Brown solid. MS (m/e): 338.4 ([M+H]\ 100%). (b)(2S.6R)-4-(2.3-Dihvdro-1H-isoindol-5~vlV2.6-dimethvl-tetrahydro-pyran-4-ol Prepared in analogy to Example A65(a) from (2S?6R)-4-(2--benzyl-23-dihydro-lH-isoindol-5-yl)-2,6Kiimethyl-tetrahydro-pyran-4- residue was purified by chromatography (SiCb, heptane/ethyl acetate) to yield the title compound as a yellow oil (40% yield). MS (m/e): 246.1 ([M+H-Me2C-CH2] \ 100%). (c) rac-5^etrahydro-pyran-3-vlV13Hiihvdro-isoindole-2K^3rfaoxvlic acid tert-butyl ester To 0.58 mmol 3-(23-dihydro-lH-isoindol-5-yl)-oxetan-3-ol in 2 ml acetonitrile and 2 ml nitromethane at -60 °C was added 1.15 mmol diethylaminosulfur trifluoride and the mixture was allowed to warm to 0 °C over 30 min. The reaction mixture was re-cooled to -60 °C and quenched by addition of 5 ml saturated aq. sodium carbonate solution. The mixture was warmed to RT and diluted with THF and ethyl acetate, then washed sequentially with water and with brine. The organic phase was separated, dried over sodium sulfate, and concentrated in vacuo to afford the title compound as a brown oil (67% yield). MS (m/e): 194.3 ([M+H]+5 100%). Example A&2 5-CycIopropyImethoxy-2^-dihydro-lH-isoindoIe trifluoroacetate (a) 5-Cvclopropylmethoxv-L3-dihvdro-isoindole-2-carboxvlic acid tert-butyl ester Prepared in analogy to Example A6(a) from 5-iodo-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and cyclopropylmethanol. Off-white solid. MS (m/e): 234.1 ([M+H-Me2C=CH2]+, 100%) (b) 5-Cyclopropylmethoxy-2.3-dihvdro-l H-isoindole trifluoroacetate Prepared in analogy to Example A2(c) from 5-cyclopropy!methoxy-1.3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. MS (m/e): 190.4 ([M+H]+. 100%). Example A83 5^3^^TriflBor€Hpropoxy)-2,3-dihydro-l H-isoindole trifluoroacetate (a) 5^333-Trifluoro-propoxvV13KiihvdTO-isoindole-2K^rboxviic acid tert-butyl ester Prepared in analogy to Example A6(a) from 5-iodo-L3-dihydro-isomdole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 3,3,3-trifluoropropanoL Off-white solid. MS (m/e): 276.3 ([M+H-Me2C-CH2]+? 100%) (b) 5-(33,3-Trifluoro-propoxv)-2.3-dihydro-lH-isoindole trifluoroacetate Prepared in analogy to Example A2(c) from 5-(33,3-trifluoro-propoxy)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Brown oil. MS (m/e): 232.1 ([M+Hf, 100%). Example A84 5-Fluoro-6-morpholin-4-yI-23-dihydro-lH-isoindole trifluoroacetate (e) 5-Fluoro-6-iodo-23-dihydro-lH-isoindole Prepared in analogy to Example Al from 5-fluoro-6-iodo-isoindole-l53-dione and borane tetrahydrofiiran complex. Yellow oil. MS (m/e): 264.0 ([M+H+; 100%). (f) 5-Fluoro-6-iodo-1.3-dihvdro-isoindole-2-carboxylic acid tert-butyl ester Prepared in analogy to Example A3(c) from 5-fluoro-6-iodo-2J-dihydro-lH-isoindole and di-tert-butyl dicarbonate. Light yellow solid. MS (m/e): 308.1 ([M4H-Me2C=CH2]+, 100%). (g) 5-Fluoro-6-morpholin-4-vl-K3-dihydro-isoindole-2-carboxylic acid tert-butyl ester Prepared in analogy to Example A3(d) from 5-fluoro-6-iodo-L3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and morpholine. Yellow solid. MS (m/e): 323.4 ([M+H]+. 