NZ713391B2 - Tricyclic triazolic compounds as sigma receptors ligans - Google Patents

Abstract

The present invention relates to new tricyclic triazolic compounds of formula (I) having a great affinity for sigma receptors, especially sigma-1 receptors, as well as to the process for the preparation thereof, to compositions comprising them, and to their use as medicaments for treating e.g. pain related diseases related diseases

Description

TRICYCLIC TRIAZOLIC COMPOUNDS AS SIGMA RECEPTORS LIGANDS FIELD OF THE INVENTION The present invention relates to new tricyclic triazolic compounds having a great affinity for sigma receptors, especially sigma-1 receptors, as well as to the process for the preparation thereof, to compositions comprising them, and to their use as medicaments.

BACKGROUND OF THE INVENTION The search for new therapeutic agents has been greatly aided in recent years by better understanding of the structure of proteins and other biomolecules ated with target diseases. One important class of these proteins are the sigma (σ) receptors, cell surface receptors of the central s system (CNS) which may be related to the dysphoric, hallucinogenic and cardiac stimulant effects of opioids.

From studies of the biology and function of sigma receptors, evidence has been presented that sigma receptor ligands may be useful in the treatment of sis and movement disorders such as dystonia and tardive dyskinesia, and motor disturbances associated with Huntington's chorea or Tourette's syndrome and in Parkinson's disease ( Walker, J.M. et al, cological Reviews, 1990, 42, 355 ).

It has been reported that the known sigma receptor ligand ole clinically shows effects in the ent of psychosis (Snyder, S.H., Largent, B.L. J. Neuropsychiatry 1989, 1, 7). The sigma binding sites have preferential ty for the dextrorotatory isomers of certain opiate benzomorphans, such as (+)SKF 10047, (+)cyclazocine, and (+)pentazocine and also for some narcoleptics such as ridol.

“The sigma receptor/s” as used in this application is/are well known and defined using the following citation: This binding site represents a typical protein different from opioid, NMDA, dopaminergic, and other known neurotransmitter or hormone or families (G. Ronsisvalle et al. Pure Appl. Chem. 73, 509 (2001)).

The sigma receptor has at least two subtypes, which may be discriminated by stereoselective isomers of these pharmacoactive drugs. SKF 10047 has nanomolar [Annotation] KEB affinity for the sigma 1 (0-1) site, and has olar affinity for the sigma 2 (0-2) site. Haloperidol has similar affinities for both subtypes.

The Sigma-1 receptor is a non-opiaceous type receptor expressed in us adult mammal tissues (e.g. central nervous system, ovary, testicle, placenta, adrenal gland, spleen, liver, kidney, intestinal tract) as well as in embryo development from its earliest stages, and is apparently involved in a large number of physiological functions. Its high affinity for various ceuticals has been described, such as for SKF-10047, (+)-pentazocine, haloperidol and rimcazole, among others, known ligands with analgesic, anxiolytic, antidepressive, antiamnesic, antipsychotic and neuroprotective activity. Sigma-1 receptor is of great interest in pharmacology in view of its possible physiological role in processes related to analgesia, y, addiction, amnesia, sion, schizophrenia, stress, neuroprotection and psychosis [Kaiser et al (1991) Neurotransmissions 7 (1): 1-5], r, J.M. et al, Pharmacological Reviews, 1990, 42, 355] and [Bowen W.D. (2000) Pharmaceutica Acta Helvetiae 74: 211-218].

The Sigma-2 receptor is also expressed in numerous adult mammal tissues (e.g. s system, immune system, endocrine system, liver, kidney). Sigma-2 receptors can be ents in a new apoptosis route that may play an important role in regulating cell proliferation or in cell development. This route seems to consist of Sigma-2 receptors joined to intracellular membranes, located in lles g calcium, such as the endoplasmic reticulum and mitochondria, which also have the ability to release calcium from these organelles. The calcium signals can be used in the ing route for normal cells and/or in induction of sis.

Agonists of Sigma-2 receptors induce changes in cell morphology, apoptosis in several types of cell lines and regulate the expression of p-glycoprotein mRNA, so that they are potentially useful as antineoplasic agents for treatment of cancer. In fact, Sigma-2 receptor agonists have been observed to induce apoptosis in mammary tumour cell lines resistant to common antineoplasic agents that damage DNA. In addition, agonists of Sigma-2 ors enhance the cytotoxic effects of these antineoplasic agents at concentrations in which the agonist is not cytotoxic.

[Annotation] KEB Thus, agonists of Sigma-2 receptors can be used as antineoplasic agents at doses ng apoptosis or at sub-toxic doses in combination with other antineoplasic agents to revert the resistance to the drug, y allowing using lower doses of the antineoplasic agent and considerably reducing its adverse effects.

Antagonists of Sigma-2 receptors can prevent the irreversible motor side effects caused by typical neuroleptic agents. In fact, it has been found that nists of Sigma-2 receptors can be useful as agents for improving the weakening effects of delayed esia ing in patients due to chronic treatment of psychosis with typical antipsychotic drugs, such as haloperidol. Sigma-2 receptors also seem to play a role in certain degenerative disorders in which blocking these receptors could be useful.

Endogenous sigma ligands are not known, although progesterone has been suggested to be one of them. Possible sigma-site-mediated drug effects include modulation of glutamate receptor function, neurotransmitter response, neuroprotection, behavior, and ion on, R. et al. Trends col. Sci., 1992, 13:85-86). Most studies have implied that sigma g sites (receptors) are plasmalemmal elements of the signal transduction cascade. Drugs reported to be selective sigma ligands have been evaluated as antipsychotics (Hanner, M. et al.

Proc. Natl. Acad. Sci., 1996, 2—8077). The existence of sigma receptors in the CNS, immune and ine systems have suggested a likelihood that it may serve as link between the three systems.

In view of the potential therapeutic applications of agonists or nists of the sigma receptor, a great effort has been directed to find selective ligands. Thus, the prior art discloses different sigma receptor ligands.

For instance, the international patent application W02007/098961 describes 4,5,6,7 tetrahydrobenzo[b]thiophene derivatives having pharmacological activity towards the sigma receptor.

[Annotation] KEB Spiro[benzopyran] or spiro[benzofuran] derivatives were also disclosed in EP1847542 as well as pyrazole derivatives (EP1634873) with pharmacological activity on sigma receptors.

W02009/071657 ses compounds structurally related to the ones the current invention which er show activity towards sigma receptors. The compounds disclosed in this document do not show, however, ient solubility in physiological media so as to assure a proper bioavailability of the compound once administered to the patient.

Surprisingly, the authors of the present invention have observed that tricyclic lic compounds with general formula (I) not only show an affinity for Sigma receptor ranging from good to excellent, what makes them particularly suitable as pharmacologically active agents in medicaments for the prophylaxis and/or ent of ers or diseases related to Sigma ors, but also they surprisingly have advantage of their high solubility in a physiological media.

Solubility in aqueous media is of upper-most interest since it potentially affects the bioavailability of the drug. Solubility is, in some instances, directly affecting the dissolution rate of the drug, which may accelerate the uptake of the drug and may therefore act .

SUMMARY OF THE ION The present invention discloses novel compounds with great affinity to sigma receptors and having high solubility in a physiological media which might be used for the treatment of sigma related disorders or diseases.

Specifically, it is an object of the present invention novel tricyclic triazolic of general formula (I): [Annotation] KEB R1—N wherein R1 is selected from: - a -(C(R3)2)m-aryl group in which the aryl group may be optionally substituted by at least one halogen atom; - a -(C(R3)2)m-heteroaryl group in which the aryl group may be optionally substituted by at least one substituent selected from a halogen, C1_ 3_alkyl, C1_3-alkoxy, C1_3-haloalkoxy or C1_3-haloalkyland in which the heteroaryl group may optionally be condensed with an additional ring system; - a -(C(R3)2)n-heterocycloalkyl group, in which the heterocycloalkyl group may be optionally tuted by at least one substituent selected from a halogen, 01.3-alkyl, 01alkoxy, 01.3-haloalkoxy or 01.3-haloalkyl and contains at least one oxygen atom; R2 is selected from: - a phenyl group optionally tuted by at least one substitutent selected from a n, 01alkoxy, C1_3_haloalkoxy, 01.3-haloalkyl or a hydroxyl group; - a heteroaryl group optionally substituted by at least one tutent selected from a halogen, C1_3-alkyl C1_3-alkoxy, C1_3-haloalkoxy, C1_3-haloalkyl or a hydroxyl group; - a heterocycloalkyl group being optionally substituted by at least one substituent selected from a halogen, C1_3-alkyl, C1_3-alkoxy, C1_3-haloalcoxy, C1_3-haloalkyl or a hydroxyl group; [Annotation] KEB R3 is H or 01.3, alkyl; m is 1 to 3; n is 0 to 3; with the proviso that when R1 is a -(C(R3)2)m-aryl group, R2 is not a phenyl group; or a pharmaceutically able salt, isomer, prodrug or solvate thereof.

It is also an object of the invention different processes for the preparation of nds of formula (I).

Another object of the invention refers to the use of such compounds of general formula I for the treatment or prophylaxis of sigma receptor mediated diseases or conditions, especially sigma-1 mediated es or conditions. Within the group of diseases or conditions mediated by sigma receptor for which the compounds of the ion are effective diarrhea, lipoprotein disorders, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, obesity, migraine, arthritis, hypertension, arrhythmia, ulcer, ma, learning, memory and attention deficits, cognition disorders, neurodegenerative diseases, demyelinating diseases, addiction to drugs and chemical substances including cocaine, amphetamine, ethanol and nicotine; e diskinesia, ischemic stroke, epilepsy, stroke, stress, cancer, psychotic conditions, in particular depression, anxiety or schizophrenia; inflammation or autoimmune diseases, may be cited. Compounds of the invention are especially useful in the treatment and prophylaxis of pain, especially neuropathic pain, inflammatory pain or other pain conditions involving allodynia and/or hyperalgesia.

It is also an object of the invention pharmaceutical compositions comprising one or more compounds of general formula (I) with at least one pharmaceutically acceptable excipient. The ceutical compositions in ance with the invention can be adapted in order to be administered by any route of administration, be it orally or parenterally, such as pulmonarily, nasally, rectally and/or intravenously. Therefore, the formulation in accordance with the invention may be d for l or systemic application, particularly for dermal, subcutaneous, [Annotation] KEB intramuscular, intra-articular, intraperitoneal, pulmonary, buccal, sublingual, nasal, percutaneous, vaginal, oral or eral application.

DETAILED DESCRIPTION OF THE INVENTION The invention first relates to compounds of general formula (I) R1—N .I/ll/l/N \ R2 wherein R1 is selected from: - a -(C(R3)2)m-aryl group in which the aryl group may be optionally substituted by at least one n atom; - a -(C(R3)2)m-heteroaryl group in which the heteroaryl group may be optionally substituted by at least one substituent selected from a halogen, C1- 3_alkyl, lkoxy, 01haloalcoxy or 01haloalkyland in which the heteroaryl group may ally be condensed with an additional ring system; - a -(C(R3)2)n-heterocycloalkyl group, in which the heterocycloalkyl group may be optionally substituted by at least one substituent selected from a halogen, 01.3-alkyl, 01alkoxy, 01.3-haloalkoxy or 01.3-haloalkyl and contains at least one oxygen atom; R2 is selected from : - a phenyl group ally substituted by at least one substitutent selected from a halogen, C1_3-alkoxy, C1_3_haloalkoxy, C1_3-haloalkyl or a hydroxyl group; [Annotation] KEB - a heteroaryl group ally substituted by at least one substitutent selected from a halogen, 01alkyl 01alkoxy, 01haloalkoxy, 01.3-haloalkyl or a hydroxyl group; - a heterocycloalkyl group being optionally substituted by at least one substituent selected from a halogen, lkyl, 01alkoxy, aloalcoxy, 01haloalkyl or a hydroxyl group; R3 is H or C1_3 alkyl; m is 1 to 3; n is 0 to 3; with the proviso that when R1 is a -(C(R3)2)m-aryl group, R2 is not a phenyl group; or a pharmaceutically acceptable salt, , prodrug or solvate f.

