MXPA06009018A - Fused hetrocyclic compounds and their use as metabotropic receptor antagonists for the treatment of gastrointestinal disorders - Google Patents

Abstract

The present invention is directed to compounds of formula:(I);wherein X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, R1, R2, R3, R4, and n are as defined for formula I in the description. The invention also relates to processes for the preparation of the compounds and to new intermediates employed in the preparation, pharmaceutical compositions containing the compounds, and to the use of the compounds for treating gastrointestinal disorders.

Description

FUSED HETEROCYCLIC COMPOUNDS AND THEIR USE AS ANTAGONISTS OF THE METABOTROPIC RECEIVER FOR THE TREATMENT OF GASTROINTESTINAL DISORDERS Background of the Invention The present invention relates to a new class of heterocyclic compounds, with pharmaceutical compositions containing the compounds and with the use of the compounds in therapies related to conditions mediated by the metabotropic glutamate receptor. The present invention also relates to processes for preparing the compounds and to new intermediates used in the preparation thereof. Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS) of mammals. Glutamate exerts its effect on neurons of the central nervous system by binding, and consequent activation of cell surface receptors. These receptors have been divided into two large classes, the ionotropic and metabotropic glutamate receptors, based on the structural characteristics of the receptor proteins, by means of which the receptors transduce signals into the cell, and of pharmacological profiles. Metabotropic glutamate receptors (mGIuRs) are G protein-coupled receptors that activate numerous intracellular secondary messenger systems after glutamate binding. The activation of mGluRs in intact mammalian neurons generates one or more of the following responses: activation of phospholipase C; Increases in the hydrolysis of phosphoinositol (Pl); release of intracellular calcium; activation of phospholipase D; activation or inhibition of adenyl cyclase; increases or decreases in the formation of cyclic adenosine monophosphate (cAMP); activation of guanylyl cyclase; increases in the formation of cyclic guanosine monophosphate (cGMP); activation of phospholipase A2; Increases in the release of arachidonic acid; and increases or decreases in the activity of ion channels activated by voltage and ligands. Schoepp I went to. , Trends Pharmacol. Sci. 14:13 (1993), Schoepp, Neurochem. Int. 24: 439 (1994), Pin et al. , Neuropharmacology 34: 1 (1995), Bordi and Ugolini, Prog. Neurobiol. 59: 55 (1999). Eight different mGluR subtypes, named mGluRl to mGluRd, have been identified by molecular cloning. Nakanishi, Neuron 13: 1031 (1994), Pin et al. , Neuropharmacology 34: 1 (1995), Knopfei ei al. , J. Med. Chem. 38: 1417 (1995). Additional diversity of receptors is produced by the expression of forms with alternative processing of certain subtypes of mGluR. Pin et al., PNAS 89: 10331 (1992), Minakami et al., BBRC 199: 1 136 (1994), Joly et al. , J. Neurosci. 15: 3970 (1995). The metabotropic subtypes of the glutamate receptor can be subdivided into three groups, Group I, Group II and Group 11, based on amino acid sequence homology, in the secondary messenger systems used by the receptors, and in their characteristics pharmacological The mGluR of Group I comprise mGluRl, mGluR5 and alternative processing variants. The binding of agonists to these receptors results in the activation of phospholipase C and the subsequent mobilization of intracellular calcium. Neurological, psychiatric and pain disorders. Attempts to elucidate the physiological functions of Group I mGluRs suggest that activation of these receptors causes neuronal excitation. Several studies have shown that agonists of Group I mGluRs can provoke postsynaptic excitation after their action on neurons of the hippocampus, cerebral cortex, cerebellum and thalamus, as well as other regions of the CNS. The evidence indicates that this excitation is due to a direct activation of the postsynaptic mGluRs, but an activation of the presynaptic mGluRs has also been suggested, which results in a greater release of the neurotransmitter. Baskys, Trends Pharmacol. Sci. 1: 92 (1992), Schoepp, Neurochem. Int. 24: 439 (1994), Pin et al. , Neuropharmacology 34: 1 (1995), Watkins et al. , Trends Pharmacol. Sci. 15: 33 (1994). Metabotropic glutamate receptors have been linked to numerous normal processes in the mammalian CNS. It has been shown that the activation of mGluR is necessary during the induction of long-term potentiation of the hippocampus and long-term depression of the cerebellum. Bashir et al, Nature 363: 347 (1993), Bortolotto et al., Nature 368: 740 (1994), Aiba et al. , Cell 79: 365 (1 994), Aiba et al., Cell 79: 377 (1 994). Some compromise has also been shown during the activation of mGluR in nociception and analgesia. Meller went to. , Neuroreport 4: 879 (1993), Bordi and Ugolini, Brain Res. 871: 223 (1999). Furthermore, it has been suggested that the activation of mGluR fulfills a modulating function in many other normal processes, including synaptic transmission, neuronal development, apoptotic neuronal death, synaptic plasticity, spatial learning, olfactory memory, central control of cardiac activity, awakening, motor control and control of the vestibulo-ocular reflex. Nakanishi, Neuron 73: 1 031 (1994), Pin ei al. , Neuropharmacology 34: 1, Knopfel et al. , J. Med. Chem. 38: 1417 (1995).

In addition, it has been suggested that particularly the metabotropic glutamate receptors of Group I perform functions in diverse acute and chronic pathophysiological processes, and in disorders that affect the CNS. These include stroke, cephalic trauma, anoxic and ischemic lesions, hypoglycemia, epilepsy, neurodegenerative disorders such as Alzheimer's disease, psychiatric disorders and pain. Schoepp I went to. , Trends Pharmacol. Sci. 14:13 (1993), Cunningham went to. , Life Sci.54: 135 (1994), Hollman et al. , Ann.

Rev. Neurosci. 17:31 (1994), Pin et al. , Neuropharmacology 34: 1 (1995), Knopfel eí al. , J. Med. Chem. 38: 1417 (1995), Spooren et al. , Trends Pharmacol. Sci. 22: 331 (2001), Gasparini et al. Curr. Opin. Pharmacol. 2:43 (2002), Neugebauer Pain 98: 1 (2002). 54: 135 (1994), Hollman et al. , Ann. Rev. Neurosci. 17:31 (1994), Pin eí al. , Neuropharmacology 34: 1 (1995), Knopfel et al. , J. Med. Chem. 38: 1417 (1995), Spooren et al., Trends Pharmacol. Sci. 22: 331 (2001), Gasparini et al. Curr. Opin. Pharmacol. 2:43 (2002), Neugebauer Pain 98: 1 (2002). Much of the pathology under these conditions is thought to be due to the excessive excitation induced by glutamate from the neurons in the CSN. Given that Group I mGluR seem to increase neuronal excitation mediated by glutamate through postsynaptic mechanisms and greater presynaptic release of glutamate, its activation probably contributes to the pathology. Accordingly, selective antagonists of Group I mGluR receptors could be used for therapeutic purposes in conditions characterized by excessive glutamate-induced excitation of CNS neurons, specifically as neuroprotective, analgesic or anticonvulsant agents. Recent advances in the elucidation of the neurophysiological functions of metabotropic glutamate receptors in general and of Group I in particular, have established these receptors as promising targets of drugs in the therapies of acute and chronic neurological and psychiatric disorders, and acute and chronic disorders. chronic pain Gastrointestinal disorders The lower esophageal sphincter (LES) is prone to relax intermittently. As a result, stomach fluids can enter the esophagus because the mechanical barrier does not work at those times, this condition is called "reflux." Gastrointestinal reflux disorder (GERD) is the most common upper gastrointestinal tract disease. The pharmacological treatments try to reduce acid gastric secretion or to neutralize the acid in the esophagus. It is considered that the main underlying mechanism of reflux depends on a hypotonic lower esophageal sphincter. However, for example Holloway &; Dent (1990) Gastroenterol. Clin. N. Amer. 19, pp. 517-535, have shown that episodes of reflux occur during periods of relaxation of the lower esophageal sphincter (TLESR), that is, relaxation that does not occur by swallowing. It has also been shown that gastric acid secretion is usually normal in a patient with GERD. It is assumed that the novel compounds according to the present invention are useful for inting transient relaxation of the lower esophageal sphincter (TLESR) and, consequently, for treating gastroesophageal reflux disorder (GERD). The expression transient relaxation of the lower esophageal sphincter ("TLESR") is defined herein in accordance with Mittal, R.K., Holloway, R.H., Penagini, R., Blackshaw, L.A. , Dent, J., 1995; Transient lower esophageal sphincter relaxation. Gastroenterology 1 09, pages. 601 -610. The term "reflux" is defined herein as the fluid from the stomach that can pass into the esophagus because, at those times, the mechanical barrier is temporarily lost. The term gastroesophageal reflux disorder ("GERD") is defined herein according to van Heerwarden, M.A., Smout A.J.P.M., 2000; Diagnosis of reflux disease. Bailliére's Clin. Gastroenterol. 14, pp. 759-774. Due to its physiological and physiopathological significance, there remains a need for new potent agonists and antagonists of mGluR with high selectivity for mGluR subtypes, in particular the receptor subtypes belonging to Group I.

Summary of the Invention The present invention relates to compounds of the formula In Formula I, X1, X2, X3, X4, and X5 are independently selected from the group consisting of C, CR5, N, O, and S, wherein at least one of X1, X2, X3, X4, and X5 is not N; X6 is selected from the group consisting of a bond and CR5R6; X7 is CR5 or N; X8 is selected from the group consisting of a bond, CR5R6, NR5, O, S, SO, and SO2; X9 is CR5 or N; and X10 is selected from the group consisting of a bond, CR5R6, (CR5R6) 2, O, S, and NR5. R1 is selected from the group consisting of hydroxy, halo, nitro, C- |. 6alkylhalo, OC1-6alkylhalo, C -6alkyl, OC1-6alkyl, C2-6alkenyl, OC2-6alkenyl, C2-Balkynyl, OC2-6alkynyl, C0-6alkylC3-6cycloalkyl, OC0-6alkylC3-6cycloalkyl, C0-6alkylaryl, OC0-6alkylaryl, CHO, (CO) R5, O (CO) R5, O (CO) OR5, O (CN) OR5, C1 -6alquiiOR5, OC2-6alkylOR5, C- ,. 6alkyl (CO) R5, OC1 -6alkyl (CO) R5, C0-6alkylCO2R5, OC1 -6alkylCO2R5, C0. 6alkylene, OC2-6alkylcyano, Co-6alkylNR5R6, OC2-6alkylNR5R6, d_6alkyl (CO) NR5R6, OC1 -6alkyl (CO) NR5R6, C0-6alkylNR5 (CO) R6, OC2. 6alkylNR5 (CO) R6, C0-6alkylNR5 (CO) NR5R6, Co-ealkylSR5, OC2. 6alkylSR5, C0-6alkyl (SO) R5, OC2-6alkyl (SO) R5, C0-6aiquilSO2R5, OC2. 6alkylSO2R5, Co-6alkyl (SO2) NR5R6, OC2-6alkyl (SO2) NR5R6, C0-6alkylNR5 (SO2) R6, OC2-6alkylNR5 (SO2) R6, C0-6alkylNR5 (SO2) NR5R6, OC2,6alkylNR5 (SO2) NR5R6, (CO) NR5R6, O (CO) NR5R6, NR5OR6, C0-6alkylNR5 (CO) OR6, OC2-6alkylNR5 (CO) OR6, SO3R5 and a 5- or 6-membered ring containing atoms selected independently from the group consists of C, N, O and S, wherein the ring can be substituted with one or more A, as defined below. R 2 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C 1 -6alkylhalo, OC 1 - 6alkylhalo, C 1-6alkyl, OC 1 --6alkyl, C 2 - 6alkenyl, OC 2 - 6alkenyl, C 2-6alkynyl, OC 2 - 6alkynyl, Co - 6alkylC3. eccycloalkyl, OC0-6alkylC3-6cycloalkyl, C0-6alkylaryl, OCo-6alkylaryl, CHO, (CO) R5, O (CO) R5, O (CO) OR5, O (CN) OR5, C1-6alkylOR5, OC2-6alkylOR5 , C1-6alkyl (CO) R5, OC1 -6alkyl (CO) R5, Co-6alkylCO2R5, 00 ,. 6alkylCO2R5, C0-6alkylcarbon, OC2.6alkylcyano, C0-6alkylNR5R6, OC2-6alkylNR5R6, C1.6alkyl (CO) NR5R6, OC1 -6alkyl (CO) NR5R6, C0- 6alkINR5 (CO) R6, OC2-6alkylNR5 (CO) R6, C0-6alkylNR5 (CO) NR5R6, C0-6alkylSR5, OC2-6alkylSR5, Co-6alkyl (SO) R5, OC2-6alkyl (SO) R5, C0. 6alkylSO2R5, OC2-6alkylSO2R5, C0-6alkyl (SO2) NR5R6, OC2- 6alkyl (SO2) NR5R6, C0-6alkylNR5 (SO2) R6, OC2-6alkylNR5 (SO2) R6, C0-6alkyNR5 (SO2) NR5R6, OC2-6alkyNR5 (SO2) NR5R6, (CO) NR5R6, O (CO) NR5R6, NR5OR6, C0-6alkylNR5 (CO) OR6, OC2-6alkylNR5 (CO) OR6, SO3R5 and a 5- or 6-membered ring containing atoms selected independently from the group consisting of C, N, O and S, wherein the ring can be substituted with one or more A. R3 is a 5- or 6-membered ring containing atoms selected independently from the group consisting of C, N, O, and S, wherein the ring can be substituted with one or more A. R4 is selected from the group consisting of hydroxy, halo, nitro, C- ,. 6alkylhalo, OC1 -6alkylhalo, C1 -6alkyl, OC1 -6alkyl, C2-6alkenyl, OC2_6aiquenyl, C2-6alkynyl, OC2-6alkynyl, C0-6alkylC3-6cycloalkyl, OC0- 6aIquilC3-6CÍcloalquilo, C0-6alquilarilo, OCo-6alquilarilo, CHO, (CO) R5, O (CO) R5, O (CO) OR5, O (CN) OR5, C1 -6alquilOR5, OC2-6alquilOR5, C 6alquil (CO) R5, OC1 -6alquil (CO) R5, C0-6alquilCO2R5, OC1.6alquilC02R5, C0 6alquilciano, OC2-6alquilciano, C0.6alquilNR5R6, OC2-6alquilNR5R6, C ^ 6alquil (CO) NR5R6, OC1.6alquil (CO) NR5R6, Co-6alkylNR5 (CO) R6, OC2- 6alkylNR5 (CO) R6, C0-6alkylNR5 (CO) NR5R6, Co-6alkylISR5, OC2. 6alquilSR5, C0-6alquil (SO) R5, OC2-6alquil (SO) R5, C0-6alquilSO2R5, OC2- 6alquilSO2R5, C0-6alquil (SO2) NR5R6, OC2.6alquil (SO2) NR5R6, C0 6alquilNR5 (SO2) R6, OC2.6alquilNR5 (SO2) R6, C0-6alquilNR5 (SO2) NR5R6, OC2-6alquilNR5 (SO2) NR5R6, (CO) NR5R6, O (CO) NR5R6, NR5OR6, C0 6alkylNR5 (CO) OR6, OC2.6alkylNR5 (CO) OR6, SO3R5 and a 5- or 6-membered ring containing atoms selected independently from the group consisting of C, N, O and S, wherein the ring can be substituted with one or more A. R5 and R6 are independently selected from the group consisting of hydrogen, C6-6alkyl, C3-7cycloalkyl and aryl. A is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C1-6alkylhalo, OC1 -6alkylhalo, C1 -6alkyl, OC1 -6alkyl, C2-6alkenyl, OC2-6alkenyl, C2.6alkynyl, OC2-6alkynyl, C0- 6alkylC3- eccycloalkyl, OCo-6alkylC3-6cycloalkyl, Coalkyl-6alkylaryl, OCo-ealkylaryl, CHO, (CO) R5, O (CO) R5, O (CO) OR5, O (CN) OR5, C1-6alkylOR5, OC2- 6alkylOR5, C? -6alkyl (CO) R5, OC1 -6alkyl (CO) R5, Co-6alkylCO2R5, OC ,. 6alquilCO2R5, C0-6alquilc¡ano, OC2-6alquilciano, Co-6alqu¡INR5R5, OC2- 6alquilNR5R8, C1 -6alquil (CO) NR5R8, OC1 -6alquil (CO) N R5R8, C0 6alquilNR5 (CO) R8, OC2-6alquilNR5 (CO) R8, C0-6alkylNR5 (CO) N R5R8, C0- 6alkISR5, OC2-6alkylSR5, C0-6alkyl (SO) R5, OC2-6alkyl (SO) R5, C0-6alkylSO2R5, OC2-6alkylSO2R5, C0.6alkyl (SO2) NR5R8, OC2- 6alquil (SO2) NR5R8, C0-6alq uilNR5 (SO2) R8, OC2-6alquilNR5 (SO2) R8, C0 6alquilNR5 (SO2) NR5R8, OC2-6alquilNR5 (SO2) NR5R8, (CO) NR5R8, O (CO) NR5R8, NR5OR8, C0-6alkylNR5 (CO) OR8, OC2-6alkylNR5 (CO) OR8, SO3R5 and a 5 or 6 member ring containing atoms selected independently from the group consisting of C, N, O and S. The variable n is 0, 1, 2, 3, or 4. In a further aspect of the invention pharmaceutical compositions are provided comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable diluent, excipient and / or an inert carrier. In yet a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of the formula I for use in the treatment of disorders mediated by the mGluRd receptor, and for use in the treatment of neurological disorders, psychiatric disorders, gastrointestinal disorders and pain disorders. In a further aspect of the invention, the compound of formula I is provided for use in therapy, especially for the treatment of disorders mediated by the mGluR5 receptor, and for the treatment of neurological disorders, psychiatric disorders, gastrointestinal disorders and pain disorders. A further aspect of the invention is the use of a compound according to formula I for the manufacture of a medicament for the treatment or prevention of obesity and disorders related to obesity, as well as the treatment of eating disorders by inhibiting excessive food intake and resulting obesity and the complications associated with it. In another aspect of the invention processes are provided for the preparation of compounds of the formula I and the intermediates used in their preparation. These and other aspects of the present invention are described in greater detail below. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS The object of the present invention is to provide compounds that exhibit activity at metabotropic glutamate receptors (mGluRs), especially at mGluR5 receptors. The following are definitions of various terms used in the description and claims to describe the present invention. For clarity it should be understood that where in this specification a group is qualified with the expression 'previously defined', 'as defined' previously defined 'the group comprises the definition that is presented first and the widest as well as each and every one of the other definitions for the group. For clarity it should be understood that in this description 'd. ß 'means a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. Similarly 'C1 -3' means a carbon group that has 1, 2 or 3 carbon atoms When the subscript is the integer 0 (zero) the group to which the subscript refers indicates that the group is absent. In this specification, unless otherwise indicated, the term "alkyl" includes both straight and branched chain alkyl groups and may be, but is not limited to, methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl or i-hexyl, t-hexyl. The term C -3alkyl has between 1 and 3 carbon atoms and can be methyl, ethyl, n-propyl or i-propyl. In this specification, unless otherwise indicated, the term "cycloalkyl" refers to a saturated, optionally substituted cyclic hydrocarbon ring system. The term "C3-7cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In this specification, unless otherwise indicated, the term "alkoxy" includes both straight or branched chain alkoxy groups, d-salkoxy may be, but is not limited to methoxy, ethoxy, n-propoxy or i-propoxy. In this specification, unless otherwise indicated, the term "link" may be a saturated or unsaturated bond or link. In this specification, unless otherwise indicated, the term "halo" and "halogen" may be fluoro, chloro, bromo or iodo. In this specification, unless otherwise indicated, the term "alkylhalo" means an alkyl group as defined, which is substituted with halo as defined. The term "C1-alkylalkyl" may include, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl or bromopropyl. The term "OCL 6alkylhalo" may include, but is not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy or difluoroethoxy. In this specification, unless otherwise indicated, the term "alkenyl" includes straight-chain and branched alkenyl groups. The term "C2-6alkene" refers to an alkenyl group having from 2 to 6 carbon atoms and one or two double bonds, and may be, but not limited to vinyl, allyl, propenyl, i-propenyl, butenyl, i -butenyl, crotyl, pentenyl, i-pentenyl and hexenyl. In this specification, unless otherwise indicated, the term "alkynyl" includes straight and branched chain alkynyl groups. The term C2-6alkynyl having from 2 to 6 carbon atoms and one or two triple bonds, and may be, but is not limited to ethynyl, propargyl, butynyl, i-butynyl, pentynyl, i-pentynyl and hexynyl. In this specification unless otherwise indicated the term "aryl" refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system containing at least one unsaturated aromatic ring. Examples and suitable values of the term "aryl" are phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indyl and indenyl. In this specification, unless otherwise indicated, the term "heteroaryl" refers to an optionally substituted monocyclic or bicyclic unsaturated ring system containing at least one heteroatom selected independently from N, O, or S.

