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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• the present invention relates to a new class of compounds, to pharmaceutical formulations containing said compounds and to the use of said compounds in therapy.
• the present invention further relates to the process for the preparation of said compounds and to new intermediates prepared therein.
• Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Glutamate produces its effects on central neurons by binding to and thereby activating cell surface receptors. These receptors have been divided into two major classes, the ionotropic and metabotropic glutamate receptors, based on the structural features of the receptor proteins, the means by which the receptors transduce signals into the cell, and pharmacological profiles.
• mGluRs metabotropic glutamate receptors
• Activation of mGluRs in intact mammalian neurons elicits one or more of the following responses: activation of phospholipase C; increases in phosphoinositide (PI) hydrolysis; intracellular calcium release; 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 A 2 ; increases in arachidonic acid release; and increases or decreases in the activity of voltage- and ligand-gated ion channels.
• PI phosphoinositide
• mGluR1 mGluR1 through mGluR8.
• mGluR1 mGluR1
• mGluR8 eight distinct mGluR subtypes, termed mGluR1 through mGluR8. Nakanishi, Neuron 13:1031 (1994), Pin et al., Neuropharmacology 34:1 (1995), Knopfel et al., J. Med. Chem. 38:1417 (1995).
• Further receptor diversity occurs via expression of alternatively spliced forms of certain mGluR subtypes. Pin et al., PNAS 89:10331 (1992), Minakami et al., BBRC 199:1136 (1994), Joly et al., J. Neurosci. 15:3970 (1995).
• Metabotropic glutamate receptor subtypes may be subdivided into three groups, Group I, Group II, and Group III mGluRs, based on amino acid sequence homology, the second messenger systems utilized by the receptors, and by their pharmacological characteristics.
• Group I mGluR comprises mGluR1, mGluR5 and their alternatively spliced variants. The binding of agonists to these receptors results in the activation of phospholipase C and the subsequent mobilization of intracellular calcium.
• Group I mGluRs agonists can produce postsynaptic excitation upon application to neurons in the hippocampus, cerebral cortex, cerebellum, and thalamus, as well as other CNS regions. Evidence indicates that this excitation is due to direct activation of postsynaptic mGluRs, but it also has been suggested that activation of presynaptic mGluRs occurs, resulting in increased neurotransmitter release. Baskys, Trends Pharmacol. Sci. 15:92 (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 implicated in a number of normal processes in the mammalian CNS. Activation of mGluRs has been shown to be required for induction of hippocampal long-term potentiation and cerebellar long-term depression. Bashir et al., Nature 363:347 (1993), Bortolotto et al., Nature 368:740 (1994), Aiba et al., Cell 79:365 (1994), Aiba et al., Cell 79:377 (1994).
• mGluR activation has been suggested to play a modulatory role in a variety of other normal processes including synaptic transmission, neuronal development, apoptotic neuronal death, synaptic plasticity, spatial learning, olfactory memory, central control of cardiac activity, waking, motor control and control of the vestibulo-ocular reflex. Nakanishi, Neuron 13: 1031 (1994), Pin et al., Neuropharmacology 34:1, Knopfel et al., J. Med. Chem. 38:1417 (1995).
• Group I metabotropic glutamate receptors and mGluR5 in particular, have been suggested to play roles in a variety of pathophysiological processes and disorders affecting the CNS. These include stroke, head trauma, anoxic and ischemic injuries, hypoglycemia, epilepsy, neurodegenerative disorders such as Alzheimer's disease and pain. Schoepp et al., Trends Pharmacol. Sci. 14:13 (1993), Cunningham et al., Life Sci. 54:135 (1994), Hollman et al., Ann. Rev. Neurosci. 17:31 (1994), Pin et al., Neuropharmacology 34:1 (1995), Knopfel et al., J. Med. Chem.
• Group I mGluRs appear to increase glutamate-mediated neuronal excitation via postsynaptic mechanisms and enhanced presynaptic glutamate release, their activation probably contributes to the pathology. Accordingly, selective antagonists of Group I mGluR receptors could be therapeutically beneficial, specifically as neuroprotective agents, analgesics or anticonvulsants.
• the object of the present invention is to provide compounds exhibiting an activity at metabotropic glutamate receptors (mGluRs), especially at the mGluR5 receptor.