“Halogen” or “halo” as referred in the present invention represent fluorine, chlorine, bromine or iodine.

Alkyl radicals C14,, as ed to in the present invention, are saturated aliphatic radicals. They may be linear or ed and are optionally substituted. C1_3_alkyl as expressed in the present invention means an alkyl radical of 1, 2 or 3 carbon atoms.

Preferred alkyl radicals according to the present invention e but are not cted to methyl, ethyl, propyl, n-propyl, isopropyl.

“Cycloalkyl” as referred to in the present invention, is understood as g saturated and unsaturated (but not aromatic), cyclic hydrocarbons having from 3 to 9 carbon atoms which can optionally be unsubstituted, mono- or polysubstituted. es for cycloalkyl radical preferably include but are not restricted to cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, noradamantyl.

Cycloalkyl radicals, as defined in the present invention, are optionally mono-or polysubstituted by substitutents independently selected from a halogen, C1_3-a|ky|, C1_3-alkoxy, C1_3-haloalcoxy, C1_3-haloalkyl or a hydroxyl group.

“Heterocycloalkyl” as referred to in the present invention, are understood as meaning saturated and unsaturated (but not aromatic), cyclic hydrocarbons having [Annotation] KEB from 3 to 9 carbon atoms which can optionally be unsubstituted, mono- or polysubstituted and which have at least one heteroatom in their structure selected from N or 0. es for heterocycloalkyl radical ably include but are not restricted to pyrroline, pyrrolidine, line, aziridine, azetidine, tetrahydropyrrole, oxirane, e, ane, tetrahydropyrane, tetrahydrofurane, dioxane, dioxolane, oxazolidine, piperidine, zine, morpholine, e or diazepane.

Heterocycloalkyl radicals, as defined in the present invention, are optionally r polysubstituted by substitutents independently selected from a halogen, 01alkyl, 01alkoxy, 01.3-haloalkoxy, 01haloalkyl or a hydroxyl group.

“Aryl” as referred to in the present invention, is understood as meaning ring systems with at least one aromatic ring but without heteroatoms even in only one of the rings.

These aryl radicals may optionally be mono-or polysubstituted by substitutents independently ed from a n, C1_3-alkoxy, C1_3_haloalcoxy, C1_3-haloalkyl or a yl group. Preferred examples of aryl radicals include but are not restricted to phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl, indanyl or anthracenyl radicals, which may ally be mono- or polysubstituted, if not defined otherwise.

“Heteroaryl” as referred to in the present invention, is understood as meaning heterocyclic ring systems which have at least one aromatic ring and may ally contain one or more heteroatoms from the group consisting of nitrogen or oxygen and may ally be mono-or polysubstituted by substitutents independently selected from a halogen, 01alkyl, 01alkoxy, 01.3-haloalkoxy, aloalkyl or a hydroxyl group. Preferred examples of heteroaryls include but are not restricted to furan, benzofuran, pyrrole, pyridine, pyrimidine, pyridazine, pyrazine, quinoline, isoquinoline, phthalazine, triazole, pyrazole, isoxazole, indole, benzotriazole, benzodioxolane, benzodioxane, benzimidazole, carbazole and quinazoline.

The term “condensed” according to the present invention means that a ring or ring- system is attached to another ring or ring-system, whereby the terms “annulated” or “annelated” are also used by those skilled in the art to designate this kind of attachment.

[Annotation] KEB The term “ring ” according to the present invention refers to ring systems comprising saturated, unsaturated or aromatic carbocyclic ring systems which contain optionally at least one heteroatom as ring member and which are optionally at least mono-substituted. Said ring systems may be condensed to other carbocyclic ring systems such as aryl groups, naphtyl groups, heteroaryl groups, cycloalkyl groups, etc.

The term “salt” is to be understood as meaning any form of the active compound according to the invention in which this assumes an ionic form or is d and is coupled with a counter-ion (a cation or anion) or is in solution. By this are also to be tood complexes of the active nd with other molecules and ions, in ular complexes which are complexed via ionic interactions.

The term “physiologically acceptable salt” or “pharmaceutically acceptable salt” is tood in particular, in the context of this invention, as salt (as defined above) formed either with a physiologically tolerated acid, that is to say salts of the particular active compound with inorganic or organic acids which are physiologically tolerated -especially if used on humans and/or mammals - or with at least one, preferably inorganic, cation which are physiologically tolerated - especially if used on humans and/or mammals. Examples of physiologically tolerated salts of particular acids are salts of: hydrochloric acid, romic acid, sulfuric acid, hydrobromide, monohydrobromide, monohydrochloride or hydrochloride, methiodide, esulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, hippuric acid picric acid and/or aspartic acid. Examples of physiologically tolerated salts of particular bases are salts of alkali metals and alkaline earth metals and with NH4.

The term “solvate” is to be understood as g any form of the active compound ing to the invention in which this compound has attached to it via non- covalent binding another molecule (most likely a polar solvent) especially including hydrates and lates, e.g. methanolate.

[Annotation] KEB The term “prodrug” is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the ion. Such tives would readily occurto those skilled in the art, and e, depending on the functional groups present in the molecule and without limitation, the ing derivatives of the compounds of the invention: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides. Examples of well known methods of producing a prodrug of a given acting nd are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al. “Textbook of Drug design and Discovery” Taylor & Francis (april 2002).

Any nd that is a prodrug of a compound of formula (I) is within the scope of the invention. Particularly favored prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally stered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.

In a particular and preferred embodiment of the invention R1 is a benzyl optionally substituted by at least one halogen; a )2)m-heteroaryl group in which the heteroaryl is a 5 or 6 membered heteroaryl radical containing from 1 to 3 heteroatoms selected from N or O and is optionally substituted by at least one substituent selected from a halogen, 01alkyl, 01.3-alkoxy or C1_3_haloalkyl; or a - (C(R3)2)n-heterocycloalkyl group, in which the heterocycloalkyl group is a tetrahydropyranyl or as tetrahydrofuranyl group.

In a still more particular and preferred embodiment R1 is selected from: [Annotation] KEB Ra N where Ra represents a en, a halogen, 01.3 alkyl, 01.3 -alkoxy or 01.3, haloalkyl, Rb represents a hydrogen or a halogen and m and n are as defined before for formula (I).

In another particular ment of the invention R2 is a phenyl optionally substituted by at least one substituent selected from a halogen or 01.3 haloalkyl; a 5 or 6 membered heteroaryl radical containing from 1 to 3 N atoms and optionally substituted by at least one substituent ed from a halogen, 01alkyl or 01.3— alkoxy; or a tetrahydropyranyl group.

In a still more particular and preferred embodiment R2 is selected from: [Annotation] KEB 4% CW /\ N— — / where R6 represents a hydrogen, halogen, C1_3 alkyl, C1_3 alkoxy, C1_3 haloalkyl.

The more preferred embodiment of the ion is that of compounds of general formula I where R1 is selected from: ation] KEB /N N / Ra N/ wRaw @172o o Rb Ra 0 R2 is selected from: [Annotation] KEB where Ra ents a hydrogen, a halogen, 01.3 alkyl, 01.3 -alkoxy or 01.3, haloalkyl, Rb represents a hydrogen or a halogen, R6 represents a en, halogen, C1_3 alkyl, C1_3 alkoxy, C1_3 haloalkyl and m and n are as defined before for formula (I).

Among all the compounds described in the general formula (I), particularly preferred are any of those compounds selected from: o (5aR,8aR)(2—fluorophenyl)(pyridinylmethyl)-4,5a,6,7,8,8a- hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aRS,8aRS)(2—fluorophenyl)(pyridinylmethyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aRS,8aRS)(2—fluorophenyl)(pyridinylmethyl)-4,5a,6,7,8,8a- dropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(4-fluorophenyl)(tetrahydro-2H-pyranyl)-4,5a,6,7,8,8a- hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(4-fluorophenyl)(tetrahyd ro-2H-pyranyl)-4,5a,6,7,8,8a- hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(2—fluorophenyl)(tetrahydro-2H-pyranyl)-4,5a,6,7,8,8a- hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(2—fluorophenyl)(tetrahydro-2H-pyranyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride . (5aS,8aS)(6-methoxypyridinyl)(tetrahyd pyranyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(2—fluorophenyl)((tetrahyd ro-2H-pyranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride [Annotation] KEB o (5aR,8aR)(2—fluorophenyl)((tetrahydro-2H-pyranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hloride 0 (5aR,8aR)(2—fluorophenyl)((6-fluoropyridinyl)methyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(2—fluorophenyl)((6-methoxypyridinyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(2—fluorophenyl)((6-methoxypyridinyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(2—fluorophenyl)((6-(trifluoromethyl)pyridinyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(2—fluorophenyl)(((R)-tetrahydrofuranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(2—fluorophenyl)(((S)-tetrahyd rofuranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 aS)(2—fluorophenyl)(((S)-tetrahydrofuranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(2—fluorophenyl)(((R)-tetrahydrofuranyl)methyl)- ,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)((6-ethoxypyridinyl)methyl)(2—fluorophenyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)((6-ethoxypyridinyl)methyl)(2—fluorophenyl)-4,5a,6,7,8,8a- hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride [Annotation] KEB o (5aRS,8aRS)(4-fluorophenyl)(furanylmethyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hloride 0 (5aS,8aS)(2,4-difluorophenyl)((2,5-dimethylfuranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(2,4-difluorophenyl)((2,5-dimethylfuranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(4-fluorobenzyl)(pyridinyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(4-fluorobenzyl)(pyridin-2—yl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aRS,8aRS)(4-fluorobenzyl)(pyridinyl)-4,5a,6,7,8,8a- hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(2,4-difluorophenyl)(tetrahydro-2H-pyranyl)-4,5a,6,7,8,8a- dropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(2,4-difluorophenyl)(tetrahydro-2H-pyranyl)-4,5a,6,7,8,8ahexahydropyrrolo ][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(4-fluorobenzyl)(3-fluoropyridinyl)-4,5a,6,7,8,8a- hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(5-fluoropyridinyl)(tetrahydro-2H-pyranyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(pyridinyl)(tetrahydro-2H-pyranyl)-4,5a,6,7,8,8a- hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride [Annotation] KEB o (5aR,8aR)benzyl(pyridinyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)benzyl(pyridinyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(4-fluorobenzyl)(pyridinyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(4-fluorobenzyl)(pyridinyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hloride 0 (5aR,8aR)(4-fluorobenzyl)(3-fluoropyridinyl)-4,5a,6,7,8,8ahexahydropyrrolo ][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(4-fluorobenzyl)(3-fluoropyridinyl)-4,5a,6,7,8,8a- hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hloride 0 (5aS,8aS)(2—chlorofluorophenyl)(tetrahyd ro-2H-pyranyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(2—chlorofluorophenyl)((6-fluoropyridinyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(2,4-difluorophenyl)(2—(tetrahydro-2H-pyranyl)ethyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(2,4-difluorophenyl)(2—(tetrahydro-2H-pyranyl)ethyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(2—chlorofluorophenyl)((tetrahydro-2H-pyranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride [Annotation] KEB o (5aS,8aS)(2—chlorofluorophenyl)((tetrahydro-2H-pyranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(2,4-dichlorophenyl)((tetrahydro-2H-pyranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hloride 0 (5aS,8aS)(2,4-dichlorophenyl)((tetrahydro-2H-pyranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(2,4-dichlorophenyl)(tetrahydro-2H-pyranyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 aR)(2—chlorofluorophenyl)(2—(tetrahyd ro-2H-pyranyl)ethyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(2—chlorofluorophenyl)(2—(tetrahyd pyranyl)ethyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(2—chlorofluorophenyl)((6-methoxypyridinyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(2—chlorofluorophenyl)((6-methoxypyridinyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(2,4-difluorophenyl)((6-methoxypyridinyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(2,4-difluorophenyl)((6-methoxypyridinyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(2,4-dichlorophenyl)(2—(tetrahydro-2H-pyranyl)ethyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride [Annotation] KEB o (5aR,8aR)(2,4-dichlorophenyl)(2—(tetrahydro-2H-pyranyl)ethyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(2—chloro(trifluoromethyl)phenyl)(tetrahyd ro-2H-pyran yl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(2,4-dichlorophenyl)(((S)-tetrahydrofuranyl)methyl)- ,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(2,4-dichlorophenyl)(((R)-tetrahydrofuranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(2,4-dichlorophenyl)(((R)-tetrahydrofuranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 aR)(2,4-dichlorophenyl)(((S)-tetrahydrofuranyl)methyl)- ,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(2,4-difluorophenyl)((2—methylfuranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(2,4-difluorophenyl)((2—methylfuranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aS,8aS)(2,4-difluorophenyl)(furanylmethyl)-4,5a,6,7,8,8a- hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(2,4-difluorophenyl)(furanylmethyl)-4,5a,6,7,8,8a- hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(4-fluorobenzyl)(tetrahydro-2H-pyranyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride [Annotation] KEB o (5aS,8aS)(4-fluorobenzyl)(tetrahydro-2H-pyranyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 0 (5aR,8aR)(4-fluorobenzyl)(1-methyl-1H-pyrazolyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride A specific embodiment of the invention is that in which the lic lic compounds of the invention represent a compound with the general a (la): (la) where R1’ is selected from is selected from: - a -(C(R3)2)m-aryl group in which the aryl group may be optionally substituted by at least one halogen atom; - a )2)m-heteroaryl group in which the heteroaryl group may be optionally tuted by at least one substituent selected from a halogen, C1- 3_alkyl, 01alkoxy, 01haloalkoxy or 01haloalkyland in which the heteroaryl group may optionally be condensed with an additional ring system; - a -(C(R3)2)n-heterocycloalkyl group, in which the heterocycloalkyl group may be optionally substituted by at least one substituent selected from a halogen, 01.3-alkyl, 01alkoxy, 01.3-haloalkoxy or 01.3-haloalkyl and contains at least one oxygen atom; R2 is selected from : - a phenyl group optionally substituted by at least one substitutent selected from a halogen, C1_3-alkoxy, C1_3_haloalkoxy, aloalkyl or a hydroxyl group; [Annotation] KEB - a heteroaryl group ally substituted by at least one substitutent selected from a halogen, 01alkyl 01alkoxy, 01haloalkoxy, 01.3-haloalkyl or a hydroxyl group; - a heterocycloalkyl group being optionally substituted by at least one substituent selected from a halogen, 01.3-alkyl, lkoxy, 01.3-haloalcoxy, 01haloalkyl or a hydroxyl group; R3 is H or C1_3 alkyl; m is 1 to 2; and n is 0 to 2; with the proviso that when R1 is a -(C(R3)2)m-aryl group, R2 is not a phenyl group; or a pharmaceutically acceptable salt, , prodrug or solvate thereof.