Examples of "heteroaryl" may be, but are not limited to, thiophene, thienyl, pyridyl, thiazolyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl and thiadiazolyl, benzoimidazolyl, benzooxazolyl , tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, benzofuryl, indolyl, isoindolyl, pyridonyl, pyridazinyl, pyrimidinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, pyridyl, imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl and purinyl. In this specification, unless otherwise indicated, the term "alkylaryl", "alkylheteroaryl" and "alkylcycloalkyl" refers to a substituent that is linked through the alkyl group to an aryl, heteroaryl and cycloalkyl group. In this specification, unless otherwise indicated, the term "heterocycloalkyl" refers to a saturated, optionally substituted, cyclic hydrocarbon ring system wherein one or more of the carbon atoms is replaced with heteroatom. The term "heterocycloalkyl" includes but is not limited to pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran, tetrahydrothiopyran. In this specification, unless otherwise indicated the term "5- or 6-membered ring containing atoms independently selected from C, N, O or S", includes aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings, which they can be partially saturated, saturated or unsaturated. Examples of such rings may be, but are not limited to, furyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, imidazolidinyl, imidazolinyl, triazolyl, morpholinyl, piperazinyl, piperidyl. , piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranoyl, thiomorpholinyl, phenyl, cyclohexyl, cyclopentyl and cyclohexenyl. In this specification, unless otherwise indicated, the term "= NR5" and "= NOR5" include imino and atom groups that have a substituent R5 and may be, or be part of, groups that include, but are not limited to, iminoalkyl, iminohydroxy, iminoalkoxy, amidine, hydroxyamidine and alkoxyamidine. In this case, where the subscript is the integer 0 (zero) the group to which the subscript refers, indicates that the group is absent, that is, there is a direct link between the groups. In this specification unless otherwise indicated the term "fused rings" refers to two rings that share 2 common atoms. In this specification, unless otherwise indicated, the term "bridge" means a molecular fragment, which contains one or more atoms, or a bond, which connects two remote atoms in a ring, thereby forming systems either or tricyclics. One embodiment of the invention relates to the compounds of the formula I and their pharmaceutically acceptable salts and hydrates: In Formula I, X1, X2, X3, X4, and X5 are independently selected from the group consisting of C, CR5, N, O, and S, wherein at least one of X1, X2, X3, X4, and X5 is not N; X6 is selected from the group consisting of a bond and CR5R6; X7 is CR5 or N, preferably N; X8 is selected from the group consisting of a bond, CR5R6, NR5, O, S, SO, and SO2. Preferably, X8 is a bond, CR5R6, NR5, O, or S. X9 is CR5 or N and X10 is selected from the group consisting of a bond, CR5R6, (CR5R6) 2, O, S, and NR5, preferably a bond , CR5R6, (CR5R6) 2, O, or S.R1 is selected from the group consisting of hydroxy, halo, nitro, d. 6alkylhalo, OC1 -6alkylhalo, C1 -6alkyl, OC1 -6alkyl, C2-6alkenyl, OC2-6alkenyl, C2-6alkynyl, OC2-6alkynyl, C0-6alkylC3-6Calkalkyl, OC0-6alkylC3-6cycloalkyl, Coalkylaryl, OC- ßalkylaryl, CHO, (CO) R5, O (CO) R5, O (CO) OR5, O (CN) OR5, C1-6alkylOR5, OC2-6alquiorI5, C6alkyl (CO) R5, OC? -6alkyl (CO ) R5, C0-6alkylCO2R5, OC1 -6alkylCO2R5, C0-6alkylcyano, OC2-6alkylcyano, C0-6alkylNR5R6, OC2-6alkylNR5R6, d. 6alkyl (CO) NR5R6, OC1 -6alkyl (CO) NR5R6, C0-6alkylNR5 (CO) R6, OC2-6alkylNR5 (CO) R6, C0.6alkylNR5 (CO) NR5R6, CoalkylSR5, OC2-6alkylSR5, C0-6alkyl (SO) R5, OC2-6alkyl (SO) R5, C0-6alkylSO2R5, OC2, 6alkylSO2R5, C0-6alkyl (SO2) NR5R6, OC2-6aliquil (SO2) NR5R6, C0-6alkylNR5 (SO2) R6, OC2-6alkylNR5 ( SO2) R6, C0-6alkylNR5 (SO2) NR5R6, OC2-6alkylNR5 (SO2) NR5R6, (CO) NR5R6, O (CO) NR5R6, NR5OR6, Co- 6alkylNR5 (CO) OR6, OC2-6alkylNR5 (CO) OR6, SO3R5 and a 5 or 6 member ring containing atoms selected independently of the group consisting of C, N, O and S, wherein the ring can be substituted with one or more A, as defined below. Preferably, R1 is halo, d-6alkylhalo, C1_6alkyl, OC1 -6alkyl, or Co-βalkylcyano. R 2 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C 1-6alkylhalo, Od.alkylhalo, d-6alkyl, OC.sub.1 -6alkyl, C 2-6alkenyl, OC.sub.2-6alkenyl, C 2-6alkynyl, OC.sub.2-6alkynyl, Co-6alkylC.sub.3- 6-cycloalkyl, OC0-6alkylC3-6cycloalkyl, Co-6alkylaryl, OC0-6alkylaryl, CHO, (CO) R5, O (CO) R5, O (CO) OR5, O (CN) OR5, C1 -6alkylo5, OC2- 6alkylOR5, C1 -6alkyl (CO) R5, OC1-6alkyl (CO) R5, Co-6alkylCO2R5, Od. 6alkylCO2R5, Coalkalkyanoate, OC2.6alkylcyano, C0-6alkylNR5R6, OC2-6alkylNR5R6, C1-6alkyl (CO) NR5R6, OC1-6alkyl (CO) NR5R6, C0- 6alkylNR5 (CO) R6, OC2-6alkylNR5 (CO) R6, C0-6alkylNR5 (CO) NR5R6, C0-6alkylSR5, OC2-6alkylSR5, C0-6alkyl (SO) R5, OC2-6alkyl (SO) R5, C0- 6alkylSO2R5, OC2.6alkylSO2R5, C0-6alkyl (SO2) NR5R6, OC2, 6alkyl (SO2) NR5R6, Co-6alkylNR5 (SO2) R6, OC2-6alkylNR5 (SO2) R6, C0-6alkylNR5 (SO2) NR5R6, OC2-6alkylNR5 (SO2) NR5R6, (CO) NR5R6, O (CO) NR5R6, NR5OR6, C0-6alkylNR5 (CO) OR6, OC2-6alkylNR5 (CO) OR6, SO3R5 and a 5- or 6-membered ring containing atoms selected independently from the group consisting of C, N, O and S, wherein the ring can be substituted with one or more A. Preferably, R2 is hydrogen or halo. R3 is a 5- or 6-membered ring containing atoms selected independently from the group consisting of C, N, O and S, wherein the ring can be substituted with one or more A. Preferably, R3 is a 6-membered ring . R4 is selected from the group consisting of hydroxy, halo, nitro, d. 6alkylhalo, Od.6alkylhalo, d_6alkyl, OC -6alkyl, C2-6alkenyl, OC2-6alkenyl, C2_6alkynyl, OC2-6alkynyl, C0-6alkylC3.6cycloalkyl, OC0- 6alkylC3-6cycloalkyl, C0-6alkylaryl, OCo-ealkylaryl, CHO, (CO) R5, O (CO) R5, O (CO) OR5, O (CN) OR5, C1-6alkylOR5, OC2-6alkylOR5, d. 6alkyl (CO) R5, OC1-6alkyl (CO) R5, Co-6alkylCO2R5, OC1-6alkylCO2R5, C0-6alkylcyano, OC2 -alkylcyano, C0-6alkylNR5R6, OC2.6aIquilNR5R6, d-6alkyl (CO) NR5R6, OC1-6alkyl ( CO) NR5R6, C0-6alkylNR5 (CO) R6, OC2- 6alkine R5 (CO) R6, C0-6alkylNR5 (CO) NR5R6, C0-6alkylSR5, OC2-6alkylSR5, C0-6alkyl (SO) R5, OC2-6alkyl (SO) R5, C0-6alkylSO2R5, OC2. 6alkylSO2R5, Co-6alkyl (SO2) NR5R6, OC2-6alkyl (SO2) NR5R6, C0- 6alkylNR5 (SO2) R6, OC2-ßalkylNR5 (SO2) R6, C0-6alkylNR5 (SO2) NR5R6, OC2-6alkylNR5 (SO2) NR5R6, (CO) NR5R6, O (CO) NR5R6, NR5OR6, C0- 6alkylNR5 (CO) OR6, OC2-6alkyNR5 (CO) OR6, SO3R5 and a 5- or 6-membered ring containing atoms selected independently from the group consisting of C, N, O and S, wherein the ring can be substituted with one or more A.R.sub.4, when it is not hydrogen, is preferably d-β-alkylhalide or d-6alkyl.