• mGluRs metabotropic glutamate receptors
• the present invention provides a compound of formula Ia
• P is selected from the group consisting of hydrogen, C 3-7 alkyl or a 3- to 8-membered ring containing one or more atoms independently selected from C, N, O and S, which ring may optionally be fused with a 5- or 6-membered ring containing one or more atoms independently selected from the group consisting of C, N, O and S;
• R 1 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C 1-6 alkylhalo, OC 1-6 alkylhalo, C 1-6 alkyl, OC 1-6 alkyl, C 2-6 alkenyl, OC 2-6 alkenyl, C 2-6 alkynyl, OC 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, OC 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, OC 0-6 alkylaryl, CHO, (CO)R 5 , O(CO)R 5 , O(CO)OR 5 , O(CN)OR 5 , C 1-6 alkylOR 5 , OC 2-6 alkylOR 5 , C 1-6 alkyl(CO)R 5 , OC 1-6 alkyl(CO)R 5 , C 0-6 alkylCO 2 R 5 , OC 1-6 alkylCO 2 R 5 ,
• M 1 is selected from the group consisting of a bond, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 0-4 alkyl(CO)C 0-4 alkyl, C 0-3 alkylOC 0-3 alkyl, C 0-3 alkyl(CO)NR 5 , C 0-3 alkyl(CO)NR 5 C 0-3 alkyl, C 0-4 alkylNR 5 , C 0-3 alkylSC 0-3 alkyl, C 0-3 alkyl(SO)C 0-3 alkyl or C 0-3 alkyl(SO 2 )C 0-3 alkyl;
• R 2 is selected from the group consisting of hydrogen, hydroxy, C 0-6 alkylcyano, oxo, ⁇ NR 5 , ⁇ NOR 5 , C 1-4 alkylhalo, halo, C 1-4 alkyl, O(CO)C 1-4 alkyl, C 1-4 alkyl(SO)C 0-4 alkyl, C 1-4 alkyl(SO 2 )C 0-4 alkyl, (SO)C 0-4 alkyl, (SO 2 )C 0-4 alkyl, OC 1-4 alkyl, C 1-4 alkylOR 5 and C 0-4 alkylNR 5 R 6 ;
• X 1 , X 2 and X 3 are independently selected from the group consisting of CR, CO, N, NR, O and S;
• R is selected from the group consisting of hydrogen, C 0-3 alkyl, halo, C 0-3 alkylOR 5 , C 0-3 alkylNR 5 R 6 , C 0-3 alkyl(CO)OR 5 , C 0-3 alkylNR 5 R 6 and C 0-3 alkylaryl;
• M 2 is selected from a group consisting of a bond, C 1-3 alkyl, C 3-7 cycloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 0-4 alkyl(CO)C 0-4 alkyl, C 0-3 alkylOC 0-3 alkyl, C 0-3 alkylNR 5 C 1-3 alkyl, C 0-3 alkyl(CO)NR 5 , C 0-4 alkylNR 5 , C 0-3 alkylSC 0-3 alkyl, C 0-3 alkyl(SO)C 0-3 alkyl and C 0-3 alkyl(SO 2 )C 0-3 alkyl;
• R 3 is selected from a group consisting of hydrogen, hydroxy, C 0-6 alkylcyano, oxo, ⁇ NR 5 , ⁇ NOR 5 , C 1-4 alkylhalo, halo, C 1-4 alkyl, O(CO)C 1-4 alkyl, C 1-4 alkyl(SO)C 0-4 alkyl, C 1-4 alkyl(SO 2 )C 0-4 alkyl, (SO)C 0-4 alkyl, (SO 2 )C 0-4 alkyl, OC 1-4 alkyl, C 1-4 alkylOR 5 and C 0-4 alkylNR 5 R 6 ;
• X 4 is selected from the group consisting of C 0-4 alkylR 5 , C 0-4 alkyl(NR 5 R 6 ), C 0-4 alkyl(NR 5 R 6 ) ⁇ N, NR 5 C 0-4 alkyl(NR 5 R 6 ) ⁇ N, NOC 0-4 alkyl, C 1-4 alkylhalo, C, O, SO, SO 2 and S;
• Q is a 5- or 6-membered ring containing one or more atoms independently selected from the group consisting of C, N, O and S, which group may optionally be fused with a 5- or 6-membered ring containing one or more atoms independently selected from the group consisting of C, N, O and S and which fused ring may be substituted by one or more A;