In another aspect, the invention refers to the processes for obtaining the compounds of general formula (I). Several procedures have been developed for obtaining all the compound derivatives of the invention, herein the procedures will be explained below in methods A, B and C.

METHOD A Method A represents the process for synthesizing compounds according to l formula (la) that is compounds of formula (I) where m and n represents at least 1.

In this sense, a process is bed for the preparation of a nd of general formula (la): /—N "”l/l/ R1' N \ R2 N\N (la) comprising the on between a compound of general formula (VI): [Annotation] KEB with an aldehyde of general a (VII): R1'—\\ (VII) where R2 is as defined for formula (I) or (Ia) and R1’ is as defined for formula (la).

The reductive amination reaction of compounds of formula (VI) and (VII) is preferably carried out in an aprotic solvent such as, for instance, dichloroethane and preferably in the ce of an organic base such as diisopropylethylamine and a reductive reagent such as sodium triacetoxyborohydride. The type of aldehyde to be used will depend on the meaning of the final substituent R1’. All aldehydes (VII) used are commercially available.

In turn compound of l formula (VI) can be prepared by yzing a compound of general formula (V) %3HU&% The hydrolyzation of compound (V) or its enatiomer or racemic is carried out in an acidic medium, preferably HCI and in an organic solvent such as, for instance, 1,4- dioxane.

Compound (V) is produced by heating a compound of l formula (IV): [Annotation] KEB or its enantiomer or racemic in xylene or toluene at a temperature range of 90- 130°C.

Finally compound (IV) can be synthesized by the reaction of a compound of formula (II): 0M0? %"0 [/N3 (II) with a nd of l formula (III): (Ill) where X is a suitable leaving group such as a halogen or a sulfonate and R2 is always as defined for compounds of a (I) or (la).

The latter reaction is preferably carried out in an aprotic t such as tetrahydrofurane (THF) preferably in the presence of an inorganic base such as NaH and tetrabutylammonium iodide as catalyst at a temperature range of 0 °C to 30 °C.

Compound of formula (II) can be prepared enantiomerically pure or as racemic following methods reported in the literature (J. Org. Chem. 1997, 62, 4197-4199; edron:Asymmetry 2001, 12, 2989-2997). Compounds of formula (III) can be prepared by conventional methods (Org. Lett. 2008, 10(8), 1617-1619).

The general synthetic route for preparing compound according to method A is represented in scheme 1: Scheme 1 [Annotation] KEB O o O HN Acid >‘NQ’ UN \ R2 0 IN \ R2 Alternatively, compound of general formula (IV) can also be ed by reacting a compound of general formula (lVa) or its enantiomer or racemic: o 0/ 3H.OJ,N3 (lVa) With a compound of general formula (X): [Annotation] KEB where Y is a suitable leaving group such as a halogen. This coupling reaction is preferably carried out in the presence of Pd(PPh3)4 and Cul as catalysts and triethylamine or mixture of triethylamine and DMF as solvent at a temperature range of 60-1 10 °C. This on is represented in scheme 2: Scheme 2 Intermediates of formula (V) can also be prepared in an alternative way a shown below in scheme 3. In addition, scheme 3 also represents the possibility of ing compound of formula (V) where R2 is a ydropyrane as a particular embodiment (compound Va).

Scheme 3 [Annotation] KEB o o 0‘3’0 Wk_~kuo 0 (V) (XII) 1:80 (XV) ’%O>HO”E§/CO ‘— ,yOWO’mMOo o o o (val (XIII) As shown above a compound of formula (IVa) or its enantiomer or racemic as prepared in the way shown is scheme 2 is ted to iodination with a iodination reagent such as N-Iodomorpholine hydriodide preferbaly in the presence of Cul as catalyst and in a solvent such as THF, to give a nd of a (XI).

Compound (XI) is then heated in xylene or e at a temperature range of 90- 130°C to give compound (XII).

Compound of formula (XII) can be either reacted with a boronic pinacol ester of formula (XIV) to directly obtain a compound of general formula (V) or if a compound of general formula (Va) is desired a different route comprising the reaction of compound (XII) with a boronic pinacol ester of formula (XV) to obtain compound (XIII) is carried out. This reaction is carried out in the presence of 3)4 as catalyst and an inorganic base preferably K2003 or Na2003 in a mixture of organic solvents and water preferably a mixture of oxyethane/ethanol/water or tquene/ethanol/water at a temperature range of 80-110 °CN Alternatively, the [Annotation] KEB reaction can be carried out in a microwave reactor. All boronic esters used are commercially available. As the final step for ing compound of formula (Va), the alkenyl ediate (XIII) or its enantiomer is reduced with ammonium formate preferably in the presence of Pd/C as catalyst in an organic solvent preferably a mixture of THF/methanol.

METHOD B Method B ents an alternative way to method A for preparing compounds of general a (la).

In this sense, a process is described for the preparation of a compound of general formula (la): HQ”0 R1' ”I’ll/IN \ R2 N\N\ (la) comprising the reduction of a compound of general formula (IX): The reduction of compound of general a (IX) can be carried out with a reductive agent such as, for instance, BH3 in an aprotic solvent preferably THF and preferably at a temperature range of 0 °C to 78 °C.

In turn, compounds of l formula (IX) can be obtained by the reaction of a compound of general formula (VI) (as decribed in method A) with a compound of general formula (VIII): [Annotation] KEB R1' x (VIII) where X is a suitable g group such as a halogen. The latter reaction is preferably carried out in the presence of an organic base preferably diisopropylethylamine in an aprotic solvent preferably dichloromethane at a temperature range from 0 °C to 30 °C. All compounds (VIII) used are commercially ble.

The synthetic route of method B is represented in scheme 4 below: Scheme4 HN::"’ O O (VIII) >—N IN \ R2 R1' 'I'N \ R2 N:N NQN (VI) (IX) Reduction R1' , 'IN \ R2 (la) METHODC Method C represents the process for synthesizing compounds according to general formula (I) where n represents 0.

The process involves the reaction of a compound of formula (VI) with a ketone of a (Vlla): [Annotation] KEB o=R1 (Vlla) where R1 represents a -(C(R3)2)n-heterocycloalkyl group being n=0 For instance, if a tetrahydro-2H-pyranyl is desired in position R1, the ing ketone should be used: 03:0 An additional aspect of the invention relates to the therapeutic use of the compounds of general formula (I). As mentioned above, compounds of general formula (I) show a strong affinity to sigma receptors and can behave as agonists, nists, inverse agonists, partial antagonists or partial agonists thereof.

Therefore, compounds of general formula (I) are useful as medicaments.

They are suitable for the treatment and the prophylaxis of disorders and diseases mediated by sigma receptors, ally, sigma-1 receptors. In this sense, compounds of formula (I) are very good anxiolitic and immunosuppressant and are very useful in the treatment and prophylaxis of diarrhoea, Iipoprotein disorders, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, obesity, migraine, arthritis, hypertension, arrhythmia, ulcer, glaucoma, learning, memory and attention deficits, cognition disorders, neurodegenerative diseases, demyelinating diseases, ion to drugs and al substances including e, amphetamine, ethanol and nicotine; tardive diskinesia, ischemic stroke, epilepsy, stroke, stress, cancer, psychotic ions, in particular depression, y or schizophrenia; inflammation or autoimmune diseases.

The compounds of formula (I) are especially suited for the treatment of pain, especially neuropathic pain, inflammatory pain or other pain ions involving allodynia and/or hyperalgesia. PAIN is d by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such [Annotation] KEB damage (IASP, fication of chronic pain, 2nd Edition, IASP Press (2002), 210).

Even though pain is always subjective its causes or syndromes can be classified.

In a preferred ment compounds of the invention are used for the treatment and prophylaxis of allodynia and more specifically mechanical or thermal allodynia.

In another preferred ment compounds of the invention are used for the treatment and prophylaxis of hyperalgesia.

In yet another preferred embodiment compounds of the invention are used for the treatment and prophylaxis of neuropathic pain and more specifically for the treatment and prophylaxis of hyperpathia.

A related aspect of the invention refers to the use of compounds of formula (I) for the manufacture of a medicament for the treatment of disorders and diseases mediated by sigma receptors, as explained before.

Another aspect of the invention is a pharmaceutical composition which comprises at least a compound of general formula (I) or a ceutically acceptable salt, prodrug, isomer or solvate thereof, and at least a pharmaceutically acceptable r, additive, adjuvant or vehicle.

The pharmaceutical composition of the invention can be formulated as a medicament in different pharmaceutical forms sing at least a compound g to the sigma receptor and optionally at least one further active substance and/or optionally at least one auxiliary substance.