R5 and R6 are independently selected from the group consisting of hydrogen, C1-6alkyl, C3-7cycloalkyl and aryl. Preferably, R 5 and R 6 are selected from hydrogen and C 1-6 alkyl. A is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C1-6alk uilhalo, OC1-6alkylhalo, d.6alkyl, OC1 -6alkyl, C2- 6alkenyl, OC2-6alkenyl, C2-6alkynyl, OC2-6alkynyl, C0-6alkylC3- eccycloalkyl, OC0-6alkylC3-6cycloalkyl, Co-ealkylaryl, OCo-ealkylaryl, CHO, (CO) R5, O (CO) R5, O (CO ) OR5, O (CN) OR5, d.6alkylOR5, OC2-6alkylOR5, C1-6alkyl (CO) R5, OC1-6alkyl (CO) R5, Co-6alkylCO2R5, Od. 6alkylCO2R5, Co-ealkylcyano, OC2-6alkylcyano, C0-6alkylNR5R5, OC2, 6alkylNR5R8, d.6alkyl (CO) NR5R8, OC1 -6alkyl (CO) NR5R8, C0-6alkylNR5 (CO) R8, OC2-6alkyN5 (CO) R8, Co-6aliquilNR5 (CO) NR5R8, C0-6alkylSR5, OC2- 6alkylSR5, C0-6alkyl (SO) R5, OC2-6alkyl (SO) R5, C0-6alkylS02R5, OC2-6alkylIS2R5, C0-6alkyl (SO2) NR5R8, OC2-6alkyl (SO2) NR5R8, C0-6alkylNR5 ( SO2) R8, OC2-6alkylNR5 (S02) R8, C0- 6alkylNR5 (S02) NR5R8, OC2-6alkylNR5 (S02) NR5R8, (CO) NR5R8, 0 (CO) NR5R8, NR5OR8, C0-6alkylNR5 (CO) OR8, OC2-6alkylNR5 (CO) OR8, S03R5 and a 5- or 6-membered ring containing atoms selected independently from the group consisting of C, N, O and S. Preferred values for A are hydrogen and halo. The variable n is 0, 1, 2, 3, or 4. Preferably, n is 0, 1, or 2. It is understood that a) when X2 = X4 = X5 = N, and either X8 or X10 is a link , then X9 is not N, b) when X7 is N at least two of X1, X2, X3, X4, and X5 are not N, and c) X1 and X3 are not O. It is also understood that the invention does not comprise the following Compounds: 8- [5- (3-Chloro-phenyl) - [1,4] oxadiazol-3-ylmethyl] -3-pyridine-4-yl-5,6,7,8-tetrahydro- [ 1, 2,4] triazolo [4,3-a] pyridine, 8- [5- (3-chloro-phenyl) - [1, 2,4] oxadiazol-3-ylmethyl] -3-thiophene -2-yl-5,6,7,8-tetrahydro- [1, 2,4] triazolo [4,3-a] pyridine, 8- [5- (5-chloro-2-fluoro-phenyl) - [ 1,4-oxadiazol-3-ymethyl] -3-pyridin-4-yl-5,6,7,8-tetrahydro [1, 2,4] triazolo [4,3-a] pyridine, 8- [ 5- (3-chloro-phenyl) - [1,4-oxadiazol-3-ylmethyl] -3-pyridin-4-yl-5,6,7,8-tetrahydro- [1,2,4] triazolo [4,3-a] pyrimidine, 8- [5- (5-chloro-2-fluoro-phenyl) - [1, 2,4] oxadiazol-3-ylmethyl] -3-pyridine-4-yl-5, 6,7,8-tetrahydro- [1, 2,4] triazolo [4,3-a] pyrimidine, 8- [5- (3-chloro-phenyl) - [1, 3,4] oxa diazol-2-ylmethyl] -3-pyridin-4-yl-5,6,7,8-tetrahydro- [1, 2,4] triazolo [4,3-a] pyrimidine, 8-. { 1 - [5- (3-Chloro-phenyl) - [1,4] oxadiazol-2-yl] -ethyl} -3-pyridin-4-yl-5,6,7,8-tetrahydro- [1, 2,4] triazolo [4,3-a] pyrimidine, 8- [5- (5-chloro-phenyl) - [ 1, 2,4] oxadiazol-3-ylmethyl] -3-furan-2-yl-5,6,7,8-tetrahydro- [1, 2,4] triazolo [4,3-a] pyrimidine, 8- . { 1 - [5- (3-Chloro-phenyl) - [1, 2,4] oxadiazol-3-yl] -ethyl} 3-pyridin-4-yl-5,6,7,8-tetrahydro- [1, 2,4] triazolo [4,3-a] pyrimidine, 3-pyridin-4-yl-8- [1- ( 5-m-tolyl- [1, 2,4] oxadiazol-3-yl) -ethyl] -5,6,7,8-tetrahydro- [1, 2,4] triazolo [4,3-a] pyrimidine, (+) - 8-. { (1 S) -1- [5- (3-chlorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -3-pyridin-4-yl-S.d ^ .d-tetrahydrofl ^^ jtriazolo ^. S-aJpyrimidine, (-) - 8-. { (1 R) -1 - [5- (3-chlorophenyl) -1,4, 2,4-oxadiazol-3-yl] ethyl} -3-pyridin-4-yl-5,6,7,8-tetrahydro [1, 2,4] triazolo [4,3-a] pyrimidine, 3- [5- (3-Pyridin-4-yl) -6,7-dihydro-5H- [1, 2,4] triazolo [4,3-a] pyrimidin-8-ylmethyl) [1, 3, 4] oxadiazol-2-yl] benzonitrile, 3-. { 5- [3- (2-Methoxypyridin-4-yl) -6,7-dihydro-5H- [1, 2,4] triazolo [4 > 3-a] pyrimidin-8-ylmethyl] [1,4] oxadiazol-2-yl} benzonitrile, 3-. { 5- [3- (2-Methoxy-pyridin-4-yl) -6,7-dihydro-5H- [1, 2,4] triazolo [4,3-a] pyrimidin-8-ylmethyl] - [1, 2,4] oxadiazol-3-yl} -benzonitrile, 3-. { 3 - [(3-pyridin-4-yl-6,7-dihydro [1, 2,4] triazolo [4,3-a] pyrimidin-8 (5H) -yl) methyl] -1,2,4-oxadiazoI-5-yl} benzonitrile, 3- (3 { [3- (2-methoxypyridin-4-yl) -6,7-dihydro [1, 2,4] triazolo [4,3-a] pyrimidin-8 (5 / - /) - il] methyl.} -1, 2,4-oxadiazol-5-yl) benzonitrile, 3-. { 5 - [(3-pyridin-4-yl-6,7-dihydro [1, 2,4] triazolo [4,3-a] pyrimidin-8 (5H) -yl) methyl] -1, 2,4- oxadiazol-3-yl} benzonitrile, and 3-. { 5- [3- (2-Hydroxy-pyridin-4-yl) -6,7-dihydro-5H- [1, 2,4] triazolo [4,3-a] pyrimidin-8-ylmethyl] - [1, 2,4] oxadiazol-3-yl} -benzo nitrile. A subset of preferred compounds corresponds to formula II: In Formula II, the structural variables have the values defined in formula I. In this context, X7 is preferably N. Another subset of preferred compounds corresponds to formula III: In Formula III, the structural variables have the values defined in the formula I. Preferably, X3 is C or N. In other embodiments of the invention, the ring containing X1, X2, X3, X4, and X5 is selected from the group consisting of: Preferably, the ring is any of: In these embodiments, X7 is preferably N, while X8 is preferably a bond. In a subset of compounds, X9 is CR5, and X10 is NR5, O, CR5R6, or (CR5R6) 2. In another subset of compounds, X8 is preferably S. In this context, X9 is preferably CR5, while X10 is a bond. In other embodiments, X9 is N. In still other embodiments of the invention, the fused ring containing X7, X8, X9, and X10 is selected from the group consisting of: Some other embodiments of the invention are represented by the following compounds exemplified: 7- [5- (5-chloro-2-fluorophenyl) -1, 2,4-oxadiazol-3-yl] -3- (2-thienyl) -6,7-dihydro-5H- [1, 2 , 4] triazolo [3,4-b] [1, 3] thiazine, 9-. { [5- (3-chlorophenyl) -1,4,4-oxadiazol-3-yl] methyl} 3-pyridin-4-yl-6,7,8,9-tetrahydro-5H- [1, 2,4] triazolo [4,3-a] [1, 3] diazepine, 9-. { 1 - [5- (3-chlorophenyl) -1,4,4-oxadiazol-3-yl] ethyl} 3-pyridin-4-yl-6,7,8,9-tetrahydro-5H- [1, 2,4] triazolo [4,3-a] [1, 3] diazepine, 7-. { [5- (3-chlorophenyl) -1,4,4-oxadiazol-3-yl] methyl} 3-pyridin-4-yl-6,7-dihydro-5H-pyrrolo [2,1-c] [1, 2,4] triazole, 9-. { [5- (3-chlorophenyl) -1,4,4-oxadiazol-3-yl] methyl} -3- (trifiuoromethyl) -6,7,8,9-tetrahydro-5H- [1, 2,4] triazolo [4,3-a] [1,3] diazepine, 8- [3- (3-chloro phenyl) - [1,4-oxadiazol-5-yl] -3- (4-methoxy-phenyl) -5,6,7,8-tetrahydro- [1,4] triazolo [4.3 -a] pyrazine, 8- [3- (3-chloro-phenyl) - [1, 2,4] oxadiazol-5-yl] -3- (4-methoxy-phenyl) -7-m ethyl-5,6 , 7,8-tetrahydro- [1, 2,4] triazolo [4,3-a] pyrazine, 9-. { [5- (3-chlorophenyl) isoxazol-3-yl] methyl} -3- (3,5-difluorophenyl) -6,7,8,9-tetrahydro-5H- [1, 2,4] triazolo [4,3-a] [1,3] diazepine, 9-. { [5- (3-chlorophenyl) isoxazol-3-yl] methyl} -3- (4-methoxyphenyl) -6,7,8,9-tetrahydro-5H- [1, 2,4] triazolo [4,3-a] [1,3] diazepine, 9-. { [5- (3-chlorophenyl) isoxazol-3-yl] methyl} 3-pyridin-4-yl-6,7,8,9-tetrahydro-5H- [1, 2,4] triazolo [4,3-a] [1, 3] diazepine, 9-. { [5- (5-chloro-2-fluorophenyl) -1,2,4-oxadiazol-3-yl] methyl} 3-pyridin-4-yl-6,7,8,9-tetrahydro-5H- [1, 2,4] triazolo [4,3-a] [1, 3] diazepine, 9-. { [5- (3-chlorophenyl) -1,4,4-oxadiazol-3-yl] methyl} -3- (3,5-difluorophenyl) -6,7,8,9-tetrahydro-5H- [1, 2,4] triazolo [4,3-a] [1, 3] diazepine, and 9-. { [5- (3-chlorophenyl) -1,4,4-oxadiazol-3-yl] methyl} -3- (4-methoxyphenyl) -6,7,8,9-tetrahydro-5H- [1, 2,4] triazoIo [4,3-a] [1, 3] diazepine and its pharmaceutically acceptable salts. The embodiments of the invention include salt forms of the compounds of Formula I. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula I. A pharmaceutically acceptable salt of the compounds of the invention is, for example, an acid addition salt, for example an inorganic or organic acid. In addition, a pharmaceutically acceptable salt of the compounds of the invention is an alkali metal salt, an alkaline earth metal salt, a salt with an organic base. Other salts and pharmaceutically acceptable methods for preparing these salts can be found in, for example, Remington's Pharmaceutical Sciences (18th Edition, Mack Publishing Co.) 1990. Some compounds of the formula I can have chiral centers and / or isomeric geometric centers (E- and Z-isomers), and it should be understood that the invention comprises all optical, diastereomeric and geometric isomers. The invention also relates to any and all tautomeric forms of the compounds of the formula I. The invention also relates to hydrate and solvate forms of the compounds of the formula I. Pharmaceutical Composition According to one aspect of the present invention there is provided a pharmaceutical composition comprising as an active ingredient an effective amount for therapeutic use of a compound of formula I or salts, solvates or salts thereof, in association with one or more inert pharmaceutically acceptable diluents, excipients and / or vehicles. The composition may be a suitable form for oral administration, for example as tablets, pills, syrups, powders, granules or capsules, for parenteral injections (including intravenous, subcutaneous, intramuscular, intravascular or infusion), as a solution, suspension or sterile emulsion, for topical administration as an ointment, patch or cream or for a rectal administration as a suppository. In general, the above compositions can be prepared in a conventional manner using one or more excipients, diluents and / or inert carriers acceptable in pharmaceutical terms. Suitable daily doses of the compounds of the formula I in the treatment of a mammal, including man, comprise approximately between 0.01 and 250 mg / kg of body weight for peroral administration and approximately between 0.001 and 250 mg / kg of body weight. body weight for parenteral administration. The typical daily dose of the active ingredients varies over a wide range and will depend on various factors, such as, for example, the particular indication, the severity of the disease to be treated, the route of administration, the age, weight and sex of the patient and the specific compound that will be used, and will be determined by the doctor.

Medical use It has been found that the compounds according to the present invention have a higher degree of potency and selectivity for the individual subtypes of the metabotropic glutamate receptors (mGluR). Accordingly, the compounds of the present invention are expected to be useful for the treatment of conditions associated with the excitatory activation of mGluRd and for the inhibition of neuronal damage caused by an excitatory activation of a mGluRd. The compounds can be used to produce an inhibitory effect on mGluRd in mammals, including man. The mGluR receptor of Group I, which include mGluRd, has a high expression in the central and peripheral nervous system and in other tissues. Accordingly, the compounds of the invention are expected to be suitable for the treatment of disorders mediated by the mGluRd receptor, such as for example acute and chronic neurological and psychiatric disorders, gastrointestinal disorders and acute and chronic pain disorders.

The invention relates to compounds of Formula I, as defined, for use in therapy. The invention relates to compounds of Formula I, as defined, for use in the treatment of disorders mediated by mGluRd. The invention relates to compounds of Formula I, as defined, for use in the treatment of Alzheimer's disease, dementia, dementia, AIDS-induced dementia, Parkinson's disease, amylotropic lateral sclerosis, Huntington's disease, migraine, epilepsy, schizophrenia, depression, anxiety, acute anxiety, ophthalmological disorders such as retinopathies, diabetic retinopathies, glaucoma, neuropathic auditory disorders, such as, for example, tinnitus, neuropathies induced by chemotherapy, postherpetic neuralgia and trigeminal neuralgia, tolerance, dependence, fragility of the X chromosome, autism, mental retardation, schizophrenia and Down Syndrome. The invention relates to compounds of formula I, as defined, for use in the treatment of migraine-related pain, inflammatory pain, neuropathic pain disorders such as diabetic neuropathies, arthritis and rheumatoid diseases, back pain, pain postoperative and pain associated with various conditions including angina, renal or biliary colic, menstruation, migraine and gout. The invention relates to compounds of Formula I as defined, for use in the treatment of cerebrovascular accidents, head trauma, anoxic and ischemic lesions, hypoglycaemia, cardiovascular diseases and epilepsy. A further aspect of the invention is the use of a compound according to formula I for the manufacture of a medicament for the treatment or prevention of obesity and disorders related to obesity, as well as the treatment of eating disorders by inhibiting excessive food intake and resulting obesity and the complications associated with it. The present invention also relates to the use of a compound of the formula I, as defined, in the manufacture of a medicament for the treatment of disorders mediated by the mGluR receptor of Group I and any of the above-mentioned disorders. One embodiment of the invention relates to the use of a compound according to Formula I for the treatment of gastrointestinal disorders. Another embodiment of the invention relates to the use of a compound according to Formula I for the preparation of a medicament for inhibiting transient relaxation of the lower esophageal sphincter, for the treatment of GERD, for the prevention of GI reflux, for the treatment of regurgitation, asthma, laryngitis, lung diseases and for management when it is impossible to achieve it. Yet another embodiment of the invention relates to the use of a compound according to Formula I for the preparation of a medicament for the treatment or prevention of disorders of gastrointestinal function., as for example, dyspepsia (FD). Yet another aspect of the invention is the use of a compound according to Formula I for the preparation of a medicament for the treatment or prevention of irritable bowel syndrome (IBS), such as IBS with constipation, I BS with diarrhea or I BS with alternative bowel movement. The invention also provides a method of treating disorders mediated by mGluR5 and any of the aforementioned disorders, in an affected patient, or at risk of contracting said condition, comprising administering to the patient an effective amount of a compound of the formula I , as defined. The dose required for the therapeutic or preventive treatment of a particular disorder necessarily varies according to the host treated, the route of administration and the severity of the disease under treatment. In the context of the present description, the term "therapy" includes treatment as well as prevention, unless expressly indicated otherwise. The terms "therapeutic" and "for therapeutic use" must be interpreted accordingly. In the present specification, unless otherwise indicated, the terms "antagonist" and "inhibitor" mean a compound that in any way partially or completely blocks the transduction path that leads to the production of a response by the ligand. The term "disorder", unless otherwise indicated, means any condition and disease associated with the activity of the metabotropic glutamate receptor.

Non-Medical Use In addition to its use in therapeutic medicine, the compounds of the formula, salts or hydrates thereof, are also useful as pharmacological means in the development and standardization of in vitro and in vivo assay systems during the evaluation of the effects of inhibitors of mGluR-related activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents. Methods of Preparation Another aspect of the present invention provides processes for preparing compounds of the formula I or salts or hydrates thereof. Processes for the preparation of the compounds of the present invention are described herein. From the following description of the processes, it should be understood that, when appropriate, protective groups suitable for the various reagents and intermediaries will be added, and subsequently removed, in a manner easily understood by the person skilled in the art of organic synthesis. . Conventional methods for using the protecting groups, as well as examples of suitable protecting groups, are described, for example, in "Protective Groups in Organic Synthesis", T.W. Green, P.G.M. Wuts, Wiley-Interscience, New York, 1999. It is further understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be made in any intermediate or final product of the synthesis towards the final product and that the type possible transformation is limited by the incompatibility of other functions performed by the molecule at that stage in the conditions or reactants used in the transformation. Such inherent incompatibilities and the way of avoiding them by means of the appropriate transformation and the correct order of the steps of the synthesis will be evident and easy to understand for the person skilled in the art of organic synthesis. Next, examples of transformations are presented, it should be noted that the described transformations are not limited only to the generic or substituent groups for which examples of transformations are given. References and descriptions of other suitable transformations can be found in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations" by R. C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in organic chemistry textbooks, such as "Advanced Organic Chemistry ", March, 4th ed. McGraw Hill (1992)," Organic Synthesis ", Smith, McGraw Hill, 1994. Intermediate and final product purification techniques include, for example, reverse phase and direct chromatography. in column or turntable, recrystallization, distillation or liquid / liquid, or solid / liquid extraction known to those skilled in the art The definitions of substituents and groups are those provided in formula I unless otherwise indicated. The terms "ambient temperature" and "ambient temperature" mean, unless otherwise indicated, a temperature between 16 and 25 ° C.

The term "reflux" means, unless otherwise indicated, in relation to a solvent employed at a temperature equivalent to or greater than the boiling point of said solvent. Abbreviations ac. aqueous atmosphere BINAP 2,2'Bis (diphenylphosphino) -1, 1'-biphenyl Boc, BOC tert-butoxycarbonyl CDl N, N'-carbonyldiimidazole dba Dibenzylidenacetone DCC N, N-Dicyclohexylcarbodiimide DCM Dichloromethane DEA N, N-Diisopropylethylamine DI BAL -H diisobutylaluminum hydride DIC N. N'-Düsopropylcarbodumide DMAP N, N-Dimethyl-4-aminopyridine DMF Dimethylformamide DMSO Dimethylsulphoxide DPPF 1, 1 '-Bis (diphenylphosphino) ferrocene EA or EtOAc ethyl acetate EDC, EDCl hydrochloride N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide Et Ethyl Et20 Diethyl ether Etl iodoethane EtOH Ethanol Et3N Triethylamine Fmoc, FMOC 9-Fluorenylmethoxycarbonyl h hour (s) HBTU O-Benzotriazole-1 -yl-? / Hexafluorophosphate ,? / ',? /' - tetramethyluronium hep heptane hex hexane (s) HetAr Heteroaryl HOBt N-Hydroxybenzotriazole CLAR high performance liquid chromatography LAH Aluminum and lithium hydride LCMS CLAR with mass spectrography MCPBA m-chlorobenzoic acid Me Methyl MeCN Acetonitrile Mel Iodomethane MeMgCI methylmagnesium chloride MeOH Methanol m Minutes NaOAc nB butyl sodium acetate nBuLi, n-BuLi 1 -butyllithium NCS N-chlorosuccinimide NMR nuclear magnetic resonance o.n. during the night OAc acetate OMs mesylate or methane sulfonate ester OTs tosylate sulfonate, toluenesulfonate or 4-methylbenzene ester PPTS pyridinium p-toluenesulfonate pTsOH p-toluenesulfonic acid RT, rt, r.t. ambient temperature sat saturated SPE solid phase extraction TBAF tetrabutylammonium fluoride tBu, t-Bu-tert-butyl tBuOH, t-BuOH eerc-butanol TEA Triethylamine THF Tetrahydrofuran. Preparation of intermediates The compounds and the corresponding intermediates, in the non-limiting synthetic routes whose preparations are indicated below, are useful for the preparation of compounds of the formula I or which may represent the same. Other starting materials can be obtained in the market or can be prepared by the methods described in the literature. [1, 2,4] triazolethiones and alkylsulfonyl [1, 2,4] triazoles Reaction Scheme 1a With reference to Reaction Scheme 1 a, the 3-alkylsulfonyl [1, 2,4] triazoles can be prepared from the corresponding [1, 2,4] triazolethions, by the initial alkylation of the sulfur atom with primary alkyl halides, such as Mel and Etl (the alkyl is Me and Et, respectively) in MeOH, EtOH, THF, acetone or the like, between -30 and 100 ° C, followed by oxidation of the sulfur atom using , for example, KMn04, in mixtures of water and acetic acid, or mCPBA in DCM, between -20 and 120 ° C, or using any other suitable oxidant.