• R 4 is selected from the group consisting of hydrogen, hydroxy, C 0-6 alkylcyano, oxo, ⁇ NR 5 , ⁇ NOR 5 , C 1-4 alkylhalo, halo, C 1-4 alkyl, OC 1-4 alkyl, OC 0-6 alkylaryl, O(CO)C 1-4 alkyl, C 0-4 alkyl(S)C 0-4 alkyl, C 1-4 alkyl(SO)C 0-4 alkyl, C 1-4 alkyl(SO 2 )C 0-4 alkyl, (SO)C 0-4 alkyl, (SO 2 )C 0-4 alkyl, C 1-4 alkylOR 5 , C 0-4 alkylNR 5 R 6 and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, wherein said ring may be substituted by one or more A;
• R 5 and R 6 are independently selected from the group consisting of hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O and S, and wherein R 5 and R 6 may together form a 5- or 6-membered ring containing one or more atoms independently selected from the goup consisting of C, N, O and S;
• any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl and C 0-6 alkylheteroaryl defined under R 1 , R 2 , R 3 , R 4 , R 5 and R 6 may be substituted by one or more A;
• A is selected from the group consisting of hydrogen, hydroxy, oxo, halo, nitro, C 0-6 alkylcyano, C 1-4 alkyl, C 0-4 alkylC 3-6 cycloalkyl, C 1-6 alkylhalo, OC 1-6 alkylhalo, C 2-6 alkenyl, OC 1-6 alkyl, C 0-3 alkylaryl, C 0-6 alkylOR 5 , OC 2-6 alkylOR 5 , C 1-6 alkylSR 5 , OC 2-6 alkylSR 5 , (CO)R 5 , O(CO)R 5 , OC 2-6 alkylcyano, C 0-6 alkylCO 2 R 5 , OC 1-6 alkylCO 2 R 5 , O(CO)OR 5 , OC 1-6 alkyl(CO)R 5 , C 1-6 alkyl(CO)R 5 , NR 5 OR 6 , C 0-6 alkylNR 5 R 6
• m is selected from 0, 1, 2, 3 and 4;
• n is selected from 0, 1, 2 and 3
• P is selected from the group consisting of thiophene, pyridyl, thiazolyl, furyl, pyrrolyl and phenyl, whereby the phenyl ring is substituted on position 3 or disubstituted on positions 2 and 5;
• R 1 is attached to P via a carbon atom on ring P and is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C 1-6 alkylhalo, OC 1-6 alkylhalo, C 1-6 alkyl, OC 1-6 alkyl, C 2-6 alkenyl, OC 2-6 alkenyl, C 2-6 alkynyl, OC 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, OC 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, OC 0-6 alkylaryl, CHO, (CO)R 5 , O(CO)R 5 , O(CO)OR 5 , O(CN)OR 5 , C 1-6 alkylOR 5 , OC 2-6 alkylOR 5 , C 1-6 alkyl(CO)R 5 , OC 1-6 alkyl(CO)R 5 , C 0-6 alkylCO
• M 1 is a bond
• X 1 selected from the group consisting of C, CO, N, O and S;
• X 2 is selected from the group consisting of C, N, O and S;
• X 3 is i) selected from the group consisting of N, O and S; or
• R is selected from the group consisting of hydrogen, C 0-3 alkyl, halo, C 0-3 alkylOR 5 , C 0-3 alkylNR 5 R 6 , C 0-3 alkyl(CO)OR 5 and CO 0-3 alkylaryl;
• M 2 is selected from a group consisting of a bond, C 1-3 alkyl, C 2-3 alkynyl, C 0-4 alkyl(CO)C 0-4 alkyl, C 0-3 alkylOC 0-3 alkyl, C 0-3 alkylNR 5 C 1-3 alkyl, C 0-3 alkyl(CO)NR 5 , C 0-4 alkylNR 5 , C 0-3 alkyl(SO)C 0-3 alkyl and C 0-3 alkyl(SO 2 )C 0-3 alkyl;