The auxiliary substances or additives can be selected among carriers, excipients, support als, lubricants, fillers, solvents, diluents, colorants, flavour conditioners such as sugars, antioxidants and/or agglutinants. In the case of itories, this may imply waxes or fatty acid esters or preservatives, emulsifiers and/or rs for eral application. The selection of these auxiliary materials and/or additives and the amounts to be used will depend on the form of application ofthe pharmaceutical composition.

[Annotation] KEB The pharmaceutical composition in accordance with the ion can be adapted to any form of administration, be it orally or erally, for example pulmonarily, nasally, rectally and/or intravenously.

Preferably, the composition is suitable for oral or parenteral administration, more ably for oral, intravenous, intraperitoneal, intramuscular, subcutaneous, intrathekal, rectal, transdermal, ucosal or nasal administration.

The composition of the invention can be formulated for oral administration in any form preferably selected from the group consisting of tablets, drageés, capsules, pills, chewing gums, powders, drops, gels, juices, syrups, solutions and suspensions.

The composition of the present invention for oral administration may also be in the form of articulates, preferably microparticles, microtablets, pellets or granules, optionally compressed into a tablet, filled into a capsule or suspended in a suitable liquid. Suitable liquids are known to those skilled in the art.

Suitable preparations for parenteral applications are solutions, suspensions, reconstitutable dry preparations or sprays.

The compounds of the invention can be ated as deposits in dissolved form or in patches, for percutaneous application.

Skin applications include nts, gels, creams, lotions, suspensions or emulsions.

The preferred form of rectal application is by means of suppositories.

The respective medicament may - ing on its route of administration - also contain one or more auxiliary substances known to those skilled in the art. The medicament according to the present invention may be ed according to standard procedures known to those skilled in the art.

[Annotation] KEB The daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, sex, weight or degree of illness and so forth. The daily dosage for humans may preferably be in the range from 1 to 2000, preferably 1 to 1500, more preferably 1 to 1000 milligrams of active substance to be administered during one or several intakes per day.

The following examples are merely rative of certain embodiments of the invention and cannot be ered as restricting it in any way.

ES Exam le of re aration of and intermediate of a IV Synthesis of (3R,4R)-tert-butylazido((3-(2-fluorophenyl)propyn yl)oxy)- pyrrolidinecarboxylate To a suspension of NaH (0.80 g, 60% dispersion in oil, 20 mmol) in dry THF (25 ml) cooled at 0 °C under nitrogen atmosphere, a solution of (3R,4R)-tert-butylazido hydroxypyrrolidinecarboxylate (3.50 g, 15.3 mmol) in dry THF (25 ml) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for 45 min. Then, tetrabutylammonium iodide (TBAI) (0.57 g, 1.53 mmol) and a solution of 1-(3-bromopropynyl)fluorobenzene (3.92 g, 18.4 mmol) in THF (50 ml) were slowly added at 0 °C. The reaction mixture was d from 0 °C to r.t. overnight. A saturated aqueous solution of NH4C| was added and the mixture extracted with EtOAc. The organic layer was washed with water, dried over NaZSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography, silica gel, gradient hexane to ethyl acetate to give the titled compound (4.68 g, 85% yield) as yellow oil.

[Annotation] KEB 1H-NMR z, CDCI3): mixture of two rotamers, 6 ppm: 7.42 (m, 1H), 7.30 (m, 1H), 7.07 (m, 2H), 4.47 (m, 2H), 4.18 (m, 1H), 4.11 (m, 1H), 3.63 (m, 2H), 3.45 (m, 2H), 1.44 (s, 9H).

This method was used for the preparation of intermediates of formula (IV) in the synthesis of examples of formula (|) 1-21.

Exam le of re aration of an intermediate of formula IV a) Synthesis of (3S,4S)-tert-butylazido(propynyloxy)pyrrolidine carboxylate (S,S-lVa) o ”0/ A solution of azido alcohol (3S,4S)-tert-butylazidohydroxypyrrolidine carboxylate (3.5 g, 15.3 mmol) in dry THF (28 ml) was added to a suspension of NaH (1.23 g, 60% dispersion in oil, 30.7mmol) in THF (25ml) under nitrogen, cooled at 0 °C. When the bubbling was finished the reaction mixture was allowed to warm to room temperature and d for 45 min. Then, gyl bromide (3.42 mL, 80% solution in toluene, 30.7 mmol) and a suspension of TBAI (0.57 g, 1.5 mmol) in THF (5 ml) were slowly added at 0 °C and the reaction was d overnight from 0 °C to rt. NH4C| sat solution was added and ted with EtOAc, washed with water, dried over NaZSO4, filtered and concentrated. Purification by flash chromatography, silica gel, gradient hexane to hexane:ethy| acetate (1:1) afforded the desired product (3.62 g, 89% yield) as yellow oil. 1H-NMR (400MHz, CDCI3), mixture of two rotamers, 6 ppm: 4.20 (m, 2H), 4.80 (m, 1H), 3.58 (m, 2H), 3.40 (m, 2H), 2.48 (s, 1H), 1.43 (s, 9H). b) sis of (3S,4S)-tert-butylazido((3-(3-fluoropyridinyl)prop ynyl)oxy)pyrrolidinecarboxylate [Annotation] KEB F /{\j O>—N #0 d.3 A mixture of Cul (20 mg, 0.10 mmol), Pd(PPh3)4 (24 mg, 0.021 mmol) and 3-fluoro- 4-iodopyridine (469 mg, 2.10 mmol) in Et3N (28 ml) under nitrogen was stirred at r.t. for 60 min. Then, a on of (3S,4S)-tert-butylazido(prop ynyloxy)pyrro|idinecarboxylate (560 mg, 2.10 mmol) in Et3N (17 ml) was added and the mixture was heated at 60 °C overnight. After cooling to r.t., water was added and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried over NaZSO4, filtered and concentrated. Purification by flash chromatography, silica gel, gradient hexane to ethyl e, afforded the desired product (398 mg, 52%) and the corresponding cyclic intermediate of general formula (V) (118 mg, 15% . 1H-NMR (400MHz, CDCI3): mixture of two rotamers, 6 ppm: 8.50 (s, 1H), 8.39 (d, J = Hz, 1H), 7.33 (t, J = 5 Hz, 1H), 4.50 (m, 2H), 4.15 (m, 1H), 4.10 (m, 1H), 3.65 (m, 2H), 3.47 (m, 2H), 1.46 (s, 9H).

This method was used for the preparation of intermediates of formula (IV) in the synthesis of examples of formula (I) 24-63.

Exam les of re aration of an intermediate of formula V Synthesis of (5aR,8aR)—tert-butyl(2-fluorophenyl)—5a,6,8,8a- tetrahydropyrrolo ] [1 ,2,3]triazolo[1 ,5-d] [1 zine-7(4H )-carboxylate A solution of (3R,4R)-tert-butylazido((3-(2-f|uorophenyl)propyny|)oxy)- pyrrolidinecarboxylate (4.68 g, 13.0 mmol) in xylene (560 ml) was heated at 120 [Annotation] KEB °C overnight. The reaction mixture was cooled and the solvent evaporated.

Purification by flash tography, silica gel, gradient hexane to ethyl acetate afforded the desired product (4.02 g, 86% yield) as a yellowish solid. 1H-NMR (400MHz, CDCI3): mixture of two rotamers, 6 ppm: 7.97 (m, 1H), 7.38 (m, 1H), 7.27 (td, J = 8,1 Hz, 1H), 7.14 (t, J = 9 Hz, 1H), 5.33 (dd, J = 16, 2 Hz, 1H), .15 (d, J =16 Hz, 1H), 4.6-4.2 (m, 2H), 8 (m, 2H), 3.59 (m, 1H), 3.39 (m, 1H), 1.50 (s, 9H).

Exam les of re aration of intermediates of formula V a) Synthesis of (3R,4R)-tert-butylazido((3-iodopropynyl)oxy)- pyrrolidinecarboxylate o o/' #ng To a solution of (3R,4R)-tert-buty|azido(propynyloxy)pyrrolidine carboxylate (0.69 g, 2.6 mol) in THF (15 ml), Cul (25 mg, 0.13 mmol) and N- iodomorpholine dide (1.0 g, 2.9 mmol) were added. The reaction mixture was stirred at r.t. for 2h, after which a precipitate had formed. The suspension was poured onto a pad of neutral a and the filtrate was collected under vacuum.

The solid phase was washed with DCM and the combined filtrate was concentrated by evaporation. The product was obtained as yellow oil (0.99 g, 97% yield). 1H-NMR (400MHz, CDCI3): mixture of two rotamers, 6 ppm: 4.38 (m, 2H), 4.07 (m, 1H), 4.03 (m, 1H), 3.61 (m, 2H), 3.44 (m, 2H), 1.46 (s, 9H). b) Synthesis of aR)—tert-butyliodo-5a,6,8,8a-tetrahydropyrrolo[3,4- b][1,2,3]triazolo[1,5-d][1,4]oxazine-7(4H)-carboxylate [Annotation] KEB 7L MCI’o 'l \ I A solution of (3R,4R)-tert-butylazido((3-iodopropyny|)oxy)pyrrolidine carboxylate (0.99 g, 2.5 mmol) in toluene (65 ml) was heated at 100 °C overnight.

The reaction mixture was cooled and the solvent evaporated. Purification by flash chromatography, silica gel, nt hexane to hexane:ethy| acetate (8:2) afforded the desired product (0.76 g, 77% yield). 1H-NMR (400MHz, CDCI3), mixture of two rotamers, 6 ppm: 5.11 (d, J = 16 Hz, 1H), 4.92 (d, J = 16 Hz, 1H), 4.5-4.2 (m, 2H), 4.0-3.8 (m, 2H), 3.51 (m, 1H), 3.37 (m, 1H), 1.49 (s, 9H). c) Synthesis of (5aR,8aR)-tert-butyl(3,6-dihydro-2H-pyranyl)- 5a,6,8,8a-tetrahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine- 7(4H)-carboxylate (XIII) To a mixture of (5aR,8aR)-tert-butyliodo-5a,6,8,8a-tetrahydropyrrolo[3,4-b][1,2,3]- triazolo[1,5-d][1,4]oxazine-7(4H)-carboxylate (250 mg, 0.64 mmol), 3,6-dihydro-2H- 4-boronic acid pinacol ester (161 mg, 0.76 mol), K2C03 (352 mg, 2.55 mmol) and Pd(Ph3)4 (37 mg, 0.032 mmol) under nitrogen, a mixture of Dimethoxyethane/ EtOH/water 4/1/0.2 (21 ml) was added. The reaction mixture was heated at 90 °C overnight. The reaction mixture was cooled down, diluted with DCM, washed with sat. NaHC03 on, dried over NaZSO4, filtered and concentrated under .

Purification by flash chromatography, silica gel, gradient hexane to hexane:ethy| e (1:1) afforded the desired product (160 mg, 72% yield). 1H-NMR (400MHz, CDCI3), mixture of two rotamers, 6 ppm: 5.85 (s, 1H), 5.28 (d, J = 16 Hz, 1H), 5.08 (d, J =16 Hz, 1H), 2 (m, 4H), 4.0-3.8 (m, 4H), 3.53 (m, 1H), 3.37 (m, 1H), 2.68 (m, 2H), 1.49 (s, 9H).