Reaction Scheme 1b With reference to Reaction Scheme 1b, [1, 2,4] triazolethions, where R 'is an appropriate side chain which may or may not be protected, as appropriate, are prepared, for example, by the initial N-acylation of a thiosemicarbazide, using any suitable acylating agent, such as chlorides, bromides or acid fluorides (LG is Cl, Br or F) in, for example, pyridine, or acids (LG is OH) which are activated by treatment with conventional activating reagents, as described below in DMF, THF, DCM at a temperature between -20 to 120 ° C, followed by the ring closure of the initially formed acyclic intermediate, either in the form spontaneous, under acylation conditions, or with heating at 50-1 d0 ° C, in pyridine or aqueous solvents, in the presence of a base, such as NaHCO3 or Na2CO3, with or without co-solvents, such as dioxane, THF, MeOH , EtOH or DMF. This acyclic intermediate can also be formed by treating the appropriate acyl hydrazide with an appropriate isothiocyanate, for example, in 2-propanol, DCM, THF or the like, between -20 and 120 ° C. [1, 2, 4] oxadiazoles G1 = = CI, Br or OH Reaction scheme 2 With reference to reaction scheme 2, [1, 2,4] oxadiazoles with an alpha carbon in the heterocycle, where G \ G2 and G3 are defined as described in reaction scheme 2, formed by the cyclization of acyloxyimidamides G1 and G2-substituted in solvents such as pyridine, DMF, or mixtures of these containing water, between 40 and 140 ° C; as an alternative, in aqueous alcoholic solvents, in the presence of sodium acetate, at temperatures between 40 and 140 ° C, where the latter method is preferred if one of the groups G1 or G2 contains a chiral stereocenter. The acyloxyimidamides are formed through coupling with an appropriate acylating agent, which contains an LG leaving group, with a G1-substituted hydroxamidine. The leaving group LG can be chlorine or any other appropriate leaving group, which, for example, can be generated by in situ treatment of the corresponding acid (LG is OH) with appropriate activation reagents, as described later in this documentation. The G1-substituted hydroxamidines are formed by the reaction of the corresponding nitrile with the free hydroxylamine base or the hydroxylamine hydrochloride, in the presence of a base, such as triethylamine, pyridine or sodium carbonate, in solvents such as ethanol, water or pyridine. , at a temperature between -20 and 120 ° C.

Amino [1, 2,4] cyclic triazoles Reaction Scheme 3 With reference to reaction scheme 3, cyclic amino [1, 2,4] triazoles, where R is X6-R3, as defined in formula I, are obtained by treating cyclic carbon-2-one hydrazones ( for example, 1, 3-diazepan-2-one hydrazone for n = 3 or the like) with an appropriate acylating agent containing a leaving group LG, in an appropriate solvent, such as THF, pyridine or DMF, between -20 and 100. ° C. The reaction leads initially to an open intermediate, which forms a triazole ring spontaneously or which can be forced to do so, with conventional or microwave-assisted heating, between dO and 200 ° C, for example, in pyridine or DMF . The leaving group LG can be chlorine, bromine or fluorine (LG is Cl, Br or F), the corresponding anhydride (LG is 0-C (= 0) R) or any other appropriate leaving group, such as, for example, one generated by an in situ treatment of the corresponding acid (LG is OH), with conventional activating reagents, as previously described herein documentation. The cyclic carbon-2-one hydrazones can be generated from isothioureas, where the S-alkyl portion (eg, S-Me or S-Et) acts as a leaving group against a hydrazine treatment, in solvents such as pyridine, methanol, ethanol, 2-propanol, THF or the like, between -20 and 1 80 ° C. The intermediate can also be generated directly, by treating isothioureas with acyl hydrazides, under the same conditions described for the reaction with hydrazine. The cyclic isothioureas are obtained by S-alkylation of the corresponding thioureas, which are commercially available or are prepared according to conventional procedures known to those trained in the art, for example, with Mel or Etl in acetone, EtOH, THF, DCM or similar, between -100 and 100 ° C. [1, 2,4] carbocyclic triazoles Reaction Scheme 4 With reference to reaction scheme 4, where R is H or alkyl (Me, Et), and R 'is X6-R3, as defined in formula I, the carbocyclic [1, 2,4] triazoles they are obtained by treating cyclic lactam hydrazones with an appropriate acylating agent, to obtain an open chain intermediate that forms the triazole ring spontaneously or by heating, as previously described herein. These cyclic lactam hydrazones are generated from the cyclic enol ether, where the O-alkyl portion (the alkyl is Me) acts as a leaving group in the hydrazine treatment, as previously described herein.

These open chain intermediates can also be formed directly, employing a treatment of lactam enol ethers with acyl hydrazides, as previously described herein. The lactam enol ethers are prepared from the corresponding lactams, using a treatment with Me3OBF or dimethyl sulfate [Org. Prep. Procedure Int; 24, 1 992, pp. 147-1 58 or Tetrahedron Lett. 42, 2001, pp. 173-1776]. R-substituted lactams are commercially available or can be prepared by alkylation at the alpha position, employing a treatment with 2 equivalents of a strong base, such as n-BuLi, followed by the addition of 1 equivalent of an alkylating agent, such as alkyl halide, mesylate or triflate, in an aprotic solvent, such as THF [J. Org. Chem. 64, 1 999, pp. 6041 -6048] or, alternatively, through the N-protected lactam, for example, trimethylsilyl valerolactam or the like, where only one base equivalent is needed to generate the anion for alkylation [J. Org. Chem. 65, 2000, pp. 2684-269d]. The alkylation results in the formation of a racemic product, which can be separated into its pure enantiomeric forms at this time or at a later stage of the synthesis route, for example, by chiral chromatography. 2-aryl-2H- [1,2,3] triazole-4-carbaldehydes fructose Reaction Scheme With reference to reaction scheme 5, where Ar is 5-R, 2-R2-phenyl, as defined in formula I, [1, 2,3] triazole-4-carbaldehydes can be obtained from of aryl glucosetriazoles, making an oxidative cut, using, for example, periodic acid in aqueous mixtures of dioxane or THF, between -20 and 120 ° C. The aryl glucosetriazoles can be obtained by the cyclization of the aryl glucoside intermediate in the presence of copper (II) sulfate, in aqueous mixtures, for example, of dioxane or THF, between -20 and 120 ° C. In turn, aryl glucose is prepared by coupling arylhydrazines with fructose in acetic acid and water, at -20-120 ° C [Buckler, R.; Hartzler, H .; Kurchacova, E .; Nichols, G .; Phillips, B .; J. Med. Chem .; 1978; 21 (12); 1264-1260, and Riebsomer, J .; Sumrell, G .; J. Org. Chem .; 1948; 13 (6): 807-814].

Esters of isoxazole-5-carboxylic acid I rent Reaction Scheme 6 With reference to reaction scheme 6, isoxazoles are formed by the reaction and in situ cyclization of dioxobutyric ester derivatives with hydroxylamine hydrochloride, in solvents such as ethanol, 2-propanol or DMF, at temperatures of between 40 and 140 ° C. The dioxide butyric esters are formed by the reaction of acetophenones with dialkyl oxolates (the alkyl is, for example, Me or Et) in the presence of a strong base, such as sodium hydride, in solvents such as DMF or toluene, at temperatures between -20 and 120 ° C. [1, 3, 4] oxadiazoles alkyl, alkyl-, G = Cl or Br Reaction Scheme 7 With reference to Reaction Scheme 7, where R is H or alkyl (Me, Et), starting from acid hydrazides, binding with an aliphatic acid chloride derivative in THF, DMF, toluene or the like, optionally in the presence of a base, such as triethylamine or a carbonate, leads to the formation of an acyl benzohydrazide derivative, which cyclizes at elevated temperatures in the presence of a dehydrating agent, such as phosphorus pentoxide, in solvents such as toluene, DMF or mixtures thereof, to generate the product of [1, 3,4] Oxadiazole Alternatively, [1, 3,4] oxadiazoles can be prepared directly from the acid hydrazide, using trialkyl ortho esters, either pure or in solvents such as toluene or xylenes, at elevated temperatures. Triazole ethers h Reaction scheme With reference to reaction scheme 8, where R is H or alkyl (Me, Et), R 'is an appropriate side chain which may or may not be protected, as appropriate, and R "is X6-R3 , as defined in formula I, triazoles attached to oxygen can be prepared by forming bonds through the nucleophilic replacement of a leaving group (LG), where an alcohol acts as O-nucleophile, under basic conditions. , NaH or Cs2C03, at temperatures between 0 and 80 ° C, in polar aprotic solvents, such as DMF or acetonitrile Examples of suitable leaving groups are alkylsulfonyls, such as methanesulfonyl and ethanesulfonyl, and halogens, such as chlorine. and Arylsulfonylhydrazones Reaction Scheme With reference to reaction scheme 9, the arylsulfonylhydrazones are prepared by a condensation between aldehydes, for example, cinnamaldehyde or glyoxalic acid, with arylsulfonylhydrazines, such as 4-toluenesulfonylhydrazine, in a suitable solvent, for example, methanol, ethanol , DMF or dialkyl ethers, at a temperature between 0 and 100 ° C, as an alternative, without solvent, under microwave irradiation. Similarly, arylhydrazones can be formed from the reaction of arylhydrazines, with aldehydes [J. Med. Chem. 1 980, 23, 631-634; Monatshefte fuer Chemie 2001, 403-406; J. Med. Chem. 2000, 43, 963-970; J. Med Chem. 1978, 21, 1264-60] Formation of tetrazole Reaction Scheme 10a With reference to reaction scheme 10a, tetrazoles, where G is an electron-capturing group, such as an olefin group, carbonyl or aryl, can be prepared by the 1,3-dipolar cycloaddition of a diazonium salt in an aryl sulfonyl hydrazone, followed by removal of the arylsulfinic acid to generate the tetrazole ring, in protic solvents, such as water and alcohol, or mixtures thereof, in basic aprotic solvents, such as pyridine, or in mixtures of these solvents with protic solvents used to generate the diazonium salt [J. Med. Chem. 2000, 43, 953-970]. In turn, the diazonium salts are available from amines suitably substituted with aryls or heteroaryls, using well known methods, by diazotization with a nitrite source, such as sodium nitrite or isoamyl nitrite, in the presence of a source of suitable acid, such as hydrochloric acid or tetrafluoroboric acid, in a solvent such as water, at a temperature between -10 and 0 ° C. In the case where a less soluble counter ion X ", such as tetrafluoroborate, is used, the diazonium salt thus formed may be collected by precipitation, and may be used in subsequent reactions under non-aqueous conditions. The soluble diazonium salts formed using other Sources of acid can be precipitated by adding an appropriate reagent, such as tetrafluoroboric acid or sodium tetrafluoroborate.

Reaction Scheme 10b With reference to reaction scheme 10b, tetrazoles can also be prepared from the reaction of an arylhydrazone, where G is as defined in Reaction Schemes 9 and 10, with an aryl azide in an appropriate solvent, such as ethanol or pyridine. [J. Med Chem. 1978, 21: 1254-60]. The aryl azides can be formed, for example, by using sodium azide with an aryl diazonium salt, which, in turn, can be prepared as previously described from an aryl amine, for example, aniline or 2,4,6- tribromoaniline. Aryl azide can be considered as a nitrogen transfer reagent, since cycloaddition in the hydrazone is followed by removal to regenerate the aryl amine precursor in the diazonium salt.

Preparation of 2-aryl tetrazole 5-carbonyls Generally, G, as detailed in reaction scheme 10a and 1 0b, is a group that can be employed as a precursor to the X6 portion in the compounds of formula I, such as an olefin, a carboxylic acid or an acid derivative. With reference to reaction scheme 1 1, when G is an aryl olefin, derived, for example, from cinnamaldehyde, where R is H, the olefin group can be separated to provide an aldehyde, directly in a process in a vessel, using a reagent such as ozone, or through the diol, using a dihydroxylation reagent, such as osmium tetroxide, as those skilled in the art know, followed by subsequent cutting using a reagent such as lead acetate (IV). When a substituted cinnamaldehyde, such as α-methylcinnamaldehyde, is used, where R 'is methyl, a ketone can be obtained as a result of cutting the olefin [J. Med. Chem. 2000, 43, 953-970].

Transformations of functional groups R OR R- ° R hetAr heTAR - hetAr "^? Alkyl petAr R LG O OH T i LG = CI O reduction hetAr 4 hetAr OH? - * - LG = Br R LG =? Ms or OTs etc. Reaction scheme 12 With Referring to the reaction scheme 12, the aliphatic alcohols can be converted into the corresponding halides, for example, using conventional methods, for example, using triphenylphosphine in combination with iodine, N-bromosuccinimide or N-chlorosuccinimide, or, alternatively, effecting a treatment with tribromophosphine or thionyl chloride The alcohols can be transformed into other leaving groups, such as mesylates or tosylates, using the sulfonyl halide or the appropriate anhydride sulfonyl, in the presence of a non-nucleophilic base, in combination with an alcohol, to obtain the corresponding sulfonates The chlorides or sulphonates can be converted to the corresponding bromides or iodides using a treatment with bromide salts, for example LiBr, or iodide salts, such as Lil. Other conventional methods for obtaining the alcohols include the reduction of the corresponding carbonyl-containing groups, such as methyl or ethyl esters, aldehydes or ketones, using common reducing agents, such as boranes, lithium borohydride, lithium aluminum hydride, or hydrogen in the presence of a transition metal catalyst, such as, for example, ruthenium or iridium complexes, or alternatively, palladium on carbon. The ketones and secondary alcohols can be obtained by effecting the treatment of the carboxylic acid esters and the aldehydes, respectively, with the appropriate carbon nucleophile, such as the alkyl-Grignard reagents or the alkyl-lithium reagents, according to the protocols. conventional The heteroaromatic aldehydes can be prepared from the corresponding primary alcohols, employing oxidation procedures well known to those skilled in the art, such as the use of Mn02 as an oxidant, or effecting an oxidation of Swern. Preparation of the final compounds The following non-limiting preparation methods of the final compounds of formula I are illustrated and exemplified in drawings, where the generic groups, or other structural elements of the intermediaries, correspond to those in the formula I. It should be understood that an intermediary containing any other generic group or structural element other than those of formula I may be used in the exemplified reactions, with the proviso that this group or element does not hinder the reaction and may be chemically converted to the group or element corresponding to formula I at a later stage, known to those skilled in the art. By intermolecular nucleophilic displacement Reaction Scheme 13 With reference to reaction scheme 13, where R "is H or alkyl (Me, Et), R is H or alkyl (Me, Et) and R 'is X6-R3, as defined in formula I , the compounds of formula I can be prepared, for example, by the formation of bonds through the nucleophilic displacement of a leaving group (LG), where the nucleophilic atom can be the amino-nitrogen atom of a heterocyclic amine or the alpha carbon of a heteroaromatic substituted with alkyl The amino-nitrogen atoms of the heterocyclic amines and the alpha carbons of the alkyl-substituted heteroaromatics generally do not react in the protonated neutral form, and, therefore, preferably are converted in whole or in part in more nucleophilic anionic forms, using a treatment with bases in appropriate solvents, such as LDA, HMDS-alkali or n-BuLi in THF, diethyl ether or toluene, or NaH, for example, in DMF, K2C03 or Cs2C03, in acetonitrile or ketones such as 2-butanone, either in situ or just before the reaction with a suitable electrophile containing a leaving group, at a temperature between -100 and 150 ° C. The nitrogen atoms of the secondary aliphatic amines are generally sufficiently nucleophilic to displace a leaving group in the corresponding neutral forms, but preferably a base, such as K2C03, Cs2C03, TEA, DEA or the like is added to facilitate the reaction, in solvents such as acetonitrile, DMF or DCM, between 0 and 150 ° C. For carbon nucleophiles, the leaving group is preferably bromine, for other examples of nitrogen nucleophiles, the appropriate LG leaving groups include chlorine, bromine, OMs and OT. Optionally, there may be catalytic or stoichiometric amounts of an alkali metal iodide, such as Lil, present in the reaction, to facilitate its development by in situ displacement of the leaving group to the iodine.

By intramolecular nucleophilic displacement Reaction scheme 14 With reference to reaction scheme 14, where R is H or alkyl (Me, Et) and X is S or O, the compounds of formula I can be prepared, for example, by the formation of an intramolecular bond, through the nucleophilic displacement of a leaving group (LG), where the nucleophilic atom can be the alpha carbon of a heteroaromat substituted with alkyl, under conditions previously described herein, for intermolecular shifts where the preferred bases are, for example, LDA, HMDS-alkali, or NaH, as previously described herein.

Preparation of fused piperazin-triazoles IV B Reaction Scheme 15a With reference to reaction scheme 15a, the triazolopiperazines can be prepared from the piperazinone derivative, by Initial N-protection to give intermediate I I. Subsequently, the intermediate can be hydrolyzed to obtain acid ll. Subsequently, the corresponding 1, 2,4-oxadiazoi IV can be generated as previously described. Consecutive to this, the triazolopiperazine intermediate VI can be obtained by converting first IV to the cyclic imidate, with a reagent such as Me30 + BF4"or dimethyl sulfate (ref: a) Sheu, Jennline; Smith, Michael B .; Oeschger, Thomas R .; Satchell, Jacqueline; Org. Prep. Int. Procedure; 24; 2; 1992: 147-168; b) Hutchinson, Ian S.; Matlin, Stefen A .; Mete, Antonio, Tetrahedron Lett.; 42; 9; 2001: 1773-1776). The alkoxy group can subsequently be displaced with an acyl hydrazide (or a hydrazine with an acylating agent, as described in Reaction Scheme 4), followed by a ring closure condensation to form the triazole heterocycle.

This can be done in ethanol, toluene, DMF or pyridine under thermal conditions, with regular heating or microwave irradiation (ref: Lawson, Edward C, Hoekstra, William J., Addo, Michael F., Andrade-Gordon, Patricia, Damiano, Bruce P., Kauffman, Jack A., Mitchell, John A., Maryanoff, Bruce E., Bioorg, Med. Chem.

Lett .; IN; eleven; 19; 2001: 2619-2622). The protecting group can then be removed to give the compounds of formula A. Compound A can then be subjected to reductive alkylation to obtain the compounds of formula B. Alternatively, compounds of formula A and B can also be obtained according to the sequence of reaction illustrated in Reaction Scheme 1 db, as indicated below.

