WO2006082001A1

WO2006082001A1 - Heterocyclic substituted phenyl methanones as inhibitors of the glycine transporter 1

Info

Publication number: WO2006082001A1
Application number: PCT/EP2006/000761
Authority: WO
Inventors: Synese Jolidon; Robert Narquizian; Roger David Norcross; Emmanuel Pinard
Original assignee: F.Hoffmann-La Roche Ag
Priority date: 2005-02-07
Filing date: 2006-01-30
Publication date: 2006-08-10
Also published as: CA2596636A1; US8188139B2; MY140012A; CN101119968B; TWI347944B; RU2405771C2; CY1109829T1; JP2008529982A; DK1848694T3; US20090203665A1; IL184557A; US7557114B2; ES2334578T3; PL1848694T3; IL184557A0; JP4647670B2; MX2007009342A; AU2006210047A1; NO340731B1; AU2006210047B2

Abstract

The present invention relates to compounds of general formula (I) wherein (i) is an aromatic or partially aromatic bicyclic amine, which may contain one or two additional N-atoms, selected from the group consisting of (a), (b), (c), (d), (e), (f), (g), (h) and to pharmaceutically acceptable acid addition salts thereof.

Description

HETEROCYCLYL SUBSTITUTED PHENYL METHANONES AS INHIBITORS OF THE GLYCINE

_TRANSPORTER i

The present invention relates to compounds of general formula I

wherein

5 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;

R¹ /R¹ are hydrogen, lower alkyl, lower alkyl substituted by halogen, -(CH₂)χ-cycloalkyl or -(CH₂)_x-aryl;

10 R² is -S(0)₂-lower alkyl, -S(O)₂NH-lower alkyl, NO₂ Or CN;

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 of the aromatic or partially aromatic

bicyclic amine maybe available in form of its oxide

;

R³ to R¹⁰ are hydrogen, hydroxy, halogen, =O, lower alkyl, cycloalkyl, heterocycloalkyl, lower alkoxy, CN, NO₂, NH₂, aryl, 5-or 6-membered heteroaryl containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen, -NH-lower alkyl, -N(lower alkyl)₂, cyclic amide, -C(O)-cyclic amide, S-lower alkyl, -S(O)₂-lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, lower alkyl substituted by hydroxy, -O-(CH₂)_rlower alkoxy, -O(CH₂)_yC(O)N(lower alkyl)₂, -C(O)-lower alkyl, -O-(CH₂)_x-aryl, -O-(CH₂)_x-cycloalkyl, -O-(CH₂)_x-heterocycloalkyl,

-C(O)O-lower alkyl, -C(O)-NH-lower alkyl, -C(O)-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-, cycloalkyl-, cyclic amide, heterocycloalkyl- or 5 or 6 membered heteroaryl groups as defined for R¹, R¹ , R¹ and R³ to R¹⁰ may be unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, =O, halogen, lower alkyl, phenyl, lower alkyl substituted by halogen or lower alkoxy;

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 to pharmaceutically acceptable acid addition salts thereof.

Compounds encompassed by the present invention are those of the following structure:

I _T AΛ

wherein the definitions are described above.

The present invention relates also to processes for preparation of those compounds, 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 (GIyT- 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 JA, Neuron, 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., BrJ. Psychiatry, 1999, 174(suppl. 28): 44-51). A complementary model of schizophrenia was proposed in the mid- 1960' based upon the psychotomimetic action caused by the blockade of the glutamate system by compounds like phencyclidine (PCP) and related agents (ketamine) which are noncompetitive NMDA receptor antagonists. Interestingly in healthy volunteers, PCP- induced psychotomimetic action incorporates positive and negative symptoms as well as cognitive dysfunction, thus closely resembling schizophrenia in patients (Javitt DC et al., 1999, Biol. Psychiatry, 45: 668-679 and refs. herein). Furthermore transgenic mice expressing reduced levels of the NMDARl subunit displays behavioral abnormalities similar to those observed in pharmacologically induced models of schizophrenia, supporting a model in which reduced NMDA receptor activity results in schizophrenia- like behavior (Mohn AR et al., 1999, Cell, 98: 427-236).

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 CoUingridge 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 (GainetdinovRR et al, 2002, Trends in Pharm. ScL, 23(8): 367-373). Glycine transporters, which form part of the sodium and chloride family of neurotransmitter transporters, play an important role in the termination of post-synaptic glycinergic actions and maintenance of low extracellular glycine concentration by reuptake of glycine into presynaptic nerve terminals and surrounding fine glial processes.

Two distinct glycine transporter genes have been cloned (GIyT-I 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 (Ia, Ib, Ic and Id). Only two of these isoforms have been found in rodent brain (GlyT-la and GIyT-Ib). GlyT-2 also presents some degree of heterogeneity. Two GlyT-2 isoforms (2a and 2b) have been identified in rodent brains. GIyT-I is known to be located in CNS and in peripheral tissues, whereas GlyT-2 is specific to the CNS. GIyT-I 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, MoI. Mem. Bϊol, 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 GIyT- 1 transporter (Bergereon R. Et al., 1998, Proc. Natl. Acad. ScL USA, 95: 15730-15734; Chen L et al., 2003, /. 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, /. 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).

Thus, increasing activation of NMDA receptors via GIyT- 1 inhibition may lead to agents that treat psychosis, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer's disease. 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.

Furthermore, the invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers.

As used herein, the term "lower alkyl" denotes a saturated straight- or branched- chain group containing rrom 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like. Preferred alkyl groups are groups with 1 - 4 carbon atoms.

As used herein, the term "cycloalkyl" denotes a saturated carbon ring, containing from 3 to 6 carbon atoms.

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 [l,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, CH₂CH₂CF₃, CH₂CH₂CH₂CF₃,

CH(CF₃)CH₂CH₃, C[(CH₃)₂]-CF₃, CH₂CH₂Cl, CH₂CF₂CF₃, CH₂CF₂CHF₂, CF₂CHFCF₃, C(CH₃)₂CF₃, CH(CH₃)CF₃ or CH(CH₂F)CH₂F. Preferred are CH₂CF₃, CF₃ or CH(CH₃)CF₃.

The term "lower alkoxy" denotes a saturated straight- or branched-chain group containing from 1 to 6 carbon 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 =O.

The term "5 or 6-membered heteroaryl" denotes for example furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyrimidinyl or the like.

The term "pharmaceutically 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 R¹ is OR¹ and R¹ is as described above.

The following specific compounds relate to this group:

(5,6-dichloro-l,3-dihydro-isoindol-2-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)- methanone, rac-(5,6-dichloro-l,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-(2,2,2-trifluoro-l- methyl-ethoxy) -phenyl] -methanone, [5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(5-trifluoromethyl- l,3-dihydro-isoindol-2-yl)-methanone,

(5,6-dichloro-l,3-dihydro-isoindol-2-yl)-(2-isopropylsulfanyl-5-methanesulfonyl- phenyl) -methanone,

[5-methanesulfonyl-2-((R)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(5- trifluoromethyl- 1 ,3 -dihydro-isoindol-2-yl) -methanone,

(5-chloro-6-methyl-l,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2- trifluoro-l-methyl-ethoxy)-phenyl]-methanone,

(5-chloro-6-methoxy-l,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2- trifluoro- l-methyl-ethoxy)~phenyl] -methanone,

(5-ethylsulfanyl-l₎3-d.ihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l- methyl-ethoxy) -phenyl] -methanone,

(2-isobutoxy-5-methanesulfonyl-phenyl)-(5-trifluoromethyl-l,3-dihydro-isoindol-2-yl)- methanone,

4-isopropoxy-N-methyl-3-(5-trifluoromethyl-l,3-dihydro-isoindole-2-carbonyl)- b enzenesulfonamide,

(5-chloro-6-methyl-l₎3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((R)-2,2,2- trifluoro- l-methyl-ethoxy)-phenyl] -methanone, (5-chloro-6-methyl-l₎3-dihydro-isoindol-2-yl)-(2-isobutoxy-5-methanesuIfonyl- phenyl)-methanone,

(5-chloro-6-ethylsulfanyl-l,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((R)-2,2,2- trifluoro-l-methyl-ethoxy)-phenyl]-methanone,

(2-isopropox7-5-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-trifiuoro-l-methyl-ethoxy)-phenyl]-(5-methoxy-6- trifluoromethyl-l,3-dihydro-isoindol-2-yl)-methanone, [5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(5- trifluoromethoxy- 1 ,3-dihydro-isoindol-2-yl) -methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-[5-(4-methyl- thiazol-2-yl)-l,3-dihydro-isoindol-2-yl] -methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-[5-(2-methyl- pyridin-4-yl)-l,3-dihydro-isoindol-2-yl]-methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-[5-(5-methyl- thiophen-3-yl)-l,3-dihydro-isoindol-2-yl] -methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(5-thiazol-2-yl-l,3- dihydro-isoindol-2-yl)-methanone, (5-ethylsulfanyl-6-trifluoromethyl-l,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-

((S)-2,2,2-trifluoro-l-methyl-ethox7)-phenyl] -methanone,

(5-chloro-6-methox7-l,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((R)-2,2,2- trifluoro- 1 -methyl-ethoxy) -phenyl] -methanone

(5-chloro-6-methox7-l,3-dihydro-isoindol-2-yl)-(2-isobutoxy-5-methanesulfonyl- phenyl) -methanone,

(5-fluoro-6-trifluoromethyl-l₎3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2- trifluoro- l-methyl-ethoxy)-phenyl] -methanone, (5-ethox7-6-trifluoromethyl-l,3-dihydro-isoindol-2-yl)-(2-isopropox7~5- methanesulfonyl-phenyl)-rnethanone,

(5-chloro-6-morpholin-4-yl-l,3-dihydro-isoindol-2-yl)-(2-isobutoxy-5- methanesulfonyl-phenyl)-methanone, (5-chloro-6-morpholin-4-yl-l,3-dihydro-isoindol-2-yl)-(2-cyclobutylmethoxy-5- methanesulfonyl-phenyl)-rnethanone,

(2-isopropoxy-5-methanesulfonyl-phenyl)-[5-(tetrahydro-pyran-4-yl)-l,3-dihydro- isoindol-2-yl] -methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-[5-(tetrahydro- pyran-4-yl) - 1 ,3-dihydro-isoindol-2-yl] -methanone,

(2-isobutoxy-5-methanesulfonyl-phenyl)-[5-(tetrahydro-pyran-4-yl)-l,3-dihydro- isoindol-2-yl] -methanone,

(2-cyclopropylmethoxy-5-methanesulfonyl-phenyl)-[5-(tetrahydro-p"yτan-4-yl)-l,3- dihydro-isoindol-2-yl] -methanone, (2-cyclobutylmethoxy-5-methanesulfonyl-phenyl)-[5-(tetrahydro-pyran-4-yl)-l,3- dihydro-isoindol-2-yl]-methanone,

[2-(2,2-dimethyl-propoxy) -5-methanesulfonyl-phenyl] - [5-(tetrahydro-pyran-4-yl)- 1,3- dihydro-isoindol-2-yl] -methanone,

[5-(3,3-difluoro-piperidin- l-yl)-l,3-dihydro-isoindol-2-yl] - [5-methanesulfonyl-2-((S)- 2,2,2-trifluoro- 1 -methyl-ethoxy) -phenyl] -methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-[5-(2,2,2-trifluoro- ethyl)-l,3-dihydro-isoindol-2-yl] -methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifl.uoro-l-methyl-ethoxy)-phenyl] - [( lR,5S)-5-(3-oxa-

8-aza-bicyclo[3.2.1]oct-8-yl)-l,3-dihydro-isoindol-2-yl]-methanone, [5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-[5-methyl-6-

(tetrahydro-ρyran-4-yl)-l,3-dihydro-isoindol-2-yl] -methanone,

[5-methanesulfonyl-2- ( (S) -2,2,2-trifluoro- 1 -methyl-ethoxy) -phenyl] - [ 5- (tetrahydro- furan-3-yl)-l,3-dihydro-isoindol-2-yl] -methanone,

[5-chloro-6-(tetrahydro-pyran-4-yl)-l_>3-dihydro-isoindol-2-yl]-[5-methanesulfonyl-2- ((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl] -methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-ρhenyl]-[5-(tetrahydro- pyran-3-yl)-l,3-dihydro-isoindol-2-yl] -methanone,

[ 5-methanesulfonyl-2- ( (S) -2,2,2-trifluoro- 1 -methyl-ethoxy) -phenyl] -( 5-pyridin-4-yl-

1 ,3-dihydro-isoindol-2-yl) -methanone, [5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(5-pyτidin-3-yl- l,3-dihydro-isoindol-2-yl)-methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(5-phenyl-l,3- dihydro-isoindol-2-yl)-methanone,

[5-(2-chloro-phenyl)-l,3-dihydro-isoindol-2-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-

1 -methyl-ethoxy) -phenyl] -methanone,

[5-methanesulfonyl-2-(2₎2,2-trifluoro-l-methyl-ethoxy-)-phenyl]-(5-thiophen-3-yl-l₎3- dihydro-isoindol-2-yl)-methanone,

[5-methanesulfonyl-2-(2,2,2-trifluoro-l-methyl-ethox7)-phenyl]-[5-(4-methyl- thiophen-2-yl) - 1 ,3-dihydro-isoindol-2-yl] -methanone,

[5-methanesulfonyl-2-(2,2,2-trifluoro-l-methyl-ethoxy')-phenyl]-[5-(3-methyl- thiophen-2-yl)-l,3-dihydro-isoindol-2-yl] -methanone, [5-(4-fluoro-phenyl)-l,3-dihydro-isoindol-2-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro- l-methyl-ethoxy)-phenyl] -methanone,

[5-(3-fluoro-phenyl)-l,3-dihydro-isoindol-2-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-

1 -methyl-ethoxy)-phenyl] -methanone,

[5-(2-fluoro-phenyl)-l,3-dihydro-isoindol-2-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro- l-methyl-ethoxy)-phenyl]-methanone,

[5-(3,5-difluoro-phenyl)-l,3-dihydro-isoindol-2-yl]-[5-methanesulfonyl-2-(2,2,2- trifluoro-l-methyl-ethoxy)-phenyl] -methanone,

[5-methanesulfonyl-2-(2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-[5-(3-methoxy- phenyl)- l,3-dihydro-isoindol-2-yl] -methanone, [5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(5-thiophen-2-yl- l,3-dihydro-isoindol-2-yl)-methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethox7)-phenyl]-[5-(4-methyl- thiophen-3-yl)-l,3-dihydro-isoindol-2-yl]-methanone,

[5-methanesulfonyl-2-((S)-2,2₎2-trifluoro-l-methyl-ethox7)-phenyl]-(5-pyrazol-l-yl- l,3-dihydro-isoindol-2-yl)-methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethox7)-ρhenyl]-[5-(2,2,2-trifluoro- ethoxy)-l,3-dihydro-isoindol-2-yl] -methanone,

[5-chloro-6-(tetrahydro-furan-3-yl)-l,3-dihydro-isoindol-2-yl]-[5-methanesulfonyl-2-

((S)-2,2,2-trifluoro-l-methyl-ethox7)-ρhenyl] -methanone, rac-(2-isopropoxy-5-methanesulfonyl-phenyl)-[5-(tetrahydro-furan-3-yl)-l,3-dihydro- isoindol-2-yl] -methanone, rac-[5-methanesulfonyl-2-(2,2₃3,3,3-pentafluoro-propox7)-phenyl]-[5-(tetrahydro- furan-3-yl)-l,3-dihydro-isoindol-2-yl] -methanone, rac- (2-isopropox7-5-methanesulfonyl-phenyl) - [ 5-(tetrahydro-pyτan-3-yl) - 1 ,3-dihydro- isoindol-2-yl] -methanone,

[5-chloro-6-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-l,3-dihydro-isoindol-2-yl]-[5- methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-phenyl] -methanone, rac-[5-methanesulfonyl-2-(2,2₃3,3,3-pentafluoro-propoxy)-phenyl]-[5-(tetrahydro- pyran-3-yl)-l,3-dihydro-isoindol-2-yl] -methanone,

((lS_>4S)-5-chloro-6-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-l,3-dihydro-isoindol-2-yl)-[5- methanesulfqnyl-2- ( (S) -2,2,2-trifluoro- 1 -methyl-ethoxy)-phenyl] -methanone, [5-fluoro-6-(tetrahydro-pyran-4-yl)-l,3-dihydro-isoindol-2-yl] - [5-methanesulfonyl-2-

((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl] -methanone,

[ 5-methanesulfonyl-2- ( (S) -2,2,2-trifluoro- 1 -methyl-ethoxy) -phenyl] - [5- (tetrahydro- pyran-4-yloxy) - 1 ,3-dihydro-isoindol-2-yl] -methanone,

[5-(3-fluoro-oxetan-3-yl)-l,3-dihydro-isoindol-2-yl]-[5-methanesulfonyl-2-((S)-2,2,2- trifluoro- 1-methyl-ethoxy) -phenyl] -methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-[5-(3,3,3-trifluoro- propoxy)-l,3-dihydro-isoindol-2-yl] -methanone,

(5-fluoro-6-morpholin-4-yl-l,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2- trifluoro- l-methyl-ethoxy)-phenyl] -methanone, (5-fluoro-6-morpholin-4-yl-l,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-(2,2,3,3,3- pentafluoro-propoxy) -phenyl] -methanone,

(2-isopropoxy-5-methanesulfonyl-phenyl)-[5-(tetrahydro-pyran-4-yloxy)-l,3-dihydro- isoindol-2-yl] -methanone,

[5-methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-[5-(tetrahydro-pyran-4- yloxy)-l,3-dihydro-isoindol-2-yl] -methanone,

[5-chloro-6-(tetrahydro-pyran-4-yloxy)-l,3-dihydro-isoindol-2-yl]-[5-methanesulfonyl-

2- ( (S) -2,2,2-trifluoro- 1 -methyl-ethoxy)-phenyl] -methanone,

[ 5-chloro-6- (tetrahydro-pyran-4-yloxy) - 1 ,3-dihydro-isoindol-2-yl] - (2-isopropoxy-5- methanesulfonyl-phenyl)-methanone, [5-fluoro-6-(tetrahydro-pyran-4-yloxy)- l,3-dihydro-isoindol-2-yl] - [5-methanesulfonyl-

2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl] -methanone,

[5-fluoro-6-(tetrahydro-pyran-4-yloxy)-l,3-dihydro-isoindol-2-yl]-(2-isopropoxy-5- methanesulfonyl-phenyl)-methanone,

[ 5-fluoro-6- (tetrahydro-pyran-4-yloxy) - 1 ,3 -dihydro-isoindol-2-yl] - [5-methanesulfonyl- 2-(2,2,3,3,3-pentafluoro-propoxy)-ρhenyl] -methanone or

[5-chloro-6-(tetrahydro-pyran-4-yloxy)-l,3-dihydro-isoindol-2-yl] - [5-methanesulfonyl- ^'

2-(2,2,3,3,3-ρentafluoro-propoxy)-ρhenyl] -methanone.

Preferred compounds of formula I A are further those, wherein R¹ is unsubstituted or substituted phenyl, for example the following compounds: (5-chloro-6-morpholin-4-yl-l,3-dihydro-isoindol-2-yl)-(4-methanesulfonyl-biphenyl-2- yl) -methanone, (5-chloro-6-morpholin-4-yl-l,3-dih7dro-isoindol-2-yl)-(3'-fluoro-4-methanesulfonyl- biphenyl-2-yl) -methanone,

(5-chloro-6-morpholin-4-yl-l,3-dih7dro-isoindol-2-yl)-(4'-fluoro-4-methanesulfonyl- biphenyl-2-yl) -methanone or (4' -fluoro-4-methanesulfonyl-biphenyl-2-yl) - [ 5- (tetrahydro-pyran-4-yl) - 1 ,3 -dihydro- isoindol-2-yl] -methanone.

The following compounds of formula I B are preferred:

(2-cyclobutyhnethoxy-5-methanesulfonyl-phenyl)-(3-trifluoromethyl-5,7-dihydro- pyrrolo [ 3 ,4-b ] pyridin-6-yl) -methanone, (2-isobutoxy-5-methanesulfonyl-phenyl)-(3-trifluoromethyl-5,7-dihydro-pyrrolo[3,4- b ] pyridin-6-yl) -methanone,

[5-methanesulfonyl-2-((R)-2,2,2-trifluoro-l-methyl-ethox7)-phenyl]-(3- trifluoromethyl-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-methanone,

(4'-fluoro-4-methanesulfonyl-biphenyl-2-yl)-(3-trifluoromethyl-5,7-dihydro- pyrrolo [3,4-b]pyridin-6-yl)-methanone,

(3',4'-difluoro-4-methanesulfonyl-biphenyl-2-yl)-(3-trifluoromethyl-5,7-dihydro- pyrrolo [ 3 ,4-b ] pyridin-6-yl) -methanone,

[5-methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-(3-trifluoromethyl-5,7- dihydro-pyrrolo[3,4-b]pyridin-6-yl)-methanone, [5-methanesulfonyl-2-(2,2,3,3-tetrafluoro-propox7)-phenyl]-(3-trifluoromethyl-5,7- dihydro-pyrrolo[3,4-b]pyridin-6-yl)-methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethox7)-phenyl]-(2-methyl-3- trifluoromethyl-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-methanone,

[3-(4-fluoro-phenyl)-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl]-[5-methanesulfonyl-2- ((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl] -methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifiuoro-l-methyl-ethoxy)-phenyl]-(3-trifluoromethyl-

5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-methanone or

[2-(4-fluoro-phenyl)-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl]-[5-methanesulfonyl-2-

((S) -2,2,2-trifluoro- 1 -methyl-ethoxy) -phenyl] -methanone

Preferred compounds of formula IC are the followings:

(2-cyclobu1ylmethox7-5-methanesulfonyl-phenyl)-(6-trifluoromethyl-l,3-dihydro- pyrrolo[3,4-c]pyridin-2-yl)-methanone,

(4'-fluoro-4-methanesulfonyl-biρhenyl-2-yl)-(6-trifluoromethyl-l,3-dihydro- pyrrolo[3,4-c]pyridin-2-yl) -methanone, (3',4'-difluoro-4-methanesulfonyl-biphenyl-2-yl)-(6-trifluoromethyl-l,3-dihydro- pyrrolo[3,4-c]pyridin-2-yl)-methanone,

[5-methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-plienyl]-(6-trifluoromethyl-l_J3- dihydro-pyrrolo [3,4-c] pyridin-2-yl)-methanone,

[5-methanesulfonyl-2-(2,2,3,3-tetrafluoro-propox7)-phenyl]-(6-trifluoromethyl-l,3- dihydro-pyrrolo [3,4-c] pyridin-2-yl) -methanone,

[6-(4-fluoro-phenyl)-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl]-[5-methanesulfonyl-2- ((S)-2,2,2-trifluoro-l-methyl-ethox7)-phenyl] -methanone or

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-ρhenyl]-(6-morpholin-4-yl- l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)-methanone.

Specific compounds of formula I D are the followings:

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(2-tπfluoromethyl-

5,7-dihydro-pyrroIo[3,4-d]pyrimidm-6-yl)-methanone,

(2-isopropoxy-5-methanesulfonyl-phenyl)-(2-trifluoromethyl-5,7-dihydro-pyrrolo[3,4- d]pyrimidin-6-yl)-methanone, (4-methanesulfonyl-biphenyl-2-yl)-(2-trifluoromethyl-5,7-dihydro-pyrrolo[3,4- d] pyrimidin-6-yl) -methanone,

(2-isoρropoxy-5-methanesulfonyl-phenyl)-(2-methyl-5,7-dihydro-pyrrolo[3,4- d]pyrimidm-6-yl)-methanone or

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethox7)-phenyl]-(2-methyl-5_>7- dihydro-pyrrolo[3,4-d]pyrimidin-6-yl)-methanone.

Preferred compounds of formula I E are l-(4-methanesulfonyl-biphenyl-2-carbonyl)-2,3-dihydro-lH-indole-4-carbonitrile, l-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-benzoyl]-2,3-dihydro- lH-indole-4-carboxylic acid methyl ester, l-(2-isopropoxy-5-methanesulfonyl-benzoyl)-2,3-dihydro-lH!-indole-4-carboxylic acid methyl ester or

(4-bromo-2,3-dihydro-indol-l-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl- ethoxy) -phenyl] -methanone.

Specific compounds of formula I F are the followings: (5-bromo-xndol-l-yl)-[5-methanesulfonyl-2-((S)-2,2_>2-trifiuoro-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- 1-yl) - [ 5-methanesulfonyl-2- ( (S) -2,2,2-trifluoro- 1 -methyl-ethoxy) - phenyl] -methanone or (4-bromo-ind.ol-l-yl)-[5-methanesulfonyl-2-(2,2,2-trifluoro-l-methyl-ethox7)-phenyl]- methanone.

Specific compounds of formula I G are the followings: [5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-metriyl-ethoxy)-phenyl]-(5-nitro-indazol-l- yl) -methanone,

(5-chloro-indazol- 1 -yl) - [5-methanesulfonyl-2- ( (S) -2,2,2-trifluoro- 1 -methyl-ethoxy) - phenyl] -methanone or

(5,7-Dichloro-mdazol-l-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl- ethoxy) -phenyl] -methanone.

A specific compound of formula I H is the following:

(5,6-dimethyl-benzoimidazol-l-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifiuoro-l-methyl- ethoxy) -phenyl] -methanone.