[Annotation] KEB d) Synthesis of (5aR,8aR)-tert-butyl(tetrahydro-2H-pyranyl)-5a,6,8,8atetrahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine-7(4H)- carboxylate (Va) A suspension of (5aR,8aR)-tert-butyl(3,6-dihydro-2H-pyranyl)-5a,6,8,8a- tetrahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine-7(4H)-carboxylate (325 mg, 0.93 mmol), ammonium formate (882 mg, 14.0 mmol) and Pd/C (20% WM, 65 mg) in MeOH/THF (1:1) (30 ml) under nitrogen atmosphere was heated at 75 °C ght. The suspension was filtered through celite and washed with MeOH. The filtrate was evaporated under vacuum and the residue obtained was portioned with DCM and water. The organic layer was washed with sat. NaHC03, dried over NaZSO4, filtered and the solvent removed under vacuum. The desired t was obtained as a white solid (319 mg, 98% yield). 1H-NMR z, CDCI3), mixture of two rotamers, 6 ppm: 5.24 (d, J = 16 Hz, 1H), .02 (d, J = 16 Hz, 1H), 4.5-4.2 (m, 2H), 4.06 (m, 2H), 4.0-3.8 (m, 2H), 3.53 (m, 3H), 3.36 (m, 1H), 3.00 (m, 1H), 1.85 (m, 4H), 1.49 (s, 9H). e) Synthesis of (5aR,8aR)(4-fluorobenzyl)—3-(1-methyl-1H-pyrazolyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine o 0 Md \ > ”1 o "’N \ \ N=N A 25 mL microwave vial was d with (5aR,8aR)-tert-butyl 3-iodo-5a,6,8,8a- tetrahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine-7(4H)-carboxylate (60 mg, 0.15 mmol), 1-Methyl-1H-pyrazoleboronic acid pinacol ester (48 mg, 0.23 mmol), [Annotation] KEB Na2C03 (49 mg, 0.46 mmol) and Pd(Ph3)4 (16 mg, 0.015 mmol) and purged with Argon before a mixture of toluene:ethanol:water (3:3:1) (4.2 ml) was added. The resulting suspension was irradiated with microwaves at 100 °C for 18 min.

The reaction mixture was cooled down, diluted with DCM and concentrated under vacuum. The residue was purified by flash chromatography, silica gel, gradient hexane to hexane:acetone (6:4) to afford the desired product (19 mg, 36% yield). 1H-NMR (400MHz, CDCI3), mixture of two rotamers, 6 ppm: 7.52 (d, J = 2 Hz, 1H) 6.15 (d, J = 2 Hz, 1H), 5.28 (d, J =16 Hz, 1H), 5.09 (d, J =16 Hz, 1H), 4.5-4.2 (m, 2H), 4.23 (s, 3H), 9 (m, 2H), 3.56 (m, 1H), 3.40 (m, 1H), 1.50 (s, 9H).

This method was used for the preparation of ediates of formula (V) in the synthesis of examples of formula (I) 64-66.

Exam le of re aration of an intermediate of formula VI Synthesis of (5aR,8aR)(2-fluorophenyl)—4,5a,6,7,8,8a-hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5-d][1,4]oxazine To a solution of (5aR,8aR)-tert-butyl(2-fluorophenyl)-5a,6,8,8a- tetrahydropyrrolo[3,4-b][1,2,3]triazolo [1,5-d][1,4]oxazine-7(4H)-carboxylate (4.01 g, 11.1 mmol) in dioxane (28 ml), a on of 4M HCl in dioxane (36.2 ml) was added and the mixture was stirred at r.t. for 3h. The mixture was trated to dryness to afford the titled compound (3.52 g, 95% yield) as ochloride. 1H-NMR z, MeOD) 6 ppm: 7.85 (td, J = 8, 1 Hz, 1H), 7.51 (m, 1H), 7.36 (td, J = 8,1 Hz, 1H), 7.28 (ddd, J = 12, 8, 1 Hz, 1H), 5.44 (dd, J =16,1 Hz, 1H), 5.28 (d, J =16 Hz, 1H), 4.71 (m, 1H), 4.5-4.3 (m, 2H), 3.87 (dd, J = 11,6 Hz, 1H), 3.76 (t, J = 11 Hz, 1H), 3.46 (t, J =11 Hz,1H).

Exam les of re aration of com ounds of eneral formula I MethodA [Annotation] KEB Example 14: (5aR,8aR)(2-fluorophenyl)((6-(trifluoromethyl)pyridinyl) methyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride NQ’ F _ ION \ \N/ NN To a suspension of aR)(2-f|uoropheny|)-4,5a,6,7,8,8ahexahydropyrro |o[3,4-b][1,2,3]triazo|o[1,5-d][1,4]oxazine dihydrochloride (45 mg, 0.135 mmol) in DOE (2.2 ml), DIPEA (71 pl, 0.40 mmol) was added and the mixture was stirred at rt for 5 min. A solution of 6-(trif|uoromethy|)nicotinaldehyde (35 mg, 0.2 mmol) in DOE (0.5 ml) and NaBH(OAc)3 (57 mg, 0.27 mmol) were added and the reaction e was d at r.t. for 16h. DCM was added and washed with NaHC03 sat. solution and brine, dried over NaZSO4, filtered and concentrated.

Purification by flash chromatography, silica gel, gradient hexane to ethyl acetate afforded the desired product (53 mg, 94% yield).

The previous product (46 mg, 0.11 mmol) was ved in AcOEt (1 ml) and a 1.25 M solution of HCI in EtOH (88 pL, 0.11 mmol) was added. After 30 min of stirring, the mixture was concentrated to afford the hydrochloride as white solid (49 mg).

HPLC retention time: 6.15 min; HRMS: 420.1435 (M+H).

The examples 15, 16, 17, 18, 56, 57, 58, 59 were obtained diastereomerically and enantiomerically pure by semipreparative HPLC (Chiralpak IA 250x10 mm, 5 pM, eluent: heptane/DCM/EtOH, 5 mL/min) of the ponding mixtures of the diastereomers obtained by reaction of the enantiomerically pure intermediate (VI) and a racemic aldehyde (VII).

Exam le of re aration of com ounds of eneral formula I Method B a) ((5aS,8aS)(2,4-difluorophenyl)-5a,6,8,8a-tetrahydropyrrolo[3,4- b][1,2,3]triazolo[1,5-d][1,4]oxazin-7(4H)-yl)(2,5-dimethylfuran yl)methanone [Annotation] KEB :NQ‘QWF\:N To a solution of (5aS, 8aS) -(2,4-d-ifluorophenyl)-4, 5a, 6, 7, 8, 8a- hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine dihydrochloride (80 mg, 0.25 mmol) and DIPEA (115 pl 0.66 mmol) in DCM (12 ml), 2,5-dimethylfuran carbonyl chloride (43 uL, 0.33 mmol) was slowly added at 0 °C, and the mixture was stirred at rt under nitrogen overnight. DCM was added and washed with saturated solution of NaH003 and brine, dried over MgSO4, filtered and concentrated to dryness. Purification by flash chromatography, silica gel, nt hexane to ethyl acetate ed the desired product (100 mg, 99% yield). 1H-NMR (400MHz, CDCI3) 6 ppm: 7.97 (m, 1H) 7.03 (td, J = 8,2 Hz, 1H), 6.91 (t, J = 9 Hz, 1H), 6.05 (s, 1H), .32 (d, J =16 Hz, 1H), 5.16 (m, 1H), 4.63 (m, 1H), 4.40 (m, 1H), 4.12 (m, 2H), 3.84 (m, 1H), 3.66 (m,1H), 2.47(s, 3H), 2.28 (s, 3H). b) Example 22: aS)—3-(2,4-difluorophenyl)((2,5-dimethylfuranyl) )-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4] oxazine hydrochloride To a 1 M solution of borane in THF (1.1 mL; 1.09 mmol) cooled at 0 °C under nitrogen atmosphere, a solution of ((5aS,8aS)(2,4-difluorophenyl)-5a,6,8,8a- tetrahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazin-7(4H)-yl)(2,5-dimethylfuran- 3-yl)methanone (87 mg, 0.22 mmol) in dry THF (2.6 ml) was added. The resulting mixture was stirred at reflux overnight. Methanol (2 ml) and 10% KOH on (1 ml) was added at 0 °C and refluxed for one hour. The reaction mixture was concentrated under vacuum and the residue was diluted with DCM and washed with brine. The organic layer was dried over NaZSO4, filtered and the solvent was [Annotation] KEB removed under reduced pressure. Purification by flash chromatography, silica gel, nt hexane to ethyl acetate afforded the desired product (27 mg, 32% yield).

The previous product (27 mg, 0.07 mmol) was ved in AcOEt (1 ml) and a 1.25 M solution of HCI in EtOH (56 pL, 0.07 mmol) was added. After 30 min of stirring, the mixture was concentrated to afford the hydrochloride as a white solid (28 mg).

HPLC retention time: 5.85 min; HRMS: 387.1647 (M+H) This method was used for the preparation of examples of formula (I) 22-23.