Reaction Scheme 15b The isoxazole compounds of the invention can be prepared as indicated in reaction scheme 16 below. One of groups A and B represents the substituted phenyl group, and the other represents the bicyclic ring system of the compounds of Formula I; alternatively, A and B represent precursors of these groups: AA Reaction Scheme 16 In greater detail, compounds of formula 16e can be prepared by a 1,3-dipolar cycloaddition between the compounds of formula 16a and 16b under basic conditions, using an appropriate base, such as sodium bicarbonate or triethylamine, at appropriate temperatures (0 ° C-100 ° C) in solvents such as toluene. The synthesis of the compounds of type 16a has been previously described in the literature, for example, Kim, Jae Nyoung; Ryu, Eung K; J. Org. Chem. (1992), 67, 6649-dO. The 1,3-dipolar cycloaddition can also be carried out with acetylenes of type 16b using substituted nitromethanes of type 16c, by activation with an electrophilic reagent, such as PhNCO, in the presence of a base, such as triethylamine, at elevated temperatures (50- 1 00 ° C). Li, C-S .; Lacasse, E.; Tetrahedron Lett. (2002) 43: 3566-3668. There are several commercially available type 16c compounds, or they can be synthesized using conventional methods known to those skilled in the art. Alternatively, compounds of formula 16d, which are available through a Claisen condensation of a methyl ketone and an ester under basic conditions, using bases such as sodium hydroxide or potassium tert-butoxide, can provide compounds of formula 16a , through condensation the subsequent cyclization using hydroxylamine, for example, in the form of the hydrochloric acid salt, at elevated temperatures (60-120 ° C). It should be understood that, for both methods, subsequent transformations of functional groups may be necessary. In the case of an ester group, these transformations may include, without limitation, any of these three procedures: a) a complete reduction using an appropriate reducing agent, such as LAH, in solvents such as THF; b) a partial reduction using an appropriate selective reducing agent, such as DIBAL, followed by an alkylation with an alkyl halide; c) an alkylation using an alkyl metal reagent, such as an alkyl magnesium halide, in solvents such as toluene or THF, followed by a reduction, for example, with sodium borohydride in methanol. * * * * * The invention is illustrated below with the following non-limiting examples. General methods All starting materials are commercially available or previously described in the corresponding literature. The 1 H and 13 C NMR spectra were recorded on Bruker 300, Bruker DPX400 or Varian +400 spectrometers operating at 300, 400 and 400 MHz for 1 H NMR respectively, using TMS or residual solvent signal as reference, in deuterated chloroform as solvent unless otherwise stated. All the chemical shifts reported are expressed in ppm on the delta scale, and the fine separation of the signals that appear in the registers (s: singlet, br s: broad singlet, d doublete, t: triplet, q: quartet, m : multiple) Separations by in-line analytical liquid chromatography followed by detection of mass spectra were recorded with a Waters LCMS equipment consisting of an Alliance 2795 spectrometer (LC) and a single-quadrupole mass spectrometer ZQ. The mass spectrometer was equipped with a source of electroatomized ions in the form of positive or negative ions. The ion atomization voltage was ± 3 kV and a mass spectrometer was scanned from m / z 100-700 with a scan time of 0.8 s. To the column = X-Terra MS, Waters, C8, 2.1 x 50 mm, 3.5 mm and a linear gradient between 5% t 100% acetonitrile in 10 mM ammonium acetate (aq.) Or 0.1% TFA (ac) was applied. Reverse phase preparative chromatography was performed in a self-prepared Gilson CLAR with detector by diode array using an XTerra MS C8, 19x300 mm, 7 mm as column. Purification by chromatotron was carried out on rotating glass plates covered with silica gel / gypsum (Merck, 60 PF-264 with calcium sulphate), with a coating layer of 1, 2, or 4 mm using a TC Research 7924T chromatotron . The purification of the products was also effected using Chem Elut Extraction Columns (Varian, cat # 1219-8002), Mega BE-SI (Bond Elut Silica) SPE Columns (Varian, cat # 12266018; 12266026; 12266034), or by flash chromatography on glass columns filled with silica. The microwave heating was carried out in a Smith Synthesizer Single mode microwave that produced a continuous irradiation at 2450 MHz (Personal Chemistry AB, Uppsaia, Sweden).

Preparation of intermediates Example 1 [3- (2-Thienyl) -5-thioxo-1,5-dihydro-4H-1, 2,4-triazol-4-yl] acetic acid N- (thioxomethylene) glycinate was heated (2.06 g) and thiophene-2-carbohydrazide (2.57 g) in isopropanol (50 ml) at 70 ° C with stirring for 16 h. The mixture was allowed to reach room temperature and the formed precipitate was collected and heated to reflux in aqueous solution of 1.0 M NaHCO 3 for 2 h. After cooling to room temperature and acidifying with conc. HCl. (aq) the product was extracted with EA, which was washed with brine and then dried over MgSO4 before concentrating to dryness to yield crude title compound that was used directly in the next step. Example 2 4- (2-Hydroxyethyl) -5- (2-thienyl) -2,4-dihydro-3H-1, 2,4-triazole-3-thione All the acid [3- (2-thienyl) -5 crude thioxo-1, 5-dihydro-4H-1, 2,4-triazol-4-yl] acetic from the previous step was dissolved in THF (20 ml). This solution was added dropwise at 0 ° C to a suspension of LAH (2 g) in THF (80 ml) with stirring before being allowed to reach room temperature for 2 h. The reaction mixture was then set with sat Na2SO4. (aq) at 0 ° C and the pH was adjusted to 3-4 before filtering through celite. The THF was removed from the filtrate by concentration and the product was extracted with EA from the remaining aqueous mixture. The EA phase was then washed with brine and dried over MgSO4 before concentrating to dryness to yield a crude material which was recrystallized from MeOH to give 485 mg of the title compound. 1 H NMR (DMSO-d6): 13.94 (broad s, 1 H), 7.86 (d, 1 H), 7.81 (d, 1 H), 7.24 (dd, 1 H), 5.09 (t, 1 H), 4.1 6 (t, 2H), 3.76 (q, 2H). Example 3 2- [3- ( { [5- (5-chloro-2-fluorophenyl) -1,2,4-oxadiazol-3-yl] methyl.} Thio) -5- (2-thienyl) -4H-1, 2,4-triazol-4-yl] ethanol. 4- (2-Hydroxyethyl) -5- (2-thienyl) -2,4-dihydro-3H-1, 2,4-triazole was stirred. 3-thione (101 mg), d- (5-chloro-2-fluorophenyl) -3- (chloromethyl) -1, 2,4-oxadiazole (16 mg), and potassium carbonate (86 mg) in a mixture of DMF (2 ml) and MeCN (15 ml) at room temperature for 3 h before concentrating to dryness and washing of the residue with water, and then with EtOAc, to give 122 mg of the title compound as a white solid. 1 H NMR (DMSO-d 6): 8.04 (dd, 1 H), 7.83 (m, 1 H), 7.78 (d, 1 H), 7.66 (d, 1 H), 7.58 (t, 1 H), 7.22 (dd, 1 H), 5.16 (t, 1 H), 4.59 (s, 2H), 4.18 (t, 2H), 3.64 (q, 2H).

Example 4 2- [3- (. {[[5- (5-Chloro-2-fluorophenyl) -1,2,4-oxadiazol-3-yl] methyl} thio) -5- (2-) methanesulfonate thienyl) -4H-1, 2,4-triazol-4-yl] ethyl To a solution of 2- [3- ( { [5- (5-chloro-2-fluorophenyl) -1, 2,4- oxadiazol-3-yl] methyl.} thio) -5- (2-thienyl) -4H-1, 2,4-triazoI-4-yl] ethanol in a mixture of DMF (1 ml) and pyridine (Od ml ) methanesulfonyl chloride (20 μl) was added. The mixture was stirred at room temperature for 24 h before being poured into water (10 ml). The crude product was filtered and purified by chromatography on silica gel using 0-d% MeOH in DCM as eluent to give 43 mg of the title compound, which was used directly in the next step.

Example 5 a) 3-pyridin-4-yl-6,7,8,9-tetrahydro-5H- [1, 2,4] triazolo [4,3-a] [1, 3] diazepine A mixture of hydroiodide of 1,3-diazepane-2-one hydrazone (1.00 g, 3.9 mmol) and isonicotinoyl chloride hydrochloride (695 mg, 3.9 mmol) was heated in a microwave reactor at 160 ° C for 10 min.

The reaction mixture was poured over NaaC03 solution, sat. , and extracted with DCM. The organic phase was dried and concentrated. Flash chromatography (DCM / MeOH 20: 1) gave 1.74 g of crude title compound which was used directly in the next step. 1 H NMR: 1.89 (s, 4H), 3.15 (m, 2H), 3.86 (m, 2H), 7.44 (d, 2H), 8.66 (d, 2 H). The following compounds were prepared in a similar manner: b) 3- (3,5-difluorophenyl) -6,7,8,9-tetrahydro-5H- [1, 2,4] triazolo [4,3-a] [ 1, 3] diazepine; 180 mg (20%) tan solid; 1 H NMR CDCI3: 1.88-1.99 (m, 4H), 3.22-3.25 (m, 2H), 3.90 (m, 2H), 5.76 (broad, 1 H) 6. 95 (m, 1 H), 7.10 (m, 2 H). c) 3- (4-methoxyphenyl) -6,7,8,9-tetrahydro-5H- [1, 2,4] tpazolo [4,3-a] [1, 3] diazepine; 300 mg (34%) white solid; 1 H NMR CDCl 3: 2.03 (m, 4 H), 3.48 (m, 4 H), 5.33 (s, 3 H), 6.96 (d, 2 H), 7.87 (d, 2 H). Example 6 3- (Trifluoromethyl) -6,7,8,9-tetrahydro-5H- [1, 2,4] triazolo [4,3-a] [1, 3] diazepine Trifluoroacetic acid anhydride ( 0.24 ml, 1.71 mmol) was added to a solution of hydrazone 1,3-diazepane-2-one hydrazone in DCM (10 ml). The reaction mixture was stirred for 24 h at room temperature. The volatile materials were removed and the residue was refluxed in aq. NaHCO 3. sat for 2 h. After cooling to room temperature the product was collected by filtration, washed with water and dried to give 101 mg (31%) of the title compound. 1 H NMR: 1.85 - 1.96 (m, 4H), 3.17 (m, 2H), 3.99 (m, 2H), 5.04 (s, 1 H).

EXAMPLE 7 1,3-Diazepane-2-hydrazone hydrazone hydrate Hydrazine hydrate (0.44 ml, 7.23 mmol) was added to a solution of 2- (methylthio) -4,5,6,7-tetrahydro-1-hydroiodide. H-1, 3-diazepine (1.79 d, 6.58 mmol) in EtOH (12 mL). The reaction mixture was refluxed for 5 h and cooled to room temperature. Et20 was added and the product was collected by filtration, washed with Et20 and dried under vacuum to give 1.46 g (1 00%) of the crude title which was used directly in the next step. Example 8 2- (Methylthio) -4,5,6,7-tetrahydro-1 H-1,3-diazepine Methyl iodide (0.55 mL, 1.1 mmol) was added to a solution of 1,3-diazepam -2-thione (1.00 g, 7.68 mmol) in acetone (8 ml). The reaction mixture was refluxed for 15 min. EtOH was added to the hot solution to dissolve the solids. After cooling to room temperature hex was added. and the precipitate was collected by filtration, washed with hex. and dried to give 1.79 g (86%) of the crude title which was used directly in the next step. Example 9 3-pipdin-4-yl-6,7-dihydro-5H-pyrrolo [2,1-c] [1, 2,4] triazole Me3OBF4 (2.66 g, 1 8 mmol) was added to a solution of 2 g. pyrrolidinone in DCM (160 ml) and the reaction mixture was stirred for 24 h. The reaction mixture was washed with sat. NaHCO 3. ac, dried and concentrated. The residue was dissolved in EtOH (4 ml) and isonicotinic hydrazide (1.37 g, 10 mmol) was added. The mixture was heated in a microwave reactor for 1 h at 120 ° C. The volatile materials were removed and the crude product was purified with column chromatography (DCM / MeOH 20: 1) to give 31 9 mg (11%) of the title compound. 1 H NMR: 2.87 (m, 2H), 3.05 (t, 2H), 4.28 (t, 2H), 7.72 (d, 2H), 8.72 (d, 2 H). Example 10 3- (Chloromethyl) -5- (3-chloro-phenyl) -1,2,4-oxadiazole Step A. The acyclic intermediate was obtained from 3-chlorobenzoic acid (2.82 g, 18 mmol), EDCl ( 3.46 g, 1.8 mmol), HOBt (2.76 g, 18 mmol) and 2-chloro-N-hydroxy-acetamidine (1.75 g, 16.2 mmol) [Chem. Ber. 1907, 40, 1639] in DMF (40 ml). Step B: The cyclic compound was obtained by heating in DMF (40 ml) and purified by SPE chromatography on silica gel using 2% acetone in hexs to give the title compound (1.46 g, 39% yield 2 steps). 1 H NMR: 8.17 (m, 1 H), 8.07 (dd, 1 H), 7.60 (m, 1 H), 7.5 d (t, 1 H), 4.69 (s, 2 H). Example 11 3- (Bromomethyl) -5- (3-chlorophenyl) -1,2,4-oxadiazole 3- (Coromethyl) -d- (3-chlorophenii) -1, 2,4-oxadiazole (1.38 g, 6.0 mmol) and LiBr (0.90 g, 1 0.3 mmol) in THF (dO ml) under reflux under a nitrogen atmosphere overnight After cooling to room temperature EA was added and the organic phase was washed with H20 and brine, dried and evaporated to give the title compound (1.40 g, 86%). MS (M ++ 1) 276. Example 12 3- (1-Chloroethyl) -5- (3-chlorophenyl) -1,2,4-oxadiazole 5 drops of DMF were added to 1 - [d- (3-chlorophenyl) ) -1,4, 2,4-oxadiazol-3-yl] ethanol (12.3 g, 64.9 mmol) in SOCI2 (160 ml) and the reaction was heated at 70 ° C for d h. The excess of SOCI2 was evaporated and the residue was purified by column chromatography (Hep to Hep-EA 6: 1) to give 12.4 g (93%) of the title compound. 1 H NMR: 1.96 (d, 3H), 5.20 (q, 1 H), 7.46 (t, 1 H), 7.59 (m, 1 H), 8.04 (m, 1 H), 8.17 (t, 1 H). Example 13 1 - [5- (3-Chlorophenyl) -1,4-oxadiazol-3-yl] ethyl methanesulfonate Methanesulfonyl chloride (40 μl, 0.49 mmol) was added to a mixture of TEA (95 μl, 0.67 mmol) and 1 - [5- (3-chlorophenyl) -1,4,4-oxadiazol-3-yl] ethanol (100 mg, 0.45 mmol) in DCM (5 mL). After shaking during min the mixture was washed with water and brine, dried and concentrated and the title compound was obtained with 136 mg of yield. 1 H NMR: 1.9 (d, 3H), 3.1 (s, 3H), d.9 (q, 1 H), 7.6 (t, 1 H), 7.6 (m, 1 H), 8.0 (m, 1 H), 8.1 (t, 1 H). Example 14 1 - [5- (3-chlorophenyl) -1,4, 2,4-oxadiazol-3-yl] ethanol 27.2 g N '- [(3-chlorobenzoyl) oxy] -2-hydroxypropanimidamide were dissolved in ethanol (260 ml) and refluxed for 1 h, and then 14.0 g (170 mmol) of sodium acetate in water (40 ml) was added. After refluxing overnight, cooling to room temperature and adding water (250 ml) the mixture was concentrated in vacuo to approximately A of its volume, yielding in a precipitate that was filtered and recrystallized from EA / Hep to yield 6.45 g (25%) of the title compound. 1 H NMR: 8.14 (s, 1 H), 8.02 (d, 1 H), 7.57 (d, 1 H), 7.47 (t, 1 H), 5.04 - 5.14 (m, 1 H), 2.51 (d, 1 H), 1 .67 (d, 3 H). Example 15 N '- [(3-chlorobenzoi I) oxy] -2-hydroxy propan imidamide 6.45 g of crude N', 2-dihydroxypropanimidamide was cooled in an ice-water bath with 23.5 ml DEA in THF (200 ml ). To this suspension was added 21.44 g of 3-chlorobenzoyl chloride. The mixture was warmed to room temperature and stirred for 2 h. Addition of Et20 (200 ml), washing with NH4CI aq. sat and re-extraction of the aqueous layer gave after combining and concentrating the organic phases, and drying under vacuum, 27.24 g of crude title compound, which was used directly in the next step. LC-MS (M ++ 1): 243. Example 16 N ', 2-dihydroxypropanimidamide 44.2 g (0.64 mol) of hydroxylamine hydrochloride and 25.5 g (0.64 mol) of sodium hydroxide in ethanol (500 ml) were dissolved in Room temperature and stirred for 3 h. After filtration, 8.1 1 g (0.1 1 mol) of 2-hydroxypropanonitrile was added to the filtrate, and then stirred for 4 h. After concentrating to dryness, the title compound was obtained, which was used directly in the next step. 1 H NMR (DMSO-D6): 8.88 (s, 1 H), 5.15 (s, 1 H), 5.02 (s, 1 H), 4.00 (q, 1 H), 1.19 (d, 3 H) . EXAMPLE 17 2-Ethoxycarbonylmethyl-3-oxo-piperazine-1-carboxylic acid tert-butylester Triethylamine (9.0 ml, 64.4 mmol) and di-tert-butyl-dicarbonate (7.0 g, 32.2 mmol) were added to acid ethyl ester ( 3-oxo-piperazin-2-yl) -acetic acid (4.0 g, 21.5 mmol) in 1,4-dioxane (4.0 ml) and water (2 ml) at room temperature and stirred overnight. The reaction mixture was concentrated and then the residue was diluted with dichloromethane. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with hexanes, filtered, and dried to give the title compound (5.66 g, 92%, white solid). H NMR (CDCl 3) d (ppm): 6.29 (broad, 1 H), 4.78 (m, 1 H), 4.16 (m, 3 H), 3.40 (m, 3 H), 2.99 (m, 1 H), 2.90 ( m, 1 H), 1.50 (s, 9H), 1.28 (t, 3H). EXAMPLE 18 2-Carboxymethyl-3-oxo-piperazine-1-carboxylic acid tert-butylester 1 N sodium hydroxide (1.4 ml, 11.4 mmol) was added to 2-ethoxycarbonylmethyl-3-tert-butylester. oxo-piperazine-1-carboxylic acid (2.5 g, 8.73 mmol) in methanol (20 ml) at room temperature and then stirred for 2.5 hours. The reaction mixture was concentrated, acidified with 2N HCl to pH ~ 2 and extracted with dichloromethane (3 times). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (1.7g, 83%, white foamy solid). 1 H NMR (CDCl 3) d (ppm): 7.68 (broad, 1 H), 4.78 (m, 1 H), 4.19 (m, 1 H), 3.45 (m, 1 H), 3.34 (m, 2H), 2. 97 (m, 2H), 1.49 (s, 9H). EXAMPLE 19 2- [3- (3-Chloro-phenyl) - [1,4-oxadiazol-5-yl] -3-oxo-piperazine-1-carboxylic acid tert-butylester Tert-butylester of acid was stirred 2-Carboxymethyl-3-oxo-piperazine-1-carboxylic acid (1.87 g, 7.25 mmol), 3-chloro-N-hydroxy-benzamidine (1.36 g, 7.98 mmol), HOBt (1.08 g, 7.98 g) mmol) and EDCI (1.53 g, 7.98 mmol) in DMF (20 ml) at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water (3 times), saturated sodium bicarbonate (2 times) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in DMF (20 ml) and then heated at 135 ° C for 4 hours. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water (3 times) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification was performed by flash chromatography on silica gel using hexanes: dichloromethane (1: 1) to give the title compound (1.48 g, 52%, white foamy solid). 1 H NMR (CDCl 3) d (ppm): 8.08 (m, 1 H), 7.97 (m, 1 H), 7.46 (m, 2 H), 6.35 (m, 1 H), 5.04 (m, 1 H), 4.31 (m, 1 H), 3. 68 (m, 1 H), 3.50 (m, 2H), 3.27 (m, 2H), 1.35 (broad, 9H). EXAMPLE 20 6- [3- (3-Chloro-phenyl) - [1,4-oxadiazol-5-yl] -5-methoxy-3,6-dihydro-2H-pyrazin-1-tert -butylester -carboxylic trimethyloxonium tetrafluoroborate (169.4 mg, 1 .15 mmol) was added to 2- [3- (3-chloro-phenyl) - [1, 2,4] oxadiazol-5-yl] -3-tert-butylester. -oxo-piperazin-1-carboxylic acid (450 mg, 1.15 mmol) in dichloromethane (3 ml) under argon at room temperature and then stirred overnight. The reaction mixture was purified directly by flash chromatography over basic alumina using 30% ethyl acetate in hexanes to give the title compound (284.6 mg, 61%). 1 H NMR (CDCl 3) d (ppm): 8.09 (m, 1 H), 7.97 (m, 1 H), 7.46 (m, 2 H), 4.88 (m, 1 H), 4.01 (m, 1 H), 3.72. (s, 3H), 3.51 (m, 3H), 3.35 (m, 1 H), 2.90 (m, 1 H), 1.34 (m, 9H). EXAMPLE 21 8- [3- (3-Chloro-phenyl) - [1, 2,4] oxadiazol-5-yl] -3- (4-methoxy-phenyl) -5,6-dihydro- tert -butylester 8H- [1, 2,4] triazolo [4,3-a] pyrazine-7-carboxylic acid 6- [3- (3-Chloro-phenyl) - [1, 2, 4] oxadiazole-tert-butylester was heated -5-yl] -5-methoxy-3,6-d ihydro-2H-pyrazin-1 -carboxylic acid (284.6 mg, 0.70 mmol) and 4-methoxy-benzoic acid hydrazide (16.2 mg, 0.70 mmol) under argon in methanol (10 ml) at reflux for 3 days. After cooling, the reaction mixture was diluted with ethyl acetate and then washed with water (3 times) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel using 40-85% ethyl acetate in hexanes afforded the title compound (72.5 mg, 20%). 1 H NMR (CDCl 3) d (ppm): 8.07 (m, 1 H), 7.96 (m, 1 H), 7.64 (m, 2 H), 7.47 (m, 2 H), 7.05 (m, 2 H), 6.04 (m. m, 1 H), 4.1 1 (m, 2H), 3.89 (s, 3H), 3.86 (m, 2H), 3.55 (m, 1 H), 3.31 (m, 1 H), 1.28 (broad, 9H).