The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by a process described below, which process consists in

a) reacting a compound of formula

selected from the group consisting of

with a compound of formula

in the presence of an activating agent, such as TBTU,

to a compound of formula

which include the following structures

I G I H wherein the definitions are given, above,

or

b) reacting a compound of formula

wherein hal is an halogen group such as Br or Cl with a compound of formula

in the presence of a base, such as sodium hydride,

to compound of formulas

wherein the substituents are as defined above, and, if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.

The compounds of formula I maybe prepared in accordance with the process variant as described above and with the following schemes 1 - 2. The starting materials are either commercially available, are otherwise known in the chemical literature, or may be prepared in accordance with methods well known in the art.

The following abbreviation has been used:

TBTU = (2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluroniumtetrafluoroborate)

Scheme 1

Preparation of compounds of formulas I A, I B, I C, I D, I E, I F, I G and I H:

wherein substituents are as defined above

A compound of formula II (II A, II B, II C, II D₅ II E, II F, II G and II H) is treated with a compound of formula III in the presence of TBTU and a base, such as N- ethyldiisopropylamine to obtain a compound of formula I (I A, I B, I C, I D, I E, I F, I G and I H).

Scheme 2

Preparation of compounds of formulas I A, I B, I C and I D for R and R' in general formula I being hydrogen:

wherein the substituents are as defined above

A compound of formula IV (A, B, C and D) is treated with a compound of formula V in the presence of sodium hydride to obtain a compound of formula I (A, B, C and D).

The acids of formula III can be prepared by various routes as shown in Schemes 3-7.

Scheme 3

where X = halogen For example, compounds of formula IHa where R¹ is lower alkyl, lower alkyl, substituted by halogen or -(CH2)_x-cycloalkyl, can be prepared by reaction of a halogen compound of formula VI with an alcohol of formula R¹ OH, optionally in the presence of a copper salt like Cu(I)Br and a base, such as triethylamine (Scheme 3), at elevated temperature.

Scheme 4

HIa

Alternatively, compounds of formula Ilia, where R¹ is lower alkyl, lower alkyl, substituted by halogen or -(CH₂)_x-cyclo alkyl 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 VTII, followed by hydrolysis in the presence of an aqueous base such as potassium hydroxide, sodium hydroxide or lithium hydroxide (Scheme 4).

Scheme 5

where X = halogen

Compounds of formula HIb where R¹ is lower alkyl, lower alkyl, substituted by halogen or -(CH₂)_x-cycloalkyl, can be prepared by reaction of a halogen compound of formula VI with a thiol of formula R¹ SH, optionally in the presence of a base, such as caesium carbonate, potassium carbonate or sodium carbonate (Scheme 5), at elevated temperature. Scheme 6

where X = halogen

Compounds of formula IIIc where R¹ is a heterocycloalkyl group, containing a N atom, can be prepared by reaction of a halogen compound of formula VT with an amine

of formula ^ — ' , optionally in the presence of a base, such as cesium carbonate, potassium carbonate or sodium carbonate (Scheme 6), at elevated temperature.

Scheme 7

πid

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(diben2ylideneacetone)dipalladium(0) , to afford intermediate compounds of formula X, followed by hydrolysis in the presence of an aqueous base such as potassium hydroxide, sodium hydroxide or lithium hydroxide (Scheme 7). The halogen-substituted and hydroxyl-substituted starting materials of formula Vl, VTI and IX (as shown in Schemes 3-7) are either commercially available, are otherwise 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 R³ and R⁴ are H can be prepared by methods well known in the art. Scheme 8

For example, compounds of formula IV A, IV B, IV Cand IV D, can be prepared by reaction of an ortho-dimethylated compound of formulas XI A, XI B, XI C and XI D, respectively, with an N-halo-succinimide such as N-bromo-succinimide (Scheme 8).

Scheme 9

Alternatively, compounds of formulas IV A, IV B, IV C and IV D can be prepared by reaction of an ortho-dihydroxyxnethylated 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 -dihydroxymethylated compound of formula XI (A, B, C and D) and XII (A, B, C and D) as shown in Schemes 8 and 9 are either commercially available, are otherwise known in the chemical literature, or maybe prepared using a variety of methods well known in the art.

The amide compounds of formula V can be prepared by methods well known in the art.

Scheme 10

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 hydrogen.

For example, compounds of formula II A, II B, II C and II D can be prepared by reaction of phtalimide compounds of formula XIII (A, B, C and D) in the presence of a reducing agent such as borane THF complex (Scheme 11).

The phtalimide compound of formula XIII (A, B, C and D) (as shown in Scheme 11) are either commercially available, are otherwise known in the chemical literature, or maybe prepared using a variety of methods well known in the art.

Scheme 12 Preparation of compounds of formula II A, II B, II C and II D Trifluoro-

TTrriipphheennyyllmmeetthhyyllaammiinnee Diisopropyiethylamine

Alternatively, compounds of formula II 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 diisopropyiethylamine 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 R³, 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 I so as to modify the substituent R³ to R⁶. Examples of such reactions include functional group interconversions (e.g. change of oxidation state, such as thioether to sulphone substituent), coupling reactions mediated by organometallic (palladium, copper) catalysts (e.g. Stille, Suzuki or Buchwald coupling reactions, in case where there is a reactive halogen substituent). Such reactions may be performed using a variety of methods well known in the art and specific examples may be had by reference to the Examples hereunder described. In cases where such reactions are performed on compounds of formula II in which the nitrogen atom is protected (i.e. Boc or Trityl), deprotection of the protective groups in acidic media (i.e. HCl, or trifluoroacetic acid) is subsequently performed.

Furthermore, aromatic or partially aromatic bicyclic amines in form of their oxides

may be prepared by oxidizing a compound of formula I with 3- chloroperbenzoic acid in dichloromethane and stirring the mixture at room temperature for about 72 hours.

Isolation and purification of the compounds

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 (GIyT-I).

The compounds were investigated in accordance with the test given hereinafter.

Solutions and materials

DMEM complete medium: Nutrient mixture F- 12 (Gibco Life-technologies), fetal bovine serum (FBS) 5 %, (Gibco life technologies), Penicillin/Streptomycinl % (Gibco life technologies), Hygromycin 0.6 mg/ml (Gibco life technologies), Glutamine 1 mM Gibco life technologies)

Uptake buffer (UB): 150 mM NaCl, 10 mM Hepes-Tris, pH 7.4, 1 mM CaCl₂, 2.5 mM

KCl₅2.5 mM MgSO₄, 10 mM (+) D-glucose.

Flp-in™-CHO (Invitrogen Cat n⁰ 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. IC₅₀, 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 μM 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 most preferred compounds show an IC₅₀ (μM) at GIyT-I < 0.05

The compounds of formula I and the pharmaceutically 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 compounds of formula I can be processed with pharmaceutically inert inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

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 I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage maybe 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.

Tablet Formulation (Wet Granulation)

Item Ingredients mg/ tablet

5 mg 25 mg 100 mg 500

1 100 1. Compound of formula I 5 25 100 500

2. Lactose Anhydrous DTG 125 105 30 150

3. Sta-Rx 1500 6 6 6 30

4. Macrocrystalline Cellulose 30 30 30 150

5. Magnesium Stearate 1 1 1 1

15 Total 167 167 167 831

Manufacturing Procedure

1. Mix items 1, 2, 3 and 4 and granulate with purified water.

2. Dry the granules at 50⁰C.

3. Pass the granules through suitable milling equipment.

20 4. Add item 5 and mix for three minutes; compress on a suitable press.

Capsule Formulation

Item Ingredients mg/capsule

5 mg 25 mg 100 mg 500

1. Compound of formula I 5 25 100 500

25 2. Hydrous Lactose 159 123 148 ___

3. Corn Starch 25 35 40 70

4. Talc 10 15 10 25

5. Magnesium Stearate 1 2 2 5

Total 200 200 300 600

30 Manufacturing Procedure

1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add items 4 and 5 and mix for 3 minutes.

3. Fill into a suitable capsule.

The following examples illustrate the invention but are not intended to limit its scope. The following abbreviations were used in the examples: n-Boc-piperazine: tert-Butyl 1-piperazinecarboxylate, Oxone^®: (potassium peroxymonosulfate) 2KHSCVKHSCVK₂SO₄, TBTU: 2- ( lH-benzotriazole- 1 -yl)- 1 , 1,3,3-tetramethyluroniumtetrafluoroborate;

Preparation of Intermediates

Example Al 6-Chloro-2,3-dihydro-lH-isoindol-5-ylamine

To 25.4 mmol 5-amino-6-chloroisoindoline-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 ({³⁷Cl}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

A mixture of 2.8 mmol 5-Bromo-2,3-dimethyl-pyridine (CAS: 27063-90-7), 5.61 mmol N-bromosuccinimide and 0.06 mmolAIBN in 5 ml tetrachloromethane was refluxed for 4 hours. The mixture was then cooled to 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-6J-dihydro-5H~pyrrolo[3,4-b1pyridine

A mixture of 0.87 mmol 5-Bromo-2,3-bis~bromomethyl-pyridine, 1.1 mmol tritylamine, and 2.61 mmol DIPEA in 3 ml DMF was stirred at 6O⁰C 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 (SiO₂, heptane/dichloromethane) to yield the title compound as a light brown solid. MS (m/e): 243.4 (trityl ion, 100%)

(c) 3-Bromo-6,7~dihydro-5H-pyrrolo[3,4-b1pyridine

To a 0⁰C solution of 0.18 mmol 3-bromo-6-trityl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridine in 0.5 ml chloroform and 0.5 ml methanol was added dropwise 1 ml trifluoroacetic acid. After 5 minutes stirring at 0⁰C and 30 minutes at RT, the reaction mixture was concentrated. The residue was taken in water/ ether and ImI IN HCl 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-Chloro-6-pyrrolidin-l-yl-2,3-dihydro-lH-isoindole-hydrochloride

(a) 5-Chloro-6-iodo-isoindole-l,3-dione

To a stirred suspension of 96.1 mmol 5-amino-6-chloroisoindoline-l,3-dione (commercial, CAS: 5566-48-3) in 170 ml water was added dropwise at 10⁰C a solution of 11 ml concentrated sulfuric acid in 50 ml water. After cooling the mixture to 5 ⁰C, a solution of 120 mmol sodium nitrite in 40 ml water was added dropwise and stirring continued at 0 ⁰C 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 ⁰C. The reaction mixture was then warmed to room temperature and subsequently heated at 35 ⁰C for 45 min and then 60 ⁰C 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-l,3-dione and borane-THF complex. Off-white solid. MS (m/e): MS (m/e): 282.0 ({³⁷Cl}M+H⁺, 35%), 279.9 ({³⁵C1}M+H⁺, 100%).

(c) 5-Chloro-6-iodo-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

To a stirred suspension of 10.4 mmol 5~cHoro-6-iodo-2,3-dihydro-lH-isoindole in 30ml dichloromethane was added 12.5 ml (Boc)₂O and the mixture stirred at room temperature for 16 h. The resulting solution was concentrated in vacuo and the residue purified by chromatography (SiO₂, heptane/ ethyl acetate) to yield the title compound as an off-white solid. MS (m/e): 326.0 ({³⁷Cl}[M+H- Me₂C=CH₂J⁺, 35%), 324.0 ({³⁵C1}[M+H- Me₂C=CH₂]⁺, 100%).

(d) 5-Chloro-6-pγrrolidin-l-yl-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

Lit. /. 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 110⁰C 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 (SiO₂, heptane/ethyl acetate) to yield the title compound as a yellow oil. MS (m/e): 325.2 ({³⁷Cl}M+H⁺, 35%), 323.2 ({³⁵C1}M+H⁺, 100%).

(e) 5-Chloro-6-pyrrolidm-l-yl-2,3-dihvdro-lH-isoindole-hydrochloride

To a stirred suspension of 0.12 mmol 5-cMoro-6-pyrrolidin-l~yl-l,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 ⁰C 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 ({³⁷C1}M+H⁺, 35%), 323.2 ({³⁵Cl}M+H⁺, 100%). Example A4 5-Chloro-6-methyl-2,3-dihydro- lH-isoindole hydrochloride

(a) 5-Chloro-6-methyl-l,3-dihγdro-isoindole-2-carboxylic acid tert-butyl ester

Lit. Tetrahedron Lett. 1999, 40, 2719-2722. To a stirred suspension of 1.58 mmol 5- chloro-6-iodo-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) in 3ml N-methylpyrolidone were added 0.05 mrnol tris(dibenzylideneacetone) dipalladium chloroform complex and 0.32 mmol triphenylphosphine and the mixture was stirred at 50 ⁰C for 10 min. 0.16 mmol copper(I) iodide was then added and the mixture stirred at 50 ⁰C for a further 10 min. Finally, 3.48 mmol tetramethyl tin was added and the reaction mixture was stirred at 80 ⁰C for 16 h. The 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 (SiO₂, heptane/ethyl acetate) to yield the title compound as a yellow solid. MS (m/e): 214.1 ({³⁷Cl} [M+H- Me₂C=CH₂]⁺, 35%), 212.0 ({³⁵C1} [M+H- Me₂C=CH₂J⁺, 100%).

(b) 5-Chloro-6-methyl-2,3-dihydro-lH-isoindole hydrochloride

Cl

Prepared in analogy to Example A3 (e) from 5-chloro-6-methyl-l,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester and HCl. Grey solid. MS (m/e): 170.1 ({³⁷C1}M+H⁺, 35%), 168.3 ({³⁵C1}M+H⁺, 100%).

Example A5 5-Chloro-6-ethylsulfanyl-2,3-dihydro- lH-isoindole hydrochloride

(a) 5-Chloro-6-ethylsulfanyl-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl 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(I) 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 ⁰C for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography (SiO₂, heptane/ ethyl acetate) to yield the title compound as a white solid. MS (m/e): 260.0 ({³⁷C1}[M+H- Me₂C=CH₂I⁺, 42%), 258.1 ({³⁵Cl}[M+H- Me₂C=CH₂]^"1", 100%).

(b) 5-Chloro-6-ethylsulfanγl-2,3-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 HCl. Off-white solid. MS (m/e): 216.2 ({³⁷C1}M+H⁺, 42%), 214.2 ({³⁵Cl}M+H⁺, 100%).

Example A6

5-Chloro-6-methoxy-2,3-dihydro-lH-isoindole hydrochloride

(a) 5-Chloro-6-methoxy-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

Lit. Org. Lett. 2002, 4(6), 973-976. To a stirred suspension of 1.84 mmol 5-chloro-6-iodo- l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) in 7 ml methanol were added 0.18 mmol copper(I) iodide, 3.69 mmol cesium carbonate and 0.37 mmol 1,20-phenanthroline and the reaction mixture was stirred at 140 ⁰C for 16 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography (SiO₂, heptane/ethyl acetate) to yield the title compound as a light red solid. MS (m/e): 230.2 ({³⁷C1}[M+H- Me₂C=CH₂J⁺, 42%), 228.2 ({³⁵C1}[M+H- Me₂C=CH₂I⁺, 100%). (b) 5-Chloro-6-methόxy-2,3-dihydro-lH-isoindole hydrochloride

Prepared in analogy to Example A3 (e) from 5-chloro-6-methoxy-l,3-dihydro-isoindole- 2-carboxylic acid tert-butyl ester and HCl. Off-white solid. MS (m/e): 186.1 ({³⁷C1}M+H⁺, 30%), 184.1 ({³⁵Cl}M+H⁺, 100%).

Example A7 5-Chloro-6-ethanesulfonyl-2,3-dihydro- lH-isoindole hydrochloride

(a) 5-Chloro-6-ethanesulfonyl-l,3-dihvdro-isoindoIe-2-carboxylic acid tert-butyl ester

To a stirred solution of 0.61 mmol 5-chloro-6-ethylsulfanyl-l,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester (Example A5(a)) in 5 ml dichloromethane was added 1.51 mmol 3-chloroperoxybenzoic acid and the reaction mixture was stirred at 50⁰C for 90 min. The mixture was then cooled to room temperature, diluted with dichloromethane and washed sequentially with aq. sodium carbonate solution and with water. The organic phase was dried over sodium sulfate and concentrated in vacuo to yield the title compound as a yellow oil which was used in the next step without further purification. MS (m/e): 292.0 ({³⁷Cl}[M+H-Me₂C=CH₂]⁺, 44%), 290.0 ({³⁵C1}[M+H- Me₂C=CH₂J⁺, 100%).

(b) 5-Chloro-6-ethanesulfonyl-2,3-dihydro- IH-isoindole hydrochloride

^GIH

Prepared in analogy to Example A3 (e) from 5-chloro-6-ethanesulfonyl-l,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester and HCl. Grey solid. MS (m/e): 248.1 ({³⁷C1}M+H⁺, 30%), 246.2 ({³⁵C1}M+H⁺, 100%). Example A8 2-Chloro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine

(a) 2-Chloro-6-trityl-6,7-dihydro-5H-Pyrrolor3,4-b] pyridine

Prepared in analogy to Example A2 (b) from 6-chloro-2,3-bis-chloromethyl-pyridine (CAS: 220001-94-5) and triphenylmethylamine. Light yellow foam. MS (m/e): 397.0 ([MH⁺, 100%).

(bi 2-Chloro-6,7-dih.ydro-5H-pyrrolo [3,4-bipyridine

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 2,3-Dihydro-lH-isoindole-4-carbonitrile

(a) 2-Trityl-2,3-dihydro-lH-isoindole-4-carbonitrile

Prepared in analogy to Example A2 (b) from 2,3-Bis-bromomethyl-benzonitrile (CAS: 66126-18-9) and triphenylmethylamine. Yellow foam.

(b) 2,3-Dihvdro-lH-isoindole-4-carbonitrile

Prepared in analogy to Example A2 (c) from 2-trityl-2,3-dihydro-lH-isoindole-4- carbonitrile and trifluoroacetic acid. Light brown solid.

Example AlO 5-Pyrrolidin-l-yl-2,3-dihydro-lH-isoindole

(a) 5-Pyrrolidin-l-yl-l,3-dihvdro-isoindole-2-carboxylic acid tert-butyl ester

Prepared in analogy to Example A3 (d) from 5-Bromo~l,3~dihydro-isoindole-2- carboxylic acid tert-butyl ester (CAS: 201940-08-1) and pyrrolidine. Orange solid. MS (m/e): 289.2 (M+H⁺, 100%).

(b) 5-Pyrrolidin- l-yl-2,3-dihydro- lH-isoindole

Prepared in analogy to Example A3 (e) from 5-Pyrrolidin-l-yl-l,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester and HCl. Brown oil. MS (m/e): 189.6 (M+H⁺, 100%).

Example All

5-Ethylsulfanyl-2,3-dihydro-lH-isoindole hydrochloride

(a) 5-Ethylsulfanyl-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

Lit. Tetrahedron 2004, 60, 7397-7403. To a stirred suspension of 1.34 mmol 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 ⁰C 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-Ethylsulfanyl-2,3-dihydro-lH-isoindole hydrochloride

Prepared in analogy to Example A3 (e) from 5-Ethylsulfanyl-l,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester and HCl. Light Brown solid. MS (m/e): 216.3 ([M+H⁺, 100%).

Example A12 5-Chloro-6-fluoro-2,3-dihydro-lH-isoindole

(a) l,2-Bis-bromomethyl-4-chloro-5-fiuoro-benzene

Prepared in analogy to Example A2 (a) from l-Chloro-2-fluoro-4,5-dimethyl-benzene (CAS: 116850-30-7) and NBS. Brown oil.

(b) 5-chloro-6-fluoro-2-trityl-2,3-dihydro-lH-isoindole

Prepared in analogy to Example A2 (b) from l,2-Bis-bromomethyl-4-chloro-5-fluoro- benzene and triphenylmethylamine. Brown oil.

(c) 5-Chloro-6-fluoro-2,3-dihydro-lH-isoindole

Prepared in analog to Example A2 (c) from 5-cMoro-6-fluoro-2-trityl-2,3-dihydro-lH- isoindole and trifluoroacetic acid. Light brown solid.

Example Al 3 6-Trifluoromethyl-2,3-dihydro- lH-pyrrolo [3,4-c]pyridine

(a) 4,5-Bis-chloromethyl-2-tri£luoromethyl-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 (SiO₂, 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-Trifluoromethyl-2-trityl-2,3-dihydro-lH-pyrrolo[3,4-c1pyridine

Prepared in analogy to Example A2 (b) from 4,5-Bis-chloromethyl-2-trifluoromethyl- pyridine and triphenylmethylamine. White solid.

(c) 6-Trifluoromethyl-2,3-dihvdro-lH-Pyrrolo[3,4-c1pyridine

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]pyridme

(a) 6-Trifluoromethyl-pyridine-2,3-dicarboxylic acid dimethyl ester

A mixture of 245 mmol periodic acid and 1.1 mmol ruthenium trichloride hydrate in 40 ml acetonitrile and 40 ml carbon tetrachloride was stirred at room temperature for 10 minutes. 17 mmol of 2-trifluoromethyl-quinoline (CAS: 1701-38-8), was added portionwise during 2.5 hours. The temperature was kept below 45° C by occasional cooling with an ice-bath. After addition, the reaction mixture was cooled to 0° C and extracted 3 times with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in 65 ml N,N-dimethylformamide. 48 mmol of - cesium carbonate was added, followed by 97 mmol of methyl iodide. After stirring at room temperature overnight, the reaction mixture is diluted with water and extracted with ethyl acetate. The crude compound obtained after concentration is purified by chromatography (SiO₂; ethyl acetate / n-heptane 1:4) to give the title compound as a yellow liquid. Yield: 37%. MS (m/e): 264.0 (MH⁺, 44%).

(b) (3-Hydroxymethyl-6-trifluoromethyl-pyridin-2-yl)-methanol

^FΛOCO

A solution of 6 mmol 6-txifluoromethyl-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 (SiO₂; ethyl acetate / n-heptane 1:1) to give the title compound as a yellow oil. Yield: 72%. MS (m/e): 208.1 (MH⁺, 100%).

{ c) 2-Trifluoromethyl-6~trityl-6 J-dihydro-5H-pyrrolo [ 3, 4-bl pyridine

A solution of 7 mmol (3-hydroxymethyl-6-trifluoromeώyl-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 methylamine and hold overnight at 60° C. The resulting mixture was concentrated, diluted with water and extracted 3 times with ethyl acetate. The crude compound was purified by chromatography (SiO₂; ethyl acetate / n-heptane 1:4) to give the title compound as a viscous yellow oil. Yield: 37%.

(d) 2-Trifluoromethyl-6J-dihydτo-5H-pyrrolof3,4-b1pyridine

Prepared in analogy to Example A2 (c) from 2-Trifluoromethyl-6-trityl-6,7-dihydro-5H- pyrrolo[3,4-b] pyridine and trifluoroacetic acid. Light yellow solid. MS (m/e): 189.3 ([M+H⁺, 100%).

Example Al 5 6-Trifluoromethyl-2,3-dihydro-lH-isoindol-5~ylamine

(a) 4-Fluoro-5-trifluoromethyl-phthalic acid

To a stirred solution of 2.34 mmol l-fluoro-4,5-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(VT) 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) S-Amino-β-trifluoromethyl-isoindole- 1,3-dione

To a stirred solution of 2.14 mmol 4-fluoro-5-trifluoromethyl-phthalic acid in 7 ml N- methylpyrolidone was added 4.28 mmol urea and the mixture was at 140 ⁰C for 2 h, and then at 160 ⁰C for 4 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and washed sequentially with water and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was triturated in ether/penane (1/1) to yield the title compound as a yellow solid. MS (m/e): 229.1 ([M-H]-, 100%)

(c) 6-Trifluoromethyl-2,3-dihydro-lH-isoindol-5-ylamine

Prepared in analogy to Example Al from 5-amino-6-trifluoromethyl-isoindole-l,3-dione and borane tetrahydrofuran complex. Yellow solid. MS (m/e): 203.3 ([M+H⁺, 100%).

Example A16

3-Trifluoromethyl-6,7-dihydro- 5H-pyrrolo [ 3 ,4-b ] pyridine

( a) ( 3 -Hydroxymethvl- 5 -trifluor omethvl-pyridin-2-vO -methanol

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 ⁰C, 2N HCl 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%)

(b) 2,3-Bis-chloromethvl-5-trifluoromethvl-pvridine

Prepared in analogy to Example A13 (a) from (3-Hydroxymethyl-5-trifluoromethyl- ρyridin-2-yl) -methanol and thionylchloride. Red oil. MS (m/e): 243.1 ([M-H⁺, 100%).

(c) 3-Trifluoromethyl-6-trityl-6,7-dihvdro-5H-pyrrolo[3,4-b1pyridine

Prepared in analogy to Example A2 (b) from 2,3-Bis-chloromethyl-5-trifluoromethyl- pyridine and triphenylmethylamine. White solid. MS (m/e): 431.3 ([MH⁺, 100%).

(d) 3-Trifluoromethyl-6,7-dihydro-5H-pyrrolor3,4-b1pyridine

Prepared in analogy to Example A2 (c) from 3-Trifluoromethyl-6-trityl-6,7-dihydro-5H- pyrrolo [ 3, 4-b] pyridine and trifluoroacetic acid. Yellow oil. MS (m/e): 189.4 ([M+H⁺, 100%).