100%). (h) 5-Fluoro-6-morpholin-4-vr-2.3-dihvdro-lH"isoindole trifluoroacetate Prepared in analogy to Example A2(c) from 5-fluoro-6-morpholin-4-yI-1.3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. MS (m/e): 223.4 (M+Hf, 100%). was destroyed by addition of a few drops of a sodium hydrogenosulfite solution. The solid was filtered, washed with water and dried (HV, 50°C, 1 hour) to yield the title compound. MS (m/e): 325.0 (M-H, 100%) Example B20 264 mmol 5-Chlorosulfonyl-2-fluoro-benzoic acid (CAS: 37098-75-2) was added portionwise onto a solution of 1.98 mol sodium sulfite in 1 L of water. The reaction mixture was kept under basic conditions by the addition of the proper amount of 20% NaOH and was stirred at room temperature for 45 minutes. After such time the reaction mixture was cooled down with an ice bath and was then acidified by the addition of 20% H2SO4 solution until reaching pH 2. Water was evaporated and 600 ml methanol was added. The mixture was stirred overnight and filtrated. The filtrate was evaporated and dried to yield the title compound as a white solid (72%). MS (m/e): 203.0 ([M-H, 100%) (b) 5-Ethanesulfonyl-2-fluoro-benzoic acid ethyl ester To 24 mmol 2-Fluoro-5-sulfino-benzoic acid in 200 ml of DMF was added 73 mmol potassium carbonate and 86 mmol ethyl iodide. The reaction mixture was then stirred at room temperature for 50 hours. After such time the reaction mixture was concentrated in vacuo and the residue was dissolved in 100 ml water. The aqueous phase was extracted 2x50 ml with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and the solvent was removed in vacuo . The residue was chromatographed over Prepared in analogy to Example B25 from 2-Iodo-5-methanesulfonyl-benzoic acid (example B 19(b)) and In a glass tube was added successively 0.29 mmol 2-Iodo-5-methanesulfonyl-benzoic acid methyl ester (example B19(c)), 0.35 mmol 4-methylpyrazole, 0.59 mmol potassium carbonate. 0.06 mmol Cul and a solution of 0.12 mmol trans-K2-diaminocyclohexane in 0.4 ml dioxane (degased). The tube was filled with argon and sealed with a cap. The reaction mixture was heated at 120°C overnight The reaction mixture was cooled down to room temperature, dichloromethane and water were added. The aqueous phase was extracted 2 times with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated. The crude compound was purified on a 1 Og Flashpack cartridge. Eluent: Heptane/ethylacetate to provide the title compound (57%) as a light yellow oil. MS (m/e): 295.0([M+Hf, 100%). (b) 5-Methanesu]fonvl-2-(4-methvl-pvrazol-l-ylVbenzoic acid Prepared in analogy to Example B3(c) from 5-Methanesulfonyl-2-(4-methyl-pyrazol-l-yl)-benzoic acid methyl ester. White solid. MS (m/e): 279.1 ([M-H], 100%). Example B33 Prepared in analogy to Example A15 (a) from l-Iodo-4,5-dimethyl-2-trifluoromethyl-benzene (CAS: 165323-73-9) and chromium(VI) oxide. Grey solid. MS (m/e): 359.0 ([M-H]", 100%). (b) 5-Iodo-6-trifluoromethyl-isoindole-l .3-dione Prepared in analogy to Example A15 (b) from 4-lodo-5-trifluoromethyl-phthalic acid and urea. Light brown solid. MS (m/e): 339.9 ([M-H]\ 100%). (c) 5-Iodo-6-trifluoromethvl-2.3-dihvdro-lH-isoindole A mixture of 0.387 mmol 2-isopropoxy-5-methanesulfonyl-benzoic acid (example Bl)r 0.464 mmol 2,3-Dihydro-lH-isoindole (commercial), 0.426 mmol TBTU and 1.935 mmol