Table | below, discloses compounds prepared according to the aforementioned methods: Table | HPLC (retention Example time, min) (5aR,8aR)(2- fluorophenyl) (pyridinylmethyl)- 3521577 4,5a,6,7,8,8a- (M+H) hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride 8aRS)(2- fluorophenyl) inylmethyl)- 4,5a,6,7,8,8a- 3521584 hexahydropyrrolo[3,4- (M+H) b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aRS,8aRS)(2- 3521583 phenyl) (M+H) (pyridinylmethyl)- 4,5a,6,7,8,8a- [Annotation] KEB HPLC (retention Example time, min) hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aS,SaS)(4- henyI) (tetra hydro-2H-pyran y|)-4,5a,6,7,8,8a- 345.1733 hexahydropyrrolo[3,4- (M+H) b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aR,8aR)(4- fluorophenyI) (tetra hydro-2H-pyran y|)-4,5a,6,7,8,8a- 345.1733 hexahydropyrrolo[3,4- (M+H) b][1,2,3]triazo|o[1,5- d][1,4]oxazine hydrochloride (5aS,8aS)(2- fluorophenyI) (tetra hydro-2H-pyran y|)-4,5a,6,7,8,8a- 367.1558 hexahydropyrrolo[3,4- (M+Na) b][1,2,3]triazo|o[1,5- d][1,4]oxazine hloride (5aR,8aR)(2— fluorophenyI) (tetra 2H-pyran yl)-4,5a,6,7,8,8a- 367.1558 hexahydropyrrolo[3,4- (M+Na) b][1,2,3]triazolo[1,5- ]oxazine hydrochloride [Annotation] KEB HPLC (retention Example time, min) (5aS,SaS)(6- ypyridin-S-yI) (tetra hydro-2H-pyran yl)-4,5a,6,7,8,8a- 380.1680 hexahydropyrro|o[3,4- (M+Na) b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aS,8aS)(2- fluorophenyI) ((tetrahyd ro-2H-pyran- ethyl)- 359.1865 618,83- (M+H) hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aR,83R)—3-(2— fluorophenyI) ((tetrahyd ro-2H-pyran- 4-yl)methyl)- 359.1886 4,5a,6,7,8,8a— (M+H) hexahydropyrrolo[3,4- b][1,2,3]triazo|o[1,5- d][1,4]oxazine hydrochloride (5aR,8aR)—3-(2— fluorophenyI)((6- fluoropyridin—3— yl)methyl)- 370.1490 11 4,5a,6,7,8,8a- (M+H) hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride [Annotation] KEB HPLC tion Example time, min) (5aR,8aR)(2- fluorophenyI)((6- methoxypyridin yl)methyl)- 12 4,5a,6,7,8,8a— (M+H) dropyrrolo[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aS,8aS)(2- fluorophenyI)((6- methoxypyridin yl)methyl)- 3821693 13 4,5a,6,7,8,8a— (M+H) hexahydropyrrolo[3,4- b][1,2,3]triazo|o[1,5- ]oxazine hydrochloride (5aR,8aR)(2- fluorophenyI)((6- (trifluoromethyl)pyridin- 3-yl)methyl)- 420.1435 14 4,5a,6,7,8,8a- (M+H) hexahydropyrro|o[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5a8,8aS)(2- fluorophenyl)(((R)— tetrahyd rofuran-S- yl)methyl)- 3451733 4,5a,6,7,8,8a- (M+H hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride [Annotation] KEB HPLC (retention Example time, min) (5aR,8aR)(2— fluorophenyI)(((S)- yd n-S- yl)methyl)- 345.1737 16 4,5a,6,7,8,8a— (M+H) hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aS,8aS)(2- fluorophenyI)(((S)- tetrahyd rofuran yl)methyl)- 345.1734 17 4,5a,6,7,8,8a— (M+H) hexahydropyrrolo[3,4- b][1,2,3]triazo|o[1,5- d][1,4]oxazine hydrochloride (5aR,8aR)(2— fluorophenyl)(((R)— tetrahyd rofuran yl)methyl)- 345.1744 18 4,5a,6,7,8,8a- (M+H) hexahydropyrro|o[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aR,8aR)((6- ethoxypyridin hy|)(2— fluorophenyl)- 396.1852 19 4,5a,6,7,8,8a- (M+H) hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride [Annotation] KEB HPLC (retention Example time, min) (5aS,8aS)((6- ethoxypyridin-B- yl)methyI)(2- fluorophenyl)- ,7,8,8a— (M+H) hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5- ]oxazine hydrochloride (5aRS,8aRS)(4— fluorophenyI)(furan- 3-ylmethy|)- ,7,8,8a— 3411426 hexahydropyrrolo[3,4- (M+H) b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aS,8aS)(2,4- difluorophenyl)((2,5- dimethylfuran-B- yl)methyl)- 3871647 22 4,5a,6,7,8,8a— (M+H) hexahydropyrrolo[3,4- b][1,2,3]triazo|o[1,5- d][1,4]oxazine hydrochloride (5aR,8aR)(2,4- difluorophenyl)((2,5- dimethylfuran-S- yl)methyl)- 3671646 23 4,5a,6,7,8,8a— (M+H) hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride [Annotation] KEB HPLC (retention Example time, min) (5aR,8aR)(4- enzyl)(pyridin- 4,5a,6,7,8,8a- 352.1570 24 hexahydropyrrolo[3,4- (M+H) b][1,2,3]triazo|o[1,5- d][1,4]oxazine hydrochloride (5aS,SaS)(4- fluorobenzyl)(pyridin- 2-y|)-4,5a,6,7,8,8a- 374.1396 hexahydropyrrolo[3,4- (M+Na) ,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aR66aRsy744— fluorobenzyl)—3-(pyridin- 4-yl)-4,5a,6,7,8,8a— 3521574 26 hexahydropyrrolo[3,4- (M+H) ,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aS,8aS)(2,4- difluorophenyl)—7- (tetra hydro-2H-pyran y|)-4,5a,6,7,8,8a- 3631639 hexahydropyrrolo[3,4- (M+H) b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aR,8aR)(2,4- difluorophenyl)—7- 3631639 28 (tetra hydro-2H-pyran yl)-4,5a,6,7,8,8a- (M+H) hexahydropyrro|o[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine [Annotation] KEB HPLC (retention Example time, min) hydrochloride (5aR,8aR)(4- fluorobenzyl)—3-(3- fluoropyridin-Z-yl)— 4,5a,6,7,8,8a— 370.1466 dropyrrolo[3,4- ' (M+H) b][1,2,3]triazo|o[1,5- d][1,4]oxazine hydrochloride (5aS,BaS)(5- fluoropyridin-Z-yI) (tetra hydro-2H-pyran y|)-4,5a,6,7,8,8a- 346.1663 dropyrrolo[3,4- ' (M+H) b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aS,8aS)(pyridin-2— yl)(tetrahydro-2H- pyran-4—yl)- 4,5a,6,7,8,8a- 328.1763 hexahydropyrrolo[3,4- ' (M+H) b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aR,8aR)benzy|—3- (pyridiny|)- 4,5a,6,7,8,8a- I 334.1663 32 hexahydropyrrolo[3,4- (M+H) ,3]triazolo[1,5- ]oxazine hydrochloride (5aS,8aS)benzyl 334.1654 (pyridiny|)- ' (M+H) 4,5a,6,7,8,8a— [Annotation] KEB HPLC (retention Example time, min) hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aS,SaS)(4- fluorobenzyl)(pyridin- 3-y|)-4,5a,6,7,8,8a— 352.1586 34 hexahydropyrrolo[3,4- (M+H) b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aR,8aR)(4- enzyl)—3-(pyridin- 3-yl)-4,5a,6,7,8,8a— hexahydropyrrolo[3,4- (M+H) b][1,2,3]triazolo[1,5- d][1,4]oxazine h drochloride (5aR,8aR)(4- enzyl)(3- fluoropyridinyl)— ,7,8,8a— 3701491 hexahydropyrrolo[3,4- (M+H) b][1,2,3]triazo|o[1,5- d][1,4]oxazine hydrochloride (5aS,8aS)(4- fluorobenzyl)—3-(3- fluoropyridiny|)— 4,5a,6,7,8,8a— 3701474 hexahydropyrrolo[3,4- (M+H) b][1,2,3]triazo|o[1,5- d][1,4]oxazine hydrochloride (5aS,8aS)(2-ch|oro- 379.1320 38 >10.00 5.02 4-fluorophenyl) (M+H) (tetra hydro-2H-pyran [Annotation] KEB HPLC tion Example time, min) yl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aR,8aR)(2—chloro- 4-fluorophenyl)((6— fluoropyridin-3— yl)methyl)- 4041096 39 ,7,8,8a- (M+H) hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aR,8aR)(2,4- difluorophenyI)(2- (tetra hydro-2H-pyran yl)ethy|)-4,5a,6,7,8,83- 42 hexahydropyrrolo[3,4- (M+H) b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride aS)(2,4- difluorophenyl)(2— (tetra hydro-2H-pyran yl)ethy|)—4,5a,6,7,8,8a- 391.1953 hexahydropyrro|o[3,4- (M+H) b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aR,8aR)(2—chloro- 4-fluorophenyl) 3931502 42 ((tetrahyd ro-2H-pyran- 4-yl)methyl)- (M+H) 4,5a,6,7,8,8a— hexahydropyrrolo[3,4- b][1,2,3]triazo|o[1,5- [Annotation] KEB HPLC (retention Example time, min) d][1,4]oxazine hydrochloride (5aS,BaS)(2-chloro- 4-fluorophenyl) ((tetrahyd ro-2H-pyran- 4-yl)methyl)- 3931502 43 4,5a,6,7,8,8a— (M+H) hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aR,8aR)(2,4- dichlorophenyI) ((tetrahyd ro-2H-pyran- 4-yl)methyl)- 4091196 44 4,5a,6,7,8,8a— (M+H) hexahydropyrrolo[3,4- b][1,2,3]triazo|o[1,5- d][1,4]oxazine hydrochloride (5aS,8aS)(2,4- dichlorophenyI) ((tetrahyd ro-2H-pyran- 4-yl)methyl)- 4091181 45 4,5a,6,7,8,8a— (M+H) hexahydropyrrolo[3,4- b][1,2,3]triazo|o[1,5- ]oxazine hydrochloride (5aS,8aS)(2,4- dichlorophenyI) (tetra hydro-2H-pyran 395.1043 46 5a,6,7,8,8a- (M+H) hexahydropyrrolo[3,4- ,3]triazo|o[1,5- ]oxazine hydrochloride [Annotation] KEB HPLC (retention Example time, min) aR)(2—chloro- 4-fluorophenyl)(2- (tetra hydro-2H-pyran yl)ethy|)-4,5a,6,7,8,8a- 407.1669 dropyrrolo[3,4- (M+H) b][1,2,3]triazolo[1,5- ]oxazine hydrochloride (5a8,8aS)(2-chloro- 4-f|uoropheny|)(2- (tetra hydro-2H-pyran 4071647 48 y|)ethy|)-4,5a,6,7,8,8a- (M+H) dropyrrolo[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aR,8aR)(2—chloro- 4-fluoropheny|)((6- methoxypyridin yl)methyl)- 4161284 49 4,5a,6,7,8,8a- (M+H) hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aS,8aS)—3-(2-ch|oro- 4-fluoropheny|)((6- methoxypyridin-B- y|)methy|)— 416.1285 50 4,5a,6,7,8,8a— (M+H) hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride [Annotation] KEB HPLC (retention Example time, min) (5aR,8aR)(2,4- difluorophenyl)((6- methoxypyridin-3— yl)methyl)- 4001596 51 4,5a,6,7,8,8a— (M+H) hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aS,8aS)(2,4- difluorophenyl)((6- methoxypyridin yl)methyl)- 4001585 52 4,5a,6,7,8,8a— (M+H) hexahydropyrrolo[3,4- ,3]triazo|o[1,5- d][1,4]oxazine hydrochloride (5aS,8aS)(2,4- dichlorophenyI)(2- (tetra hydro-2H-pyran y|)ethy|)-4,5a,6,7,8,8a- 1 hexahydropyrrolo[3,4- (M+H) b][1,2,3]triazo|o[1,5- d][1,4]oxazine hloride (5aR,8aR)(2,4- dichlorophenyI)(2- (tetra hydro-2H-pyran y|)ethy|)-4,5a,6,7,8,8a- 4231341 hexahydropyrrolo[3,4- (M+H) b][1,2,3]triazolo[1,5- ]oxazine hydrochloride 4291316 55 (5aS,8aS)(2-chloro- 5.68 (M+H) [Annotation] KEB HPLC (retention Example time, min) (trifluoromethyl)phenyl)- 7-(tetrahydro-2H-pyran- 4-y|)-4,5a,6,7,8,8ahexahydropyrrolo [3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aS,8aS)(2,4- dichlorophenyI)(((S)- yd rofuran hy|)- 395.1038 56 4,5a,6,7,8,8a- (M+H) hexahydropyrro|o[3,4- b][1,2,3]triazolo[1,5- ]oxazine hydrochloride (5aR,8aR)(2,4- dichlorophenyI)(((R)- yd rofuran yl)methyl)— 395.1030 57 4,5a,6,7,8,8a— (M+H) hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aS,8aS)(2,4- dichlorophenyl)—7-(((R)- tetrahyd rofuran-S- yl)methyl)— 395.1027 58 4,5a,6,7,8,8a— (M+H) hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride 395.1027 59 (5aR,8aR)(2,4- dichlorophenyI)(((S)- (M+H) tetrahyd rofuran-S- [Annotation] KEB HPLC tion time, min) yl)methyl)- 4,5a,6,7,8,8a— hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aR,8aR)(2,4- difluorophenyl)((2— methylfu ran yl)methyl)- 373.1481 60 4,5a,6,7,8,8a- (M+H) hexahydropyrrolo[3,4- ,3]triazo|o[1,5- d][1,4]oxazine hydrochloride (5aS,8aS)(2,4- difluorophenyl)((2— methylfu ran hyl)- 373.1473 61 4,5a,6,7,8,8a— (M+H) hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aS,8aS)(2,4- difluorophenyl) (furanylmethyl)— 4,5a,6,7,8,8a— 359.1302 hexahydropyrrolo[3,4— (M+H) b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aR,8aR)(2,4- difluorophenyl) 359.1330 (furanylmethy|)- (M+H) 4,5a,6,7,8,8ahexahydropyrro |o[3,4- [Annotation] KEB HPLC (retention Example time, min) b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride aR)—7-(4- fluorobenzyl)—3- (tetra hydro-2H-pyran y|)-4,5a,6,7,8,8a- 359 1888 hexahydropyrrolo[3,4- (M+H) b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aS,8aS)(4- fluorobenzyl) (tetra hydro-2H-pyran yl)-4,5a,6,7,8,8a- 359.1894 hexahydropyrro|o[3,4- (M+H) b][1,2,3]triazolo[1,5- d][1,4]oxazine hydrochloride (5aR,8aR)(4- fluorobenzyI)(1 - methyl-1H-pyrazol 5a,6,7,8,8a- 355.1686 dropyrrolo[3,4- (M+H) b][1,2,3]triazol0[1,5- d][1,4]oxazine hydrochloride ical HPLC were performed using ZORBAX Eclipse XDB-C18 (4.6 x 150 mm, 5 pm) columns; flux: 1 ml/ min.; A: H20 (0.05% TFA). B: ACN; conditions: 1st Gradient % to 95% Bin 7 min., 2nd lsocratic 95% B 5 min.