Example Al 7 4-Fluoro-6-trifluoromethyl-2,3-dihydro-lH-isoindole

Ca) 3-Fluoro-N,N-diisopropyl-5-trifluoromethyl-benzamide

To a suspension of 15.9 mmol 3-Fluoro-5-(Trifluoromethyl) benzoic acid in 20 ml toluene containing 2 drops of DMF was added 79.7 mmol thionylchloride at 0⁰C. The mixture was heated at 85°C for 5 hours. The solvent was carefully removed in vacuo. The colorless liquid was dissolved in 25 ml dichloromethane and cooled to 0⁰C. 63.8 mmol diisopropylamine was added dropwise. The mixture was allowed to warm to RT. After 1 hour the solvent was removed in vacuo. The residue was taken in ethyl acetate and washed twice with water. The washings were extracted once with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO₂, heptane/ ethyl acetate) to yield the title compound as a light yellow solid (85% yield). MS (m/e): 291.9 (M⁺, 100%)

(b) 3-Fluorθ"2-formyl-N,N-diisopropyl-5-trifluoromethyl-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 (SiO₂, heptane/ ethyl acetate) to yield the title compound as a light yellow solid (90% yield). MS (m/e): 320.1 (M+H⁺, 100%)

(c) 4-Fluoro-6-trifluoromethyl-3H-isobenzofuran-l-one

To a solution of 5.39 mmol 3-fluoro-2-formyl-N,N-d.iisopropyl-5-trifluoromethyl- benzamide in 17 ml ethanol was added portionwise 5.39 mmol sodium borohydride. The temperature was maintained at 30⁰C with a water bath. The mixture was then stirred at room temperature for 50 minutes then cooled in an ice-water bath. Excess sodium borohydride was destroyed by adding HCl 2N. Ethanol was removed in vacuo. The residue was taken in 25 ml HCl 6N and refluxed at 12O⁰C for 2 hours. The mixture was cooled to room temperature and extracted 3 times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO₂, heptane/ ethyl acetate) to yield the title compound as a white solid (71% yield). MS (m/e): 220.2 (M⁺, 100%)

(d) (2-Fluoro-6-hydroxymethvl-4-trifluoromethvl-ρhenyl)-methanol

Prepared in analogy to Example A16 (a) from 4-Fluoro-6-trifluoromethyl-3H- isobenzofuran-1-one e and sodium borohydride. Colorless oil. MS (m/e): 225.1 ([M+H⁺, 100%).

(e^") 4-Fluoro-6-trifluoromethyl-2-trityl-2,3-dihydro-lH-isoindole

Prepared in analogy to Example A14 (c) from (2-Fluoro-6-hydroxymethyl-4- trifluorornethyl-phenyl) -methanol. Yellow oil.

(f) 4-Fluoro-6-trifluoromethyl-2,3-dihydro-lH-isoindole

Prepared in analogy to Example A2 (c) from 4-Fluoro-6-trifluoromethyl-2-trityl-2,3- dihydro-lH-isoindole and trifluoroacetic acid. Yellow oil. MS (m/e): 206.1 ([M+H⁺, 100%).

Example Al 8 5-Trifluoronaethoxy-2,3-dihydro- lH-isoindole

(a) N,N-Diisopropyl-4-trifluoromethoxy-benzamide

Prepared in analogy to Example A17(a) from 4-(trifuoromethoxy)-benzoic acid. Yellow oil. MS (m/e): 290.2 ([M+H]⁺, 100%)

(b) 2-Formyl-N,N-diisopropyl-4-trifluoromethoxy-benzamide

Prepared in analogy to Example A17(b) from N,N-Diisopropyl-4-trifluoromethoxy- benzamide. Yellow oil. MS (m/e): 318.1 ([M+Hf, 100%)

(c) 5-Trifluorometfaoxy-3H-isobenzofuran-l-one

Prepared in analogy to Example A17(c) from 2-Formyl-N,N-diisopropyl-4~ trifluoromethoxy-benzamide. White needle. MS (m/e): 219.1 ([M+H]⁺, 100%) Cd) (2-Hydroxymethyl-5-trifluoromethoxy-phenyl^')-methanol

Prepared in analogy to Example A16(a) from 5-Trifluoromethoxy-3H-isobenzofuran-l- one. Colorless oil.

(e) 5-Trifluoromethoxy-2-trityl-2,3-dihydro-lH-isoindole

Prepared in analogy to Example A14(c) from (2-Hydroxymethyl-5-trifluoromethoxy- phenyl) -methanol. Light red oil.

(f) 5-Trifluoromethoxy-2,3-dihydro- lH-isoindole

Prepared in analogy to Example A2(c) from 5-Trifluoromethoxy-2-trityl-2,3-dihydro- lH-isoindole. Dark brown oil.

Example A19 5-difluoromethoxy-2,3-dihydro-lH-isoindoline trifluoroacetic acid

(a) 5-Difluoromethoxv-l,3-dihydro-isomdole-2-carboxvlic acid tert-butyl ester

A mixture containing 0.68 mmol 5-Hydroxy-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (CAS: 226070-47-9), 0.68 mmol potassium carbonate and 0.68 mmol ethyl chlorodifluoroacetate in 1.5 ml DMF was stirred overnight at 65 ⁰C. 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 by chromatography on silica gel (eluant: n-heptane/ethylacetate) to afford the title compound as a white solid (40 % yield).

(b) 5-difluoromethoxy-23-dihydro~lH-isoindoline trifluoro acetic acid

Prepared in analogy to Example A3(e) from 5-Difluoromethoxy-l,3-dihydro-isoindole- 2-carboxylic acid tert-butyl ester by using trifluoroacetic acid instead of hydrochloride acid. Dark brown oil.

Example A20 2-Methyl-3-trifluoromethyl-6,7-dihydro-5H-pyrrolo [ 3 ,4-b] pyridine

fa) 6-Methyl-5-trifluoromethyl-pyridine-2-carboxylic acid diisopropylamide

Prepared in analogy to Example A17(a) from 6-Methyl-5-trifluoromethyl-pyridine-2- carboxylic acid (CAS: 855916-28-8). Yellow oil. MS (m/e): 289.1 ([M+H]⁺, 100%)

(b) 3-Formyl-6-methyl-5-trifluoromethyl-pyridme-2-carboxylic acid diisopropylamide

Prepared in analogy to Example A17(b) from 6-Methyl-5-trifluoromethyl-pyridine-2- carboxylic acid diisopropylamide. Yellow oil. MS (m/e): 316.9 ([M+H]⁺, 100%)

(c) 2-Methyl-3-trifluoromethyl-5H-furo[3,4-b1ρyridin-7-one

Prepared in analogy to Example A17(c) from 3-Formyl-6-methyl-5-trifluoromethyl- pyridine-2-carboxylic acid diisopropylamide. White solid. MS (m/e): 218.1 ([M+H]⁺, 100%)

(d) (3-Hvdroxymethγl-6-methyl-5-trifluoromethyl-pyridin-2-yl)-methanol

Prepared in analogy to Example A16(a) from 2-Methyl-3-trifluoromethyl-5H-furo[3,4- b]pyτidin-7-one. White solid. MS (m/e): 222.1 ( [MH-H]⁺, 100%)

(e) 2,3-Bis-chloromethyl-6-methyl-5-trifluoromethyl-pyridine

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-trifluoromethyl-6-trityl-6,7-dihydro-5H-pyrrolo[3,4-b1pyridine

Prepared in analogy to Example A2(b) from 2,3-Bis-chloromethyl-6-methyl-5- trifluoromethyl-pyridine. Light yellow solid. MS (m/e): 445.1 ([M+H]⁺, 100%)

(g) 2-Methyl-3-trifluoromethyl-6,7-dihydro-5H-pyrrolo[3,4-blpyridine

Prepared in analogy to Example A2(c) from 2-Methyl-3-trifluoromethyl-6-trityl-6,7- dihydro-5H-pyrrolo[3,4-b] pyridine. Light yellow oil. MS (m/e): 202.8 ([M+H]⁺, 100%)

Example A21 Rac-5-Methyl-3-trifluoromethyl-6,7-dihydro-5H-pyrrolo[3₎4-b]pyridine

(a) 3-Acetyl-5-trifluoromethyl-pyridine-2-carboxyiic acid diisopropylamide

Prepared in analogy to Example A17(b) from 5-Trifluoromethyl-pyridine-2~carboxylic acid diisopropylamide (CAS: 765298-31-5) and N-methoxy-N-methylacetamide instead of dimethylformamide. Orange solid. MS (m/e): 317.1 ( [M+H]⁺, 100%)

(b ) rac- 5-Methyl-3 -trifluoromethyl-5H-furo I^" 3 ,4-b 1 pyridin- 7-one

Prepared in analogy to Example A17(c) from 3-Acetyl-5-trifluoromethyl-pyridine-2- carboxylic acid diisopropylamide. White solid. MS (m/e): 217.1 ([M+H]⁺, 100%)

( c) rac- 1 - (2-Hydroxymethyl-5-trifluoromethyl-pyridin-3-yl) -ethanol

Prepared in analogy to Example Al6(a) from rac-5-Methyl-3-trifluoromethyl-5H- furo[3,4-b]pyridin-7-one. Colorless oil. MS (m/e): 222.2 ([M+H]⁺, 100%) (d) rac-5-Methyl-3-trifluoromethyl-6-tritτl^7-dmydro-5H-pyrrolo f 3,4-bl pyridine

Prepared in analogy to Example A14(c) from rac-l-(2-Hydroxymethyl-5- trifluoromethyl-pyridin-3-yl)-ethanol. Yellow oil.

(e) rac-5-Methyl-3-trifluoromethγl-6,7-dihydro-5H-pyrrolo[3,4-b1pyridine

Prepared in analogy to Example A2(c) from rac-5-Methyl-3-trifluoromethyl-6-trityl-6,7- dihydro-5H-pyrrolo[3,4-b] pyridine. Yellow oil. MS (m/e): 203.3 ([M+H]⁺, 100%)

Example A22 6-Chloro-2,3-dihydro- lH-pyrrolo [3,4-c]pyridine

( a) β-Chloro-N^-diisopropyl-nicotmamide

Prepared in analogy to Example A17(a) from 2-chlorpyridine-5-carboxylic acid. Yellow oil. MS (m/e): 241.3 ([M+H]⁺, 100%)

(b) 6-Chloro-4-formyl-N,N-diisopropyl-nicotinamide

Prepared in analogy to Example A17(b) from N,N-Diisopropyl-4-trifluorornethoxy- benzamide. Yellow oil. MS (m/e): 269.2 ([M+H]⁺, 100%)

(c) 6-Chloro-lH-furo[3,4- clpyridin-3 -one

Prepared in analogy to Example A17(c) from 6-Chloro-4-formyl-N,N-diisopropyl- nicotinamide. White solid.

( d) ( 6-Chloro-4-hydroxymethyl-pyridin-3-yl) -methanol

Prepared in analogy to Example Al 6 (a) from 6-CHoro-lH-faro[3,4-c]pyridin~3-one. White solid. MS (m/e): 172.0 ([M-H], 100%)

(e) 6-Chloro-2-trityl-2,3-dihvdro-lH-pyrrolo[3,4-c1 pyridine

Prepared in analogy to Example A14(c) from (6-Chloro-4-hydroxymethyl-pyridin-3-yl)- methanol. White foam.

(f) 6-Chloro-2,3-dihvdro-lH-pyrrolo[3,4-clpyridine

Prepared in analogy to Example A2(c) from 6-Chloro-2-trityl-2,3-dihydro-lH- pyrrolo[3,4-c]pyridine. White solid. MS (m/e): 155.1 ([M+H]⁺, 100%) Example A23 5-(4-Methyl-thiazol-2-yl)-2,3-dihydro-lH-isoindole

(a) 5-(4,4,5,5-Tetramethyl-[l,3,2idioxaborolan-2-yl^')-l,3-dihy(iro-isoindole-2-carboxylic acid tert-butyl ester

A mixture containing 5.03 mmol 5-Bromo-l,3-dihydro-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 l,l-bis(diphenylphosphino)ferrocene dichloro palladium (II) dichloromethane adduct in 15 ml degazed DMF was stirred at 70⁰C 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 (m/e): 346.1 ([M+H]⁺, 100%)

(b) 5-(4-Methyl-thiazol-2-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

A mixture containing 3.2 mmol 5-(4,4,5,5-TetramethyI-[l,3,2]dioxaborolan-2-yl)-l,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 tetrakistriphenylphosphine in 11 ml degazed DMF was stirred at 90⁰C for 43 hours. The solvent was removed in vacuo. The residue was taken in ethyl acetate. The mixture was washed twice with water. The aqueous layer was extracted once with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered and the solvent was removed in vacuo. The crude oil was purified on a 5Og Flashpack cartridge (Eluent: Heptane/ AcOEt) to afford the title compound as a white solid (36 % yield). MS (m/e): 316.1 (M⁺, 100%)

rc⁾ 5-(4-Methyl-thiazol-2-yl)-2,3-dihydro-lH-isoindole

Prepared in analogy to Example A3(e) from 5-(4-Methyl-thiazol~2-yl)-l,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester and using trifluoacetic acid instead of hydrochloride acid. Brown solid. MS (m/e): 217.1 ([M+H]⁺, 100%)

Example A24

5-(2-Methyl-pyridin-4-yl)-2,3-dihydro-lH-isoindole

(a) 5-(2-Methyl-pyridin-4-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

A mixture containing 1.4 mmol 5-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-l,3- dihydro-isoindole-2-carboxylic acid tert-butyl ester, 4.8 mmol potassium fluoride, 1.4 mmol 4-chloro-2-picoline (commercial) and 0.03 mmol bis(tri-tert- butylphosphine)palladium in 5 ml degazed dioxane was stirred at 100⁰C for 1.5 hours. The solvent was removed in vacuo. The residue was taken in ethyl acetate. The mixture was washed twice with water. The aqueous layer was extracted once with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered and the solvent was removed in vacuo. The crude oil was purified on a 2Og Hashpack cartridge (Eluent: Heptane/ AcOEt) to afford the title compound as a yellow oil (69 % yield). MS (m/e): 311.2 ([M+H]⁺, 100%)

(b) 5-f2-Methyl-pyridin-4-yl)-2,3-dihvdro-lH-isoindole

Prepared in analogy to Example A3(e) from 5-(2-Methyl-pyridm-4~yl)~l,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester and using trifluoacetic acid instead of hydrochloride acid. Brown solid. MS (m/e): 211.0 ([M+H]⁺, 100%) Example A25 5-(5~Methyl-thiophen-3-yl)-2,3-dmydro-lH-isoindole

(a) 5-(5-Methyl-miophen-3-yl)-l,3-dihydro-isomdole-2-carboxylic acid tert-butyl ester

Prepared in analogy to Example A23(b) from 5-(4,4,5,5-Tetramethyl- [l,3,2]dioxaborolan-2-yl)~l,3-dihydro-isoindole-2-carboxyric acid tert-butyl ester and 4- bromo-2-methylthiophene (commercial). Light yellow solid. MS (m/e): 315.2 ([M]⁺, 100%)

(b) 5-(5-Methyl-thiophen-3-yl)-23-dihvdro-lH-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]⁺, 100%)

Example A26 5-(5-Methyl-thiazol-2-yl)-2,3-dihydro-lH-isoindole

(a) 5-(5-Methyl-thiazol-2-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

Prepared in analogy to Example A23(b) from 5-(4,4,5,5-Tetramethyl- [l,3,2]dioxaborolan-2-yl)-l,3-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%) (b) 5-(5-Methyl-thiazol-2-yl)-2,3-dihvdro-lH-isoindole

Prepared in analogy to Example A3(e) from 5-(5-Methyl-thiazol-2-yl)-l,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester and using trifluoacetic acid instead of hydrochloride acid. Brown gum. MS (m/e): 217.0 ( [M+H]⁺, 100%)

Example A27 5-Thiazol-2-yl-2,3-dihydro-lH-isoindole

(a) 5-Thiazol-2-yl-l,3-dihγdro-isoindole-2-carboxylic acid tert-butyl ester

Prepared in analogy to Example A23(b) from 5-(4,4,5,5-Tetramethyl- [l,3,2]dioxaborolan-2-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and 2- Iodo-thiazole (CAS: 3034-54-6). Yellow oil. MS (m/e): 303.1 ([M+H]⁺, 100%)

Cb) 5-Thiazol-2-yl-2,3-dihvdro- lH-isoindole

Prepared in analogy to Example A3(e) from 5-Thiazol-2-yl-l,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-Trifluoromethyl-6,7-dihydro-5H-pyrrolo [3,4-d] pyrimidine

a) 3-[l-Dimethylamino-meth-(Z)-ylidene1-4-oxo-pyrrolidine-l-carboxylic acid tert- butyl ester

A solution of 13.5 mmol N-BOC-3-pyrrolidone and 13.5 mmol N,N- dimethylformamide-dimethylacetal in 50 ml N,N-dimethylformamide was hold overnight at 60° C. The reaction mixture was quenched by addition of 50 ml water and 5 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-Trifluoromethyl-5,7-dihydro-pyrrolo[3,4-d1pyrimidine-6-carboxylic acid tert-butyl ester

A fresh solution of sodium ethanolate was prepared by dissolving 182 mg of sodium in 50 ml of ethanol. To this solution was added 7.9 mmol ) 3-[l~Dimethylamino-meth-(Z)- ylidene]-4-oxo-pyrrolidine-l-carboxylic acid tert. -butyl ester and 7.9 mmol trifluoroacetamidine and the mixture refluxed overnight. The resulting solution was 15 concentrated, hydrolysed and extracted 3 times with ethyl acetate. Chromatography (silica gel; ethyl acetate / heptane) gave the title compound in a yield of 44%. MS (m/e): 290.3 ([M+H]⁺, 40 %).

c) 2-Trifluoromethyl-6J-dihydro-5H-pyrrolo[3,4-dlpyrimidine trifluoroacetate

20 3.4 mmol of 2-Trifluoromethyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic 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]⁺, 100 %).

Example A29

25 4-Trifluoromethyl-2,3-dihydro- 1 H-indole a) Dimethyl-[fEV2-(2-nitro-6-trifluoromethyl-phenyl)-vinyll-amine

A solution of 17 mmol 2-methyl-3-nitroben2otrifluoride and 43 mmol N₅N- dimethylformamide-dimethylacetal in 30 ml N,N-dimethylfbrmamide 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 %).

b) 4-Trifluoromethyl-lH-indole

7.7 mmol Dimethyl- [(E)-2-(2-nitro-6-trifluoromethyl-phenyl)-vinyl] -amine was dissolved in 20 ml methanol. 200mg of palladium 5 % on charcoal was added and the reaction mixture hydrogenated at room temperature and atmospheric pressure. When no further hydrogen is absorbed (ca. 3 hours), the reaction mixture is filtered, concentrated and dissolved in diethyl ether. The organic phase is washed with 2 M hydrochloric acid and brine and concentrated to yield the title compound as a yellowish solid. Yield = 58 %. MS (m/e): 184.9 ( [M+H]⁺, 100 %).

c) 4-Trifluoromethyl-2,3-dihydro- lH-indole

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

2,3-Dihydro-lH-indole-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-2,3-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-(2,3-Dihydro-lH-indol-4-yloxy)-N,N-dimethyl-acetamide

This compound was prepared in analogy to example A29c), starting from 2-(lH-Indol-4- yloxy)-N,N-dimethyl-acetamide. Yield = 36 %. MS (m/e): 221.1 ([M+H]⁺, 100 %). Example A33

4-Chloro-5-methoxy-2,3-dihydro-lH-indole

This compound was prepared in analogy to example A29c), starting from 4-Chloro-5- methoxy-2,3-dihydro-lH-indole (CA = [68935-48-8]).. Yield = 42 %. MS (m/e): 184.1 ([M+H]⁺, 100 %).

Example A34 (2,3-Dihydro-lH-indol-4-yl)-methanol

This compound was prepared in analogy to example A29c)_> starting from 4-formyl- indole. Yield = 81 %. MS (m/e): 150.3 ([M+H]⁺, 100 %).

Example A35 5-Ethylsulfanyl-6-trifluoromethyl-2,3-dihydro- lH-isoindole hydrochloride

(a) 4-Iodo-5-trifluoromethyl-phthalic acid

Prepared in analogy to Example A15(a) from l-iodo-4,5-dimethyl-2-trifluoromethyl- benzene (CAS: 165323-73-9) and chromium(VT) oxide. Grey solid. MS (m/e): 359.0 ([M- H]^", 100%)

Cb) S-Iodo-β-trifluoromethyl-isoindole- 1,3-dione

Prepared in analogy to Example Al5(b) from 4-iodo-5-trifluoromethyl-phthalic acid and urea. Brown solid. MS (m/e): 339.9 ([M-H]^", 100%) (c) 5-Iodo-6-trifluoromethγl-2,3-dihydro- lH-isoindole

Prepared in analogy to Example Al from 5-iodo~6-trifluoromethyl-isoindole-l,3-dione andborane tetrahydrofuran complex. Brown solid. MS (m/e): 314.0 ([M+H⁺, 100%).

f d) 5-Iodo-6-trifluoromethyl-l,3-dihydro-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=CH₂I⁺, 100%).

(e) S-Ethylsulfanyl-ό-trifluoromethyl-l^-dihydro-isoindole-Z-carboxylic acid tert-butyl ester

Prepared in analogy to Example A5(a) from 5-iodo-6-trifluoromethyl-l,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester and ethyl mercaptan. White solid. MS (m/e): 292.1 ([M+H-Me₂C=CH₂]⁺, 100%).

(f) 5-Ethylsulfanγl-6-trifluoromethyl-2,3-dihydro-lH-isoindole hydrochloride

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-2,3-dihydro- lH-isoindole trifluoroacetate

(a) 4-Fluoro-5-trifluoromethyl-phthalic acid dimethyl ester

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-MeO]⁺, 100%).

(b) f4-Fluoro-2-hydroxymethyl-5-trifluoromethyl-phenyl)-methanol

To 23.6 mmol LiAlELj in 10 ml THF was added dropwise over 5 min a solution of 3.93 mmol 4-fluoro-5-trifluoromethyl-phthalic acid dimethyl ester in 5 ml THF. The mixture was stirred at room temperature for 2 h, and then heated at 50⁰C for 20 min. The reaction mixture was quenched by dropwise addition of 8 ml ethyl acetate, stirred for a further 15 min at 50⁰C, then cooled to room temperature and acidified to pH 1 by dropwise addition of 5 M aq HCl. 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+OAc)]\ 100%), 223.1 ([M-H]^", 20%).

(c) 5-Fluoro-6-trifluoromethyl-2-tri1yl-2,3-dihydro-lH-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 0⁰C were added dropwise 3.28 mmol methanesulfonyl chloride and 6.25 mmol triethylamine. The mixture was stirred at 0⁰C 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 N₅N- diisopropylethylamine and 2.03 mmol triphenylmethylamine were added sequentially. The mixture was heated at 60⁰C for 1 day and then at 80 ⁰C 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). EI-MS (m/e): 370.1 ([M-Ph]⁺, 100%).

(d) 5-Fluoro-6-trifluoromethyl-2₁3-dihydro- IH-isoindole trifluoroacetate

To a mixture of 0.33 mmol 5-fluoro-6-trifluoromethyl-2-trityl-2₎3-dihydro-lH-isoindole in 1.5 methanol and 1.5 ml chloroform at 0 ⁰C 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-Chloro-6-piperidin-l-yl-2,3-dihydro-lH-isoindole hydrochloride

(a) 5-Chloro-6-piperidin-l-yl-l,3-dihvdro-isoindole-2-carboxylic 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 ({³⁷Cl}M+H⁺, 29%), 337.1 ({³⁵Cl}M+H⁺, 100%).

(b) 5-Chloro-6-piperidin-l-yl-2,3-dihydro-lH-isoindole hydrochloride

Prepared in analogy to Example A3(e) from 5-chloro-6-piperidin-l-yl-l,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Brown solid. MS (m/e): 239.2 ({³⁷C1}M+H⁺, 35%), 237.1 ({³⁵C1}M+H⁺, 100%).

Example A38 5-(2-Methox7-ethoxy)-2,3-dihydro-lH-isoindole hydrochloride (a^*) 5-Iodo-2,3-dihydro-lH-isomdole

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-l,3-dihvdro-isoindole-2-carboxylic 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=CH₂]⁺, 100%).

(c) 5-(2-Metb.oxy-ethoxy)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

Prepared in analogy to Example A6(a) from 5-iodo-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and 2-methoxyethanol. White solid. MS (m/e): 237.9 ([M+H- Me₂C=CHa]⁺, 100%)

(d) 5-(2-Methoxy-ethoxy)-2,3-dihγdro-lH-isoindole hydrochloride

Cl

Prepared in analogy 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-isoindol-5-yl)-pyrrolidin-2-one hydrochloride (a) 5-(2-Qxo-pyrrolidm-l-yD-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

Lit. /. Am. Chem. Soc. 2001, 123, 7727-7729. To a stirred suspension of 0.58 mmol 5- iodo-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) in 4 ml dioxane were added 0.12 mmol copper(I) iodide, 1.74 mmol potassium carbonate, 0.17 mmol trans- 1,2-diaminocyclohexane and 2.90 mmol 2-pyrrolidone and the reaction mixture was stirred at 140 ⁰C 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 (SiO₂, heptane/ ethyl acetate) to yield the title compound as a white solid. MS (m/e): 247.3

100%).

(b) l-(2,3-Dihydro-lH-isoindol-5-yl)-pyrrolidin-2-one hydrochloride

Cl

Prepared in analogy to Example A3(e) from 5-(2-oxo-pyrrolidin-l-yl)-l,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Off-white solid. MS (m/e): 203.4 ([M+H]⁺, 100%).