Example 22 [5- (3-chloro-phenyl) -isoxazol-3-yl] -methanol a) 4- (3-chloro-phenyl) -2,4-dioxo-butyric acid ethyl ester: Sodium hydride was added ( dispersion in 60% oil, 1.24 g, 31.1 mmol) in portions to a solution of 3-chloroacetophenone (4.0 g, . 9 mmol) and diethyl oxalate (4.54 g, 31.1 mmol) in DMF (32 ml) at 0 ° C. The mixture was stirred at room temperature for 1 h and then heated at 80 ° C for half an hour. After cooling, the mixture was treated with 3N HCl and then diluted with ethyl acetate. The organic layer was washed with water (3X) and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was then purified by flash column chromatography on silica using 0-10% ethyl acetate in hexanes to give 4- (3-chloro-phenyl) -2,4-dioxo-butyric acid ethyl ester (4.43 g, 67%). %, yellow solid). 1 H NMR (CDCl 3) d (ppm): 15.12 (broad s, 1 H), 7.98 (s, 1 H), 7.88 (d, 1 H), 7. 58 (d, 1 H), 7.47 (t, 1 H), 7.05 (s, 1 H), 4.39 (m, 2H), 1.41 (m, 3H). b) 5- (3-chloro-phenyl) -isoxazole-3-carboxylic acid ethyl ester: A solution of 4- (3-chloro-phenyl) -2,4-dioxo-butyric acid ethyl ester (3.0 g, 1 1 .8 mmol) and hydroxylamine hydrochloride (2.46 g, 35.4 mmol) in methanol (60 ml) was heated at 80 ° C for 4 h. After cooling, the mixture was filtered and washed with cold methanol to give 5- (3-chloro-phenyl) -isoxazole-3-carboxylic acid ethyl ester (2.0 g, 71%, white solid). 1 H NMR (CDCl 3) d (ppm): 7.82 (s, 1 H), 7.72 (m, 1 H), 7.47 (m, 2 H), 4.03 (s, 3 H). Mixture of methyl ester and ethyl ester (mostly methyl ester). c) [5- (3-chloro-phenyl) -isoxazol-3-yl] -methanol; Slowly lithium aluminum hydride (320 mg, 8.4 mmol) was added to a solution of 5- (3-chloro-phenyl) -isoxazole-3-carboxylic acid ethyl ester (2.0 g, 8.4 mmol) in THF (100 mL). at room temperature. After 1 hour, the reaction mixture was set with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was then purified by flash column chromatography using 15-40% ethyl acetate in hexane to give [5- (3-chloro-phenyl) -isoxazol-3-yl] -methanol (1.32 g, 75% , yellow solid). 1 HOUR NMR (CDCl 3) d (ppm): 7.78 (s, 1 H), 7.68 (m, 1 H), 7.43 (m, 2 H), 6.63 (s, 1 H), 4.84 (d, 2 H), 2.23 (t , 1 HOUR).

EXAMPLE 23 5- (3-Chloro-phenyl) -isoxazol-3-ylmethyl ester of methanesulfonic acid Triethylamine (965 mg, 9.5 mmol) and methanesulfonyl chloride (820 mg, 7.2 mmol) were added to a solution of [5- (3 -chloro-phenyl) -isoxazol-3-yl] -methanol (1.0 g, 4.8 mmol) in dichloromethane (50 ml) at 0 ° C. After 1 hour, the reaction mixture was set with saturated cold sodium bicarbonate and then the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 5- (3-chloro-phenyl) ) -isoxazole-3-ylmethyl ester of methanesulfonic acid (1.4 g, 100%, light brown solid). 1 H NMR (CDCl 3) d (ppm): 7.80 (s, 1 H), 7.70 (m, 1 H), 7.45 (m, 2 H), 6.73 (s, 1 H), 5.37 (s, 2 H), 3.16. (s, 3H).

Example 24 5- (5-Chloro-2-fluoro-phenyl) -3-chloromethyl- [1, 2,4] oxadiazole The acyclic intermediate was prepared from 2-fluoro-5-chlorobenzoic acid (550 mg, 3.15 mmol ), EDCl (665 mg, 3.47 mmol), HOBT (469 mg, 3.47 mmol) and 2-chloro-N-hydroxy-acetamidine (377 mg, 3.47 mmol) in DMF (10 mL). To effect the cyclization to oxadiazole, DMF (15 ml) was added to the intermediate residue and the mixture was heated for 1 hour. The product was purified by flash column chromatography using 10% ethyl acetate in hexane to give the title compound (438 mg, 56% yield after 2 steps, white solid). 1 H NMR (CDCl 3) d (ppm): 8.16 (m, 1 H), 7.58 (m, 1 H), 7.29 (m, 1 H), 4.72 (s, 3 H). Preparation of the final compounds Example 25 7- [5- (5-Chloro-2-fluorophenyl) -1,2,4-oxadiazol-3-yl] -3- (2-thienyl) -6,7-dihydro-5H - [1, 2,4] triazolo [3,4-b] [1,3] thiazine To a solution of methanesulfonate of 2- [3- ( { [5- (5-chloro-2-fiuorophenyl) - 1, 2,4-oxadiazol-3-yl] methyl.} Thio) -5- (2-thienyl) -4H-1, 2,4-triazoI-4-yl-ethyl (43 mg) in DMF (2 ml) Sodium hydride (10 mg) was added at -78 ° C with stirring. The mixture was allowed to reach room temperature and was stirred for another 3 h before adding MeOH (1 ml) and subsequent concentration on silica gel. Purification by chromatography on silica gel using DCM: EA: MeOH 70: 30: 2 as eluent gave 2.8 mg of the title compound. 1 H NMR: 8.07 (dd, 1 H), 7.56 (m, 1 H), 7.51 (dd, 1 H), 7.47 (dd, 1 H), 7.17-7.23 (m, 2H), 4.86 (dd, 1 H), 4.60 (m, 1 H), 4.38 (m, 1 H), 2.82 (m, 2H). Example 26 a) 9-. { [5- (3-chlorophenyl) -1,4,4-oxadiazol-3-yl] methyl} 3-pyridin-4-yl-6,7,8,9-tetrahydro-5H- [1, 2,4] triazolo [4,3-a] [1, 3] diazepine NaH (65 mg, 0.28 was added mmol) to a solution of 3-pyridin-4-yl-6,7,8,9-tetrahydro-5H- [1, 2,4] triazolo [4,3-a] [1,3] diazepine (54 mg , 0.25 mmol) in DMF (5 ml). After 10 min, 3- (chloromethyl) -5- (3-chlorophenyl) -1,2,4-oxadiazole (65 mg, 0.28 mmol) was added at room temperature. Stirring was continued overnight and sat. NH4Cl, and the mixture was extracted with EA. The organic phase was dried and concentrated. Flash chromatography (DCM / MeOH 20: 1) gave 56 mg (54%) of the title compound. 1 H NMR: 1.89 - 2.01 (m, 4H), 3.33 - 3.42 (m, 2H), 3.90 - 3.98 (m, 2H), 4.88 (s, 2H), 7.42 - 7.49 (m, 3H) , 7.53 (m, 1 H), 7.98 (m, 1 H), 8.09 (m, 1 H), 8.71 (d, 2 H). The following compounds were prepared in a similar manner: b) 9-. { [5- (3-chlorophenyl) isoxazol-3-yl] methyl} -3- (3,5-difluorophenyl) -6,7,8,9-tetrahydro-5H- [1, 2,4] triazolo [4,3-al [1,3] diazepine; Yield 31.8 mg (61%) yellow solid; 1 H NMR CDCl 3: 7.95 (s, 1 H), 7.68 (m, 1 H), 7.41 (m, 2 H), 7.13 (m, 2 H), 6.95 (m, 2 H), 4.77 (s, 2 H), 3.91 ( m, 2H), 3.22 (m, 2H), 1.93 (broad, 4H). c) 9-. { [5- (3-chlorophenyl) isoxazol-3-yl] methyl} -3- (4-methoxyphenyl) = 6,7,8,9-tetrahydro-5H- [1, 2,4] triazolo [4,3-a] [1, 3] diazepine; yield 17.2 mg (45%) yellow solid; 1 H NMR CDCI3: 7.52 (broad, 1 H), 7.49 (m, 1 H), 7.41 (d, 2H), 7.28 (m, 2H), 7.01 (d, 2H), 4.77 (s, 2H), 3.89 (s, 4H), 3.2 (m, 2H), 2.32 (s, 2H), 2.01 (m, 4H). d) 9-. { [5- (3-chlorophenyl) isoxazol-3-yl] methyl} -3-pyridin-4-yl-6,7,8,9-tetrahydro-5H- [1,2,4] triazolo [4,3-a] [1,3] diazepine; 47.4 mg (65%) yellow solid; 1 H NMR CDCl 3: 8.79 (broad, 2H), 7.79 (m, 1H), 7.68 (d, 1H), 7.53 (m, 2H), 7.51 (d, 2H), 6.99 (s, 1H), 4.79 (s, 2H), 3.96 (m, 2H), 3.22 (s, 2H), 1.94 (m, 4H). e) 9-. { [5- (5-chloro-2-fluorophenyl) -1,2,4-oxadiazol-3-yl] methyl} 3-pyridin-4-yl-6,7,8,9-tetrahydro-5H- [1,2,4] triazolo [4,3-a] [1,3] diazepine; 28 mg (33%) white solid; 1 H NMR CDCl 3: 1.90 - 2.01 (m, 4H), 3.37 - 3.41 (m, 2H), 3.95 - 3.998 (m, 2H), 4.94 (s, 2H), 7.22 (t, 1H), 7.49 -7.59 (m, 3H), 8.11 (q, 1H), 8.76 (q, 2 H). f) 9-. { [5- (3-chlorophenyl) -1,2,4-oxadiazol-3-yl] methyl} -3- (3,5-difluorophenyl) -6,7,8,9-tetrahydro-5H- [1,2,4] triazolo [4,3-a] [1,3] diazepine; 10 mg (10%) white solid; 1 H NMR CDCl 3: 1.89-2.01 (m, 4H), 3.38 - 3.46 (m, 2H), 3.90 - 3.98 (m, 2H), 4.90 (s, 2H), 6.85-6.95 ( m, 1H) 7.08-7.15 (m, 2H), 7.49 (t, 1H), 7.58 (d, 1H), 8.03 (d, 1H), 8.14 (m, 1 H). g) 9-. { [5- (3-chlorophenyl) -1,2,4-oxadiazol-3-yl] methyl} -3- (4-methoxyphenyl) -6,7,8,9-tetrahydro-5H- [1,2,4] triazolo [4,3-a3 [1,3] diazepine; 8 mg (6%) tan solid; 1 H NMR CDCl 3: 1.64 (broad, 4H), 3.18 (m, 2H), 3.60 (m, 5H), 4.56 (s, 2H), 6.87 (d, 2H) 7.26 (d, 2H), 7.48 (m, 1H), 7.55 (m, 1H), 7.88 (m, 1 H).

Example 27 9-. { 1- [5- (3-chlorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} 3-pyridin-4-yl-6,7s8,9-tetrahydro-5H- [1,2,4] triazolo [4,3-a] [1,3] diazepine The title compound was prepared in a manner analogous to 9-. { [5- (3-chlorophenyl) -1,4,4-oxadiazol-3-yl] methyl} -3-pyridin-4-yl-6,7,8,9-tetrahydro-5H- [1,2,4] triazolo [4,3-a] [1, 3] diazepine from methanesulfonate of 1- [ 5- (3-chlorophenyl) -1,2,4-oxadiazol-3-yl] ethyl (186 mg, 0.61 mmol), 3-pyridin-4-yl-6,7,8,9-tetrahydro-5H- [ 1,2,4] triazolo [4,3-a] [1,3] diazepine (200 mg, 0.56 mmol) to give 8.1 mg (4%) of the title compound. 1 H NMR: 1.83 (d, 3H), 1.86 - 1.95 (m, 4H), 3.16 - 3.27 (m, 1H), 3.43 - 3.53 (m, 1H), 3.75 - 3.87 (m, 1H), 3.95 - 4.07 (m, 1H), 5.54 ( q, 1H), 7.41-7.52 (m, 3H), 7.52-7.5 (m, 1H), 8.01 (m, 1H), 8.12 (m, 1H), 8.73 (m, 2 H).