SOLUBI LITY STUDY Kinetic solubility [Annotation] KEB To a buffered aqueous solution at pH=7.4 (1 mL), a 10mM DMSO solution of the test compound (10 pL) was added and the mixture stirred for 4 hours. After centrifugation, the compound concentration in the supernatant was determined by liquid chromatography by fitting in a ation curve of the compound. s regarding the solubility of the different compounds are shown in table | above.

In addition, the following table II provides some comparative examples where compounds of the present invention are compared in their kinetic lity to compounds of general formula (I) prior art document W02009/071657.

Compound of the t Kin.

Solub. invention (PM) Compound of W02009071657 Example 1 ”CEWF >20.00 / \ m _N -HCl Example 10 N0’0 6 W\I >10.00 4,18 -HC| Example 16 03c 0’0 F N [so >10.00 -HC| Example 5 [Annotation] KEB Compound of the present Kin.

Solub. invention (PM) Compound of 071657 >10.00 Example 23 NO: WFF >10.00 Ix; ~_ -HCl Example 26 0’WES/QM/ >10.00 -HC| Example 44 Q o >10.00 0.93 NO:Wm -HC| >10.00 7 8 Example 54 [Annotation] KEB Compound of the present Kin.

Solub. invention (HM) Compound of 071657 O DIGWmCI ’N -HC| Example 55 OC>—N%WCI F <O.40 >10.00 -HC| Example 64 0’0Whig/CO -HC| >10.00 Example 66 CF \ "IN \ \ >10.00 39 -HC| Example 8 (DO—”OxW0\\ I / >10.00 ”l \ N -HC| Example 11 3.08 — GER/b >10.00 [Annotation] KEB Compound of the present Kin.

Solub. tion.

(HM) Compound of W02009071657 -HC| Example 25 0:NW~/ >10.00 Table III represents a comparative example between compound 47 of W02009/071657 with some of the more ural related compounds of the present invention: Compound of the present Compound of W02009071657 invention 0' Example 1 Cl \NxNQ’O [Annotation] KEB Compound of the present Compound of W02009071657 invention 0 0’”,pr -HCI Example 6 0051 b -HC| Example 7 oGOZN‘W N -H CI Example 11 — Wm Example 39 0? Cl _. ’N \ / N=N -HC| [Annotation] KEB As observed in comparative table II and table lll, although compounds of W02009/071657 are structurally related to the compounds of the present invention, the latter have a clearly improved solubility when compared to those of the prior art.

In addition, it should be stressed that some of the compounds of W02009/071657 with heteroaryl groups attached to the nitrogen of the pyrrolidine of the tricyclic structure such as compounds 48, 51 and 52 of W02009/071657, were not soluble in DMSO which in practice makes them practically useless from the pharmacological point of view. On the contrary, all nds of the present invention have a good solubility in DMSO.

BIOLOGICAL ACTIVITY Pharmacological study Human Sigma 1 receptor radioligand assay To investigate binding properties of sigma 1 receptor ligands to human sigma 1 receptor, transfected HEK-293 membranes and [3H](+)-pentazocine n Elmer, NET-1056), as the radioligand, were used. The assay was carried out with 7 pg of ne suspension, 5 nM of [3H](+)-pentazocine in either absence or presence of either buffer or 10 uM Haloperidol for total and non-specific binding, respectively.

Binding buffer contained Tris-HCl 50 mM at pH 8. Plates were incubated at 37 °C for 120 minutes. After the incubation period, the on mix was then transferred to MultiScreen HTS, FC plates (Millipore), filtered and plates were washed 3 times with ice-cold 10 mM Tris—HCL ). s were dried and counted at approximately 40% efficiency in a MicroBeta llation counter (Perkin-Elmer) using nt liquid scintillation il.

Some of the results obtained are shown in table ”I.

Table III ation] KEB LOOJVO) 21.6 209.1 227.2 16.1 13.9 1 1 240.7 12 51.5 13 391.8 14 86.9 29.7 16 97.6 17 49.2 18 171.2 19 83.3 21 16.6 22 118.6 23 41.9 24 21 26 133.2 27 20.4 29 119 63.4 31 241.5 32 37 33 224.6 85.7 36 74.2 38 21.8 39 165.5 40 25.9 41 19.9 42 33.3 43 20.5 44 30.8 45 13.7 46 15.1 47 26.8 48 11.7 49 111.6 50 99.9 51 233.8 52 271.9 53 16.8 54 71.4 55 23.3 56 22.7 57 195.4 58 25.4 59 180.5 60 101.9 61 73.7 62 39.2 63 37.7 64 71.8 66 138.1 Definitions of specific embodiments of the invention as claimed herein . ing to a first embodiment of the invention, there is provided a compound of general formula (I) R1 N N R2 N N wherein R1 is selected from: - a )2)m-aryl group in which the aryl group may be optionally substituted by at least one halogen atom; - a -(C(R3)2)m-heteroaryl group in which the heteroaryl group may be optionally substituted by at least one substituent selected from a halogen, C1- 3-alkyl, C1alkoxy, C1haloalcoxy or C1haloalkyl and in which the heteroaryl group may ally be condensed with an additional ring system; - a -(C(R3)2)n-heterocycloalkyl group, in which the heterocycloalkyl may be optionally substituted by at least one substituent selected from a halogen, C1- 3-alkyl, C1alkoxy, C1haloalcoxy or C1haloalkyl and contains at least one oxygen atom; R2 is selected from: - a phenyl group optionally substituted by at least one substitutent selected from a halogen, C1alkoxy, C1haloalcoxy, C1haloalkyl or a hydroxyl group; - a heteroaryl group optionally substituted by at least one substitutent ed from a n, C1alkyl C1alkoxy, C1haloalcoxy, C1haloalkyl or a hydroxyl group; - a heterocycloalkyl group and being optionally substituted by at least one substituent selected from a halogen, C1alkyl, C1alkoxy, C1haloalcoxy, C1haloalkyl or a hydroxyl group; R3 is H or C1-3 alkyl; m is 1 to 3; and n is 0 to 3; with the proviso that when R1 is a -(C(R3)2)m-aryl group, R2 is not a phenyl group; or a pharmaceutically able salt or solvate thereof.

According to a second embodiment of the invention, there is provided a compound according to the first embodiment when used as a medicament.

According to a third embodiment of the invention, there is ed the use of the compound according to the first ment, in the manufacture of a medicament for the treatment or prophylaxis of a sigma or mediated disease or condition.

According to a fourth embodiment of the invention, there is ed a process for the preparation of a compound of general formula (Ia): R1' N R2 N N (Ia) comprising the reaction between a nd of l formula (VI): N R2 (VI) with an aldehyde of general formula (VII): O (VII) where R2 is as defined in the first embodiment and R1’ is selected from is selected from: - a -(C(R3)2)m-aryl group in which the aryl group may be optionally substituted by at least one halogen atom; - a -(C(R3)2)m-heteroaryl group in which the heteroaryl group may be optionally tuted by at least one substituent selected from a halogen, C1- 3-alkyl, C1alkoxy, C1haloalkoxy or C1haloalkyland in which the heteroaryl group may optionally be condensed with an additional ring system; - a -(C(R3)2)n-heterocycloalkyl group, in which the heterocycloalkyl group may be optionally substituted by at least one tuent selected from a halogen, C1alkyl, C1alkoxy, C1haloalkoxy or C1haloalkyl and contains at least one oxygen atom; being R3 is H or C1-3 alkyl; m is 1 to 2; and n is 0 to 2; with the proviso that when R1 is a -(C(R3)2)m-aryl group, R2 is not a phenyl group.

According to a fifth embodiment of the invention, there is provided a process for the ation of a compound of general formula (Ia): R1' N R2 N N (Ia) comprising the reduction of a compound of general formula (IX): O O R1' N R2 (IX) where R2 is as defined in the first embodiment and R1’ is selected from is selected from: - a )2)m-aryl group in which the aryl group may be optionally tuted by at least one halogen atom; - a -(C(R3)2)m-heteroaryl group in which the heteroaryl group may be optionally substituted by at least one substituent selected from a n, C1- 3-alkyl, C1alkoxy, C1haloalkoxy or C1haloalkyland in which the heteroaryl group may optionally be condensed with an additional ring system; - a -(C(R3)2)n-heterocycloalkyl group, in which the cycloalkyl group may be optionally tuted by at least one substituent selected from a halogen, C1alkyl, lkoxy, C1haloalkoxy or C1haloalkyl and contains at least one oxygen atom; being R3 is H or C1-3 alkyl; m is 1 to 2; and n is 0 to 2; with the proviso that when R1 is a -(C(R3)2)m-aryl group, R2 is not a phenyl group.

According to a sixth embodiment of the invention, there is provided a process for the preparation of a compound of general formula (I): R1 N N R2 N N comprising the reaction between a compound of general formula (VI): N R2 (VI) with an ketone of general formula (VIIa): O R1 (VIIa) where R1 represents a )2)n-heterocycloalkyl group, in which the heterocycloalkyl group may be optionally tuted by at least one substituent selected from a halogen, C1alkyl, lkoxy, C1haloalkoxy or C1haloalkyl and contains at least one oxygen atom, and n=0.

According to a seventh embodiment of the invention, there is provided a pharmaceutical composition which comprises at least one compound as defined in the first embodiment or a pharmaceutically acceptable salt or solvate thereof, and at least a pharmaceutically acceptable carrier, additive, adjuvant or vehicle.

Claims (14)

1. A compound of general formula (I) 5 O R1 N N R2 N N 15 (I) wherein R1 is selected from: - a -(C(R3)2)m-aryl group in which the aryl group may be optionally substituted by at least one halogen atom; 25 - a -(C(R3)2)m-heteroaryl group in which the heteroaryl group may be optionally substituted by at least one substituent selected from a n, C1- 3-alkyl, C1alkoxy, C1haloalcoxy or C1haloalkyl and in which the heteroaryl group may optionally be condensed with an onal ring system; - a -(C(R3)2)n-heterocycloalkyl group, in which the heterocycloalkyl may be optionally substituted by at least one substituent selected from a n, C1- 3-alkyl, C1alkoxy, C1haloalcoxy or C1haloalkyl and contains at least 35 one oxygen atom; R2 is selected from: - a phenyl group optionally substituted by at least one tutent selected from a halogen, C1alkoxy, C1haloalcoxy, C1haloalkyl or a hydroxyl group; 5 - a heteroaryl group optionally substituted by at least one substitutent selected from a n, C1alkyl C1alkoxy, C1haloalcoxy, C1haloalkyl or a hydroxyl group; - a cycloalkyl group and being optionally substituted by at least one 10 substituent selected from a halogen, C1alkyl, C1alkoxy, C1haloalcoxy, C1haloalkyl or a hydroxyl group; R3 is H or C1-3 alkyl; m is 1 to 3; and 15 n is 0 to 3; with the proviso that when R1 is a )2)m-aryl group, R2 is not a phenyl group; or a ceutically acceptable salt or solvate thereof. 20

2. A compound according to claim 1 where R1 is a benzyl optionally substituted by at least one halogen; a -(C(R3)2)m-heteroaryl group in which the heteroaryl is a 5 or 6 membered aryl radical containing from 1 to 3 heteroatoms selected from N or O and is optionally substituted by at least one substituent selected from a halogen, C1alkyl, C1alkoxy or C1haloalkyl; or a -(C(R3)2)n-heterocycloalkyl group, in 25 which the heterocycloalkyl group is a tetrahydropyranyl or as tetrahydrofuranyl group.