Example A40 5-Isopropoxy-2,3-dihydro- lH-isoindole hydrochloride

(a) 5-Isopropoxy-l,3-dihydro-isoindole-2-carboxyh^'c 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 2-propanol. White solid. MS (m/e): 222.1 ([M+H-Me₂C=CH₂]⁺, 100%).

(b) 5-Isopropoχy-2,3-dihydro-lH-isoindole hydrochloride

Prepared in analogy to Example A3(e) from 5-isopropoxy-l,3-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-2,3-dihydro- lH-isoindole hydrochloride

(a) 5-Ethoxy-l,3-dihydro-isoindole-2-carboxylic 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 ethanol. Light brown solid. MS (m/e): 208.1 ([M+H-Me₂C=CH₂]⁺, 100%).

(b) 5-Ethoxy-2,3-dihydro-lH-isoindole hydrochloride

Prepared in analogy to Example A3(e) from 5-ethoxy-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Brown solid. MS (m/e): 164.4 ( [M+H]⁺, 100%).

Example A42 5-(4,4-Difluoro-piperidin-l-yl)-2,3-dihydro-lH-isoindole hydrochloride

fa) 5-(4,4-Difluoro-piperidin-l-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

Prepared in analogy to Example A3(d) from 5-iodo-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 4,4-difluoropiperidine hydrochloride. Yellow solid. MS (m/e): 339.1 ([M+H]⁺, 100%).

fb) 5-(4,4-Difluoro-piperidiri-l-yl)-2,3-dihydro-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-2,3-dihydro-lH-isoindole hydrochloride

(a) 5-Ethoxy-6-trifluoromethyl-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

Prepared in analogy to Example A6(a) from 5-iodo-6-trifluoromethyl-l,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester (Example A35(d)) and ethyl mercaptan. White solid. MS (m/e): 276.3 ( [M+H-Me₂C=CH₂]⁺, 100%).

(b) 5-Ethoxy-6-trmuoromethyl-2,3-dihydro-lH-isomdole hydrochloride

Prepared in analogy to Example A3(e) from 5-ethoxy-6-trifluoromethyl-l,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. White solid. MS (m/e): 232.1 ([M+H]⁺, 100%).

Example A44 5-Chloro-6-morpholin-4-yl-2,3-dihydro- 1 H-isoindole hydrochloride (a) 5-Chloro-6-morpholin-4-vl-l,3-dihvdro-isoindole-2-carboxvlic 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 morpholine. Yellow solid. MS (m/e): 341.3 ({³⁷C1}M+H⁺, 20%), 339.1 ({³⁵Cl}M+H⁺, 100%).

(b) 5-Chloro-6-morpholm-4-γl-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 ({³⁷Cl}M+H⁺, 52%), 239.3 ({³⁵C1}M+H⁺, 100%).

Example A45 5-Ethyl-6-trifluoromethyl-2,3-dihydro- lH-isoindole hydrochloride

(a) 5-Trifluoromethyl-6-vinyl-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

To a stirred solution 0.61 mmol 5-iodo-6-trifluoromethyl-l,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 ⁰C 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 (SiO₂, heptane/ethyl acetate) to yield the title compound as a yellow solid (93% yield).

(b) 5-Ethyl-6-trifluoromethyl-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

To a stirred solution 0.54 mmol 5-trifluoromethyl-6-vinyl-l,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 (SiO₂, heptane/ethyl acetate) to yield the title compound as a white solid (20% yield). MS (m/e): 260.0 ([M+H-Me₂C=CH₂]⁺, 100%).

(c) 5-Ethyl-6-trifluoromethyl-2,3-dihydro-lH-isoindole hydrochloride

Cl

Prepared in analogy to Example A3(e) from 5-ethyl-6-trifluoromethyl-l,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. White solid. MS (m/e): 216.4 ([M+H]⁺, 100%).

Example A46 5-Morpholin-4-yl-6-trifluoromethyl-2,3-dihydro-lH-isoindole hydrochloride

(a) 5-Morpholin-4-yl-6-trifluoromethyl-13-dihydro-isoindole-2-carboxylic acid tert- butyl ester

Prepared in analogy to Example A3(d) from 5-iodo-6-trifluoromethyl-l,3-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-Morpholin-4-yl-6-trifluoromethyl-2,3-dihydro- lH-isoindole hydrochloride

Cl

Prepared in analogy to Example A3(e) from 5-morpholin-4-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%).

Example A47 1 - (2,3-Dihydro- lH-isoindol-5-yl)-ethanone

To a stirred solution 0.72 mmol 5-iodo-l,3-dihydro-isoindole-2-carboxylic acid tert- butyl ester (Example A38(b)) in 3 ml dioxane were added 0.05 mmol palladium(II) acetate and 0.22 mmol triphenylarsine and the mixture was stirred at RT for 10 min. 1.01 mmol 1-ethoxyvinyltributylstannane was then added and the mixture was heated at 100 ⁰C for 16 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-2,3-dihydro-lH-isoindol-5-yl)-ethanone

Prepared in analogy to Example A47 from 5-iodo-6-trifluoromethyl-l,3-dihydro- ^• isoindole-2-carboxylic acid tert-butyl ester (Example A35(d)) and 1- ethoxyvinyltributylstannane. White solid. MS (m/e): 230.3 ([M+H]⁺, 100%).

Example A49 5-(Tetrahydro-pyran-4-yl)-2,3-dihydro-lH-isoindole hydrochloride

(a) 5-(3,6-Dihydro-2H-pyran-4-yl)-l,3-dihγdro-isoindole-2-carboxylic acid tert-butyl ester

To a stirred solution 6.32 mmol 5-iodo-l,3-dihydro-isoindole-2-carboxylic acid tert- butyl ester (Example A38(b)) in 20 ml DMF were added 12.6 mmol tribufyl-(3,6- dihydro-2H-pyran-4-yl)-stannane, 3.79 mmol triphenylarsine, 0.76 mmol bis(triphenylphosphine)palladium(II) chloride, 50.5 mmol lithium chloride and 0.63 mmol 2,6-di-t-butyl-p-cresol and the mixture was heated at 100⁰C for 6 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography (SiO₂, heptane/ethyl acetate) to yield the title compound as a yellow solid (74% yield). MS (m/e): 246.1 ([M+H-Me₂C=CH₂]⁺, 100%).

(b) 5-(Tetrahydro-pyran-4-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl Ester

To a stirred solution 7.27 mmol 5-(3,6-dihydro-2H-pyran-4-yl)~l,3-dihydro-isoindole-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 (SiO₂, heptane/ethyl acetate) to yield the title compound as a white solid (92% yield). MS (m/e): 248.3 ([M+H-Me₂C=CH₂]⁺, 100%). (c) 5-(Tetrahydro-pyran-4-yl)-23-dihydro-lH-isoindole hydrochloride

Prepared in analogy to Example A3(e) from 5-(tetrahydro-pyran-4-yl)-l,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. White solid. MS (m/e): 204.3 ([M+H]⁺, 100%).

Example A50 5- (Tetrahydro-pyran-4-yl)-6-trifluoromethyl-2,3-dihydro- lH-isoindole hydrochloride

(a) 5-(3,6-Dihydro-2H-pyran-4-yl)-6-trifluoromethyl-l,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester

Prepared in analogy to Example A49(a) from 5-iodo-6-trifluoromethyl-l,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester (Example 35(d)) and tributyl-(3,6-dihydro- 2H-pyran-4-yl)-stannane. Yellow solid. MS (m/e): 314.0 ([M+H-Me₂C=CH₂]⁺, 100%).

(b) 5-(Tetrahydro-pyran-4-yl)-6-trifluoromethyl-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

Prepared in analogy to Example A49(b) from 5~(3,6-dihydro-2H-pyran-4-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-Me₂C=CH₂]⁺, 100%).

(c) 5-(Tetrahydro-pyran-4-yl)-6-trifluoromethyl-2,3-dihydro-lH-isoindole hydrochloride

Prepared in analogy to Example A3(e) from 5-(tetrahydro-pyran-4-yl)-6- trifluorometiiyl-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Yellow solid. MS (m/e): 272.3 ([M+H]⁺, 100%).

Example A51

5-(l,l-Dioxo-l-thiomorpholin-4-yl)-2,3-dihydro-lH-isoindole hydrochloride

(a) 5-(l,l- Dioxo-1-thiomorpholin -4-yl)-l,3-dihydro-isoindole-2-carboxylic acidtert- butyl ester

Prepared in analogy to Example A3(d) from 5-iodo-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and tetrahydro-2H-l,4-thiazine 1,1-dioxide. Brown solid. MS (m/e): 353.0 ([M+H]⁺, 100%).

(b) 5-(U-Dioxo-l-thiomorpholin-4-yl)-2,3-dihydro-lH-isoindole hydrochloride

Prepared in analogy to Example A3(e) from 5- (1,1- dioxo-llambda*6*-thiornorpholin 4-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Brown solid. MS (m/e): 253.1 ([M+H]⁺, 100%).

Example A52 5-(3,3-Difluoro-piperidin-l-yl)-2,3-dihydro-lH-isoindole hydrochloride

(a) 5-(3,3-Difluoro-piperidin-l-yl)-l,3-dihvdro-isoindole-2-carboxylic acid tert-butyl ester

Prepared in analogy to Example A3(d) from 5-iodo-l_>3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 3,3-difluoropiperidine hydrochloride. Pink solid. MS (m/e): 339.1 ([M+H]⁺, 100%).

fb) 5-(3,3-Dmuoro-piperidin-l-yl)-23-dihydro-lH-isoindole hydrochloride

Prepared in analogy to Example A3(e) from 5-(3,3-difluoro-piperidin-l-yl)-l,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Brown solid. MS (m/e): 239.3 ([M+H]⁺, 100%).

Example A53 l-(2,3-Dihydro-lH-isoindol-5~yl)-4-phenyl-piperidin-4-ol hydrochloride

(a) 5-(4-Hydroxy-4-phenyl-piperidin-l-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert- butyl ester

Prepared in analogy to Example A3(d) from 5-iodo-l,3-dihydro-isoindole~2-carboxylic acid tert-butyl ester (Example A38(b)) and 4-hydroxy-4-phenylρiperidine. Yellow solid. MS (m/e): 395.1 ([M+H]⁺, 100%).

(b) l-(2,3-Dihydro-lH-isoindol-5-yl^')-4-phenyl-piperidin-4-ol hydrochloride

Prepared in analogy to Example A3(e) from 5-(4-hydroxy-4-phenyl~piperidin-l-yl)-l,3- dihydro-isoindole-2-carbox7lic acid tert-butyl ester and hydrochloric acid. Off-white solid. MS (m/e): 295.4 ([M+H]⁺, 100%).

Example A54 5-Methyl-6-morphoh^'n-4-yl-2,3-dihydro-lH-isoindole hydrochloride

(a) 5-Methyl-6-morpholin-4-yI-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl Ester

To a stirred solution 0.38 mmol 5-chloro-6-morpholin-4-yl-l,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester (Example A44(a)) in 3 ml dioxane were added 0.02 mmol bis(tri-tert-butylphosphine)palladium(0), 0.84 mmol cesium fluoride and 0.77 mmol tetramethylstannane and the mixture was heated at 80⁰C for 5 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography (SiO₂, heptane/ethyl acetate) to yield the title compound as a light yellow solid (43% yield). MS (m/e): 219.4

100%).

fb) 5-Methvl-6-morpholin-4-vl-2,3-dihydro-lH-isoindole hydrochloride

Prepared in analogy to Example A3 (e) from 5-methyl-6-morpholin-4-yl-l,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Brown solid. MS (m/e): 219.3 ([M+H]⁺, 100%).

Example A55

5-(2,2,2-Trifluoro-ethyl)-2,3-dihydro-lH-isoindole hydrochloride

(a) 5-Vinyl-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl Ester

Prepared in analogy to Example A45(a) from 5-iodo-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and vinyltributylstananne. Colourless oil. MS (m/e): 190.4 ([M+H-Me₂C=CH₂]⁺ ₎ 100%).

(b) 5-Formyl-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl Ester

To a stirred solution of 3.79 mmol 5-vinyl-l,3-dihydro-isoindole-2-carboxylic acid tert- butyl ester in 25 ml THF and 5 ml water were added 11.4 mmol sodium metaperiodate and 0.08 mmol osmium tetroxide solution (2.5% in tBuOH) and the mixture was stirred at RT for 2 h before being taken up in ethyl acetate and washed sequentially with water and brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO₂, heptane/ ethyl acetate) to yield, the title compound as a white solid (62% yield). MS (m/e): 192.1 ([M+H-Me₂C=CH₂]⁺, 100%).

(c) 5-(2,2-Difluoro-vinyl)-13-dihγdro-isoindole-2-carboxylic acid tert-butyl Ester

To a stirred solution of 4.69 mmol triphenylphosphine in 5 ml DMF at 0 ⁰C was added dropwise a solution of 4.69 mmol dibromodifluoromethane in 1 ml DMF and the mixture was stirred at RT for 30 min. 2.35 mmol 5~formyl-l,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester was then added at 0⁰C and then 4.69 mmol zinc dust was added in small portions. The mixture was stirred at RT for 16 and then concentrated in vacuo. The residue was purified by chromatography (SiO₂, heptane/ ethyl acetate) to yield the title compound as a white solid (31% yield). MS (m/e): 226.1 ([M+H-Me₂C=CH₂]⁺, 100%).

(d) 5-(2,2,2-Trifluoro-ethyl)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl Ester

To a stirred solution of 0.71 mmol 5-(2,2-difiuoro-vinyl)-l,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester in 5 ml DMSO and 0.25 ml water was added 4.98 mmol potassium fluoride and the mixture was heated at 120 ⁰C for 2 h. The mixture was cooled to room temperature and then taken up in THF and washed sequentially with water and with brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO₂, heptane/ethyl acetate) to yield the title compound as a white solid (48% yield). MS (m/e): 246.3 ([M+H-Me₂C=CH₂]⁺, 100%).

(el 5-(2,2,2-Trifluoro-ethyl^')-2,3-dihvdro-lH-isoindole hydrochloride

Prepared in analogy to Example A3(e) from 5-(2,2,2-trifluoro-ethyl)-l,3-dihydro- isoindole-2-carboxylic acid tert-butyl Ester and hydrochloric acid. Off-white solid. MS (m/e): 202.4 ([M+H]⁺, 100%).

Example A56

5-(3-Methoxy-azetidin-l-yl)-2,3-dihydro-lH-isoindole trifluoro-acetate

(a) 5-(3-Methoxy-azetidin-l-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl Ester

Prepared in analogy to Example A3(d) from 5-iodo-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 3-methoxy-azetidine hydrochloride. Orange oil. MS (m/e): 305.4 ([M+H]⁺, 100%). (b) 5-(3-Methoxy-azetidin-l-yl)-2,3-dihydro-lH-isoindole trifluoro-acetate

Prepared in analogy to Example A2(c) from 5-(3-methoxy-azetidin-l-yl)-l,3~dihydro- isoindole-2-carboxylic acid tert-butyl Ester and trifluoroacetic acid. Brown foam. MS (m/e): 205.1 ([M+H]⁺, 100%).

Example A57 5-(4-Methoxy-piperidin-l-yl)-2,3-dihydro-lH-isoindole hydrochloride

(a) 5-(4-Methoxy-piperidin-l-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

Prepared in analogy to Example A3(d) from 5-iodo-l,3-dihydro~isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 4-methoxy-piperidine trifluoroacetate. Yellow oil. MS (m/e): 333.3 ([M+H]⁺, 100%).

(b) 5-(4-Methoxy-piperidin-l-γl)-2,3-dihydro-lH-isoindole hydrochloride

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%).

Example A58 (lS,4S)-5-(2-Oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-2,3-dihydro-lH-isoindole trifluoroacetate

(a) (lS,4S)-5-(2-Qxa-5-aza-bicvclo[2.2.11heρt-5-yl)-L3-dihvdro-isoindole-2-carboxylic acid tert-butyl ester Chiral

Prepared in analogy to Example A3(d) from 5-iodo-l₅3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and (lS,4S)~2-oxa-5-aza-bicyclo[2.2.1]heptane trifluoroacetate. Orange oil. MS (m/e): 317.3 ( [M+H]⁺, 100%).

(b) (lS,4S)-5-(2-Qxa-5-aza-bicvclof2.2.11hept-5-yl)-23-dihvdro-lH-isoindole trifluoroacetate

Prepared in analogy to Example A2(c) from (lS,4S)-5-(2-oxa-5-aza-bicyclo[2.2.1]hept-5- yl)-l,3-dihydro~isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Orange oil. MS (m/e): 217.4 ([M+H]⁺, 100%).

Example A59 8-(2,3-Diliydro-lH-isoindol-5-yl)-3-oxa-8-aza-bicyclo[3.2.1]octane trifluoro-acetate

(a) 5-(3-Oxa-8-aza-bicyclo[3.2.11oct-8-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert- butyl ester

Prepared in analogy to Example A3(d) from 5-iodo-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride. Yellow oil. MS (m/e): 331.4 ([M+H]⁺, 100%).

(b) 8- C2,3-Dihvdro-lH-isoindol-5-yl)-3-oxa-8-aza-bicvcloF3.2.n octane trifluoro- acetate

Prepared in analogy to Example A2(c) from 5-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-l,3- dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Brown oil. MS (m/e): 231.1 ([M+H]⁺, 100%).

Example A60 5-Cyclopropyl-6-morpholin-4-yl-2,3-dihydro-lH-isoindole trifluoroacetate

(a) 5-Cyclopropγl-6-morpholin-4-yl-13-dihydro-isoindole-2-carboxylic acid tert-butyl ester

Prepared in analogy to Example A54(a) from 5-chloro-6-morpholin-4-yl-l,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester (Example A44(a)) and tributylcyclopropylstannane. Yellow solid. MS (m/e): 345.4 ([M+H]⁺, 100%).

(b) 5-Cyclopropyl-6-morpholin-4-yl-2,3-dihydro-lH-isoindole trifluoroacetate

Prepared in analogy to Example A2(c) from 5-cyclopropyl-6-morpholin-4-yl-l,3- dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Brown solid. MS (m/e): 245.4 ([M+H]⁺, 100%).

Example A61 5-Cyclopropyl-6-(tetrahydro-pyran-4-yl)-2,3-dihydro-lH-isoindole trifluoro-acetate

fa) 5-Chloro-6-(3,6-dihydro-2H-pyran-4-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl Ester

Prepared in analogy to Example A49(a) from 5-chloro-6-iodo-l,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester (Example A3(c)) and tributyl-(3,6-dihydro-2H-pyran-4- yl)-stannane. Yellow solid. MS (m/e): 282.3 ({³⁷Cl}[M+H-Me₂C=CH₂]⁺, 49%), 280.3 ({³⁵Cl}[M+H-Me₂C=CH₂]⁺, 100%).

(b) 5-Cyclopropyl-6-(3,6-dihγdro-2H-pyran-4-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

Prepared in analogy 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 and tributylcyclopropylstannane. Yellow oil. MS (m/e): 286.1 ([M+H-Me₂C=CH₂]⁺, 100%).

( c) S-Cyclopropyl-ό- (tetrahydro-pyran-4-yl) - 1 ,-3 -dihydro-isoindole-2-carboxylic acid - tert-butyl Ester

Prepared in analogy to Example A49(b) from 5-cyclopropyl-6-(3,6-dihydro-2H-ρyran-4- yl)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and ammonium formate. Colourless oil. MS (m/e): 288.0 ([M+H-Me₂C=CH₂]⁺, 100%).

(d) 5-Cyclopropyl-6-(tetrahydro-pyran-4-yl)-2,3-dihydro- lH-isoindole trifluoro-acetate

Prepared in analogy to Example A2(c) from S-cyclopropyl-ό- (tetrahydro-pyran-4-yl) - l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Brown solid. MS (m/e): 244.4 ([M+H]⁺, 100%).

Example A62 4- (2,3-Dihydro- lH-isoindol-5-yl)-tetrahydro-pyran-4-ol (a) 2-Benzyl-5-bromo-2,3-dihvdro-lH-isomdole

Prepared in analogy to Example A3(b) from 2-benzyl-5-bromo-isoindole~l,3-dione (CAS: 82104-06-1) and borane tetrahydrofuran complex. White solid. MS (m/e): 290.0 ({⁸¹Br}[M+H]⁺, 100%), 288.1 ({⁷⁹Br}[M+H]⁺, 100%).

(b) 4-(2-Benzyl-2,3-dihydro-lH-isoindol-5-yl)-tetrahvdro-pyran-4-ol

To a stirred suspension of 1.54 mmol 2₇benzyl-5-bromo-2,3-dihydro-lH-isomdole in 3 ml THF at -78 ⁰C 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 ⁰C for 30 min and then allowed to warm to room temperature. The reaction was quenched by addition of 1 M aq HCl, 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 (SiO₂, heptane/ ethyl acetate) to yield the title compound as a yellow solid (25% yield). MS (m/e): 310.3 ([M+H]⁺, 100%).

(c) 4-(2_>3-Dihydro-lH-isoindol-5-yl)-tetoahydro-pyran-4-ol

To a stirred solution 0.39 mmol 4-(2-benzyl-2,3-dihydro-lH-isoindol-5~yl)~tetrahγdro- 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-yl)-2,3-dihydro-lH-isoindole trifluoro-acetate

(a) 5-(3,6-Dihydro-2H-pyτan-4-yl)-6-methyl-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl Ester

Prepared in analogy to Example A54(a) from 5-cHoro-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-Me₂O=CH₂]⁺ ₅ 100%).

(b) 5-Methyl-6-(tetrahydro-pyran-4-yl)-l,3-dihydro-isomdole-2-carboxylic acid tert- butyl ester

Prepared in analogy to Example A49(b) from 5-(3,6-dihydro-2H-pyran-4-yl)-6-methyl- l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and ammonium formate. Yellow- solid. MS (m/e): 262.1 ([M+H-Me₂C=CH₂]⁺, 100%).

(c) 5-Methyl-6-(tetrahydro-pyran-4-yl)-2,3-dih.ydro-lH-isoindole trifluoro-acetate

Prepared in analogy to Example A2(c) from 5-methyl-6-(tetrahydro-ρyran-4-yl)-l,3- dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. MS (m/e): 218.4 ([M+H]⁺, 100%).

Example A64

3-(2,3-Dihydro-lH-isoindol-5-yl)-2-methyl-tetrahydro-furan-3-ol

(a) 3-(2-Benzyl-2,3-dihydro-lH-isoindol-5-yl)-2-methyl-tetrahydro-furan-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+H]⁺, 100%).

(b^') 3-(^'2,3-Dihγdro-lH-isoindol-5-γl^')-2-methyl-tetrahvdro-furan-3-ol

Prepared in analogy to Example A62(c) from 3-(2-benzyl-2,3-dihydro-lH-isoindol-5-yl)- 2-methyl-tetrahydro-furan-3-ol and hydrogen. Yellow oil. MS (m/e): 220.3 ([M+H]⁺, 100%).

Example A65

5-(2-Methyl-tetrahydro-turan-3-yl)-2,3-dihydro-lH-isoindole

(a) 2-Benzyl-5-(2-meth.yl-2,5-dihydro-furan-3-yl)-2,3-dihvdro-lH-isoindole

To a solution of 0.65 mmol 3-(2-benzγl-2,3-dihydro-lH-isoindol-5-γl)-2-methyl- tetrahydro-furan-3-ol (Example A64(a)) and 1.81 mmol triethylamine in 2 ml dichloromethane at 0 ⁰C was added dropwise a solution of 0.84 methanesulfonyl chloride in 0.3 ml dichloromethane. The mixture was stirred at room temperature for 2 h and then re-cooled to 0 ⁰C. 1.94 mmol DBU was added and the mixture stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo and the residue was purified by chromatography (SiO₂, 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-furan-3-yl)-2,3-dihydro-lH-isomdole

Prepared in analogy to Example A62(c) from 2-benzyl-5-(2-methyl-2,5-dihydro-furan-3- yl)-2,3-dihydro-lH-isoindole and hydrogen. Yellow oil. MS (m/e): 204.1 ([M+H]⁺, 100%).

Example A66 3-(2,3-Dihydro-lH-isoindol-5-yl)-tetrahydro-furari-3-ol

(a) 3-(2-Benzyl-2,3-dihydro-lH-isoindol-5-yl)-tetrahydro-furan-3-ol

Prepared in analogy to Example A62(b) from 2-benzyl-5-bromo-2,3-dihydro-lH- isoindole (Example A62(a)) and tetrahydrofuran-3-one. Brown oil. MS (m/e): 296.4 ([MH-H]⁺, 100%).

(b) 3-(2,3-Dihvdro-lH-isoindol-5-yl)-tetrahvdro-ruran-3-ol

Prepared in analogy to Example A62(c) from 3~(2~benzyl-2,3-dihydro-lH-isoindol-5-yl)- tetrahydro-furan-3-ol and hydrogen. Brown oil. MS (m/e): 206.1 ([MH-H]⁺, 100%).

Example A67

5-(Tetrahydro-furan-3-yl)-2,3-dihydro-lH-isoindole

(a) 2-Benzyl-5~(2,5-dihydro-furan-3-yl)-2,3-dihydro-lH-isoindole

Prepared in analogy to Example A65(a) from 3-(2-benzyl-2,3-dihydro-lH-isoindol-5-yl)- tetrahydro-furan-3-ol (Example A66(a)) and methanesulfonyl chloride, triethylamine, and DBU. Brown solid. MS (m/e): 278.0 ([M+H]⁺, 100%).