DIPEA in 1.4 ml DMF was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo. The residue was taken in water and extracted with ethylacetate. The combined organic phases were washed with saturated sodium bicarbonate solution, dried " •' over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (Si(>25 heptane/ethyl acetate) to yield the title compound as a light brown solid (88% yield). MS (m/e): 360.2 [M+H]+, 100%) In analogy to Example 1, compounds 2 to 91 of the following table were prepared from the acid derivatives and amine derivatives: To a RT suspension of 0.61 mmol sodium hydride (50% in mineral oil) in 0.5 ml dry DMF, a solution of 0.29 mmol 2-Isopropoxy-5-methanesuIfonyi-benzamide (example B20) in 1 ml dry DMF was added dropwise. After 15 minutes at RT and 15 minutes at 50 C7 the reaction mixture was cooled to 0 °C; and treated by a solution of 0.29 mmol 12-Bis-bromomethyl-3-fluoro-benzene (CAS: 62590-16-3) in 1 ml dry DMF. The reaction mixture was allowed to warm to RT and stirred for 15 minutes then cooled to 0°C. quenched with water and extracted with ethylacetate. The combined organic phases were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The * Prepared in analogy to Example A6(a) from (4-Iodo-l53-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((S)-2,2?2-trifluoro-l-methyl-ethoxy)-phenyl]-methanone (Example C1). Light brown solid. MS (m/e): 444.4 In analogy to Example 1, compounds 101 to 312 of the following table were prepared from the acid derivatives and amine derivatives: Example 314 [5-MethanesulfonyI-2-((S)-2,2,2-trifluoro-l-methyI^thoxy)-phenyl]-(2-(tetrahydr^ pyran-4-yI)-5,7-dihydro-pyrroio[3,4-b]pyridin-6-yl]-methanone (aM2-(3.6-Dihvdro-2H-pyran^-vl)-5J-d^ mj^thanesu^ '^_ Prepared in analogy to Example A54(a) from (2-chloro-557-dihydro-pyrrolo[3,4- b]pyndm-6-yl)-[5-methanesulfonyl-2^ methanone (Example C4) and tributyl-(3,6-dihydro-2H-p3Tan-4-yl)-stannane. White solid. MS (m/e): 497.4 [M+H]+? 100%). (b) [5-Methanesulfonyl-2-((Sy2,2,24rifluoro-l-methYl^th^ pyran^-ylV5,7-dihydro-pyrrolo[3il4-blpvridin-6-yl]-methanone Prepared in analogy to Example A49(b) from [2-(3,6-dihydro-2H-pyran-4-yl)-5.7- t^ dihydro-pyn-olo[3,4-b]pyridin-6-ylH ethoxy)-phenyl]-methanone and ammonium formate. White solid. MS (m/e): 499.3 [M+H]\ 100%). In analogy to Example A4(a), compounds 315 to 320 of the following table were prepared from (5-Iodo-l ;3-dihydro-tsoindol-2-yl)-[5-methanesulfonyl-2-((S)-2,2;2-trifluoro-l-methyl»ethoxy)-phenyl]-methanone (Example C3) and organostananne derivative: To a solution of 0.19 mmol (5-Iodo-l J-dihydro-isoindol^-yl^S-methanesulfonyl-^-^S^^^^rifluoro-l-methyl-ethoxy^phenylj-methanone (Example C3) in 1ml DMF under argon was added successively 0.018 mmol tetrakistriphenylphosphine. 