3. A compound according to claim 1 or 2 where R1 is selected from: m m m N N Ra Ra N m m n Rb Ra where Ra represents a hydrogen, a halogen, C1-3 alkyl, C1-3 -alkoxy or C1-3 haloalkyl, Rb represents a hydrogen or a n and m and n are as defined in claim 1. 5

4. A compound according to claim 1 where R2 is a phenyl optionally substituted by at least one substituent selected from a halogen or C1-3 haloalkyl; a 5 or 6 membered heteroaryl l containing from 1 to 3 N atoms and optionally substituted by at least one substituent selected from a halogen, C1alkyl or C1 alkoxy; or a tetrahydropyranyl group.

5. A compound ing to claim 1 or 4 where R2 is selected from: Rc Rc Rc Rc Rc N where Rc represents a hydrogen, n, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl. 5

6. A compound according to claim 1 where R1 is selected from: m m m N N Ra Ra N m m n Rb Ra R2 is ed from: Rc Rc Rc Rc Rc N where Ra represents a hydrogen, a halogen, C1-3 alkyl, C1-3 -alkoxy or C1-3 haloalkyl, Rb represents a hydrogen or a halogen, Rc represents a hydrogen, halogen, C1-3 5 alkyl, C1-3 alkoxy, C1-3 haloalkyl and m and n are as d in claim 1

7. A compound according to claim 1 selected from the group consisting of: • (5aR,8aR)(2-fluorophenyl)(pyridinylmethyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aRS,8aRS)(2-fluorophenyl)(pyridinylmethyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aRS,8aRS)(2-fluorophenyl)(pyridinylmethyl)-4,5a,6,7,8,8a- 15 dropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aS,8aS)(4-fluorophenyl)(tetrahydro-2H-pyranyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aR,8aR)(4-fluorophenyl)(tetrahydro-2H-pyranyl)-4,5a,6,7,8,8a- 5 hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aS,8aS)(2-fluorophenyl)(tetrahydro-2H-pyranyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 10 • aR)(2-fluorophenyl)(tetrahydro-2H-pyranyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hloride • (5aS,8aS)(6-methoxypyridinyl)(tetrahydro-2H-pyranyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aS,8aS)(2-fluorophenyl)((tetrahydro-2H-pyranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hloride • (5aR,8aR)(2-fluorophenyl)((tetrahydro-2H-pyranyl)methyl)- 20 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aR,8aR)(2-fluorophenyl)((6-fluoropyridinyl)methyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 25 • (5aR,8aR)(2-fluorophenyl)((6-methoxypyridinyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aS,8aS)(2-fluorophenyl)((6-methoxypyridinyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aR,8aR)(2-fluorophenyl)((6-(trifluoromethyl)pyridinyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aS,8aS)(2-fluorophenyl)(((R)-tetrahydrofuranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hloride • (5aR,8aR)(2-fluorophenyl)(((S)-tetrahydrofuranyl)methyl)- 5 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • aS)(2-fluorophenyl)(((S)-tetrahydrofuranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 10 • (5aR,8aR)(2-fluorophenyl)(((R)-tetrahydrofuranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aR,8aR)((6-ethoxypyridinyl)methyl)(2-fluorophenyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aS,8aS)((6-ethoxypyridinyl)methyl)(2-fluorophenyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aRS,8aRS)(4-fluorophenyl)(furanylmethyl)-4,5a,6,7,8,8a- 20 hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aS,8aS)(2,4-difluorophenyl)((2,5-dimethylfuranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 25 • (5aR,8aR)(2,4-difluorophenyl)((2,5-dimethylfuranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aR,8aR)(4-fluorobenzyl)(pyridinyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aS,8aS)(4-fluorobenzyl)(pyridinyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aRS,8aRS)(4-fluorobenzyl)(pyridinyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hloride • (5aS,8aS)(2,4-difluorophenyl)(tetrahydro-2H-pyranyl)-4,5a,6,7,8,8a- 5 hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aR,8aR)(2,4-difluorophenyl)(tetrahydro-2H-pyranyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 10 • (5aR,8aR)(4-fluorobenzyl)(3-fluoropyridinyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aS,8aS)(5-fluoropyridinyl)(tetrahydro-2H-pyranyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aS,8aS)(pyridinyl)(tetrahydro-2H-pyranyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aR,8aR)benzyl(pyridinyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4- 20 b][1,2,3]triazolo[1,5-d][1,4]oxazine hloride • (5aS,8aS)benzyl(pyridinyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4- b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 25 • (5aS,8aS)(4-fluorobenzyl)(pyridinyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aR,8aR)(4-fluorobenzyl)(pyridinyl)-4,5a,6,7,8,8ahexahydropyrrolo ][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aR,8aR)(4-fluorobenzyl)(3-fluoropyridinyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aS,8aS)(4-fluorobenzyl)(3-fluoropyridinyl)-4,5a,6,7,8,8ahexahydropyrrolo ][1,2,3]triazolo[1,5-d][1,4]oxazine hloride • (5aS,8aS)(2-chlorofluorophenyl)(tetrahydro-2H-pyranyl)- 5 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aR,8aR)(2-chlorofluorophenyl)((6-fluoropyridinyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 10 • (5aR,8aR)(2,4-difluorophenyl)(2-(tetrahydro-2H-pyranyl)ethyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • aS)(2,4-difluorophenyl)(2-(tetrahydro-2H-pyranyl)ethyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aR,8aR)(2-chlorofluorophenyl)((tetrahydro-2H-pyranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aS,8aS)(2-chlorofluorophenyl)((tetrahydro-2H-pyranyl)methyl)- 20 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aR,8aR)(2,4-dichlorophenyl)((tetrahydro-2H-pyranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 25 • (5aS,8aS)(2,4-dichlorophenyl)((tetrahydro-2H-pyranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aS,8aS)(2,4-dichlorophenyl)(tetrahydro-2H-pyranyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aR,8aR)(2-chlorofluorophenyl)(2-(tetrahydro-2H-pyranyl)ethyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aS,8aS)(2-chlorofluorophenyl)(2-(tetrahydro-2H-pyranyl)ethyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aR,8aR)(2-chlorofluorophenyl)((6-methoxypyridinyl)methyl)- 5 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aS,8aS)(2-chlorofluorophenyl)((6-methoxypyridinyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hloride 10 • (5aR,8aR)(2,4-difluorophenyl)((6-methoxypyridinyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aS,8aS)(2,4-difluorophenyl)((6-methoxypyridinyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aS,8aS)(2,4-dichlorophenyl)(2-(tetrahydro-2H-pyranyl)ethyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • aR)(2,4-dichlorophenyl)(2-(tetrahydro-2H-pyranyl)ethyl)- 20 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aS,8aS)(2-chloro(trifluoromethyl)phenyl)(tetrahydro-2H-pyran yl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aS,8aS)(2,4-dichlorophenyl)(((S)-tetrahydrofuranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • aR)(2,4-dichlorophenyl)(((R)-tetrahydrofuranyl)methyl)- 30 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aS,8aS)(2,4-dichlorophenyl)(((R)-tetrahydrofuranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aR,8aR)(2,4-dichlorophenyl)(((S)-tetrahydrofuranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aR,8aR)(2,4-difluorophenyl)((2-methylfuranyl)methyl)- 5 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aS,8aS)(2,4-difluorophenyl)((2-methylfuranyl)methyl)- 4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride 10 • (5aS,8aS)(2,4-difluorophenyl)(furanylmethyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hloride • (5aR,8aR)(2,4-difluorophenyl)(furanylmethyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aR,8aR)(4-fluorobenzyl)(tetrahydro-2H-pyranyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • aS)(4-fluorobenzyl)(tetrahydro-2H-pyranyl)-4,5a,6,7,8,8a- 20 hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride • (5aR,8aR)(4-fluorobenzyl)(1-methyl-1H-pyrazolyl)-4,5a,6,7,8,8ahexahydropyrrolo [3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hloride

8. Use of the compound according to any one of claims 1 to 7, in the manufacture of a medicament for the treatment or prophylaxis of a sigma receptor mediated disease or condition. 30

9. The use according to claim 8, wherein the disease is pain, especially neuropathic pain, inflammatory pain or other pain ions involving allodynia and/or hyperalgesia.

10. The use according to claim 8, wherein the disease or condition is diarrhea, lipoprotein disorders, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, obesity, migraine, tis, hypertension, arrhythmia, ulcer, ma, learning, memory and attention deficits, ion disorders, neurodegenerative diseases, 5 demyelinating diseases, addiction to drugs and chemical substances including cocaine, amphetamine, ethanol and nicotine; tardive diskinesia, ischemic stroke, epilepsy, stroke, , cancer, psychotic ions, in particular depression, anxiety or schizophrenia; inflammation or autoimmune diseases.

11. Process for the preparation of a compound of general formula (Ia): R1' N R2 N N (Ia) comprising the reaction between a compound of general formula (VI): N R2 (VI) with an aldehyde of general formula (VII): (VII) where R2 is as defined in claim 1 and R1’ is selected from is selected from: - a -(C(R3)2)m-aryl group in which the aryl group may be optionally substituted by at least one halogen atom; 5 - a -(C(R3)2)m-heteroaryl group in which the heteroaryl group may be optionally substituted by at least one substituent selected from a n, C1alkyl, C1- xy, C1haloalkoxy or C1haloalkyland in which the heteroaryl group may optionally be condensed with an additional ring ; - a -(C(R3)2)n-heterocycloalkyl group, in which the heterocycloalkyl group may 10 be optionally substituted by at least one substituent selected from a halogen, C1alkyl, C1alkoxy, C1haloalkoxy or C1haloalkyl and contains at least one oxygen atom; being R3 is H or C1-3 alkyl; m is 1 to 2; and 15 n is 0 to 2; with the proviso that when R1 is a -(C(R3)2)m-aryl group, R2 is not a phenyl group.

12. Process for the preparation of a compound of general formula (Ia): R1' N R2 N N (Ia) comprising the reduction of a compound of general formula (IX): O O R1' N R2 (IX) where R2 is as d in claim 1 and R1’ is selected from is selected from: - a -(C(R3)2)m-aryl group in which the aryl group may be optionally substituted by at least one halogen atom; - a -(C(R3)2)m-heteroaryl group in which the heteroaryl group may be optionally 5 substituted by at least one substituent selected from a halogen, C1alkyl, C1- 3-alkoxy, aloalkoxy or C1haloalkyland in which the heteroaryl group may optionally be condensed with an additional ring system; - a -(C(R3)2)n-heterocycloalkyl group, in which the cycloalkyl group may be optionally substituted by at least one substituent selected from a halogen, 10 C1alkyl, C1alkoxy, C1haloalkoxy or C1haloalkyl and contains at least one oxygen atom; being R3 is H or C1-3 alkyl; m is 1 to 2; and n is 0 to 2; 15 with the proviso that when R1 is a -(C(R3)2)m-aryl group, R2 is not a phenyl group.

13. s for the ation of a compound of general formula (I): R1 N N R2 N N 25 (I) comprising the reaction between a compound of general formula (VI): N R2 (VI) with an ketone of general formula (VIIa): O R1 (VIIa) where R1 represents a -(C(R3)2)n-heterocycloalkyl group, in which the heterocycloalkyl group may be optionally substituted by at least one substituent selected from a 5 halogen, C1alkyl, C1alkoxy, C1haloalkoxy or aloalkyl and contains at least one oxygen atom, and n=0.

14. A pharmaceutical composition which comprises at least one compound as defined 10 in any one of claims 1-7 or a ceutically acceptable salt or solvate thereof, and at least a pharmaceutically acceptable carrier, additive, adjuvant or vehicle.