(b) 5-(Tetrahydro-furan-3-yl)-2,3-dihydro-lH-isoindole

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-yl)-2,3-dihydro-lH-isoindole trifluoro-acetate

(a) 5-Chloro-6-(tetrahydro-pyran-4-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert- butyl ester

To a stirred solution 0.81 mmol 5-chloro-6-(3,6-dihydro-2H-pyran-4-yl)-l,3-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 16 h. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (SiO₂, heptane/ ethyl acetate) to yield the title compound as a white solid (38% yield). MS (m/e): 284.3 ({³⁷Cl}[M+H-Me₂C=CH₂]⁺, 49%), 282.3 ({³⁵Cl}[M+H-Me₂C=CH₂]⁺, 100%).

(b) 5-Chloro-6-(tetrahvdro-pvran-4-yl)-23-dihvdro-lH-isoindole trifluoro-acetate

Prepared in analogy to Example A2(c) from 5-chloro-6-(tetrahydro-pyran-4-yl)-l,3- dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. MS (m/e): 240.2 ({³⁷C1}[M+H]⁺, 39%), 238.1 ({³⁵Cl}[M+H]⁺, 100%).

Example A69 5-Ethyl-6-(tetrahydro-pyran-4-yl)-2,3-dihydro-lH-isoindole trifluoro-acetate (a) 5-(3,6-Dihydro-2H-pyran-4-yl)-6-vinyl-l,3-dihyd.ro-isoindole-2-carbox7lic acid tert- butyl ester

Prepared in analogy 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 vinyltributylstannane. White solid. MS (m/e): 272.4 ([M+H-Me₂C=CH₂]⁺, 100%).

(b) 5-Ethyl-6-(tetrah.ydro-pyran-4-yl)-l,3-dib.ydro-isoindole-2-carboxylic acid tert-butyl ester

Prepared in analogy to Example A49(b) from 5-(3,6-dmydro-2H-pyran-4-yl)-6-vinyl- l,3-dihydro-isoindole-2~carboxylic acid tert-butyl ester and ammonium formate. Yellow oil. MS (m/e): 276.3 ([M+H-Me₂C=CH₂]⁺, 100%).

(c) 5-Ethyl-6-(tetrahydro-pyran-4-yπ-2,3-dihydro-lH-isoindole trifluoro-acetate

Prepared in analogy to Example A2(c) from 5-ethyl-6-(tetrahydro-pyran-4-yl)-l,3- 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-(2,3-Dihydro-lH-isoindol-5-yl)-2,6-dimethyl-tetrahydro-pyran-4-ol

(a) (2S,6R)-4-(2-Benzyl-2,3-dihydro-lH-isoindol-5-yl)-2,6-dimethyl-tetrahydro-pyran- 4-ol

Prepared in analogy to Example A62(b) from 2-benzyl-5-bromo-2,3-dihydro-lH- isoindole (Example A62( a)) and (2R,6S)-2,6-dimethyl-tetrahydro-pyran-4-one. Brown solid. MS (m/e): 338.4 ([M+H]⁺, 100%).

(tO (2S,6RV4-(23-Dihvdio-lH-isokdol-5-vD-2,6-dimethyl-tetrahvdro-ρyran-4-ol

Prepared in analogy to Example A62(c) from (2S,6R)~4-(2-benzyl-2,3-dihydro-lH- isoindol-5-yl)-2,6-dimethyl-tetrahydro-pyran-4-ol and hydrogen. Brown oil. MS (m/e): 248.3 ([M+H]⁺, 100%).

Example A71

5-((2S,6R)-2,6-Dimethyl-tetrahydro-pyran-4-yl)-2,3-dihydro-lH-isoindole

(a) 2-Benzyl-5-((2S,6R)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-2,3-dihvdro-lH- isoindole

Prepared in analogy to Example A65(a) from (2S,6R)-4-(2-benzyl-2,3-dihydro-lH- isoindol-5~yI)-2,6-dimethyl-tetrahydro-pyran-4-ol (Example A70(a)) and methanesulfonyl chloride, triethylamine, and DBU. Brown oil. MS (m/e): 320.3 ([M+H]⁺, 100%).

(b) 5-((2S,6R')-2,6-Dimethyl-tetrahvdro-pyran-4-yl)-2,3-dihydro-lH-isoindole

Prepared in analogy to Example A62(c) from 2-benzyl-5-((2S,6R)-2,6-dimethyl-3,6- dihydro-2H-pyran-4-yl)-2,3-dihydro-lH-isoindole and hydrogen. Brown oil. MS (m/e): 232.1 ([M+H]⁺, 100%).

Example A72 5-[l,4]Dioxan-2-yl-2,3-dihydro-lH-isoindole

(^"a') 2-Benzyl-5-(5₁6-dihvdro-fl,4idioxin-2-yl)-2,3-dihvdro-lH-isoindole

Prepared in analogy to Example A49(a) from 2-benzyl-5-bromo-2,3-dihydro-lH- isoindole (Example A62(a)) and tributyl-(5,6-dihydro-[l,4]dioxin-2-yl)-stannane. Light brown solid. MS (m/e): 294.4 ([M+H]⁺ _> 100%).

(b) 5-fl,4iDioxan-2-yl-2,3-dihvdro-lH-isomdole

Prepared in analogy to Example A49(b) from 2-benzyl-5-(5,6-dihydro-[l,4]dioxin-2-yl)- 2,3-dihydro-lH-isoindole and ammonium formate. Purple solid. MS (m/e): 206.3 ([M+H]⁺, 100%).

Example A73 5-(Tetrahydro-pyran-3-yl)-2,3-dihydro-lH-isoindole

(a) 5-(4,4,5,5-Tetramethyl-d3,2ldioxaborolan-2-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

To a solution of 17.1 mmol 5-bromo-l,3-dihydro-isoindole-2-carboxylic acid tert-buryl ester (Example A10(a)) in 50 ml DMF were added 19.3 mmol bis(pinacolato)diboron, 56.0 mmol potassium acetate and 0.57 mmol l,l-bis(diphenylphosphino)ferrocene dichloro palladium (II) dichloromethane adduct. The mixture was stirred at 70 ⁰C for 17 hours. The solvent was removed in vacuo and the residue was stirred in 50 ml dichloromethane. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: heptane/ethyl acetate) to yield the title compound as a white solid (yield 76%).

(b) 5-(5,6-Dihydro-4H-pyran-3-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

To a stirred solution of 1.59 mmol 5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-l,3- dihydro-isoindole-2-carboxylic acid tert-butyl ester and 1.44 mmol 5-bromo-3,4- dihydro-2H-pyran (CAS: 26274-19-1) in 9 ml ethanol and 21 ml toluene was added 0.08 mmol l,l-bis(diphenylphosphino)ferrocene dichloro palladium (II) dichloromethane adduct. The mixture was heated to 80 ⁰C and then 10 ml of a solution of 2 M aqueous sodium carbonate was added dropwise. After stirring for a further 2 h at 80⁰C, the reaction mixture was diluted with 50 ml water and extracted with 3 x 50 ml ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO₂, heptane/ethyl acetate) to yield the title compound as a yellow oil (40% yield). MS (m/e): 246.1 ([M+H-Me₂G=CH₂]⁺, 100%).

(c) rac-5-(Tetrahydro-pyran-3-yl')-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

Prepared in analogy to Example A49(b) from 5-(5,6-dihydro-4H~pyran-3-yl)-l,3- dihydro-isoindole-2-carboxylic acid tert-butyl ester and ammonium formate. Light yellow oil. MS (m/e): 248.1 ( [M+H-Me₂C=CH₂]⁺, 100%).

(d) rac-5-(Tetrahydro-pyran-3-yl)-2,3-dihydro-lH-isoindole

Prepared in analogy to Example A3(e) from rac-5-(tetrahydro-pyran~3-yl)-l,3-dihydro~ isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Brown oil. MS (m/e): 204.3 ([M+H]⁺, 100%).

Example A74 5- (2,2,2-Trifluoro-ethoxy)-2,3-dihydro- lH-isoindole trifluoroacetate

(a) 5-(2,2,2-Trifluoro-ethoxy)-l,3-dihydro-isoindole-2-carboxylic 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 2,2,2-trifluoroethanol. Yellow solid. MS (m/e): 262.0 ([M+H-Me₂C=CH₂]⁺, 100%)

fb) 5-(2,2,2-Trifluoro-ethoxy^')-2,3-dihvdro-lH-isoindole trifluoroacetate

Prepared in analogy to Example A2(c) from 5-(2,2,2-trifluoro-ethoxy)-l,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Brown oil. MS (m/e): 218.4 ([M+H]⁺, 100%).

Example A75 5- (Tetrahydro-pyran-2-yl)-2,3-dihydro- lH-isoindole

(a) 2-Ben2yl-5-(5,6-dihydro-4H-pyran-2-yl)-2,3-dihydro-lH-isoindole

Prepared in analogy to Example A49(a) from 2-benzyl-5-bromo-2,3-dihydro-lH- isoindole (Example A62( a)) andtributyl-(5,6-dihydro-4H-pyran-2-yl)-stannane. Orange oil. MS (m/e): 292.1 ([M+H]⁺, 100%).

(b) 5-(Tetrahydro-pyran-2-yD-2,3-dihydro- 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]⁺ ₅ 100%).

Example A76 5-Chloro-6-(tetrahydro-furan-3-yl)-2,3-dihydro-lH-isoindole trifluoroacetate

(a) 5-Chloro-6-(2₁5-dihydro-ruran-3-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert- butyl ester

Prepared in analogy to Example A49(a) from 5-chloro-6-iodo-l,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester (Example A3(c)) and tributyl-(2,5-dihydro-furan-3-yl)- stannane. Off-white solid. MS (m/e): 268.3 ([{³⁷Cl} M+H-Me₂C=CH₂]⁺, 32%), 266.1 ([{³⁵C1} MH-H-Me₂C=CH₂] ⁺, 100%).

(b) 5-Chloro-6-(tetrahydro-furan-3-yl)-l,3-dihydro-isoindole-2-carboxylic acid tert- butyl ester

Prepared in analogy to Example A68(a) from 5-chloro-6-(2,5-dihydro-furan-3-yl)-l,3- dihydro-isoindole-2-carboxylic acid tert-butyl ester and platinum(IV) oxide. Off-white solid. MS (m/e): 270.3 ([{³⁷Cl} M+H-Me₂C=CH₂]⁺, 38%), 268.3 ([{³⁵Cl} M+H- Me₂C=CH₂J⁺, 100%).

(c) 5-Chloro-6-(tetrahydro-furan-3-yl)-2,3-dihydro-lH-isoindole trifluoroacetate

Prepared in analogy to Example A2(c) from 5-chloro-6-(tetrahydro-furan-3-yl)-l,3- dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Brown oil. MS (m/e): 226.2 ([{³⁷Cl}M+H]⁺, 33%), 224.2 ([{³⁵Cl}M+H]⁺, 100%).

Example A77

8-(6-Chloro-2,3-dihydro-lH-isoindol-5-yl)-3-oxa-8-aza-bicyclo[3.2.1]pctane trifluoro- acetate

(a) 5-Chloro-6-(3-oxa-8-aza-bicyclo[3.2.11oct-8-yl)-l,3-dihydro-isomdole-2-carboxylic 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 3-oxa~8-azabicyclo[3.2.1]octane hydrochloride. YeUow solidl. MS (m/e): 367.1 ([{³⁷Cl}M+H]⁺, 35%), 365.1 ([{³⁵C1}M+H]⁺, 100%).

(b) 8-f6-Chloro-2,3-dihydro-lH-isoindol-5-γl)-3-oxa-8-aza-bicyclor3.2.noctane trifluoro-acetate

Prepared in analogy to Example A2(c) from 5-chloro-6-(3-oxa-8-aza-bicyclo [3.2.1 ]oct-8- yl)-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Brown oil. MS (m/e): 267.1 ([{³⁷C1}M+H]⁺, 43%), 265.1 ([{³⁵Cl}M+H]⁺, 100%). Example A78

5-Chloro-6-(lS,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-2,3-dihydro-lH-isoindole trifluoroacetate

(a) 5-Chloro-6-(lS,4S)-2-oxa-5-aza-bicyclo|^'2.2.11hept-5-yl-13-dihvdro-isoindole-2- carboxylic 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 (lS,4S)-2-oxa-5-aza- bicyclo[2.2.1]heptane trifluoroacetate. Light yellow solid. MS (m/e): 353.1 ([{³⁷C1}M+H]⁺, 36%), 351.1 ([{³⁵Cl}M+H]⁺, 100%).

(b) 5-Chloro-6-(lS,4S^')-2-oxa-5-aza-bicyclor2.2.nhept-5-yl-2,3-dihvdro-lH-isoindole trifluoroacetate

Prepared in analogy to Example A2(c) from 5-chloro-6-(lS,4S)-2-oxa-5-aza- bicyclo[2.2.1]hept-5-yl-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Brown oil. MS (m/e): 253.1 ([{³⁷C1}M+H]⁺, 26%), 251.1 ([{³⁵C1}M+H]⁺, 100%).

Example A79 5-Fluoro-6-(tetrahydro-pyran-4-yl)-2,3-dihydro-lH-isoindole

(a) l-Fluoro-2-iodo-4,5-dimethyl-benzene

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 ⁰C 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 ⁰C for 60 min. A solution of 173 mmol potassium iodide in 50 ml water was then added dropwise over 30 min while maintaining the reaction temperature between 0 and 5 ⁰C. The reaction mixture was then warmed to room temperature and stirred for 3 h before being quenched with aqueous sodium thiosulphite solution and diluted with ethyl acetate. The phases were separated and the organic phase was washed with water and then dried over sodium sulfate and concentrated in vacuo to yield the title compound as a brown solid (69% yield). MS (m/e): 251 ([M+H]⁺, 100%).

(b) 4-Fluoro-5-iodo-phthalic acid

To a stirred solution of 34.7 mmol l-fluoro-2-iodo-4,5-dimethyl-benzene in 200 ml acetic acid was added dropwise at 0⁰C 40 ml concentrated sulfuric acid. 277 mmol chromium(VI) oxide was then added in small portions. The reaction mixture was then cautiously warmed to 40 ⁰C, whereupon an exothermic reaction started and the temperature rose to 95⁰C. Once the initial exotherm was over, the reaction mixture was stirred at 60 ⁰C overnight. The reaction mixture was then diluted with ethyl acetate, tetrahydrofuran and brine. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford the title compound as a brown solid which was used in the next step without further purification (60% yield). MS (m/e): 309.0 ([M-H]^", 100%).

(c) 4-Fluoro-5-iodo-phthalic acid dimethyl ester

To a stirred solution of 19.4 mmol 4-fluoro-5-iodo-phthalic acid in 60 ml DMF was added 58.1 mmol potassium carbonate. The mixture was then warmed to 35 ⁰C and 38.7 mmol methyl iodide was added dropwise. The mixture was heated at 35 ⁰C for 2 h and then at 60 ⁰C for 4 h before being concentrated in vacuo. The residue was resuspended in ethyl acetate and water and the phases were separated. The organic phase was washed sequentially with 0.5 M aq. sodium hydroxide solution and with brine, then dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silical gel (eluant ethyl acetate / heptane) to afford the title compound as an orange oil (53% yield). EI-MS (m/e): 338.0 (M⁺, 50%), 307.0 ([M-OMe]⁺, 100%).

(d) (5-Fluoro-2-hydroxymethyl-4-iodo-phenyl)-niethanol

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 ml 1 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%).

(e) Methanesulfonic acid 4-fluoro-5-iodo-2-methanesulfonyloxymethyl-benzyl ester

To a suspension of 8.86 mmol (5-fluoro-2-hydroxymefhyl-4-iodo-phenyl)-methanol in 30 ml dichloromethane at 0 ⁰C were added dropwise 22.2 mmol triethylamine and 19.5 mmol methanesulfonyl chloride. The mixture was stirred at 0⁰C for 1 h, and then at room temperature for 5 h. The reaction mixture was diluted with water and extracted four times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a yellow oil (67% yield) which was used in the next step without further purification.

ff) 2-Benzhydryl-5-fluoro-6-iodo-2,3-dihydro-lH-isoindole

To a mixture of 5.93 mmol methanesulfonic acid 4-fluoro-5-iodo-2- . met±tanesulfonyloxyrnethyl-benzyl ester and 14.8 mmol N,N-diisopropylethylamine in 7 ml DMF at 0 ⁰C was added dropwise a solution of 6.53 mmol diphenylmethylamine in 5 ml DMF. The mixture was heated at 60 ⁰C for 16 h and was then cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was washed sequentially with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: ethyl acetate/heptane) to afford the title compound as a light yellow solid (55% yield).

(g) 2-Benzhvdryl-5-(3,6-dihvdro-2H-pyran-4-yl)-6-fluoro-2,3-dihvdro-lH-isoindole

Prepared in analogy to Example A49(a) from 2-benzhydryl-5-fluoro-6-iodo-2,3-dihydro~ lH-isoindole and tributyl-(3,6-dihydro-2H-pyran-4-yl)-stannane. Yellow solid. MS (m/e): 386.1 ([M+H]⁺, 100%).

(h) 2-Benzhvdryl-5-fluoro-6-(tetrahvdro-pyran-4-yl)-2,3-dihvdro-lH-isoindole

Prepared in analogy to Example A68(a) from 2-benzhydryl-5-(3,6-dihydro-2H-pyran-4- yl)-6-fluoro-2,3-dihydro-lH-isoindole. White solid. MS (m/e): 388.1 ([M+H]⁺, 100%).

(i) 5-Fluoro-6-(tetrahvdro-pyran-4-yl)-2,3-dihvdro-lH-isoindole

To a stirred solution 0.12 mmol 2-benzhydryl-5-fluoro-6-(tetrahydro-ρyran-4-yl)-2,3- dihydro-lH-isoindole in 4 ml methanol was added 4 mg 10% palladium on charcoal and the mixture was stirred under an atmosphere of hydrogen for 16 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): 222.1 ([M+H]⁺, 100%). Example A80 5- (Tetrahydro-pyran-4-yloxy)-2,3-dihydro- lH-isoindole trifluoroacetate

(a) 5-(Tetrahydro-pyran-4-yloxyVl,3-dihydro-isoindole-2-carboxylic 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 tetrahydro-4H-pyran-4-ol. White solid. MS (m/e): 264.1 ([M+H-Me₂G=CH₂]⁺, 100%)

(b) 5-(Tetrahydro-pyran-4-yloxy)-2,3-dihvdro-lH-isomdole trifluoroacetate

Prepared in analogy to Example A2(c) from 5-(tetrahydro-pyran-4-yloxy)-l,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. MS (m/e): 220.3 ([M+H]⁺, 100%).

Example A81 5-(3-Fluoro-oxetan-3-yl)-2,3-dihydro-lH-isoindole

(a) 3-(2-Benzyl-2,3-dihydro-lH-isoindol-5-yl)-oxetan-3-ol

Prepared in analogy to Example A62(b) from 2-benzyl-5-bromo-2,3-dihydro-lH- isoindole (Example A62(a)) and oxetan-3-one (CAS: 6704-31-0). Brown solid. MS (m/e): 282.4 ([M+H]⁺, 100%).

(b) 3-(2,3-Dihydro-lH-isoindol-5-yl)-oxetan-3-ol

Prepared in analogy to Example A62(c) from 3-(2-benzyl-2,3-dihydro-lH-isoindol-5-yl)- oxetan-3-ol and hydrogen. Brown solid. MS (m/e): .192.3 ([M+H]⁺, 100%).

(c) 5-(3-Fluoro-oxetan-3-yl)-2,3-dihydro-lH-isoindole

To 0.58 mmol 3-(2,3-dihydro-lH-isoindol-5-yl)-oxetan-3-ol in 2 ml acetonitrile and 2 ml nitromethane at -60⁰C was added 1.15 mmol diethylaminosulfur trifluoride and the mixture was allowed to warm to 0⁰C over 30 min. The reaction mixture was re-cooled to -60 ⁰C 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]⁺, 100%).

Example A82 5-Cyclopropyhnethoxy-2,3-dihydro- lH-isoindole trifluoroacetate

(a) 5-Cyclopropylmethoxy-l,3-dihydro-isoindole-2-carboxylic 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-dihγdro-lH-isoindole trifluoroacetate

Prepared in analogy to Example A2(c) from 5~cyclopropylmethoxy-l,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₎3,3-Trifluoro-propoxy)-2,3-dihydro-lH-isoindole trifluoroacetate

(a) 5-(3,33-Trifluoro-propoxy)-l,3-dihvdro-isoindole-2-carboxylic 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 3,3,3-trifluoropropanol. Off-white solid. MS (m/e): 276.3 ([M+H-Me₂C=CH₂]⁺, 100%)

(b) 5-(3,3,3-Trifluoro-propoxy)-2,3-dihvdro- IH-isoindole trifluoroacetate

^F- .o.

^F F

Prepared in analogy to Example A2(c) from 5-(3,3,3-trifluoro-propoxy)-l,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Brown oil. MS (m/e): 232.1 ([M+H]⁺, 100%).

Example A84 5-Fluoro-6-morpholin-4-yl-2,3-dihydro- IH-isoindole trifluoroacetate

(a) 5-Fluoro-isoindole-l,3-dione

A mixture of 144 mmol 4-fluorophthalic anhydride and 1.16 mol formamide was heated at 200 ⁰C for 2 h. The reaction mixture was poured onto ice-water and the resulting crystals collected by filtration and dried in vacuo to afford the title compound as a yellow solid (100% yield). MS (m/e): 164.4 ([M-H]^", 100%).

(b) 5-Fluoro-6-mtro-isoindole-l,3-dione

To 753 mmol fuming nitric acid at O ⁰C 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 50⁰C 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-Ammo-6-fluoro-isoindole-l,3-dione

To a suspension of 99.9 mmol 5-fluoro-6-nitro-isoindole-l,3-dione in 400 ml 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 (m/e): 179.1 ([M-H]^", 100%).

(d) 5-Fluoro-6-iodo-isoindole-l,3-dione

To 99.9 mmol copper(I) iodide in dry acetonitrile was added 112 mmol tert-butyl nitrite and the resulting suspension was heated at 65 ⁰C. 66.6 mmol 5-amino-6-fluoro- isoindole-l,3-dione was then added portionwise and the reaction mixture stirred at 65 ⁰C for 2 h and then allowed to cool to room temperature. The mixture was poured onto cold 1 M aq hydrochloric acid and then the acetonitrile was removed in vacuo. The aqueous residue was stirred at 0 ⁰C for 20 min, and the resulting solid was collected by filtration and dried in vacuo to afford the title compound as a brown solid (87% yield). MS (m/e): 290.0 ([M-H]^", 100%). (e) 5-Fluoro-6-iodo-2,3~dihydro-lH-isoindole

Prepared in analogy to Example Al from 5-fluoro-6-iodo-isoindole-l,3-dione and borane tetrahydrofuran complex. Yellow oil. MS (m/e): 264.0 ([M+H⁺, 100%).

(f) 5-Fluoro-6-iodo-13-dihvdro-isoindole-2-carboxγlic acid tert-butyl ester

Prepared in analogy to Example A3(c) from 5-fluoro-6-iodo-2,3-dihydro-lH-isoindole and di-tert-butyl dicarbonate. Light yellow solid. MS (m/e): 308.1 ([M+H-Me₂C=CH₂]⁺, 100%).

(g) 5-Fluoro-6-morpholin-4-vl-l,3-dihydro-isoindole-2-carboxvlic acid tert-butvl ester

H ^■f r> XX

Prepared in analogy to Example A3(d) from 5-fluoro-6-iodo-l,3-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-yl-2,3-dihydro- lH-isoindole trifluoroacetate

Prepared in analogy to Example A2(c) from 5-fluoro-6-morpholin-4-yl-l,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. MS (m/e): 223.4 (M+H]⁺, 100%).

Example A85

5-Chloro-6- (tetrahydro-pyran-4-yloxy)-2,3-dihydro- IH-isoindole trifluoroacetate (a) 5-Chloro-6-(tetrahydro-pyran-4-yloxy)-L3-dihvdro-isoindole-2-carboxylic acid τert- butyl ester

Prepared in analogy to Example A6(a) from 5-chloro-6-iodo-l,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester (Example A3(c)) and tetrahydro-4H-pyran-4-ol. Off- white solid. MS (m/e): 300.1 ([{³⁷Cl}M+H-Me₂C=CH₂]⁺, 36%), 298.3 ([{³⁵C1}M+H- Me₂C=CH₂]⁺, 100%).

(b) 5-Chloro-6-(tetrah.vdro-pyran-4-yloxy)-2,3-dihvdro-lH-isoindole trifluoroacetate

Af. Prepared in analogy to Example A2(c) from 5-chloro-6-(tetrahydro-pyran-4-yloxy)-l,3- dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. 256.3 ([{³⁷C1}M+H]⁺, 50%), 254.3 ([{³⁵Cl}M+H]⁺, 100%).

Example A86

5-Fluoro-6-(tetrahydro-pyran-4-yloxy)-2,3-dihydro-lH-isoindole trifluoroacetate RO5083128-001

(a) 5-Fluoro-6-(tetrahydro-pyran-4-yloxy)-l,3-dihydro-isoindole-2-carboxylic acid tert- butyl ester

Prepared in analogy to Example A6(a) from 5-fluoro-6-iodo-l,3-dihydro-isoindole-2~ carboxylic acid tert-butyl ester (Example A84(f)) and tetrahydro-4H~pyran-4-ol. Yellow solid. MS (m/e): 282.3 ([M+H-Me₂C=CH₂]⁺, 100%).

(b) 5-Fluoro-6-(tetrahydro-pyran-4-γloxy)-2,3-dihydro-lH-isoindole trifluoroacetate A*.