0.28 mmol phenyl boronic acid and 0.56 mmol potassium carbonate. The reaction mixture was 224 heated at 120CC for 2 hours then cooled to room temperature and filtered. The filtrate was evaporated to dryness and the residue was treated with sat. NaCl. The resulting mixture was extracted 3 times with dichloromethane. The organics phases were dried over sodium sulfate and evaporated. The crude compound was purified on a lOg of Si-Amine cartridge: n-Heptane/Ethylacetate to provide the title compound (50%). Off-white solid. MS (m/e): 490.0 [M+H]\ 100%). In analogy to Example 323, compounds 324 to 346 of the following table were prepared from (5-Iodo-l 3^^ydro-isoindol-2-yl)-[5-metiianesulfonyl-2-((S)-2,252-trifluoro-l -methyl-ethoxy)-phenyl]-methanone (Example C3) and boronic acid derivative: Taa solution of 0.21 mmol [5-Methanesulfonyl-2-((S)-2^?2-trifluoro-l-methyl-ethoxy)- phenyl]^3-trifluoromethyl-5,7^ihydro- (example 61) in 2 ml dichloromethane was added 0.31 mmol 3-chloroperbenzoic acid. The mixture was stirred at room temperature for 72 hours. The mixture was diluted with dichloromethane. The solution was washed twice with a sat bicarbonate solution and once with a 10% sodium carbonate solution to destroy any residual peroxides, dried over sodium sulfate, filtered and the solvent was removed in vacuo. The crude solid was purified on a 5g Flashpack cartridge. Eluent: Heptane/ethylacetate to provide the title compound (92%). White foam. MS (m/e): 516.1 [M+NILJ^ 100%). Example 354 6-Chloro-2-(2-isopropoxy-5-methanesulfonyl-beiizoyl)-2^-dihydro-isoindoH-one 0.4 mmol 6-chloro-l-isoindolinone (CAS : 58083-59-3) was dissolved in 3 ml of pyridine. 0.05 mmol of 4-dimethylaminopyridine was added, followed by slow addition of a solution of 0.5 mmol 2-isopropoxy-5-methanesulfonyl-benzoyl chloride (prepared from example Bl and oxalyl chloride in dichloromethane) in 2 ml dichloromethane at room temperature. The reaction mixture is stirred for 10 minutes at room temperature-then the dichloromethane is stripped off in the rotatory evaporator. The remaining solution was then refluxed for 3 hours. The dark red solution was quenched with water, acidified by addition of diluted hydrochloric acid and extracted 3 times with ethyl acetate. The organic phase is dried and concentrated- Chromatography (silica gel; ethyl acetate / heptane) gave the title compound as a slightly yellowish solid. Yield - 55 %. MS (m/e): 408.2 [M+H]+, 100%). Example 355 [5-MethanesuIfonyl-2-((S)-2,2^-trifluoro-l~methyl-ethoxy)-phenyl]^4-morphoIin-4- yl^^-dihydro-indol-l-yl^methanone A mixture of 0.2 mmol (4-Bromo-2,3^ihydro-indol-l-yl)-[5-niethanesulfonyl-2-((S)-2,2,2-trifluorol-niethyl-ethoxy)-phenyl]-inethaDone (example 211), 0.4 mmol morpholine, 03 mmol sodium tert-butylate, 2.5 mg rac.BINAP and 2.0 mg tris-(dibenzylidenaceton)-dipalladium chloroform complex in 5 ml toluene is heated at 80° C for 3 hours. Fresh morpholine (0.4 mmol) is added and the mixture hold at 80° overnight. The reaction mixture is concentrated. Chromatography of the residue (silica gel; ethyl acetate / heptane) yields the title compound as a slightly yellow solid. Yield = 57 %. MS (m/e): 499.3 [M+H]+5 100%). n, m, o, p, q, r, s and t are 1 or 2; x is 0, 1 or 2; y is 1 or 2; and pharmaceutical^ acceptable acid addition salts thereof, with the exception of (2-hydroxy-5-nitro~phenyl)-(6-nitro-indazol-l-yl)-methanone, heterocycloalkyl, Cj^-alkoxy, CN, N02> NH2, aryl, 5-or 6-membered heteroaryl containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen, -NH- Q^-alkyl, -N(Q_6-alkyi)2, cyclic amide, -C(0)-cyclk amide, S-Ci_6-alkyl, -S(0)2- Cj^-alkyl, Ci^-allcyl