Example 28 7-. { [5- (3-chlorophenyl) -1,2,4-oxadiazol-3-yl] methyl} 3-pyridin-4-yl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazole nBuLi (2.5 M, hex., 600 μl) was added to a solution of 3-pyridin-4-yl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazole (250 mg, 1.33 mmol) in THF (13 ml) at 0 ° C. After 10 min the reaction mixture was cooled to -78 ° C and 3- (bromomethyl) -5- (3-chlorophenyl) -1,2,4-oxadiazole (400 mg, 1.46 mmol) in THF (10 mg) was added. ml). After stirring at -78 ° C for 30 min stirring was continued at 0 ° C reaching room temperature overnight. Saturated aqueous NH 4 Cl was added and the mixture was extracted with EA. The organic phase was washed with water and brine, dried and concentrated. Flash chromatography (DCM / MeOH 40: 1) followed by preparative HPLC afforded 6.5 mg (1%) of the title compound. 1 H NMR: 2.72 (m, 1 H), 3.13 (m, 2 H), 3.62 (m, 1 H), 3.93 (m, 1 H), 4.31 (m, 2 H), 7.47 (t, 1 H), 7.56 (m, 1 H ), 7.74 (d, 2H), 7.98 (m, 1H), 8.08 (m, 1H), 8.74 (m, 2H).

Example 29 9-. { [5- (3-chlorophenyl) -1,4,4-oxadiazol-3-yl] methyl} -3- (trifluoromethyl) -6,7,8,9-tetrahydro-5H- [1, 2,4] triazolo [4,3-a] [1, 3] diazepine The title compound was prepared in a manner analogous to 9-. { [5- (3-chlorophenyl) -1,4,4-oxadiazol-3-yl] methyl} -3-pyridin-4-yl-6,7,8,9-tetrahydro-5H- [1, 2,4] triazolo [4,3-a] [1, 3] diazepine from 3- (chloromethyl) -5- (3-chlorophenyl) -1, 2,4-oxadiazole (89 mg, 0.39 mmol), 3- (trifluoromethyl) -6,7,8,9-tetrahydro-5H- [1, 2.4 ] triazolo [4,3-a] [1, 3] diazepine (73 mg, 0.35 mmol.) Column chromatography (hep./EA 1: 1) yielded 85 mg (61%) of the title compound. NMR: 1.88 (m, 2H), 1.94 (m, 2H), 3.26 - 3.35. (m, 2H), 3.98 - 4.07 (m, 2H), 4.83 (s, 2H), 7.46 (m, 1 H), 7.50 - 7.57 (m, 1 H), 7.98 (m, 1 H), 8.09 ( m, 1 H). EXAMPLE 30 8- [3- (3-Chloro-phenyl) - [1, 2,4] oxadiazol-5-yl] -3- (4-methoxy-phenyl) -5,6,7,8-tetrahydro- [ 1, 2, 4] triazole [4,3-a] pyrazine Trifluoroacetic acid (0.5 ml) was added to a solution of tert-butylester of 8- [3- (3-chloro-phenyl) - [1, 2,4] oxadiazol-5-yl] -3- (4-methoxy-phenyl) -5,6-dihydro-8H- [1, 2,4] triazolo [4,3-a] pyrazine-7-carboxylic acid (72.5 mg, 0.14 mmoi) in dichloromethane (1 ml) at 0 ° C. The reaction mixture was then diluted with dichloromethane. After 15 minutes, the reaction was warmed to room temperature and stirred for an additional hour. It was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated. Purification was performed by flash column chromatography on silica gel using 85-90% ethyl acetate in hexanes to 2% ammonia in methanol in dichloromethane followed by trituration with diethylether to give the title compound (40.6 mg, 69% ). 1 H NMR (CDCl 3) d (ppm): 8.10 (m, 1 H), 8.00 (m, 1 H), 7.67 (m, 2 H), 7.48 (m, 2 H), 7.05 (m, 2 H), 7.86 (m , 1 H), 4.09 (m, 3 H), 3.89 (s, 3 H), 3.47 (m, 2 H), 3.24 (m, 1 H), 2.83 (broad, 1 H). EXAMPLE 31 8- [3- (3-Chloro-phenyl) - [1,4] oxadiazol-5-yl] -3- (4-methoxy-phenyl) -7-methyl-5,6,7,8 -tetrahydro- [1, 2,4] triazolo [4,3-a] pyrazine Formic acid (0.1 ml), formaldehyde (37% by weight in solution in water, 0.1 ml) and sodium cyanoborohydride (1.0) were added. M in THF, 0. 1 ml) to a solution of 8- [3- (3-chloro-phenyl) - [1, 2,4] oxadiazol-5-yl] -3- (4-metsxy-phenyl) -5, 6,7,8-tetrahydro- [1, 2,4] triazolo [4,3-a] pyrazine (30 mg, 0.071 mmol) in methanol (0.8 ml) at room temperature. After stirring for 30 minutes, the reaction mixture was diluted with water and then extracted with chloroform (4 times), dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel using 50% ethyl acetate in hexanes, ethyl acetate and 2M 2M ammonia in methanol in dichloromethane afforded the title compound (23.8 mg, 77%). 1 H NMR (CDCl 3) d. (ppm): 8.04 (m, 1 H), 7.93 (, 1 H), 7.68 (m, 2H), 7.42 (, 2H), 7.03 (m, 2H), 4.37 (m, l H), 4.07 (m, 2H), 3.89 (m, 3H), 3.82 (m, 2H), 3.1 1 (m, 1 H), 2.88 (m, 1 H), 2.56 (s, 3H) ). Pharmacology The pharmacological properties of the compounds of the invention can be analyzed using standard assays of functional activity. Examples of assays with glutamate receptors are well known in the art and are described, for example, in Aramori et al., Neuron 8: 757 (1992), Tanabe et al. , Neuron 8: 1 69 (1992), Miller et al., J. Neuroscience 15: 6103 (1995), Balazs, et al., J. Neurochemistry 69: 151 (1997). The methodology described in these publications is incorporated in this document as a reference. Conveniently, the compounds of the invention can be studied by means of an assay that measures the mobilization of intracellular calcium, [Ca2 +] ¡in cells expressing mGluR5. For FLI PR analysis, cells expressing human mGluRd were seeded, as described in patent WO97 / 05262, on plates with 96 clear cavities and black sides coated with collagen and the mobilization of [Ca2 +] was analyzed. 24 hours after planting. Experiments with FLIPR were carried out using a 0.800 W laser device and a CCD camera shutter speed of 0.4 seconds. Each experiment with FLIPR began with 160 μl of buffer in each well of the plate. After each addition of the compound, samples of the fluorescence signals were taken, 60 times at 1 second intervals followed by 3 samples at intervals of d seconds. The responses were measured as the peak height of the response within the same period. Determinations of the values of CE5o and Cl50 were made from the data obtained from response-concentration curves of 8 points (CRC) made in duplicate. The agonist CRC was generated by scaling up all the responses with respect to the maximum response observed for plaque. The antagonist block of the agonist test was normalized for the average response of the agonist test in 14 control cavities of the same plate. The authors have validated a secondary functional assay for mGluRdd, as described in patent WO97 / 06252, based on the replacement of inositol phosphate (IP3). The accumulation of IP3 is measured as an index of phospholipase C turnover mediated by the receptor. GHEK cells, stably expressing human mGluRdd receptors, were incubated with [3 H] myo-inositol overnight, washed three times with HEPES saline buffer and preincubated for 10 minutes with 10 mM LiCl. The compounds (agonists) were added and incubated for 30 minutes at 37 ° C. Antagonist activity was determined by preincubation of the test compounds for 15 minutes, then incubation in the presence of glutamate (80 μM) or DHPG (30 μM) for 30 minutes. The reactions were terminated with the addition of perchloric acid (5%). Samples were collected and neutralized, and the inositol phosphates were separated using Gravity-Fed ion exchange columns. In the assay described below, a detailed protocol of the tests with the compounds of the invention is provided. Assay of the receptor antagonistic activity of Group I For the FLI PR assay, cells expressing human mGluR5 were seeded, as described in patent WO97 / 05252, on plates with 96 transparent bottom cavities and black sides coated with collagen and the mobilization of [Ca2 +] ¡24 hours after sowing was analyzed. The cell cultures of the 96-well plates were loaded with a solution of the 4 μM acetoxymethyl ester form of the fluorescent calcium fluoride-3 (Molecular Probes, Eugene, Oregon) in 0.01% pluronic. All tests were carried out in a buffer solution containing 127 mM NaCl, 5 mM KCl, 2 mM MgCl 2, 0.7 mM NaH 2 P0 4, 2 mM CaCl 2, 0.422 mg / ml NaHCO 3, 2.4 mg / ml HEPES, glucose 1. 8 mg / ml and Fraction IV BSA 1 mg / ml (pH 7.4). Experiments with FLIPR were performed using a 0.800 W laser device and a CCD camera shutter speed of 0, 4 seconds with excitation and emission wavelengths of 488 nm and 562 nm, respectively. Each experiment with FLIPR began with 160 μl of buffer in each well of the plate. An addition of 40 μl of the antagonist plate was made and then a 50 μl addition of the agonist plate. After each addition, samples of the fluorescence signals were taken, 50 times at 1 second intervals followed by 3 samples at 5 second intervals. The responses were measured as the peak height of the response within the same period. Determinations of the EC50 and Cl50 values were made from the data obtained from response-concentration curves of 8 points (CRC) made in duplicate. The agonist CRC was generated by scaling up all the responses with respect to the maximum response observed for plaque. The antagonist block of the agonist test was normalized for the average response of the agonist test in 14 control cavities of the same plate.

Measurement of inositol phosphate turnover in intact whole cells GHEK cells, stably expressing human mGluR5d receptors, were incubated on 24-well plates coated with poly-L-lysine at a rate of 40 x 104 cells / well in medium that contains 1 μCi / cavity [3H] myo-inositol. The cells were incubated overnight (16 h), washed three times with HEPES saline buffer and incubated for 1 hour at 37 ° C in HEPES saline buffer (146 mM NaCl, 4.2 mM KCl, 0.5 mM MgCl 2, glucose 0.1%, 20 mM HEPES, pH 7.4) supplemented with glutamate pyruvate transaminase 1 unit / ml and 2 mM pyruvate. The cells were washed once with HEPES saline buffer and pre-incubated for 10 minutes in HEPES saline buffer solution containing 10 mM LiCl. The compounds (agonists) were added and incubated at 37 ° C for 30 minutes. The antagonist activity was determined by pre-incubation of the test compounds for 15 minutes, then by incubation in the presence of glutamate (80 μM) or DHPG (30 μM) for 30 minutes. The reaction was terminated by adding 0.5 ml of perchloric acid (5%) on ice, with incubation at 4 ° C for at least 30 minutes. Samples were collected in 1 d Falcon tubes and the inositol phosphates were separated using Dowex columns, as described below.

Test with inositol phosphates using Gravity-Fed ion exchange columns Preparation of the ion exchange columns The ion exchange resin (Dowex AG1 -X8 forms formate, 200-400 mesh, BIORAD) was washed three times with distilled water and stored at 4 ° C. 1.6 ml of resin was added to each column and then washed with 3 ml of 2.6 mM HEPES, 0 mM EDTA, pH 7.4. a) Sample treatment Samples were collected in 15 ml Falcon tubes and neutralized with 0.375 M HEPES, 0.75 M KOH. 4 ml of HEPES / EDTA (2.5 / 0.5 mM, pH 7.4) was added to precipitate perchlorate of potassium The supernatant was added to the already prepared Dowex columns. b) Separation of nositol phosphate The glycero phosphatidyl inositol was eluted with 8 ml of 30 mM ammonium formate. The total inositol phosphates were eluted with 8 ml of 700 mM ammonium formate / 100 mM formic acid and the eluate was collected in scintillation vials. The eluate was counted with 8 ml of flashing liquid. One aspect of the invention relates to a method for inhibiting mGluRd activation, which comprises treating a cell containing the receptor with an effective amount of the compound of formula I.

Testing of active compounds against TLESR Adult Labrador Retriever dogs of both sexes are used, trained to stand on a Pavlov sling. Esophagostomies of mucosa to skin are practiced and the dogs are allowed to recover completely before proceeding to the experiments. Measurement of motility In summary, after a fasting of about 17 hours with unlimited amount of water, a multilumen tube / lateral hole assembly (Dentsleeve, Adelaide, South Australia) is introduced through the esophagostomy to measure gastric pressures , of the lower esophageal sphincter (LES) and esophageal sphincter. The whole is perfused with water using a low-rate manometer perfusion pump (Dentsleeve, Adelaide, South Australia). A tube is perfused with air in the oral direction to make measurements when swallowing and a pH monitored by antimony electrode 3 cm above the LES. All signals are amplified and transferred to a personal computer at 10 Hz. When a free baseline measurement of gastric phase / SLE motor activity is obtained, a placebo is administered intravenously (NaCl at 0.9%) or the test compound (iv 0.5 ml / kg) in an antepierna vein. Ten minutes after intravenous administration, a nutritious food is infused (10% peptone, 5% D-glucose, 5% lntralipid, pH 3.0) into the stomach through the central lumen at a rate of 100 ml / min to a final volume of 30 ml / kg. After the infusion of the nutrient food, air is infused at a rate of 600 ml / min until an intragastric pressure of 10 ± 1 mmHg is obtained. The pressure is maintained at this level throughout the experiment by an infusion pump to continue infusing air or to expel air from the stomach. The duration of the experiment from the start of the infusion of the nutrient until the completion of the insufflation of air is 45 minutes.

The procedure has been validated as a reliable means of provoking TLESRs. TLESRs are defined as a reduction in the pressure of the lower esophageal sphincter (with reference to intragastric pressure) at a rate of > 1 mmHg / s. Relaxation should not be preceded by a pharyngeal signal of = 2s before, in which case, relaxation can be classified as induced by swallowing. The pressure difference between the LES and the stomach should be less than 2 mmHg, and the duration of complete relaxation greater than 1 s. Abbreviations atm atmosphere ac. aqueous BOC tert-butoxycarbonyl BSA Bovine serum albumin nBu butyl normal CCD Device coupled to charges MCPBA meta-chloroperoxybenzoic acid CRC Response curve-Concentration DCM dichloromethane DEAD diethyl azodicarboxylate DHPG 3,5-dihydroxyphenylglycine DMAP 4 (? /,? / - dimethylamino) pyridine DMF? /,? / - dimethylformamide EA ethyl acetate EDC 1 Ethyl-3- (3-dimethylaminopropyl) carbodiimide EDTA Ethylenediaminetetraacetic acid FLIPR Fluorometric imaging plate reader GHEK Human embryonic kidney containing GLAST aspartate / glutamate transporter h hour HBTU O-Benzotriazole hexafluorophosphate-1 - l -? /,? /,? / ',? /' - tetramethi I uronium HEPES 4- (2-hydroxyethyl) -1-piperazinetansulfonic acid (buffer) hep heptane hex hexane (s) IP3 inositol triphosphate LAH lithium aluminum hydride Novozyme 436® Candida Antartica Lipase with polymer support (Novozymes, Bagsvaerd, Denmark) o.n. overnight pCc pyridinium chlorochromate PPTS p-toluensulfonate priridinium prep r.t. ambient temperature sat saturated TBAF tetrabutylammonium fluoride THF tetrahydrofuran pTsOH p-toluenesulfonic acid Results The typical values of CI5o. measured in the assays that were just described, are 1 0 μM or less. In one aspect of the invention, the Cl50 value is less than 2 μM. In another aspect of the invention, the Cl50 value is less than 0.2 μM. In a further aspect of the invention the IC50 value is less than 0.06 μM. The following are examples of Cl50 values for individual compounds: Composite FLIPR Cl 50 7- { [5- (3-chlorophenyl) -1,4,4-oxadiazol-3-yl] methyl} -3-pyridin-4- 49 nM il-6,7-dihydro-5H-pyrrolo [2,1-c] [1, 2,4] triazole 9-. { [5- (3-chlorophenyl) -1,4,4-oxadiazol-3-yl] ethyl} -3-pyridin-4-yl-81 nM 6,7,8,9-tetrahydro-dH- [1, 2,4] triazolo [4,3-a] [1, 3] diazepine

Claims (38)