Prepared in analogy to Example A2(c) from 5-fluoro-6-(tetrahydro-pyran-4-yloxy)-l,3- dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. 238.1 ([M+H]⁺, 100%).

Example Bl

2-Isopropoxy-5-methanesulfonyl-benzoic acid

(a) 2-Chloro-5-methanesulfonγl-benzoic acid

To 99 mmol 2-chloro-5-(methylthio) benzoic acid (purchased from Aldrich) in 400 ml methanol at 0 °C was added 296 mmol oxone^® and the mixture was allowed to stir at RT for 3.5 h. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was extracted 3 times with 400 ml ethyl acetate and the combined organic phases washed twice with 300 ml 1 N HCl and with 300 ml saturated aqueous NaCl solution and dried with MgSO₄. Evaporation under reduced pressure yielded the title compound which was used in the next step without further purification.

(b) 2-Isopropoxy-5-methanesulfonyl-benzoic acid

A mixture of 2.13 mmol 2-chloro-5-methanesulfonyl-benzoic acid, 0.64 mmol Cu(I)Br in 5 ml triethylamine and 25 ml isopropanol was heated to 120⁰C for 16 h in a sealed tube. The volatiles were removed in vacuo and the residue was taken up in 70 ml 1 N HCl. Extraction with ethyl acetate, drying of the combined organic fractions and evaporation yielded a residue which was purified by reversed phase preparative HPLC eluting with an acetonitrile/water gradient. Evaporation of the product fractions yielded the title compound. MS (m/e): 257.0 ([M-H]^", 100%) Example B2 Rac-5-Methanesulfonyl-2-(2,2,2-trifluoro-l-methyl-ethoxy)-benzoic acid

Prepared in analogy to Example Bl (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example Bl(a)) and rac-l,l,l-trifluoro-propan-2-ol. The crude material was purified by preparative HPLC to yield the title compound as a white solid. MS (m/e): 311.3 ([M-H]^", 100%).

Example B3

5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-benzoic acid (a) rac-5-Methanesulfonyl-2-(2,2,2-trifluoro-l-methyl-ethoxy^>)-benzoic acid methyl ester

A mixture of 21.7 mmol 2-hydroxy-5-methanesulfonyl-benzoic acid methyl ester (WO 2002074774), 32.5 mmol trifluoro-methanesulfonic acid 2,2,2-trinuoro-l-methyl- ethyl ester [212556-43-9] and 43.4 mmol potassium carbonate in 87 ml DMF was stirred at 80⁰C for 48 hours . After cooling to room temperature, the mixture was concentrated in vacuo, resuspended in water and stirred for 1 hour. Filtration yielded the title compound.

(b) 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-benzoic acid methyl ester

The title compound was obtained by separation of rac-5-methanesulfonyl-2-(2,2,2- trifluoro-l-methyl-ethoxy)-benzoic acid methyl ester by chiral HPLC (Chiralcel OD, 15 % ethanol/heptane, flow 35 ml min^"1, 220 nra, retention time: 86 min.).

(c) 5-Methanesulfonyl-2-(^'(S)-2,2,2-trifluoro-l-methyl-ethoxy^')-benzoic acid

To 0.604 mmol 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)- benzoic acid methyl ester in 1.97 ml ethanol was added 1.21 mmol 2 N aq NaOH solution and the reaction mixture was stirred at 80 ⁰C for 0.5 hour. After such time the solvent was removed in vacuo, the residue was taken in water and acidified by addition of 2N HCl to yield after filtration the title compound as a white solid (88%) .MS (m/e): 311.0 ([M-H]^", 100%)

Example B4 2-Isopropylsulfanyl-5-methanesulfonyl-benzoic acid

a) 2~Fluoro-5-methylsulfanyl-benzoic acid

The title compound was prepared by following the procedure described in: Journal of Organometallic Chemistry 1991, 419(1-2), 1-8.

b) 2-Fluoro-5-methanesulfonyl-benzoic acid

To 2.68 mmol 2-fluoro-5-methanesulfanyl-benzoic acid in 5 ml methanol at 0 ⁰C was added 8.05 mmol oxone® and the mixture was allowed to stir at RT for 72 h. The precipitate was filtered off and the filtrate was 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%).

c) 2-Isopropylsulfanyl-5-methanesulfonyl-benzoic acid

To a solution of 4.58 mmol 2~fluoro-5-methanesulfonyl-benzoic acid in 6 ml N₅N- dimethylacetamide were added 15.2 mol cesium carbonate and 10.1 mmol 2- propanethiol and the mixture was stirred at 90 ⁰C for 3 h. 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 arid concentrated in vacuo ^"to afford the title compound as a light yellow liquid which was used in the next step without further purification (yield 99%). EI-MS (m/e): 274.1 (M⁺, 35%), 232.1 ([M-C₃H₆]⁺, 30%, 214.1 (M-C₃H₆-H₂O)⁺, 100%).

Example B5 5-Methanesulfonyl-2-((R)-2,2,2-trifluoro-l-methyl-ethoxy)-benzoic acid

(a) 5-Methanesulfonyl-2-((R)-2,2,2-trifluoro-l-methyl-ethoxy)-benzoic acid methyl ester ral

The title compound was obtained by separation of rac-5-methanesulfonyl-2- (2,2,2- trifluoro-l-methyl-ethoxy)-benzoic acid methyl ester (Example B3(a)) by chiral HPLC (Chiralcel OD, 15 % ethanol/ Heptane, flow 35 ml min^"1, 220 nm, retention time: 74 min.).

(b) S-Methanesulfonyl^-ffRV∑^^-τrifluoro-l-methyl-ethoxyVbenzoic acid

- Ill -

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-Ethylsulfanyl-5-methanesulfonyl~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 9.25 mmol ethanethiol and the mixture was stirred at 90⁰C 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 white solid which was used in the next step without further purification (yield 99%), MS (m/e): 259.0 ([M-H]^", 100%).

Example B7 5-Methanesulfonyl-2-(2,2,2-trifluoro-ethylsulfanyl)-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

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 9.97 mmol 2-methyl- 1 -propanediol and the mixture was stirred at 90 ⁰C 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 white solid which was used in the next step without further purification (yield 99%). MS (m/e): 287.0 ([M-H]^", 100%).

Example B9 5-Methanesulfonyl-2-methylsulfanyl-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 10.0 mmol sodium methanethiolate and the mixture was stirred at 90 ⁰C 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 colourless oil which was used in the next step without further purification (yield 99%). MS (m/e): 244.9 ([M-H]^", 100%). Example BlO

5-MeΛanesulfonyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid

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]^", 100%).

Example BIl 2-Isobutoxy-5-methanesulfonyl-benzoic acid

Prepared in analogy to Example Bl (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example Bl (a)) and isobutanol. The crude material was purified by flash chromatography to yield the title compound as a white solid. MS (m/e): 271.1 ([M-H]^", 100%).

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 HCl and extracted three times with ethyl acetate. The combined organic extracts were washed sequentially with 1 N HCl 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 Bl 3 2-Methoxy-5-methylsulfamoyl-benzoic acid

(a) 5-Chlorosulfonyl-2-hydroxy-benzoic acid

To 3.26 mol chlorosulfonic acid at 0 ⁰C 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 ⁰C for 1 h, and finally at 70 ⁰C 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 ([(³⁷ClJM-H]^", 33%), 235.0 ([{³⁷Cl}M- H]^", 100%)

(b) 2-Hydroχy-5-methylsulfamoyl-benzoic acid

5 To 63 mmol 5-chlorosulfonyl-2-hydroxy-benzoic acid in 120 ml dichloromethane at RT was added dropwise 317 mmol methylamine (8 M solution in ethanol) and the mixture was allowed to stir at RT for 1 h. The mixture was then concentrated in vacuo. The residue was suspended in 1 M aq NaOH solution and extracted twice with ether. The aqueous phase was acidified with 5 M aq HCl, saturated with NaCl, and extracted 3 times ϊδ " wϊth'THF; The' combined'THF- extracts were washed twice with saturated aqueous-NaCL- solution and dried with Na₂SC>₄. Evaporation in vacuo yielded the title compound. MS (m/e): 249.0 (M+NH₄ ⁺, 100%), 231.9 (M+H⁺, 63%)

(c) 2-Hydroxy-5-methylsulfamoyl-benzoic acid methyl ester

15 To 77 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid in 300 ml THF was added 85 mmol CDI and the mixture heated at 70 ⁰C for 1 h. 770 mmol methanol was then added and the mixture was heated at 70⁰C for 16 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane/ dichloromethane 45:45:10) to afford the title compound.

20 MS (m/e): 244.1 ([M-H]^", 100%)

d) 2-Methoxy-5-methylsulfamoyl-benzoic acid methyl ester

To 2.04 mmol 2~hydroxy-5-methylsulfarnoyl-benzoic acid methyl ester, 2.2 mmol methanol and 2.34 mmol triphenylphosphine in 10 ml THF was added 2.24 mmol di- tert-butyl azodicarboxylate and the mixture was stirred at RT for 2 h. The mixture was then concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane) to afford the title compound.

e) 2-Methoxy-5-methylsulfamoyl-beήzoic acid

Prepared in analogy to Example B3(c) from 2-Methoxy-5-methylsulfamoyl-benzoic acid methyl ester. MS (m/e): 244.1 ( [M-H]^", 100%)

Example B14 2-Ethoxy-5-methylsuh^camoyl-benzoic acid

Prepared in analogy to Example B13(d-e) from 2-Hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and ethanol. MS (m/e): 257.9 ( [M-H]^', 100%)

Example B 15 5-Methylsulfamoyl-2-trifluoromethoxy-benzoic acid

(a) 5-Chlorosulfonyl-2-trifluoromethoxy-benzoic acid

A solution of 2-trifluoromethoxy benzoic acid [1979-29-9] (1.0 g) was added in small batches to chlorosulfonic acid (3.2 mL) at 0⁰C. After completion of the addition, the reaction mixture was stirred at 7O⁰C for 4 hours then left at room temperature overnight and heated at 75°C for another 3 hours. After such time the reaction was slowly poured onto ice, and the precipitate was then filtered, washed with water and dried to yield the title compound as a white solid (1.2 g). MS (m/e): 303.3 (M-H, 100%).

Cb) 5-Methylsulfamoyl-2-trifluoromethoxy-benzoic acid

To a solution of 5-Chlorosulfonyl-2-trifluoromethoxy-benzoic acid (0.15 g) in dichloromethane (1.5 ml) was added a solution of methylamine in methanol (8M, 0.31 mL) and the reaction mixture was stirred for 2 minutes after precipitation was compele. The reaction mixture was then concentrated in vacuo and the residue was dissolved in IN NaOH (2 mL) and extracted with diethylether. The aqueous phase was then acidified using 3 N hydrochloric acid solution (2 mL) and the solution was extracted with dichloromethane (2 x 10 mL). The combined organic phases were dried with sodium sulfate and concentrated in vacuo to yield the title compound as a white solid (0.12 g). MS (m/e): 298.0 (M-H, 100%).

Example B 16 2-Isopropoxy-5-methylsulfamoyl-benzoic acid

Prepared in analogy to Example B13(d-e) from 2-Hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and 2-Proρanol. MS (m/e): 272.2 ( [M-H] ^", 100%) Example B17 5-Methylsulfamoyl-2- (2,2,2-trifluoro-ethoxy)-benzoic acid

(a) 5-Methylsulfamoyl-2-(2,2,2-trifluoro-ethoχy)-benzoic acid methyl ester

To 3.3 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester (example B 13c)) and 3.3 mmol potassium carbonate in 50 ml acetone was added dropwise 4.9 mmol 2,2,2- trifluoro-ethyl trifluoromethanesulfonate and the mixture was heated at 60 ⁰C for 16 h. The mixture was then concentrated in vacuo. The residue was suspended in dichloromethane and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 3:7) to afford the title compound. MS (m/e): 328.0 (M+H⁺, 100%)

Cb) 5-Methylsulfamoyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid

To 2.3 mmol 5-methylsulfamoyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid methyl ester in 10 ml THF was added 20 mmol 2 M aq NaOH and the mixture was heated at 50 ⁰C for 2 h. The mixture was then cooled to RT and extracted twice with ether. The aqueous phase was acidified with 10% aq citric acid and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na₂SO₄. Evaporation in vacuo followed by trituration in ether afforded the title compound. MS (m/e): 312.0 ([M-H]^', 100%)

Example Bl 8

Rac-5-methylsulfamoyl-2- (2,2,2-trifluoro- l-methyl-ethoxy)-benzoic acid

(a) rac-5-Methylsulfamoyl-2-(2,2,2-trifluoro-l-methyl-ethoxy)-benzoic acid methyl ester

To 4.1 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and 4.1 mmol potassium carbonate in 5 ml DMF was added dropwise 6.1 mmol trifluoro- methanesulfonic acid 2,2,2-trifluoro-l-methyl-ethyl ester and the mixture was heated at 90 ⁰C for 16 h. The mixture was then cooled to RT, poured onto water and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na₂SO₄. Evaporation in vacuo followed by chromatography on silica gel (eluant: dichloromethane) afforded the title compound. MS (m/e): 359.2 (M+NH₄ ⁺, 80%), 342.0 (M+H⁺, 100%)

(b) rac-5-Methylsulfamoyl-2- (2,2,2 -trifluoro- l-methyl-ethoxy)-benzoic acid

To 1.6 mmol rac-5-methylsulfamoyl-2-(2,2,2-trifluoro-l-methyl-ethoxy)-benzoic acid methyl ester in 10 ml THF was added 20 mmol 2 M aq NaOH and the mixture was heated at 50 ⁰C for 2 h. The mixture was then cooled to RT and extracted twice with ether. The aqueous phase was acidified with 10% aq citric acid and extracted twice with ethyl acetate. The combined organic phases were dried with Na₂SO^ Evaporation in vacuo followed by trituration in ether and hexane afforded the title compound. MS (m/e): 326.2 ([M-H]^", 100%)

Example B19 4-Methanesulfonyl-biphenyl-2-carboxylic acid

(a) 2-Amino-5-methanesulfonyl-benzoic acid

A mixture of 4.26 mmol 2-chloro-5-methanesulfonyl-benzoic acid (example BIa)), stepl), 0.39 mmol Copper powder and 10 ml ammonium hydroxide 25% was heated at 125-130°C with stirring for 18 hours. Mixture was cooled to room temperature and filtered. The solid was washed with methanol. The filtrate was concentrated in vacuo. The residue was acidified with HCl IN to pH=2. The obtained solid was washed with water and dried (HV, 5O⁰C, 1 hour) to yield the title compound. MS (m/e): 214.1 (M-H, 100%) (b) 2-Iodo-5-methanesulfonyl-benzoic acid

To a suspension of 3.0 mmol 2-amino-5-methanesulfonyl-benzoic acid in a mixture of 1.7 ml sulfuric acid and 1.7 ml water was added dropwise a solution of 3.92 mmol sodium nitrite in 1.7 ml water at such rate that the temperature did not exceed 3°C. The mixture was stirred at 0⁰C for 1 hour. A solution of 3.0 mmol KI in 1.7 ml water was added dropwise at 0⁰C. The brown suspension was allowed to warm to rt and stirred for 30 minutes. Excess iodine was destroyed by addition of a few drops of a sodium hydrogenosulfite solution. The solid was filtered, washed with water and dried (HV, 50⁰C, 1 hour) to yield the title compound. MS (m/e): 325.0 (M-H, 100%)

(c) 2-Iodo-5-methanesulfonyl-benzoic acid methyl ester

To 30.7 mmol 2-Iodo-5-methanesulfonyl-benzoic acid in 250 ml THF was added 33.7 mmol CDI and the mixture was heated at 70⁰C for 1 h. Methanol (12.4 ml) was then added and the mixture was heated at 70⁰C for a further 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed over SiO₂ (ethyl acetate/dichloromethane 4:1) to afford the title compound (86%) as a white crystalline solid.

(d) 4-Methanesulfonyl-biphenyl-2-carboxylic acid methyl ester

A mixture of 3.53 mmol 2-Iodo-5-methanesulfonyl-benzoic acid methyl ester, 3.88 mmol Phenyltri-n-butyltin, 0.25 mmol Tris(dϊbenzylideneacetone)dipalladium(0), 0.35 mmol Triphenylarsine and 1.62 mmol Copper iodide in N,N-Dimethylformamide (30 ml) was heated at 90 ⁰C for 16 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was chromatographed over SiO₂ (ethyl acetate/heptane gradient) to provide the title compound (99%) as an off-white crystalline solid. MS (m/e): 291.0 (MH⁺, 100%)

(e) 4-Methanesulfonyl-biphenyl-2-carboxylic acid

To 3.44 mmol 4-Methanesulfonyl-biphenyl-2-carboxylic acid methyl ester in 5 ml THF was added 37.9 mmol 5 M aq. NaOH solution and the mixture was heated at 60 ⁰C for 16 h. The mixture was then cooled to RT, acidified to pH 1 with cone, hydrochloric acid, and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na₂SO₄. Evaporation in vacuo afforded the title compound (95%) as an off-white crystalline solid. MS (m/e): 275.1 (M-H, 100%)

Example B20 2-Isopropoxy-5-methanesulfonyl-benzamide

Prepared in analogy to Example A17(a) from 2-Isopropoxy-5-methanesulfonyl-benzoic acid (example Bl) and ammonium hydroxyde. MS (m/e): 258.1 ([M+H⁺, 100%)

Example B21

Rac-5-Ethanesulfonyl-2-(2,2,2-trifluoro- l-methyl-ethoxy)-benzoic acid

(a) 2-Fluoro-5-sulfino-benzoic acid

264 mmol 5-CMorosulfonyl-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% H₂Sθ₄ 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 SiO₂ (ethyl acetate/heptane gradient) to provide the title compound (51%) as a colorless oil. MS (m/e): 261.1 ([M+H]⁺, 100%)

(c) 5-Ethanesulfonyl-2-fluoro-benzoic acid

Prepared in analogy to Example B3(c) from 5-Ethanesulfonyl-2-fluoro-benzoic acid ethyl ester using lithium hydroxide instead of sodium hydroxide. White solid. MS (m/e): 232.1 (M⁺, 100%).

(d) rac-5-Ethanesulfonyl-2-(2,2,2-trifluoro-l-methγl-ethoxy)-benzoic acid

Prepared in analogy to Example B4(c) from 5-Ethanesulfonyl-2-fluoro-benzoic acid and rac~l,l,l-Trifluoro~propan-2-ol (commercial). White solid. MS (m/e): 325.1([M-H], 100%).

Example B22

rac-5-Methanesulfonyl-2-(l-trifluoromethyl-propoxy)-benzoic acid

Prepared in analogy to Example B4(c) from 2-Fluoro-5-methanesulfonyl-benzoic acid (example B4(b)) and rac- l,l,l-Trifluoro-butan-2-ol (CAS: 431-36-7). White solid. MS (m/e): 325.0 ([M-H], 100%).

Example B23

2- ( (S)-sec-Butoxy)-5-methanesulfonyl-benzoic acid

Prepared in analogy to Example B4(c) from 2-Fluoro-5-methanesulfonyl-benzoic acid (example B4(b)) and S-(+)-2-butanol. White solid. MS (m/e): 271.1 ([M-H], 100%).

Example B24

2-((R)-sec-Butoxy)-5-methanesulfonyl-benzoic acid

Prepared in analogy to Example B4(c) from 2-Fluoro-5~methanesulfonyl-benzoic acid (example B4(b)) and R-(-)-2-butanol. White solid. MS (m/e): 271.1 ([M-H], 100%).

Example B25

4'-Fluoro-4-methanesulfonyl-biphenyl-2-carboxylic acid

A mixture of 6.1 mmol 2-Iodo-5-methanesulfonyl -benzoic acid (example B19(b)), 12.2 mmol 4-fluorobenzeneboronic acid, 18.4 mmol sodium carbonate and 0.3 mmol palladium (II) acetate in 30 ml water was stirred at room temperature for 48 hours. The mixture was filtered and the filtrate was acidified with HCl 37%. The mixture was stirred at room temperature for 30 minutes. The solid was filtered, washed with water and dried to provide the title compound (92%). Yellow solid. MS (m/e): 293.2 ([M-H], 100%).

Example B26

3'-Fluoro-4-methanesulfonyl-biphenyl-2-carboxylic acid

Prepared in analogy to Example B25 from 2-Iodo-5-methanesulfonyl~benzoic acid (example B19(b)) and 3-fluorobenzeneboronic acid. Yellow solid. MS (m/e): 293.2 ([M- H], 100%).

Example B27

2'-Fluoro-4-methanesulfonyl-biphenyl-2-carboxylic acid

Prepared in analogy to Example B25 from 2-Iodo~5-methanesulfonyl-benzoic acid (example B19(b)) and 2-fluorobenzeneboronic acid. Light brown solid.

Example B28

4'-Chloro-4-methanesulfonyl-biphenyl-2-carboxylic acid

Prepared in analogy to Example B25 from 2-Iodo-5-methanesulfonyl-benzoic acid (example B19(b)) and 4-chloro-benzeneboronic acid. Light brown solid. MS (m/e): 309.1 ([M-H], 100%).

Example B29

3',4'-Difluoro-4-methanesulfonyl-biphenyl-2-carboxyh^'c acid

Prepared in analogy to Example B25 from 2-Iodo-5-methanesulfonyl-benzoic acid (example B19(b)) and 3,4-difluoro-benzeneboronic acid. Light brown solid. MS (m/e): 311.1 ([M-H], 100%).

Example B30

3',5'-Difluoro-4-methanesulfonyl-biphenyl-2-carboxylic acid

Prepared in analogy to Example B25 from 2-Iodo-5-methanesulfonyl-benzoic acid (example B19(b)) and 3,5-difluoro-benzeneboronic acid. Light brown solid. MS (m/e): 311.1 ([M-H], 100%).

Example B31

5-Methanesulfonyl-2-pyridin-4-yl-benzoic acid

a) 5-Methanesulfonyl-2-pyridin-4-yl-benzoic acid methyl ester

Prepared in analogy to Example B19(d) from 2-Iodo-5-methanesulfonyl-benzoic acid methyl ester (example B19(c)) and 4-tributylstananne-pyridine (commercial). Light yellow solid. MS (m/e): 291.9([M+H]⁺, 100%).

(b) 5-Methanesulfonyl-2-pyridin-4-yl-benzoic acid

Prepared in analogy to Example B3(c) from 5-Methanesulfonyl-2-ρyridin-4-yl-benzoic acid methyl ester. Light yellow solid. MS (m/e): 276.1 ([M-H], 100%).

Example B32

5-Methanesulfonyl-2-(4-methyl-pyrazol-l-yl)-benzoic acid

a) 5-Methanesulfonyl-2-(4-methyl-pyrazol-l-yl)-benzoic acid methyl ester

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 CuI and a solution of 0.12 mmol trans- 1,2-diaminocyclohexane in 0.4 ml dioxane (degased). The tube was filled with argon and sealed with a cap. The reaction mixture was heated at 120⁰C 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 1Og Flashpack cartridge. Eluent: Heptane/ ethylacetate to provide the title compound (57%) as a light yellow oil. MS (m/e): 295.0([M+H]⁺, 100%).

(b) 5-Methanesulfonyl-2-(^'4-methyl-pyrazol-l-yl)-benzoic 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]₅ 100%).

Example B33

5-Methanesulfonyl-2-(tetrahydro-pyran-4-yl)-benzoic acid

Prepared in analogy to Example B49(b) from 2-(3,6-Dihydro-2H~pyran-4-yl)-5- methanesulfonyl-benzoic acid (CAS: 847547-05-1). Colorless oil. MS (m/e): 283.2([M- H], 100%).

Example Cl

(4-Iodo-l,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl ethoxy) -phenyl] -methanone

(a) l,2-Bis-bromomethyl-3-iodo-benzene

Prepared in analogy to Example A2 (a) from l-Iodo-2,3-dimethyl-benzene (commercial) and NBS. Brown oil.

(b) 4-Iodo-2-trityl-2,3-dihydro-lH-isoindole

Prepared in analogy to Example A2 (b) from l,2-Bis-bromomethyl-3-iodo-benzene and triphenylmethylamine. White solid.

(c) 4-Iodo-2,3-dihydro-lH-isoindole

Prepared in analogy to Example A2 (c) from 4-Iodo-2-trityl-2,3-dihydro-lH-isoindole and trifluoroacetic acid. Light yellow solid.

Cd) (^"4-Iodo-l,3-dihvdro-isoindol-2-yl)-f5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l- . methyl ethoxy) -phenyl] -methanone

Prepared in analogy to Example 1 from 4-Iodo-2,3-dihydro-lH-isoindole and 5- Methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-benzoic acid (example B3). Off white solid. MS (m/e): 540.0 (MH⁺, 100%).

Example C2 (5-Iodo-6-trifluoromethyl-l,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2- trifluoro- l-methyl-ethoxy)-phenyl] -methanone

(a) 4-Iodo-5-trifluoromethyl-phthalic acid

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 Al 5 (b) from 4-Iodo-5-trifluoromethyl-phthalic acid and urea. Light brown solid. MS (m/e): 339.9 ([M-H]^", 100%).

(c) 5-Iodo-6-trifluoromethyl-2,3-dihvdro-lH-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): 313.9 ([M+H⁺, 100%).