substituted by halogen, Q_6-aLkoxy substituted by halogen, O-e-alkyl substituted by hydroxy, -0-(CH2)r Q-6-alkoxy, -0(CH2)yC(0)N(C1^alkyl)2> -C(O)- d^alkyl, -0-(CH2)x-aryl, -CHCH^x-cycloalkyl, -0-(CH2)x-heterocycloalkyl, -C(0)0- Ci^-alkyl,-C(0)-NH- Ci_6-alkyl>-C{0)-N(Ci-6-alkyl)2, 2-oxy-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R, R* are independently from each other hydrogen or Ci-6-alkyl; and wherein all aryl-, cycloalkyl-, cyclic amide, heterocycloalkyl- or 5 or 6 membered heteroaryl groups as defined for R , R , R and R may be unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, =0, halogen, Q_6-alkyl, phenyl, Q-a-alkyl substituted by halogen or Ci_6-alkoxy; n is 1 or 2; x is 0,1 or 2; y is 1 or 2; and pharmaceutical!^ acceptable acid addition salts thereof. 3. Compounds of formula I B according to claim 1 wherein R is halogen, -OR , -SR , cycloalkyl, cyclic amide, heterocycloalkyl, aryl or 5-or 6- membered heteroaryl, containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen; i * i" R'/R' are hydrogen, Ci-6-alkyl, Ci_6-alkyl substituted by halogen, —(CH2)X-cycloalkyl or -(CH2)x-aryl; R2 is -S(0)2- CWalkyl, -S(0)2NH- C^-alkyl, N02 or CN; and wherein the additional N-ring atom of the bicyclic amine maybe available in form of its R4 is hydrogen, hydroxy, halogen, =0, Cj^-alkyl, cycloalkyl, heterocycloalkyl, Ci-e-alkoxy, CN, N02, NH2> aryl, 5-or 6-membered heteroaryl containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen, -NH-Cj^-alkyl, -N(Ci_6-alkyl)2, cyclic amide, -C(0)-cyclic amide, S-Cj^-alkyl, -S(0)2- Ci-6-alkyl, Q-6-alkyl substituted by halogen, Q-e-alkoxy substituted by halogen* Ct^-alky! substituted by hydroxy, -0-(CH2)y- CK6-alkoxy, -0(CH2)vC(0)N(Ci^-alkyl)2, -C(O)- Ci.6-alkyl, ~0-(CH2)x-aryl, -0-(CH2)x-cycloalkyl, -0-(CH2)x-heterocycloalkyl, -C(0)0- C^-alkyl, -C(0)-NH- C,.6-alkyl, -C(0)-N(CU6-alkyl)2, 2-oxy-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8~aza-bicycIo[3.2.1]oct-8-yl; R, RJ are independently from each other hydrogen or Q^-alkyl; and wherein all aryl-, cycloalkyl-, cyclic amide, heterocycloalkyl- or 5 or 6 rnembered heteroaryl groups as defined for R , R1 , R* and R may be unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, -O, halogen, Ci_e-allcyl, phenyl, Q.e-alkyl substituted by halogen or Ci-6-alkoxy; m is 1 or 2; x is 0, 1 or 2; y is 1 or 2; and pharmaceutical acceptable acid addition salts thereof. 4. Compounds of formula I C according to claim 1 wherein R is halogen, -OR1 > -SR1 , cycloalkyl, cyclic amide, heterocycloalkyl, aryl or 5-or 6- rnernbered heteroaryl, containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen; R'/Rl are hydrogen, Ci_6-alkyl, Ci_6-alkyl substituted by halogen, ~(CH2)x-cycloallcyl or -(CH2)x-aryl; R2 is -S(0)2- Q^-alkyl, -S(0)2NH- d-e-alkyl, N02 or CN; and wherein the additional N-ring atom of the bicyclic amine may be available in form of its R5 is hydrogen, hydroxy, halogen, =0, Cj.g-alkyl, cycloalkyl, heterocycloalkyl, Cj_6-alkoxy, CN, N02, NH2, aryl, 5-or 6-membered heteroaryl containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen, -NH- C^-alkyl, ~N(Ci_6-alkyl)2» cyclic amide, -C(0)-cyclic amide, S- Q-6-alkyl, -S(0)2- C^-alky!, Ci-e-alkyi