1. REIVI NDICATIONS A compound of formula I: wherein X1, X2, X3, X4, and X5 are independently selected from the group consisting of C, CR5, N, O, and S, wherein at least one of X1, X2, X3, X4, and X5 does not is N; X6 is selected from the group consisting of a bond and CR5R6; X7 is CR5 or N; X8 is selected from the group consisting of a bond, CR5R6, NR5, O, S, SO, and S02; X9 is CR5 or N; X10 is selected from the group consisting of a bond, CR5R6, (CR5R6) 2, O, S, and NR5; R1 is selected from the group consisting of hydroxy, halo, nitro, C-i. 6alkylhalo, OC-? _6alkylhalo, C1 -6alkyl, OC1 -6alkyl, C2-6alkenyl, OC2-6alkenyl, C2-6alkynyl, OC2-6alkynyl, C0-6alkylC3-6alciumalkyl, OC0-6alkylC3-6cycloalkyl, Coalkylaryl , OCo-6alkylaryl, CHO, (CO) R5, 0 (CO) R5, 0 (CO) OR5, 0 (CN) OR5, C1 -6alkylOR5, OC2-6alkylOR5, C ^. 6alkyl (CO) R5, OC1-6alkyl (CO) R5, C0-6alkylCO2R5, OC1 -6alkylCO2R5, C0-6alkylcyano, OC2.6alkylcyano, C0-6alkylNR5R6, OC2-6alkylNR5R6, C6alkyl (CO) NR5R6, OC1- 6alkyl (CO) NR5R6, Co-6alkylNR5 (CO) R6, 0C2-6alkylNR5 (CO) R6, Co-6alkylNR5 (CO) NR5R6, C0-6alkylSR5, 0C2- 6alkylSR5, C0-6alkyl (SO) R5, OC2-6alkyl (SO) R5, C0-6alkylSO2R5, 0C2-6alkylS02R5, Co-6alkyl (S02) NR5R6, OC2-6alkyl (S02) NR5R6, C0-6alkININ (S02) R6, OC2-6alkINR5 (S02) R6, C0-6alkylNR5 (SO2) NR5R6, OC2-6alkINR5 (S02) NR5R6, (CO) NR5R6, 0 (CO) NR5R6, NR5OR6, C0-6alkylNR5 (CO) OR6 , OC2-6alkylNR5 (CO) OR6, S03R5 and a d or 6-membered ring containing atoms selected independently from the group consisting of C, N, O and S, wherein the ring may be substituted with one or more A; R2 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C1-6alkylhalo, OC1-6alkylhalo, C1-6alkyl, OC6-6alkyl, C2- 6alkylene, OC2-6alkenyl, C2.6alkynyl, OC2-6alkynyl, C0-6alkylC3- eccycloalkyl, OC0-6alkylC3.6cycloalkyl, Co-6alkylaryl, OCo-6alkylaryl, CHO, (CO) R5, 0 (CO) R5, 0 (CO ) OR5, 0 (CN) OR5, C1-6alkylOR5, OC2-6alkylOR5, d ^ alki COJR5, OC1 -6alkyl (CO) R5, C0-6alkylCO2R5, Od. 6alkylC02R5, C0-6alkylcyano, OC2-6alicyclic, C0-6alquiINR5R6, OC2, 6alkylNR5R6, C1-6alkyl (CO) NR5R6, OC1.6alkyl (CO) NR5R6, C0, 6alkylNR5 (CO) R6, OC2-6alkylNR5 (CO) R6, C0-6alkylNR5 (CO) NR5R6, C0. 6alkylSR5, OC2-6alkylSR5, C0-6alkyl (SO) R5, OC2-6alkyl (SO) R5, C0-6alkylS02R5, OC2-6alkylS02R5, C0-6alkyl (SO2) NR5R6, OC2-6alkyl (S02) NR5R6, Co- 6alkylNR5 (S02) R6, OC2-6alkINR5 (S02) R6, C0. 6alkylNR5 (S02) NR5R6, OC2-6alkylNR5 (S02) NR5R6, (CO) NR5R6, 0 (CO) NR5R6, NR5OR6, C0-6alkylNR5 (CO) OR6, OC2-6alkylNR5 (CO) OR6, S03R5 and a d or 6 member ring containing atoms selected independently from the group consisting of C, N, O and S, wherein the ring can be substituted with one or more A; R3 is a 5- or 6-membered ring containing atoms selected independently from the group consisting of C, N, O and S, wherein the ring can be substituted with one or more A; R4 is selected from the group consisting of hydroxy, halo, nitro, d. 6alkylhalo, OC -6alkylhalo, C1 -6alkyl, OC1 -6alkyl, C2-6alkenyl, OC2- 6alkenyl, C2_6aIquinyl, OC2-6alkynyl, C0-6alkylC3-6cycloalkyl, OC0-6alkylC3-6cycloalkyl, Co-ealkylaryl, OCy-ealkylaryl, CHO, (CO) R5, 0 (CO) R5, 0 (CO) OR5, 0 (CN) OR5, C1 -6alkylOR5, OC2-6alquiIOR5, d. 6alkyl (CO) R5, OC1 -6alkyl (CO) R5, C0-6alkylCO2R5, Od.ealkylCOsR5, C0-6alkylcyano, OC2-6alkylcyano, Co-6alkylNR5R6, OC2-6alkylNR5R6, d. 6alkyl (CO) NR5R6, OC1 -6alkyl (CO) NR5R6, C0-6alkylNR5 (CO) R6, OC2-6alkINIR (CO) R6, C0-6alkylNR5 (CO) NR5R6, C0-6alkylSR5, OC2_6alkylSR5, C0.6alkyl (SO) R5, OC2-6aiquil (SO) R5, C0-6alkylSO2R5, OC2. 6alkylS02R5, C0-6alkyl (SO2) NR5R6, OC2-6alkyl (S02) NR5R6, C0-6alkylNR5 (S02) R6, OC2-6alkylNR5 (S02) R6, C0-6alkylNR5 (SO2) NR5R6, OC2-6alkylNR5 (S02) NR5R6, (CO) NR5R6, 0 (CO) NR5R6, NR5OR6, C0-6alkylNR5 (CO) OR6, OC2-6alkylNR5 (CO) OR6, S03R5 and a d or 6-membered ring containing selected atoms independently of the group consisting of C, N, O and S, wherein the ring can be substituted with one or more A; R5 and R6 are independently selected from the group consisting of hydrogen, C1 -6alkyl, C3-7cycloalkyl and aryl; A is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C1-6alkylhalo, OC1 -6alkylhalo, C1 -6alkyl, OC1 -6alkyl, C2, 6alkenyl, OC2-6alkenyl, C2-6alkynyl, OC2-6alkynyl, C0-6alkylC3- eccycloalkyl, OC0-6alkylC3-6cycloalkyl, Co-ealkylaryl, OC0-6alkylaryl, CHO, (CO) R5, 0 (CO) R5, 0 (CO) OR5, 0 (CN) OR5, C1-6alkylo5 , OC2-6alkylOR5, C1-6alkyl (CO) R5, OC1 -6alkyl (CO) R5, Co-6alkylIC2R5, Od. 6alkylC02R5, Co-6alkylcyano, OC2-6alkylcyano, C0-6alkylNR5R5, OC2-6alkylNR5R8, d.6alkyl (CO) NR5R8, OC1 -6alkyl (CO) N R5R8, C0- 6alkylNR5 (CO) R8, OC2-6alkIN R5 (CO) R8, C0-6alkINR5 (CO) N R5R8, C0-6alkylSR5, OC2-6alkISIS5, C0-6alkyl (SO) R5, OC2-6alkyl ( SO) R5, C0-6alkylS02R5, OC2-6alkylS02R5, C0-6alkyl (SO2) NR5R8, OC2- 6alkyl (SO2) NR5R8, C0-6alkylNR5 (SO2) R8, OC2-6alkylNR5 (S02) R8, C0-6alkylNR5 (S02) NR5R8, OC2-6alkylNR5 (S02) NR5R8, (CO) NR5R8, 0 (CO) NR5R8, NR5OR8, C0-6alkylNR5 (CO) OR8, OC2-6alkylNR5 (CO) OR8, S03R5 and a 5- or 6-membered ring containing atoms selected independently from the group consisting of C, N, O and S; n is 0, 1. 2, 3 or 4; or a pharmaceutically acceptable salt or hydrate thereof; with the following caveats: a) when X2 = X4 = X5 = N, and either X8 or X10 is a bond, then X9 is not N, b) when X7 is N at least two of X1, X2, X3, X4 , and X5 are not N, c) X1 and X3 are not O; and with the proviso that the compound is not: 8- [d- (3-chloro-phenyl) - [1, 2,4] oxadiazol-3-ylmethyl] -3-pyridine-4-yl-5,6, 7,8-tetrahydro- [1, 2,4] triazolo [4,3-a] pyridine, 8- [5- (3-chloro-phenyl) - [1, 2,4] oxadiazol-3-ylmethyl] - 3-thiophen-2-yl-d, 6,7,8-tetrahydro- [1,4] triazolo [4,3-a] pyridine, 8- [d- (d-chloro-2-fluoro-phenyl) ) - [1, 2,4] oxadiazol-3-ylmethyl] -3-pyridin-4-yl-5,6,7,8-tetrahydro [1, 2,4] triazolo [4,3-a] pyridine, 8- [d- (3-chloro-phenyl) - [1, 2,4] oxadiazol-3-ylmethyl] -3-pyridin-4-yl-5,6,7,8-tetrahydro- [1, 2,4] triazolo [4,3-a] pyrimidine, 8- [5- (d-chloro-2-fluoro-phenyl) - [1, 2,4] oxadiazol-3-ylmethyl] -3 -pyridine-4-ld, 6, 7, 8-tetrah id ro- [1, 2, 4] triazolo [4,3-a] pyrimidine, 8- [5- (3-chloro-phenyl) - [1 , 3,4] oxadiazol-2-ylmethyl] -3-pyridin-4-yl-5, 6, 7, 8-tetrah id ro- [1, 2, 4] triazolo [4,3-a] pyrimidine, 8 -. { 1 - [5- (3-Chloro-phenyl) - [1,4] oxadiazol-2-yl] -ethyl} -3-pyridin-4-yl-d, 6,7,8-tetrahydro- [1, 2,4] triazolo [4,3-a] pyrimidine, 8- [d- (d-chloro-2-fluoro- phenyl) - [1, 2,4] oxadiazol-3-ylmethyl] -3-furan-2-yl-5, 6, 7, 8-tetrah id ro- [1, 2, 4] triazolo [4,3- a] pyrimidine, 8-. { 1 - [d- (3-Chloro-phenyl) - [1, 2,4] oxadiazol-3-yl] -ethyl} -3-pyridin-4-yl-5,6,7,8-tetrahydro- [1, 2,4] triazolo [4,3-a] pyrimidine, 3-pyridin-4-yl-8- [1 - ( dm-tolyl- [1, 2,4] oxadiazoI-3-yl) -ethyl] -5,6,7,8-tetrahydro- [1, 2,4] triazolo [4,3-a] pyrimidine, (+ -8-. { (1 S) -1- [5- (3-chlorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -3-pyridin-4-y1-5,6,7,8-tetrahydro [1, 2, 4] triazolo [4,3-a] pyrimidine, (-) - 8-. { (1 R) -1 - [5- (3-chlorophenyl) -1,4, 2,4-oxadiazol-3-yl] etii} -3-pyridin-4-yl-d, 6,7,8-tetrahydro [1, 2,4] triazolo [4,3-a] pyrimidine, 3- [d- (3-pyridin-4-yl-6 , 7-dihydro-dH- [1, 2,4] triazolo [4,3-a] pyrimidin-8-ylmethyl) [1, 3, 4] oxadiazol-2-yl] benzonitrile, 3-. { 5- [3- (2-Methoxypyridin-4-yl) -6,7-dihydro-5H- [1, 2,4] triazolo [4,3-a] pyrimidin-8-ylmethyl] [1, 3,4 ] oxadiazole-2-yl} benzonitrile, 3-. { d- [3- (2-Methoxy-pyridin-4-yl) -6,7-dihydro-5H- [1, 2,4] triazolo [4,3-a] pyrimidin-8-ylmethi] - [1, 2,4] oxadiazol-3-yl} -benzonitrile, 3-. { 3 - [(3-pyridin-4-yl-6,7-dihydro [1, 2,4] triazolo [4,3-a] pyrimidin-8 (5H) -yl) methyl] -1, 2,4- Oxadiazol-5-yl} benzonitrile, 3- (3 { [3- (2-methoxypyridin-4-yl) -6,7-dihydro [1, 2,4] triazolo [4,3-a] pyrimidin-8 (5H) - il] methyl.} -1, 2,4-oxadiazol-d-yl) benzonitrile, S-id-pyridin-1-yl-dihydroxytriazolo ^. S-a-pyrimidin-dyd H) -yl) methyl ] -1, 2,4-oxadiazol-3-yl} benzonitrile, and 3-. { d- [3- (2-Hydroxy-pyridin-4-yl) -6,7-dihydro-dH- [1, 2,4] triazolo [4,3-a] pyrimidin-8-ylmethyl] - [1, 2,4] oxadiazol-3-yl} -benzonitrile.
2. 2. The compound according to claim 1, provides that the compound is not 8- [d- (5-chloro-phenyl) - [1, 2,4] oxadiazol-3-ylmethyl] -3-furan-2-yl-5,6,7,8-tetrahydro- [1, 2,4] triazolo [4,3-a] pyrimidine.
3. 3. The compound according to claim 1, wherein R1 is halo, C6-6alkylhalo, C6-6alkyl, OC1 -6alkyl, or Co-ealkylcyano.
4. 4. The compound according to claim 1, wherein R2 is hydrogen or halo.
5. 5. The compound according to claim 1, wherein R2 is fluorine.
6. 6. The compound according to claim 1, of formula 7. The compound according to claim 6, wherein X7 is N. 8. The compound according to claim 1, of formula The compound according to claim 8, wherein X 3 is C. The compound according to claim 8, wherein X 2 is N. 1 1. The compound according to claim 1, wherein the ring containing X1, X2, X3, X4, and X5 is selected from the group consisting of: The compound according to claim 1, wherein the ring is selected from group consisting of: 13. The compound according to claim 1, wherein X7 is N. 14. The compound according to claim 13, wherein X8 is a bond. 15. The compound according to claim 13, wherein X8 is S. 16. The compound according to claim 14, wherein X9 is CR5. 17. The compound according to claim 16, wherein X10 is NR5. 18. The compound according to claim 16, wherein X10 is O. 19. The compound according to claim 16, wherein X10 is CR5R6. 20. The compound according to claim 16, wherein X10 is (CR5R6) 2. twenty-one . The compound according to claim 16, wherein X10 is a bond. 22. The compound according to claim 16, wherein X9 is CR5. 23. The compound according to claim 22, wherein X10 is a bond. 24. The compound according to claim 14, wherein X9 is N. 25. The compound according to claim 1, wherein the fused ring containing X7, X8, X9, and X10 is selected from the group consisting of: 26. The compound according to claim 1, selected from the group consisting of: 7- [5- (5-chloro-2-fluorophenyl) -1, 2,4-oxadiazol-3-yl] -3- (2-thienii) ) -6,7-dihydro-dH- [1, 2,4] triazolo [3,4-b] [1,3] thiazine, 9-. { [d- (3-chlorophenyl) -1,4, 2,4-oxadiazol-3-yl] meth i} 3-pyridin-4-yl-6,7,8,9-tetrahydro-6H- [1, 2,4] triazolo [4,3-a] [1, 3] diazepine, 9-. { 1 - [d- (3-chlorophenyl) -1,4,4-oxadiazol-3-yl] ethyl} 3-pyridin-4-yl-6,7,8,9-tetrahydro-6H- [1, 2,4] triazolo [4,3-a] [1, 3] diazepine, 7-. { [d- (3-chlorophenyl) -1,4,4-oxadiazol-3-yl] methyl} 3-pyridin-4-yl-6,7-dihydro-dH-pyrrolo [2, 1-c] [1, 2,4] triazole, 9-. { [d- (3-chlorophenyl) -1,4,4-oxadiazol-3-yl] methyl} -3- (trifluoromethyl) -6,7,8,9-tetrahydro-5H- [1, 2,4] triazolo [4,3-a] [1, 3] diazepine, 8- [3- (3-chloro -fenii) - [1, 2,4] oxadiazol-5-yl] -3- (4-methoxy-phenyl) -d, 6,7,8-tetrah id ro- [1, 2, 4] triazolo [4 , 3-a] pyrazine, 8- [3- (3-chloro-phenyl) - [1,4] oxadiazol-d-yl] -3- (4-methoxy-phenyl) -7-m ethyl -d, 6,7,8-tetrahydro- [1, 2,4] triazolo [4,3-a] pyrazine, 9-. { [d- (3-chlorophenyl) isoxazol-3-yl] methyl} -3- (3,5-difluorophenyl) -6,7,8,9-tetrahydro-6H- [1, 2,4] triazolo [4,3-a] [1,3] diazepine, 9-. { [d- (3-chlorophenyl) isoxazol-3-yl] methyl} -3- (4-methoxyphenyl) -6,7,8,9-tetrahydro-dH- [1, 2,4] triazolo [4,3-a] [1,3] diazepine, 9-. { [d- (3-chlorophenyl) isoxazol-3-yl] metii} 3-pyridin-4-yl-6,7,8,9-tetrahydro-dH- [1, 2,4] triazolo [4,3-a] [1, 3] diazepine, 9-. { [d- (d-chloro-2-f luorofenyl) -1,2,4-oxadiazol-3-yl] methyl} -3-pyridin-4-yl-ß .d.? -tetrahydro-dH-tl ^ ltriazolo-^ -Jtl ^ jdiazepine, 9-. { [d- (3-chlorophenyl) -1,4,4-oxadiazol-3-yl] methyl} -3- (3, d-difluorophenyl) -6,7,8, 9-tetrahydro-5H- [1, 2,4] triazolo [4,3-a] [1, 3] diazepine, 9-. { [d- (3-chlorophenyl) -1,2) 4-oxadiazol-3-yl] methyl} -3- (4-methoxyphenyl) -6,7,8,9-tetrahydro-6H- [1, 2,4] triazolo [4,3-a] [1, 3] diazepine, and their pharmaceutically acceptable salts. 27. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound according to any of claims 1-26, and one or more excipient diluents and / or inert pharmaceutically acceptable carriers. 28. The pharmaceutical composition according to claim 27, for use in the treatment of disorders mediated by mGluRd. 29. The compound according to any of claims 1 -26, for use in therapy. 30. The compound according to any of claims 1 -26, for use in the treatment of mGluRd-mediated transorbances. 31 Use of the compound according to any of claims 1-26 in the manufacture of a medicament for the treatment of disorders mediated by mGluRd. 32. A method for the treatment of mGluRd-mediated disorders, which comprises administering to a mammal a therapeutically effective amount of the compound according to any of claims 1 -26. 33. The method according to claim 32, wherein the mammal is a human. 34. The method according to claim 32, wherein the disorder is a neurological disorder. 35. The method according to claim 32, wherein the disorder is a psychiatric disorder. 36. The method according to claim 32, wherein the disorders are selected from chronic and acute pain disorders. 37. The method according to claim 32, wherein the disorder is a gastrointestinal disorder. 38. A method for inhibiting the activation of mGluRd receptors, comprising contacting a cell containing the receptors with an effective amount of a compound according to any of claims 1-26.