(d) (5-Iodo-6-trifluoromethyl-l,3-dihydro-isoindol-2-yl)-f5-methanesulfonyl-2-((S)- 2,2,2-trifluoro- 1 -methyl-ethoxy) -phenyll -methanone

Prepared in analogy to Example 1 from 5-Iodo-6-trifluoromethyl-2,3-dihydro-lH- isoindole and 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-eth.oxy)-benzoic acid (example B3). Yellow foam. MS (m/e): 607.0 (M⁺, 100%).

Example C3

(5-Iodo- 1 ,3-dihydro-isoindol-2~yl)- [5-methanesulfonyl-2- ( (S)-2,2,2-trifluoro- 1-methyl ethoxy)-phenyl] -methanone

Prepared in analogy to Example 1 from 5-Iodo-2,3-dihydro-lH-isoindole (example A38(a)) and 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-benzoic acid (example B3). Off white solid. MS (m/e): 539.1 (M⁺, 100%).

Example C4 (2-Chloro-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-[5-methanesulfonyl-2-((S)-2,2,2- trifluoro-l-methyl-ethoxy)-phenyl]-methanone RO4988168-000

Prepared in analogy to Example 1 from 2-chloro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (Example A8(b)) and 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)- benzoic acid-(example B3),. Yellow foam. MS (m/e): 451.0 ({³⁷Cl}[M+H]⁺, 41%), 449.2. ({³⁵Cl}[M+H]⁺, 100%).

Example 1

Preparation of (l,3-Dihydro-isoindol-2-yl)-(2-isopropoxy-5-methanesulfonyl- phenyl) -methanone

A mixture of 0.387 mmol 2-isopropoxy-5-methanesulfonyl-benzoic acid (example Bl), 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 (SiO₂, 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:

Expl. Systematic Name

Structure Starting materials MW No. MW found [M+H⁺]

(5,6-Dichloro-l,3-dihydro- isoindol-2-yi)-(2- 5,6-Dichloro-2,3-dihydro-lH- isopropylsulfanyl-5- isoiπdole (CAS: 15997-90-7)

16 methanesulfonyl-phenyl) - and 2-IsopropylsuIfanyl-5- 444.4 methanone methanesulfonyl-benzoic acid

447.9 (³⁷Cl, ³⁷Cl), 445.9 (³⁷Cl' (example B4)

³⁵Cl), 444.0 (³⁵Cl-³⁵Cl)

5-Trifluoromethyl-2,3-dihydro-

[5-MethanesuIfonyl-2-((R)- lH-is 2,2,2-trifluoro-l-methyl- oindole (CAS: 342638-03-3) and ethoxy) -phenyl] -(5-

17 5-Methanesulfonyl-2- ( (R) - 481.4 trifluoromethyl- 1 ,3 -dihydro-

2,2,2-trifluoro-l-πieth.yl- _.

isoinαoi-z-yi; -metnanone ethox)')-benzoic acid (example 482.0

B5)

6-Bromo-4-fluoro-2,3-dihydro-

(6-Bromo-4-fluoro- 1,3- lH-isoindole (CAS: 689214-92- dihydro-isoindol-2-yl) - [5- 4) and 5-Methanesulfonyl-2- methanesulfonyl-2-((S)-2,2,2-

18 ((S)-2,2,2-trifluoro-l-methyl- 510.3 trifluoro-1-methyl-ethoxy)- ethoxy)-benzoic acid (example

phenyl] -methanone

510.2

B3)

(5,6-Dichloro-l,3-dihydro-

5,6-Dichloro-2,3-dihydro-lH- isoindol-2-yl) - (2-ethylsulfanyl- isoindole (CAS: 15997-90-7)

5-metb.anesulfonyl-phenyl) -

19 and 2-Ethylsulfanyl-5- 430.4 methanone methanesulfonyl-benzoic acid

434.0 (³⁷Cl, ³⁷Cl), 432.0 (³⁷Cl' (example B6)

^0, 430.0 (³⁵Cl-³⁵Cl)

519.5

Expl. Systematic Name

Structure Starting materials MW No. MW found [M+H⁺]

(5-Bromo-2,3-dihydro-indol-l- 5-Bromo-2,3-dihydro-lH- yl)-[5-methanesulfonyl-2-((S)- indole (CAS: 22190-33-6) and

82 2,2,2-trifluoro- 1-methyl- 5-Methanesulfonyl-2-((S)-2,2,2- 492.3

ethoxy)-phenyl] -methanone trifluoro- 1 -methyl-ethoxy)- 492.2 benzoic acid (example B3)

(3,3-Dimethyl-2,3-dihydro- 3,3-Dimethyl-2,3-dihydro-lH- indol- l-yl)- [5-methanesulfonyl- indole (CAS: 1914-02-9) and 5-

83 2-((S)-2,2,2-trifluoro-l-methyl- Methanesulfonyl-2-((S)-2,2,2- 441.5

ethoxy) -phenyl] -methanone trifluoro- 1 -methyl-ethoxy) - 442.1 benzoic acid (example B3)

(5-Bromo-indol-l-yl)-[5- 5-bromoindole (commercial) jnethanesulfonyl-2-((S)-2_J2,2- and 5-Methanesuifonyl-2-((S)r

84 trifluoro-1 -methyl-ethoxy) - 2,2,2-trifluoro- 1 -methyl- 490.3

phenyl] -methanone ethoxy)-benzoic acid (example 492.1 B3)

l-[5-Methanesulfonyl-2-((S)- lH-Indole-6-carbonitrile (CAS: 2,2,2-trifluoro-l-methyl- 15861-36-6) and 5-

85 ethoxy)-benzoyl] -lH-indole-έ MethanesuIfonyl-2-((S)-2,2,2- 436.4

carbonitrile trifluoro- 1 -methyl-ethoxy)- 454.4 (M+NH/) benzoic acid (example B3)

(6-Chloro-indoI-l-yl)-[5- 6-Chloro-lH-indole methanesulfonyl-2-((S)-2,2,2- (commercial) and 5-

86 trifluoro-1 -methyl-ethoxy)- Methanesulfonyl-2-((S)-2,2,2- 445.9

phenyl] -methanone trifluoro- 1 -methyl-ethoxy) - 446.1 benzoic acid (example B3)

(4-Bromo-indol- 1 -yl) - [5- 4-Bromo- lH-indole methanesulfonyl-2-(2,2,2- (commercial) and 5-

87 trifluoro- 1 -methyl-ethoxy) - Methanesulfonyl-2-((S)-2,2,2- 490.3

phenyl] -methanone trifluoro- 1 -methyl-ethoxy) - 490.1 benzoic acid (example B3)

Example 92

Preparation of (4-Fluoro-l,3-dihydro-isoindol-2-yl)-(2-isopropoxy-5- methanesulfonyl-phenyl) -methanone

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-methanesulfonyl-benzamide (example B20) in 1 ml dry DMF was added dropwise. After 15 minutes at RT and 15. minutes at 50 C, the reaction mixture was cooled to 0⁰C, and treated by a solution of 0.29 mmol 1,2- 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 O⁰C, 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 residue was purified by chromatography (SiO₂, heptane/ethyl acetate) to yield the title compound as a white solid (27% yield). MS (m/e): 378.3 [M+H⁺], 100%)

In analogy to Example 92, compounds 93 to 96 of the following table were prepared from 2-Isopropoxy-5-methanesulfonyl-benzamide (example B20) and the corresponding 1,2- Bis-bromomethyl-aryl derivatives.

Example 97

[5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(4-methyl-l,3- dihydro-isoindol-2-yl)-methanone

Prepared in analogy to Example A4(a) from (4-Iodo-l,3-dih.ydro-isoindol-2-yl)-[5- methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl] -methanone (Example Cl). Light brown solid. MS (m/e): 428.3 [M+H]⁺, 100%).

Example 98

[5-Methanesulfonyl-2- ( (S)-2,2,2-trifluoro- l-methyl-ethoxy)-phenyl] - (4-methoxy- 1,3- dihydro-isoindol-2-yi) -methanone

Prepared in analogy to Example A6(a) from (4-Iodo-l,3-dihydro-isoindol-2-yl)-[5- methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl] -methanone (Example Cl). 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-methyl-6- trifluoromethyl-l,3-dihydro-isoindol-2-yl)-methanone

Prepared in analogy to Example A4(a) from (5-iodo-6-trifluoro methyl- 1,3-dihydro- isoindol-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]- methanone (Example Cl). White solid. MS (m/e): 496.0 [M+H]⁺, 100%).

Example 100

[[5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(5-methoxy-6- trifluoromethyl-l,3-dihydro-isoindol-2-yl)-methanone

Prepared in analogy to Example A6(a) from (5-Iodo-6-trifluoromethyl-l,3-dihydro- isoindol-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]- methanone (Example Cl). 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:

[5-(tetrahydro-pyran-3- and 5-Methanesulfonyl- yl)-l,3-dihydro-isoindol- 2-((S)-2,2,2-tiifluoro-l- 2-yl] -methanone methyl- ethoxy ) -benzoic acid (example B3)

Example 313

[5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(2-pyridin-4-yl- 5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-methanone

Prepared in analogy to Example A54( a) from (2-chloro-5,7-dihydro-pyrrolo[3,4- b] pyridin-6-yl) - [ 5-methanesulfonyl-2- ( (S) -2,2,2-trifluoro- 1-methyl-ethoxy) -phenyl] - methanone (Example C4) and 4-tributylstannanylpyridine. White solid. MS (m/e): 492.1 [M+H]⁺, 100%).

Example 314

[5-Methanesulfonyl-2-((S)-2,2₎2-trifluoro-l-methyl-ethoxy)-phenyl]-[2-(tetrahydro- pyran-4-yl)-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl]-methanone Ca) r2-f3,6-Dihγdro-2H-pyτan-4-yl)-5J-dihydro-pyrro1of3,4-b1pyridin-6-yl1-f5- methanesxilfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxyVphenyll-methanone

Prepared in analogy to Example A54(a) from (2-chloro-5,7-dihydro-pyrrolo[3,4- b] pyridin-6-yl) - [ 5-methanesulfonyl-2- ( (S)-2,2,2-trifluoro~ 1 -methyl-ethoxy) -phenyl] - methanone (Example C4) and tributyl-(3,6-dihydro-2H-pyran-4-yl)-stannane, White solid. MS (m/e): 497.4 [M+H]⁺, 100%).

(b) r5-Methanesulfonyl-2-((S^N)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyπ-r2-(^'tetrahvdro- Pyran-4-yl)-5,7-dihydro-pyrrolo[3,4-b1pyridin-6-yll -methanone

Prepared in analogy to Example A49(b) from [2-(3,6-dihydro-2H-pyran-4-yl)-5,7- dih7dro-pyrrolo[3,4-b]pyridin-6-yl]-[5-methanesulfonyl-2-((S)-2,2,2-tri£luoro-l- methyl-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_J3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l- methyl-ethoxy) -phenyl] -methanone (Example C3) and organostananne derivative:

Example 321

[6-(4-Fluoro-phenyl)-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl]-[5-methanesulfonyl-2- ( (S)-2,2,2-trifluoro- l-methyl-ethoxy)-phenyl] -methanone

In a glass tube were placed 0.07 mmol 6-Chloro-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)- [5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl] -methanone (Example 167), 0.07 mmol 4-fluorophenyl boronic acid, 0.2 mmol sodium carbonate, 0.003 mmol Pd(OAc)₂, 0.07 mmol tetrabutylammonium bromide, 0.15ml water and a magnetic stir bar. The vessel was sealed with a septum and placed into the microwave cavity. The temperature was ramped from room temperature to 150⁰C. Once 150⁰C was reached, the reaction mixture was held at this temperature for 5 minutes. After the mixture was allowed to cool to room temperature, the reaction vessel was opened and the contents were poured into a separating funnel. Water and dichloromethane were added, and the aqueous layer was extracted 3 times with dichloromethane. The solvent was removed in vacuo. The residue was purified on a 5.0 g Flashpack cartridge: Eluent: Heptane/AcOEt to provide the title compound (50%). White solid. MS (m/e): 509.3 [M+H]⁺, 100%). Example 322

[3- (4-Fruoro-phenyl)-5,7~dihydro-pyrrolo [3,4-b]pyridin-6-yl] - [5-methanesulfonyl-2- ((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-methanone

Prepared in analogy to Example 321 from (3-Bromo-5,7-dihydro-pyrrolo[3,4-b]pyridin- 6-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-methanone (example 22) and 4-fluorophenyl boronic acid. White solid. MS (m/e): 509.2 [M+H]⁺, 100%).

Example 323 [5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(5-phenyl-l,3- dihydro-isoindol-2-yl)-methanone

To a solution of 0.19 mmol (5-Iodo-l,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2- ((S)~2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-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 heated at 120⁰C 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 1Og 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-l₅3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((S)-2,2_>2-trifluoro-l- methyl- ethoxy) -phenyl] -methanone (Example C3) and boronic acid derivative:

In analogy to Example B32(a), compounds 347 to 352 of the following table were prepared from (5-Iodo-l,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2- trifluoro-l-methyl-ethoxy)-phenyl]-methanone (Example C3) and heterocyclic derivatives in the presence of the mentioned ligand:

Example 353

[5-Methanesulfonyi-2- ( (S)-2,2,2-trifluoro- l-methyl-ethoxy)-phenyl] - ( l-oxy-3- trifluoromethyl- 5 ,7-dihydro-pyrrolo [3 ,4-b ] pyridin-6-yl)-methanone

To a solution of 0.21 mmol [5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)- phenyl]-(3-trifluoromethyl-5_>7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-methanone (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+NH₄]⁺, 100%).

Example 354 6-Chloro-2-(2-isopropoxy-5-methanesulfonyl-benzoyl)-2,3-dihydro-isoindol-l- 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-Methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(4-morpholin-4- yl-2,3-dihydro-indol- l-yl)-methanone

A mixture of 0.2 mmol (4-Bromo-2,3-dihydro-indol-l-yl)-[5-methanesulfonyl-2-((S)- 2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-methanone (example 211), 0.4 mmol morpholine, 0.3 mmol sodium tert-butylate, 2.5 mg racBINAP 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]⁺, 100%).

Example 356

[5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(6-morpholin-4- yl-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)-methanone

A mixture of 0.33 mmol (6-Chloro-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)-[5- methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-methanone (example 167), 0.67 mmol morpholine in 2 ml dimethylacetamide is heated at 180° C for 30 minutes in a microwave oven. The solvent was removed in vacuo. Chromatography of the residue (silica gel; ethyl acetate / heptane) yields the title compound as a white solid. Yield = 13 %. MS (m/e): 500.1 [M+H]⁺, 100%).

In analogy to Example 1, compounds 357 to 380 of the following table were prepared from the acid derivatives and amine derivatives:

Example 381

[5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-[2-(3- trifluoromethyl-phenyl)-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl]-methanone

Prepared in analogy to Example A54(a) from (2-chloro-5,7-dihydro-pyrrolo[3,4- b ] pyridin-6-yl) -[ 5-methanesulfonyl-2- ( (S)-2,2,2-trifluoro- 1 -methyl-ethoxy) -phenyl] - methanone (Example C4) and tributyl-[3-(trifluoromethyl)phenyl]-stannane. White solid. MS (m/e): 559.2 [M+H]⁺, 100%).

Example 382

[2-(4-Fluoro-phenyl)-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl]-[5-methanesulfonyl-2- ((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-methanone

Prepared in analogy to Example A54(a) from (2-chloro-5,7-dihydro-pyrrolo[3,4- b]pyridin-6-yl)-[5-methanesulfonyl-2-((S)-2₎2,2-trifluoro-l-methyl-ethoxy)-phenyl]- methanone (Example C4) and tributyl(4-fluorophenyl)stannane. Wliite solid. MS (m/e): 509.1 [M+H]⁺, 100%).

Claims

1. Compounds of general formula

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;

R¹ /R¹ are hydrogen, lower alkyl, lower alkyl substituted by halogen, -(CH₂)_x-cycloalkyl or -(CH₂)_x-aryl;

R² is -S(O)₂-lower alkyl, -S(O)₂NH-lower alkyl, NO₂ or CN;

(het ^N

^-—^ is an aromatic or partially aromatic bicydic amine, which may contain one or two additional N-atom, selected from the group consisting of

and wherein one additional N-ring atom of the aromatic or partially aromatic bicyclic

amine maybe available in form of its oxide

;

R³ to R¹⁰ are hydrogen, hydroxy, halogen, =0, lower alkyl, cycloalkyl, heterocycloalkyl, lower alkoxy, CN₅ NO₂, NH₂, aryl, 5-or 6-membered heteroaryl containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen, -NH -lower alkyl, -N(lower alkyl)₂, cyclic amide, -C(O)-cyclic amide, S-lower alkyl, -S(O)₂-lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, lower alkyl substituted by hydroxy,

-O-(CH₂)_y-lower alkoxy, -O(CH₂)_yC(O)N(lower alkyl)_2j -C(O)-lower alkyl, -O-(CH₂)_x-aryl, -O-(CH₂)_x-cycloalkyl, -O~(CH₂)_x-heterocycloalkyl, -C(O)O-lower alkyl, -C(O)-NH-lower alkyl, -C(O)-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-, cycloalkyl-, cyclic amide, heterocycloalkyl- or 5 or 6 membered heteroaryl groups as defined for R¹, R¹ , R¹ and R³ to R¹⁰ maybe unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, =O, halogen, lower alkyl, phenyl, lower alkyl substituted by halogen or lower alkoxy;

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 to pharmaceutically acceptable acid addition salts thereof.

2. Compounds of formula I A 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;

R¹ /R¹ are hydrogen, lower alkyl, lower alkyl substituted by halogen, -(CH₂)_x-cycloalkyl or -(CH₂)_x-aryl; R² is -S(O)₂-lower alkyl, -S(O)₂NH-lower alkyl, NO₂ or CN;

R³ is hydrogen, hydroxy, halogen, =O, lower alkyl, cycloalkyl, heterocycloalkyl, lower alkoxy, CN, NO₂, NH₂, aryl, 5-or 6-membered heteroaryl containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen, -NH-lower alkyl, -N(lower alkyl)₂, cyclic amide, -C(O)-cyclic amide, S-lower alkyl, -S(O)₂-lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, lower alkyl substituted by hydroxy, -O-(CH₂)_y-lower alkoxy, -O(CH₂)_yC(O)N(lower alkyl)₂, -C(O)-lower alkyl, -O-(CH₂)_x-aryl, -O-(CH₂)_x-cycloalkyl, -O-(CH₂)_x-heterocycloalkyl,

-C(O)O-lower alkyl, -C(O)-NH-Iower alkyl, -C(O)-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, R' are independently from each other hydrogen or lower alkyl;

and^'wherein alTaryl-, cycloalkyl-, cyclic amide, heterocycloalkyl- or^"5 of 6 membered/ ^■ heteroaryl groups as defined for R¹, R¹ , R¹ and R³ 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 is 1 or 2; x is 0, 1 or 2; y is 1 or 2;

and pharmaceutically acceptable acid addition salts thereof.

3. Compounds of formula I B 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; R¹ /R¹ are hydrogen, lower alkyl, lower alky! substituted by halogen, -(CH₂)_x-cycloalkyl

R² is -S(O)₂-lower alkyl, -S(O)₂NH-lower alkyl, NO₂ or CN;

and wherein the additional N-ring atom of the bicyclic amine may be available in form of

its oxide

;

R⁴ is hydrogen, hydroxy, halogen, =O, lower alkyl, cycloalkyl, heterocycloalkyl, lower alkoxy, CN, NO₂, NH₂, aryl, 5-or 6-membered heteroaryl containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen, -NH-lower alkyl, -N(lower alkyl)₂, cyclic amide,

-C(O)-cyclic amide, S-lower alkyl, -S(O)₂-lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, lower alkyl substituted by hydroxy, -O÷(CH₂)_y4oweralkoxy, -O(CH₂)_yG(O)N(lower alkyl)₂, -C(O)-lower alkyl, -O-(CH₂)_x-aryl, -O-(CH₂)_x-cycloaIkyl, -O-(CH₂)_x-heterocycloalkyl, -C(O)O-lower alkyl, -C(O)-NH-lower alkyl, -C(O)-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, R' are independently from each other hydrogen or lower alkyl;

and wherein all aryl-, cycloalkyl-, cyclic amide, heterocycloalkyl- or 5 or 6 membered heteroaryl groups as defined for R¹, R¹ , R¹ and R⁴ 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;

m is 1 or 2; x is 0, 1 or 2; y is 1 or 2;

and pharmaceutically acceptable acid addition salts thereof.

4. Compounds of formula I C according to claim 1

wherein

R¹ is halogen, -OR¹ , -SR¹ , cydoalkyi, 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;

R¹ /R¹ are hydrogen, lower alkyl, lower alkyl substituted by halogen, -(CH₂)_x-cycloaIkyl or -(CH₂)_x-aryl;

R² is -S(O)₂-lower alkyl, -S(O)₂NH-lower alkyl, NO₂ or CN;

' and wherein ^"the additional N-ring- atonr of the bϊcyclic amine may be available in form of ■

its oxide

;

R⁵ is hydrogen, hydroxy, halogen, =O, lower alkyl, cycloalkyl, heterocycloalkyl, lower alkoxy, CN, NO₂, NH₂, aryl, 5-or 6-membered heteroaryl containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen, -NH-Io wer alkyl, -NQower alkyl)₂, cyclic amide,

-C(O)-cyclic amide, S-lower alkyl, -S(O)₂-lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, lower alkyl substituted by hydroxy, -O-(CH₂)_y-lower alkoxy, -O(CH₂)_yC(O)N(lower alkyl)₂, -C(O)-lower alkyl, -O-(CH₂)_x~aryl, -O-(CH₂)χ-cycloalkyl, -O-(CH₂)_x-heterocycloalkyl, -C(O)O-lower alkyl, -C(O)-NH-lower alkyl, -C(O)-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, R' are independently from each other hydrogen or lower alkyl;

and wherein all aryl-, cycloalkyl-, cyclic amide, heterocycloalkyl- or 5 or 6 membered heteroaryl groups as defined for R¹, R¹ , R¹ and R⁵ maybe unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, =O, halogen, lower alkyl, phenyl, lower alkyl substituted by halogen or lower alkoxy; o is 1 or 2; x is 0, 1 or 2; j is 1 or 2;

and pharmaceutically acceptable acid addition salts thereof.

5. Compounds of formula I D according to claim 1

wherein

R¹ /R¹ are hydrogen, lower alkyl, lower alkyl substituted by halogen, -(CH₂)_x-cycloalkyl

R² is -S(O)₂-lower alkyl, -S(O)₂NH-lower alkyl, NO₂ or CN;

and wherein one additional N-ring atom of the bicyclic amine may be available in form of

its oxide

;

R⁶ is hydrogen, hydroxy, halogen, =O, lower alkyl, cycloalkyl, ° heterocycloalkyl, lower alkoxy, CN, NO₂, NH₂, aryl, 5-or 6-membered heteroaryl containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen, -NH-lower alkyl, -N(lower alkyl)₂, cyclic amide, -C(O)-cyclic amide, S-lower alkyl, -S(O)₂-lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, lower alkyl substituted by hydroxy, , -O-(CH₂)_y-lower alkoxy, -O(CH₂)_yC(O)N(lower alkyl)₂, -C(O)-lower alkyl, -O-(CH₂)_x-aryl, -O-(CH₂)_x-cycloalkyl, -O-(CH₂)_x-heterocycloalkyl,

-C(0)0-lower alkyl, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)₂, 2-oxy-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicydo[3.2.1]oct-8-yl; R, R' are independently from each other hydrogen or lower alkyl;

and wherein all aryl-, cydoalkyl-, cyclic amide, heterocycloalkyl- or 5 or 6 membered heteroaryl groups as defined for R¹, R¹ , R¹ and R³ to R¹⁰ maybe 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;

p is 1 or 2; x is 0, 1 or 2; y is 1 or 2;

and pharmaceutically acceptable acid addition salts thereof.

6. Compounds of formula I E according to claim 1

wherein

R¹ /R¹ are hydrogen, lower alkyl, lower alkyl substituted by halogen, -(CH₂)_x-cycloalkyl or -(CH₂)_x-aryi;

R² is -S(O)₂-lower alkyl, -S(O)₂NH-lower alkyl, NO₂ or CN;

R⁷ is hydrogen, hydroxy, halogen, =0, lower alkyl, cycloalkyl, heterocycloalkyl, lower alkoxy, CN, NO₂, NH₂, aryl, 5-or 6-membered heteroaryl containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen, -NH-lower alkyl, -N(lower alkyl)₂, cyclic amide, -C(O)-cyclic amide, S-lower alkyl, -S(O)₂-lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, lower alkyl substituted by hydroxy, -O-(CH₂)_rlower alkoxy, -O(CH₂)_yC(O)N(lower alkyl)* -C(O)-lower alkyl, -O-(CH₂)_x-aryl, -O-(CH₂)_x-cycloalkyl, -O-(CH₂)_x-heterocycloalkyl, -C(O)O-lower alkyl, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)₂₎ 2-oxy-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-biqrclo[3.2.1]oct-8-yl;

R and R in group e) may form together with -(CH₂),_!- a six membered ring; or

5 R, R', R" and R'" are independently from each other hydrogen or lower alkyl;

and wherein all aryl-, cycloalkyl-, cyclic amide, heterocycloalkyl- or 5 or 6 membered heteroaryl groups as defined for R¹, R¹ , R¹ and R⁷ maybe unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, =O, halogen, lower alkyl, phenyl, lower alkyl substituted by halogen or lower alkoxy;

O q is 1 or 2; x is 0, 1 or 2; y is 1 or 2;

and pharmaceutically acceptable acid addition salts thereof.