substituted by halogen, Cj-6-alkoxy substituted by halogen, Q-e-alkyl substituted by hydroxy, -0-(CH2)r Q_6-aIkoxy, -0(CH2)yC(0)N(CN6-alkyl)2, -C(O)- Q.6-alkyI, -0-(CH2)x-aryl) -0-(CH2)x-cycloa]kyl, -0-(CH2)x-heterocycloalkyl, -C(0)0- Ci-6-aIkyl,-C(0)-NH- C^-alkyl, -C(0)-N(Ci.6-alkyl)2, 2-oxy-5-aza-bicyclo[2.2.1)hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R, R' arc independently from each other hydrogen or Ci-6-alkyl; and wherein all aryl-, cycloalkyl-, cyclic amide, heterocycloallcyl- or 5 or 6 membered heteroaryl groups as defined for R1, R!, R1 and R5 may be unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, =0, halogen, Q_6-alkyl, phenyl, Q_6-alkyl substituted by halogen or d-6-alkoxy; o is 1 or 2; x is 0,1 or 2; y is 1 or 2; and pharmaceutical acceptable acid addition salts thereof. 5. Compounds of formula I D according to claim 1 wherein R is halogen, -OR , -SR , cycloalkyl, cyclic amide, heterocycloalkyl, aryl or 5-or 6- membered heteroaryl, containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen; are hydrogen, Ci^-alkyl, Q-6-alkyl substituted by halogen, — (CH^x-cyd03^)^ or -(CH2)x-aryl; R2 is -S(0)2- d-6-alkyl, -S(0)2NH- C^-alkyl, N02 or CN; and wherein one additional N-ring atom of the bicyclic amine maybe available in form of its R6 is hydrogen, hydroxy, halogen, =0, Q_6-alkyl, cycloalkyl, heterocycloalkyl, Ci_6-alkoxy, CN, N02, NH2, aryl, 5-or 6-membered heteroaryl containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen, -NH- Ci.6-alkyl, -N(Ci_6-alkyl)2, cyclic amide, -C(0)-cyclic amide, S- Q-6-alkyl, -S'(0)2- Ci.6-alkyl, Q.g-alkyl substituted by halogen, Q-6-alkoxy substituted by halogen, C]_6-alkyl substituted by hydroxy, -0-(CH2)r C,.6-alkoxy, «0(CH2)yC(0)N(Ci.6-alky])2, -C(O)- C^-alkyl, ~0-(CH2)x-aryi, -0-(CH2)x-cycloalkyl, -0-(CH2)x-heterocycloaIkyl, -C(0)0- Q_6-alkyl,-C(0)-NH- C1.6-alkyl,-C{0)^N(C1_6-alkyl)2) 2-oxy-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R, R' are independently from each other hydrogen or Q-6-alkyl; and wherein all aryi-, cycloalkyl-, cyclic amide, heterocycloalkyl- or 5 or 6 membered heteroaryl groups as defined for R , R , R and R may be unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, =0, halogen,, Q^-alkyl, phenyl,, Ci.6-alkyl substituted by halogen or , Ci_6-alkoxy; r is 1 or 2; x is 0,1 or 2; y is 1 or 2; and pharmaceutical^ acceptable acid addition salts thereof. 8. Compounds of formula I G according to claim 1 wherein R1 is halogen, -OR1, -SR1 , cycloalkyl, cyclic amide, heterocycloalkyl, aryl or 5-or 6-membered heteroaryl, containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen; R /R are hydrogen, Q.6-alkyl, Q.e-alkyl substituted by halogen, ~(CH2)x-cycloalky! or -(CH2)x-aryl; R2 is -S(0)2-, Ci^alky], -S(0)2NH-> C^-alkyl, N02 or CN; R is hydrogen, hydroxy, halogen, =0, > Q^-alky], cycloallcyl, heterocycloalkyl,, Ci^-alkoxy, CN, N02, NH2, aryl, 5-or 6-membered heteroaryl containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen, -NH-, CN6-alkyl, -N(, Ci_6-alkyl)2, cyclic amide, -C(0)-cyclic amide, S-, C^-alkyl, -S(0)2-, Ci_6~alkyl,, C]_6-alkyl substituted by halogen,, Q^-alkoxy substituted by halogen,, Ci^-alkyl substituted by