• R 3 is selected from a group consisting of hydroxy, C 0-6 alkylcyano, oxo, ⁇ NR 5 , ⁇ NOR 5 , C 1-4 alkylhalo, halo, C 1-4 alkyl, O(CO)C 1-4 alkyl, C 1-4 alkyl(SO)C 0-4 alkyl, C 1-4 alkyl(SO 2 )C 0-4 alkyl, (SO)C 0-4 alkyl, (SO 2 )C 0-4 alkyl, OC 1-4 alkyl, C 1-4 alkylOR 5 and C 0-4 alkylNR 5 R 6 ;
• X 4 is selected from the group consisting of C 0-4 alkylR 5 R 6 , C 3-7 cycloalkyl, C 1-4 alkyl(NR 5 R 6 ), NR 5 , C 0-4 alkyl(NR 5 R 6 ) ⁇ N, NR 5 C 0-4 alkyl(NR 5 R 6 ) ⁇ N, NOC 0-4 alkyl, C 1-4 alkylhalo, O, SO, SO 2 and S, and wherein the bond between M 2 and X 4 is a single bond;
• Q is i) selected from the group consisting of triazolyl, imidazolyl, oxadiazolyl, imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl and thiadiazolyl, and wherein any substitutable nitrogen atom in the ring is substituted with R 4 on such nitrogen atom and any suitable carbon atom is optionally substituted with R 4 ; and
• R 4 is selected from the group consisting of C 0-6 alkylcyano, ⁇ NC 1-4 alkyl, ⁇ NOR 5 , C 1-4 alkylhalo, halo, C 1-6 alkyl, OC 1-4 alkyl, C 2-4 alkenyl, C 0-2 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, OC 0-6 alkylaryl, OC 0-6 alkylheteroaryl, NC 0-6 alkylaryl, NC 0-6 alkylheteroaryl,C 0-6 alkylOaryl, C 0-6 alkylOheteroaryl, C 0-6 alkylNaryl, C 0-6 alkylNheteroaryl, OC 0-6 alkylOaryl, OC 0-6 alkylOheteroaryl, OC 0-6 alkylNaryl, 0-6 alkylNheter
• ii) selected from the group consisting of benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, pyridonyl, pyridazinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl and purinyl; and
• R 4 is selected from the group consisting of hydrogen, hydroxy, C 0-6 alkylcyano, ⁇ NR 5 , ⁇ NOR 5 , C 1-4 alkylhalo, halo, C 1-6 alkyl, OC 1-4 alkyl, OC 0-6 alkylaryl, O(CO)C 1-4 alkyl, C 0-4 alkyl(S)C 0-4 alkyl, C 1-4 alkyl(SO)C 0-4 alkyl, C 1-4 alkyl(SO 2 )C 0-4 alkyl, (SO)C 0-4 alkyl, (SO 2 )C 0-4 alkyl, C 1-4 alkylOR 5 , C 0-4 alkylNR 5 R 6 and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O and S, which ring may optionally be fused with a 5- or 6-membered ring containing one or more atoms independently selected from the group consisting of
• R 5 and R 6 are independently selected from the group consisting of hydrogen and C 1-6 alkyl; wherein any C 1-6 alkyl defined under R 1 , R 2 and R 4 may be substituted by one or more A;
• A is selected from the group consisting of hydrogen, hydroxy, halo, nitro, oxo, C 0-6 alkylcyano, C 0-4 alkylC 3-6 cycloalkyl, C 1-6 alkyl, C 1-6 alkylhalo, OC 1-6 alkylhalo, C 2-6 alkenyl, C 0-3 alkylaryl, C 0-6 alkylOR 5 , OC 2-6 alkylOR 5 , C 1-6 alkylSR 5 , OC 2-6 alkylSR 5 , (CO)R 5 , O(CO)R 5 , OC 2-6 alkylcyano, OC 1-6 alkylCO 2 R 5 , O(CO)OR 5 , OC 1-6 alkyl(CO)R 5 , C 1-6 alkyl(CO)R 5 , NR 5 OR 6 , OC 2-6 alkylNR 5 R 6 , C 0-6 alkyl(CO)NR 5 R 6 , OC
• m1 is selected from 0, 1, 2, 3 and 4;
• m2 is selected from 0, 1, 2 and 3;
• n is selected from 0, 1 and 2;
• t is 0 or 1