5 7. Compounds of formula I F 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 0 group consisting of oxygen, sulphur or nitrogen;

R² is -S(O)₂-lower alkyl, -S(O)₂NH-lower alkyl, NO₂ or CN;

5 R⁸ is hydrogen, hydroxy, halogen, =0, lower alkyl, cycloalkyl, heterocycloalkyl, lower alkoxy, CN, NO₂, NH₂, aryl, 5-or 6-membered heteroaryl containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen, -NH-lower alkyl, -N (lower alkyl)₂, cyclic amide, -C(O)-cyclic amide, S-lower alkyl, -S(O)₂-lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, lower alkyl substituted by hydroxy, -O-(CH₂)_rlower alkoxy, -O(CH₂)_yC(O)N(lower alkyl)₂, -C(O)-lower alkyl, -O-(CH₂)_x-aryl, -O-(CH₂)_x-cycloalkyl, -O-(CH₂)_x-heterocycloalkyl,

-C(O)O-lower alkyl, -C(O)-NH-lower alkyl, -C(O)-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;

and wherein all aryl-, cycloalkyl-, cyclic amide, heterocycloalkyl- or 5 or 6 membered heteroaryl groups as defined for R¹, R¹ , R¹ and R⁸ maybe unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, =O, halogen, lower alkyl, phenyl, lower alkyl substituted by halogen or lower alkoxy;

r is 1 or 2; x is 0, 1 or 2; y- is 1 or 2;

and pharmaceutically acceptable acid addition salts thereof.

8. Compounds of formula I G according to claim 1

R² is -S(O)₂-lower alkyl, -S(O)₂NH-lower alkyl, NO₂ Or CN;

R⁹ is hydrogen, hydroxy, halogen, =O, lower alkyl, cycloalkyl, heterocycloalkyl, lower alkoxy, CN, NO₂, NH₂, aryl, 5-or 6-membered heteroaryl containing one, two or three heteroatoms, selected from the group consisting of ' oxygen, sulphur or nitrogen, -NH-lower alkyl, -N (lower alkyl)₂, cyclic amide, -C(O) -cyclic amide, S-lower alkyl, -S(O)₂-lower alkyl, lower alkyl substituted by halogen, lower alkoxy. substituted by halogen, lower alkyl substituted by hydroxy, -O-(CH₂)_y-lower alkoxy, -O(CH₂)_yC(O)N(lower alkyl)* -C(O)-lower alkyl,

-O-(CH₂)χ-aryl, -O-(CH₂)_x-cycloalkyl, -O-(CH₂)_x-heterocycloalkyl, -C(0)0-lower alkyl, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)₂, 2-oxy-5-aza-bicyclo[2.2J]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl;

its oxide

; and wherein all aryl-, cycloalkyl-, cyclic amide, heterocycloalkyl- or 5 or 6 membered heteroaryl groups as defined for R¹, R¹ , R¹ and R⁹ may be unsubstituted or substituted by one or more substituents selected from the group consisting_.of hydroxy,.

lower alkyl, phenyl, lower alkyl substituted by halogen or lower alkoxy;

s is 1 or 2; x is 0, 1 or 2; y is 1 or 2;

and pharmaceutically acceptable acid addition salts thereof.

9. Compounds of formula I H according to claim 1

wherein

R¹ is halogen, -OR^1', -SR^1", 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; R¹ /R¹ are hydrogen, lower alkyl, lower alkyl substituted by halogen, -(CH₂)_x-cycloalkyl ^■ or.-(CH₂)_x-arylj ^{" '}■ . . • ..

R² is -S(O)₂-lower alkyl, -S(Q)₂NH-lower alkyl, NO₂ or CN;

R¹⁰ is hydrogen, hydroxy, halogen, =O, lower alkyl, cycloalkyl, heterocycloalkyl, lower alkoxy, CN, NO₂, NH₂, aryl, 5-or 6-membered heteroaryl containing one, two or three heteroatoms, selected from the group consisting of^' oxygen, sulphur or nitrogen, -NH-lower alkyl, -N(lower alkyl) ₂, cyclic amide, -C(O)-cyclic amide, S-lower alkyl, -S(O)₂-lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, lower alkyl substituted by hydroxy,

-O-(CH₂)_y-lower alkoxy, -O(CH₂)_yC(O)N(lower alkyl)₂, -C(O)-lower alkyl, -O-(CH₂)_x-aryl, -O-(CH₂)_x~cycloalkyl, -O-(CH₂)_x-heterocycloalkyl, -C(O)O-lower alkyl, -C(O)-NH-lower alkyl, -C(O)-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;

its oxide

;

and wherein all aryl-, cycloalkyl-, cyclic amide, heterocycloalkyl- or 5 or 6 membered heteroaryl groups as defined for R¹, R¹ , R¹ and R¹⁰ may be unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, =O, halogen, lower alkyl, phenyl, lower alkyl substituted by halogen or lower alkoxy;

t is 1 or 2; x is 0, 1 or 2; y is 1 or 2;

and pharmaceutically acceptable acid addition salts thereof.

10. Compounds of general formula I A according to claims 1 and 2, wherein R¹ is OR¹ and R¹ is as described in claims 1 and 2.

11. Compounds of general formula I A according to claim 10, wherein the compounds are: (5,6-dichloro-l,3-dihydro-isoindol-2-yl)-(2-isopropox7-5-methanesulfonyl-phenyl)- methanone, , . ^■ . r-ac-(5,6-dichloro-l,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-(2,2,2-trifluoro-l- methyl-ethoxy) -phenyl] Ktnethanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-inethyl-ethoxy)-phenyl]-(5-trifluoroniethyl- l,3-dihydro-isoindol-2-yl)-methanone,

(5,6-dichloro-l_>3-dihydro-isoindol-2-yl)-(2-isopropylsulfanyl-5-methanesulfonyl- phenyl) -methanone,

[5-methanesulfonyl-2-((R)-2,2,2-triflubro-l-methyl-ethoxy)-phenyl]-(5- trifluoromethyl-l,3-dihydro-isoindol^:-2-yl)-methanone, (5-chloro-6-methyl-l,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2- trifluoro- 1 -methyl-ethoxy) -phenyl] -methanone,

(5-chloro-6-methoxy-l,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2- trifluoro- l-methyl-ethoxy)-phenyl] -methanone,

(5-ethylsulfanyl-l,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l- jfnethyl.-ethoxy).-phenvll -methanone,

(2-isobutox7-5-methanesulfonyl-phenyi;-(_ii>-tπtluorometh.yl-l,3-clihydro-isoindol-2-yl)- methanone,

4-isopropoxy-N-methyl-3-(5-trifluoromethyl-l,3-dihydro-isoindole-2-carbonyl)- benzenesulfonamide, (5-chloro-6-methyl-l₎3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((R)-2₎2₅2- trifluoro-l-methyl-ethoxy)-phenyl] -methanone,

( 5 - chloro-6-methyl- 1 ,3 -dihydr o-isoindol-2 -yl) - (2-isobutoxy-5-methanesulfonyl- phenyl) -methanone,

(5-chloro-6-ethylsulfanyl-l,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((R)-2,2_>2- trifluoro- 1-methyl-ethoxy) -phenyl] -methanone,

(2-isopropox7-5-methanesulfonyl-phenyl)-(5-methox7-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-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(5- trifluoromethoxy-l,3-dihydro-isoindol-2-yl)-methanone,

[ 5-methanesulfonyl-2- ( (S) -2,2,2 -trifluoro- 1 -methyl-ethoxy) -phenyl] - [5- (4-methyl- thiazol-2-yl)-l,3-dihydro-isoindol-2~yl] -methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethox7)-ρhenyl]-[5-(2-methyl- pyridin-4-yl)-l,3-dihydro-isoindol-2-yl]-methanone, [5-methanesulfonyl-2-((S)-2₎2,2-trifluoro-l-methyl-ethoxy)-phenyl]-[5-(5-methyl- thiophen-3-yl) - 1 ,3-dihydro-isoindol-2-yl] -methanone,

((S)-2,2,2-trifluoro-l-methyl-ethox7)-phenyl]-methanone_>

(5-chloro-6-methoxy-l,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((R)-2₎2,2- trifluor o - 1 -methyl-ethoxy) -phenyl] -methanone

( 5-chloro-6-methoxy- 1 ,3-dihydro-isoindol-2-yl) - (2-isobutoxy-5-methanesulfonyl- phenyl)-methanone,

(5-fluoro-6-trifluoromethyl-l,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2- trifluoro- 1 -methyl-ethoxy) -phenyl] -methanone,

( 5 -ethoxy-6-trifluoromethyl- 1,3- dihydro-isoindol-2 -yl) - (2 -isopropoxy-5- methanesulfonyl-phenyl)-methanone, ,= (5rchloro-6-morpholin-4-yl-l,3-dihydro-isoindolr2-yl)-(2-isobutoxy-5- methanesulfonyl-phenyl)-methanone,

(5-chloro-6-morpholin-4-yl-l,3-dihydro-isoindol-2-yl)-(2-cyclobu1ylmethoxy-5- methanesulfonyl-phenyl)-methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-[5-(tetrahydro- pyran-4-yl)-l,3-dihydro-isoindol-2-yl] -methanone,

(2-isobutoxy-5-methanesulfonyl-phenyl)-[5-(tetrahydro-pyran-4-yl)-l,3-dihydro- isoindol-2-yl] -methanone, (2-cydopropylmethox7-5-methanesulfonyl-phenyl) - [5- (tetrahydro-pyran-4-yl) - 1 ,3- dihydro-isoindol-2-yl] -methanone,

(2-cyclobutylmethoxy-5-methanesulfonyl-phenyl)-[5-(tetrahydro-pyran-4-yl)-l,3- dihydro-isoindol-2 -yl] -methanone,

[2-(2,2-dimethyl-propoxy-)-5-methanesulfonyl-phenyl]-[5-(tetrahydro-ρyran-4-yl)-l,3- dihydro-isoindol-2-yl] -methanone,

[5-(3,3-difluoro-piperidin-l-yl)-l,3-dihydro-isoindol-2-yl]-[5-methanesulfonyl-2-((S)-

2,2,2-trifluoro-l-methyl-ethoxy)-ρhenyl]-methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethox7)-phenyl]-[5-(2,2,2-trifluoro- ethyl) - 1 ,3 -dihydro-isoindol-2-yl] -methanone, [5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-[(lR,5S)-5-(3-oxa-

S-aza-bicyclofS^.lJoct-δ-y^-l^-dihydro-isoindol^-yl] -methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-[5-methyl-6- (tetrahydro-pyran-4-yl)-13-dihydro-isoindol-2-yl] -methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifl.uoro-l-methyl-ethoxy)-plienyl]-[5-(tetrahydro- furaή-3-yl)-l,3-dihydro-isoindol-2-yl]-methanone,

[5-chloro-6-(tetrahydro-pyran-4-yl)-l,3-dihydro-isoindol-2-yl]-[5-methanesulfonyl-2- ((S)-2,2,2-txifluoro- 1 -methyl-ethoxy) -phenyl] -methanone,

[5-methanesulfonyl-2-((S)-2,2₎2-trifluoro-l-methyl-ethoxy)-phenyl]-[5-(tetrahydro- pyran-3-yl)-l,3-dihydro-isoindol-2-yl] -methanone,

[5-methanesulfonyl-2- ( (S) -2,2,2-trifluoro- 1 -methyl-ethoxy) -phenyl] - (5-pyridin-4-yl- l,3-dihydro-isoindol-2-yl)-methanone, [5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(5-pyridin-3-yl- l,3-dihydro-isoindol-2-yl)-methanone,

[5-rQethanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(5-phenyl-l,3- dihydro-isoindol-2-yl)-methanone,

[5-methanesulfonyl-2-(2,2₎2-tri£luoro-l-methyl-ethoxy)-phenyl]-(5-thiophen-3-yl-l,3- dihydro-isoindol-2-yl)-methanone,

[5-methanesulfonyl-2-(2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-[5-(4-methyl- thiophen-2-yl)-l,3-dihydro-isoindol-2-yl] -methanone, [5-methanesulfonyl-2-(2,2,2-trifluoro-l-methyl-ethoxy)-phenyl] - [5-(3-methyl- thiophen-2-yl)-l,3-dihydro-isoindol-2-yl]-methanone,

[5-(4-fluoro-phenyl)-l_>3-dihydro-isoindol-2-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-

1 -methyl- ethoxy) -phenyl] -methanone,

[5-(3-fluoro-phenyl)-l,3-dihydro-isoindol-2-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro- 1 -methyl-ethoxy) -phenyl] -methanone,

[5-(2-fluoro-phenyl)-l,3-dihydro-isoindol-2-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro- l-methyl-ethoxy)-phenyl] -methanone,

[5-(3,5-difluoro-phenyl)-l,3-dihydro-isoindol-2-yl]-[5-methanesulfonyl-2-(2,2,2- trifluoro- l-methyl-ethoxy)-phenyl] -methanone, [5-methanesulfonyl-2-(2,2,2-trifluoro-l-methyl-ethoxy)-phenyl] - [5-(3-methoxy- phenyl)-l,3-dihydro-isoindol-2-yl] -methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(5-thiophen-2-yl- l,3-dihydro-isoindol-2-yl)-methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-[5-(4-methyl- thiophen-3-yl)-l,3-dihydro-isoindol-2-yl] -methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethox7)-phenyl]-(5-pyrazol-l-yl- l,3-dihydro-isoindol-2-yl)-methanone, [5-methanesulfonyl-2-((S)-2,2₃2-trifluoro-l-methyl-ethoxy)-phenyl]-[5-(2₅2_J2-trifluoro- ethoxy)-l,3-d.ihydro-isoindol-2-yl]-methanone, ^• _{. .}

[5-chloro-6-(tetrahydro-furan-3-yl)-l_>3-dihydro-isoindol-2-yl]-[5-methanesulfonyl-2-

((S)-2,2,2-trifluoro-l-methyl-ethoxy')-phenyl]-methanone, 5 rac-(2-isopropox7-5-methanesulfonyl-phenyl)-[5-(tetrahydro-furan-3-yl)-l,3-dihydro- isoindol-2-yl]-methanone, ^' rac- [5-methanesulfonyl-2-(2,2,3,3_>3-pentafluoro-propoxy)-phenyl] •- (^.-(tetrahydro- foran-S-yO-ljS-dihydro-isomdol^-yπ-methanone, rac-(2-isopropoxy-5-methanesulfonyl-phenyl)-[5-(tetrahydro-pyran-3-yl)-l,3-dihydro- 10 isoindol-2-yl] -methanone,

[5-chloro-6-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-l,3-dihydro-isoindol-2-yl]-[5- methanesulfonyl-2-(2,2,3₎3,3-pentafluoro-propoxy)-phenyl]-meth.anone, rac- [5-methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-phenyl] - [5-(tetrahydro- pyran-3-yl)-l,3-dihydro-isoindol-2-yl] -methanone, 15... _.((lS,4S)-5-cωoro-6-_.2-oxa-5-aza-bicyclo[2.2Λ]hept-5-yl-l,3-dih^ydro_risomφl-2-yl)-[5- methanesulfonyl-2- ( (S)-2,2,2-trifluorθ'- 1 -methyl-ethόxy) -phenyl] -methanone,

[5-fluoro-6-(tetrahydro-pyran-4-yl)-l,3-dihydro-isoindol-2-yl]-[5-methanesulfonyl-2-

((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl] -methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro- 1-methyl-ethoxy) -phenyl] - [5-(tetrahydro- 20 pyran-4-yloxy)- l,3-dihydro-isoindol-2-yl] -methanone,

[5-(3-fluoro-oxetan-3-yl)-l,3-dihydro-isoindol-2-yl]-[5-methanesulfonyl-2-((S)-2,2,2- trifluoro-l-methyl-ethoxy)-phenyl] -methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-[5-(3,3,3-trifluoro- propoxy)-l,3-dihydro-isoindol-2-yl] -methanone, 25 (5-fluoro-6-morpholin-4-yl-l,3-dihydro-isomdol-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2- trifluoro- 1-methyl-ethoxy) -phenyl] -methanone,

(5-fluoro-6-morpholin-4-yl-l,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-(2,2,3,3,3- pentafluor o-propoxy) -phenyl] -methanone,

(2-isopropoxy-5-methanesulfonyl-phenyl)-[5-(tetrahydro-pyran-4-yloxy)-l,3-dihydro- 30 isoindol-2-yl] -methanone,

[5-methanesulfonyl-2-(2,2,3,3,3-pentafluoro-proρoxy)-phenyl]-[5-(tetrahydro-pyran-4- yloxy) - 1 ,3-dihydro-isoindol-2-yl] -methanone,

2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-methanone, 35 [5-chloro-6-(tetrahydro-pyran-4-yloxy)-l,3-dihydro-isoindol-2-yl] -(2-isopropoxy-5- methanesulfonyl-phenyl)-methanone,

[5-fluoro-6-(tetrahydro-pyτan-4-yloxy)- l,3-dihydro-isoindol-2-yl] - [5-methanesulfonyl- 2~ ( (S) -2,2,2-trifluoro- 1-methyl-ethoxy) -phenyl] -methanone,

[5-fluoro-6-(tetrahydro-pyran-4-ylox7)-l,3-d.ihydro-isoindol-2-yl]-(2-isopropoxy'-5- methanesulfonyl-phenyl)-niethanone,

[5-fluoro-6-(tetrahydro-pyran-4-ylox7)-l,3-ciihydro-isoindol-2-yl]-[5-inethanesulfonyl- 2-(2,2,3,3,3-pentafluoro-propoxy)-phenyl] -methanone or

[5-chloro-6-(tetrahydro-pyran-4-yloxy)-l,3-dihydro-isoindol-2-yl]-[5-methanesulfonyl- 2-(2,2,3₅3,3-pentafluoro-propoxy)-ρhenyl]-methanone.

12. Compounds of general formula I A according to claims 1 and 2, wherein R¹ is unsubstituted or substituted phenyl, for example the following compounds: (5-chloro-6-morpholin-4-yl-l,3-dihydro-isoindol-2-yl)-(4-methanesulfonyl-biphenyl-2- yl)-methanone,

(5-chloro-6-morpholin-4-yl-l,3-dihydro-isoindol-2-yl)-(3'-fluoro-4-methanesulfonyl- biphenyl-2-yl)-methanone,

(5-chloro-6-morpholin-4-yl-l,3-dihydro-isoindol-2-yl)-(4'-fluoro-4-methanesulfonyl- biphenyl-2-yl) -methanone or

(4'-fluoro-4-methanesulfonyl-biphenyl-2-yl)-[5-(tetrahydro-pyran-4-yl)-l,3-dihydro- isoindol-2-yl] -methanone.

13. Compounds of general formula I B according to claim 3, wherein the compounds are (2-cyclobutylmethoxy-5-methanesulfonyl-phenyl)-(3-trifluoromethyl-5,7-dihydro- ρyrrolo[3,4-b]pyridin-6-yl)-rnethanone,

(2-isobutoxy-5-methanesulfonyl-phenyl)-(3-trifluoromethyl-5,7-dihydro-pyrrolo[3,4- b] pyridin-6-yl) -methanone,

[ 5-methanesulfonyl-2-( (R) -2,2,2-trifluoro- 1 -methyl-ethoxy) -phenyl] - ( 3- trifluoromethyl-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-methanone,

(4'-fluoro-4-methanesulfonyl-biphenyl-2-yl)-(3-trifluoromethyl-5,7-dihydro- ρyrrolo[3,4-b]pyridin-6-yl)-methanone,

(3',4'-difluoro-4-methanesulfonyl-biphenyl-2-yl)-(3-trifluoromethyl-5,7-dihydro- pyrrolo [ 3 ,4-b ] pyridin-6-yl) -methanone, [5-methanesulfonyl-2-(2,2₎3,3,3-pentafluoro-ρropoxy)-phenyl]-(3-trifluoromethyl-5,7- dihydro-pyrrolo[3,4-b]pyridin-6-yl)-methanone,

[5-methanesulfonyl-2-(2,2,3,3-tetrafluoro-propoxy)-phenyl]-(3-trifluoromethyl-5,7- dihydro-pyrrolo[3,4-b]pyridin-6-yl)-methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(2-methyl-3- trifluoromethyl-5,7-dihydro-pyrrolo [3,4-b] pyridin-6-yl)-methanone, [3-(4-fluoro-phenyl)-5,7-dihydro-pyrrolo [3,4-b]pyridin-6-yl] - [5-methanesulfonyl~2- ((S)-2,2,2^trifluoro-l-methyl^:ethoxy)-phenyl]-methanone,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(3-trifluoi:omethyl- 5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-methanone or [2-(4-fluoro-phenyl)-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl]-[5-inethanesulforiyl-2- ( (S)-2,2,2rtrifluoro- 1 -methyl- ethoxy) -phenyl] -methanone

14. Compounds of general formula I C according to claim 4, wherein the compounds are: (2-cyclobutylmethoxy-5-methanesulfonyl-phenyl)-(6-trifluoromethyl-l,3-dihydro- pyrrolo[3,4~c]pyridin~2-yl)-methanone,

(4'-fluoro-4-methanesulfonyl-biphenyl-2-yl)-(6-trifluoromethyl-l,3-dihydro- pyτrolo[3,4-c]pyridin-2-yl)-methanone,

(3',4'-difluoro-4-methanesulfonyl-biphenyl-2-yl)-(6-tri£luoromethyl-l,3-dihydro- pyrrolo[3,4-c]pyridin-2-yl)-methanone, [5-metnanesuironyl-Z-(2,2,3,3,3-pentafluoro-propoxy)-phenyl] -(6-trifluoromethyl-ϊ,3- dihydro-pyrrolo[3,4-c]pyridin-2-yl)-rnethanone,

[5-methanesulfonyl-2-(2,2,3,3-tetrailuoro-propoxy)-phenyl]-(6-trifluoromethyl-l,3- dihydro-pyrrolo [3,4-c] pyridin-2-yl)-methanone,

[6-(4-fluoro-phenyl)-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl]-[5-methanesulfonyl-2- ((S)-2,2,2-trifluoro-l-methyl-ethoxy)-ρhenyl] -methanone or

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxf)-ρhenyl]-(6-morpholin-4-yl- l,3-dihydro-ρyrrolo[3,4-c]pyridin-2-yl)-methanone.

15. Compounds of general formula I D according to claim 5, wherein the compounds are: [5-methanesulfonyl-2-((S)-2,2_>2-trifluoro-l-methyl-ethoxy)-phenyl]-(2-trifluoromethyl-

5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-yl)-methanone,

(2-isopropoxy-5-methanesulfonyl-phenyl)-(2-trifluoromethyl-5,7-dihydro-pyrrolo[3,4- d] pyrimidin-6-yl) -methanone,

(4-methanesulfonyl-biρhenyl-2-yl)-(2-trifluoromethyl-5i7-dihydro-pyrrolo[3,4- d]pyrimidin-6-yl)-methanone,

(2-isopropoxy-5-methanesulfonyl-phenyl)-(2-methyl-5,7-dihydro-pyrrolo[3,4- d] pyrimidin-6-yl) -methanone or

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]-(2-methyl-5,7- dihydro-pyrrolo[3,4-d]pyrimidin-6-yl)-methanone.

16. Compounds of general formula I E according to claim 6, wherein the compounds are: . . l-(4-methanesulfonyl-biphenyl-2-carbonyl)-2,3-dihydro-lH-indole-4-carbonitrile, l-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-benzoyl]-2,3-dihydro- lH-indole-4-carboxylic acid methyl ester, l-(2-isopropoxy-5rmethanesulfonyl-benzoyl)-2,3-dihydro-lH!-indole-4-carbox^lic acid methyl ester or

17. Compounds of general formula I F according to claim 7, wherein the compounds are:

(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- 1 -yl)- [ 5-methanesulfonyl-2- (2,2,2-trifluoro- 1 -methyl-ethoxy) -phenyl] - methanone.

18. Compounds of general formula I G according to claim 8, wherein the compounds are:

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethox7)-phenyl]-(5-nitro-indazol-l- yl) -methanone, (5-chloro-indazol-l-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)- phenyl] -methanone or

(5,7-Dichloro-indazol-l-yl)-[5-methanesulfonyl-2-((S)-2₎2,2-trifluoro-l-methyl- ethoxy) -phenyl] -methanone.

19. A compounds of general formula I H according to claim 9, wherein the compound is:

( 5,6-dimethyl-benzoimidazol- 1 -yl) - [ 5-methanesulfonyl-2- ( (S) -2,2,2-trifluoro- 1 -methyl- ethoxy) -phenyl] -methanone.

20. A process for preparing a compound of formula I as defined in claims 1 to 19, which process comprises a) reacting a compound of formula

selected from the group consisting of

with a compound of formula

in the presence of an activating agent, such as TBTU,

to a compound of formula

which include the following structures

wherein the definitions are given in claim 1,

or

b) reacting a compound of formula

wherein hal is an halogen group such as Br or Cl with a compound of formula

in the presence of a base, such as sodium hydride,

to compound of formulas

wherein the substituents are as defined in claim 1, and,

if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.

21. A compound according to any one of claims 1 to 19, whenever prepared by a process as claimed in claim 20 or by an equivalent method.

22. A medicament containing one or more compounds as claimed in any one of claims 1 to 19 and pharmaceutically suitable excipients.

23. A medicament according to claim 22 for the treatment of illnesses based on the glycine uptake inhibitor.

24. A medicament according to claim 23, 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.

25. 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 cognitive processes are impaired, such as attention deficit disorders or Alzheimer's disease.

26. The invention as herein before described.