hydroxy, -0-(CH2)y-, Q-6-alkoxy, -0(CH2)yC(0)N(, C^-alkyl)2> -C(O)-, d_6-alkyl, -0-(CH2)x-aryl, -0(CH2)x~cycloalkyl, -0-(CH2)x-heterocycloalkyl, -C(0)0-, C^-alkyl, -C(0)-NH-, C^aHcyl, -C(0)-N(> Q_6-aIkyl)2, 2-oxy-5-aza-bicyclo[2.2.1]hept-5-ylor 3-oxa-8-aza-biq^clo[3.2.1]oct-8-yl; and wherein the additional N-ring atom of the bicyclic amine maybe available in form of its oxide ° ; and wherein all aryl-, cycloallcyl-, cyclic amide, heterocycloalkyl- or 5 or 6 membered heteroaryl groups as defined for R , R , R and R may be unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, =0, halogen,, Ci_6-alkyl, phenyl, Q.6-alkyl substituted by halogen or, Ci-6-alkoxy; s is 1 or 2; x is 0, 1 or 2; y is 1 or 2; and pharmaceutical^ acceptable acid addition salts thereof with the exception of {2-hydroxy-5-nitro-phenyl)-(6-nitro-indazol-l-yl)-methanone. 9. Compounds of formula I H according to claim 1 wherein R is halogen, -OR , -SR , cycloalkyl, cyclic amide, heterocycloalkyl, aryl or 5-or 6- membered heteroaiyl, containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen; R'/RJ are hydrogen,, Q.6-alkyl,, Q-6-alkyl substituted by halogen,— (CH2)x-cycloalkyl or -(CH2)x-aryi; R2 is -S(0)2-, Q-e-alkyi, -S(Q)2NH-, C^-alkyl, N02 or CN; R10 is hydrogen, hydroxy, halogen, =0,, Ci-6-alkyl, cycloalkyl, heterocycloalkyl,, Q-g-alkoxy, CN, N02> NH2, aryl, 5-or 6-membered heteroaiyl containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen, -NH-, Q-6-alkyl, -N(, Ci^-alkyi)2» cyclic amide, -C(0)-cyclic amide, S-, Ci^-alkyl, -S(0)2-, Q-e-alkyi,, Ci_6-alkyl substituted by halogen,, Ci^-alkoxy substituted by halogen,, Q-6-alkyl substituted by hydroxy, -0-(CH2)r, d^-alkoxy, -0(CH2)yC(0)N(, C^-alkyl)2) -C(O)- , C^-alkyl, -0(CH2)x-aryl> -0-(CH2)x-cycloalkyl, -0-(CH2)x-heterocydoalkyl, -C(0)0, Q_6-alkyl, -C(0)-NH-, Q-6-alkyl, -C(0)-N(, C,^-alkyl)2, 2-oxy-5»aza-bicyclo[2.2.1]hept-5-ylor3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; and wherein the additional N-ring atom of the bicyclic amine may be available in form of its and wherein all aryl-, cycloalkyl-, cyclic amide, heterocycloalkyl- or 5 or 6 membered heteroaryl groups as defined for R , R , R and R may be unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, =0, halogen,, Q_6-alkyl, phenyl, Ci_6-alkyl substituted by halogen or Ci_6-alkoxy; t is 1 or 2; x is 0, 1 or 2; y is 1 or 2; and pharmaceutical^ acceptable acid addition salts thereof. 10. Compounds of general formula I A according to claims 1 and 2, wherein R is OR and R is as described in claims 1 and 2. 11. Compounds of general formula 1 A according to claim 10, wherein thecompounds are: (5>6-dichloro-l,3-dihydro-isoindol-2-yl)-(2-isopropox)?'-5-methanesulfonyl-phenyl)-methanone, rac-(5,6-dichloro-l>3-dihydro-isoindol-2-yl)-[5-rnethanesulfonyl-2-(2?2,2-trifluoro-l-methyl-ethoxy)-phenyl]-methanone> [5-methanesulfonyl-2-((S)-2,2>2-trifluoro-l-methyl-ethoxy)-phenyl]-(5-lTifluoromethyl-l>3-dihydro-isoindol-2-yl)-methanone, (5,6-dichloro-13-dihydro-isoindol-2-yl)-(2-isoprop>dsulfanyl-5-methanesulfonyl-phenyl)-methanone, [5-methanesulfonyl-2-((R)-2,2>2-trifluoro-l-met^^ dihydro-isoindol-2-yl)-methanone, (5-cWoro-6-methyl-l,3-dihydro-isoindol-2-yl)-[5-mefr^ methyi-ethoxy)-phenyl] -methanone, (5-chloro-6-methoxy-l^-dihydxo-isoindol^^ l-methyl-ethoxy)-phenyI]-methanone, (5-ethylsulfanyl-13-dihydro-isoindol-2-yl)-[5-m methyl-ethoxy) -phenyl] -methanone, (2-isobutoxy-5-methanesulfonyl-phenyl)-(5-trifluoromethyi-l,3-dihydro-isoindol-2-yl)-methanone, 4-isopropoxy-N-methyl-3-(5-trifluoromethyl-l>3-ciihydro-isoindole-2-carbonyl)-benzenesulfonamide, (5-ch]oro-6-methyl-13-dihydro-isoindol-2^ methyl-ethoxy)-phenyl] -methanone, (5-chloro-6-methyl-l,3-dihydro-isoindol-2-yl)-{2-isobutoxy-5-methanesulfonyl-phenyl)-methanone, (5-chloro-6-etJiylsidfanyl-l>3-dihydro-isoindol-2-yl)-[5-methanesulfonyI-2-({R)-2>2,2-trifluoro-1 -methyl-ethoxy)-phenyI] -methanone, (2-isopropoxy-5-methanesulfonyl~phenyl)-(5-methoxy-l,3-dihydro-isoindol-2-yl)-methanone, [[5-methanesulfonyl-2-((S)-2,2>2-trifluoro-l-methyl-ethoxy)-phenyl]-(5-methyl-6-trifluoromethyl-l,3-dihydro-isoindol-2-yl)-methanone, [[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(5-methoxy-6-trifluoromethyl-l,3-dihydro-isoindol-2-yl)-methanone> [5-methanesu]fonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(5-trifluoromethoxy-l,3-dihydro-isoindol-2-y3)-methanone, [5-methanesulfonyl-2-((S)-2>2>2-trifluoro-l-methyl-ethoxy)-phenyl]-[5-(4-m€thyl-thiazol-2- |
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3463-CHENP-2007 AMENDED PAGES OF SPECIFICATION 10-12-2014.pdf
3463-CHENP-2007 AMENDED CLAIMS 10-12-2014.pdf
3463-CHENP-2007 AMENDED CLAIMS 30-06-2014.pdf
3463-CHENP-2007 AMENDED PAGES OF SPECIFICATION 30-06-2014.pdf
3463-CHENP-2007 AMENDED PAGES OF SPECIFICATION 1 30-06-2014.pdf
3463-CHENP-2007 CORRESPONDENCE OTHERS 06-06-2013.pdf
3463-CHENP-2007 CORRESPONDENCE OTHERS 22-08-2013.pdf
3463-CHENP-2007 EXAMINATION REPORT REPLY RECEIVED 18-11-2013.pdf
3463-CHENP-2007 EXAMINATION REPORT REPLY RECEIVED 10-12-2014.pdf
3463-CHENP-2007 FORM-3 10-12-2014.pdf
3463-CHENP-2007 FORM-3 18-11-2013.pdf
3463-CHENP-2007 OTHER PATENT DOCUMENT 10-12-2014.pdf
3463-CHENP-2007 OTHER PATENT DOCUMENT 18-11-2013.pdf
3463-CHENP-2007 OTHERS 10-12-2014.pdf
3463-CHENP-2007 OTHERS 30-06-2014.pdf
3463-CHENP-2007 CORRESPONDENCE OTHERS 19-11-2014.pdf
3463-CHENP-2007 FORM-3 06-06-2013.pdf
3463-CHENP-2007 EXAMINATION REPORT REPLY RECEIVED 30-06-2014.pdf
3463-chenp-2007-correspondnece-others.pdf
3463-chenp-2007-description(complete).pdf
HIGHLIGHTED COPY OF FORMS 1 AND 5.pdf
| Patent Number | 264364 | |||||||||||||||
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| Indian Patent Application Number | 3463/CHENP/2007 | |||||||||||||||
| PG Journal Number | 52/2014 | |||||||||||||||
| Publication Date | 26-Dec-2014 | |||||||||||||||
| Grant Date | 23-Dec-2014 | |||||||||||||||
| Date of Filing | 07-Aug-2007 | |||||||||||||||
| Name of Patentee | F. HOFFMANN-LA ROCHE AG | |||||||||||||||
| Applicant Address | 124 GRENZACHERSTRASSE, CH-4070 BASEL, | |||||||||||||||
Inventors:
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| PCT International Classification Number | C07D 209/44 | |||||||||||||||
| PCT International Application Number | PCT/EP06/00761 | |||||||||||||||
| PCT International Filing date | 2006-01-30 | |||||||||||||||
PCT Conventions:
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