• the compound is not 5-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-thiophen-3-yl-[1,2,4]oxadiazole, 1,2-di ⁇ 2-(3-amino-phenyl)-[1,3,4]oxadiazole-yl)ethane, 1,2-di ⁇ 5-[5-(4-nitro-phenyl)furan-2-yl]-[1,3,4]oxadiazol-yl)ethane, 1,2-di ⁇ 5-[5-(4-bromo-phenyl)furan-2-yl]-[1,3,4]oxadiazol-yl)ethane, 1,2-di ⁇ 5-[5-(4-chloro-phenyl)furan-2-yl]-[1,3,4]oxadiazol-yl)ethane and 1,2-di ⁇ 5-[5-(2,4-dibromo-phen
• the present invention provides a compound of formula Ib
• P is selected from the group consisting of thiophene, pyridyl, thiazolyl, furyl, pyrrolyl and phenyl, whereby the phenyl ring is substituted on position 3 or disubstituted on positions 2 and 5;
• R 1 is attached to P via a carbon atom on ring P and is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C 1-6 alkylhalo, OC 1-6 alkylhalo, C 1-6 alkyl, OC 1-6 alkyl, C 2-6 alkenyl, OC 2-6 alkenyl, C 2-6 alkynyl, OC 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, OC 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, OC 0-6 alkylaryl, CHO, (CO)R 5 , O(CO)R 5 , O(CO)OR 5 , O(CN)OR 5 , C 1-6 alkylOR 5 , OC 2-6 alkylOR 5 , C 1-6 alkyl(CO)R 5 , OC 1-6 alkyl(CO)R 5 , C 0-6 alkylCO
• M 1 is a bond
• X 1 selected from the group consisting of C, CO, N, O and S;
• X 2 is selected from the group consisting of C, N, O and S;
• X 3 is selected from the group consisting of N, O and S, or X 3 is CH when X 2 is N, O or S;
• R is selected from the group consisting of hydrogen, C 0-3 alkyl, halo, C 0-3 alkylOR 5 , C 0-3 alkylNR 5 R 6 , C 0-3 alkyl(CO)OR 5 and C 0-3 alkylaryl;
• M 2 is selected from a group consisting of a bond, C 1-3 alkyl, C 2-3 alkynyl, C 0-4 alkyl(CO)C 0-4 alkyl, C 0-3 alkylOC 0-3 alkyl, C 0-3 alkylNR 5 C 1-3 alkyl, C 0-3 alkyl(CO)NR 5 , C 0-4 alkylNR 5 , C 0-3 alkyl(SO)C 0-3 alkyl and C 0-3 alkyl(SO 2 )C 0-3 alkyl;
• R 3 is selected from a group consisting of hydroxy, C 0-6 alkylcyano, oxo, ⁇ NR 5 , ⁇ NOR 5 , C 1-4 alkylhalo, halo, C 1-4 alkyl, O(CO)C 1-4 alkyl, C 1-4 alkyl(SO)C 0-4 alkyl, C 1-4 alkyl(SO 2 )C 0-4 alkyl, (SO)C 0-4 alkyl, (SO 2 )C 0-4 alkyl, OC 1-4 alkyl, C 1-4 alkylOR 5 and C 0-4 alkylNR 5 R 6 ;
• X 4 is selected from the group consisting of C 0-4 alkylR 5 R 6 , C 3-7 cycloalkyl, C 1-4 alkyl(NR 5 R 6 ), NR 5 , C 0-4 alkyl(NR 5 R 6 ) ⁇ N, NR 5 C 0-4 alkyl(NR 5 R 6 ) ⁇ N, NOC 0-4 alkyl, C 1-4 alkylhalo, O, SO, SO 2 and S, and wherein the bond between M 2 and X 4 is a single bond;
• Q is i) selected from the group consisting of triazolyl, imidazolyl, oxadiazolyl, imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl and thiadiazolyl, and wherein any substitutable nitrogen atom in the ring is substituted with R 4 on such nitrogen atom; and
• R 4 is selected from the group consisting of C 0-6 alkylcyano, ⁇ NC 1-4 alkyl, ⁇ NOR 5 , C 1-4 alkylhalo, halo, C 1-6 alkyl, OC 1-4 alkyl, C 2-4 alkenyl, C 0-2 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, OC 0-6 alkylaryl, OC 0-6 alkylheteroaryl, NC 0-6 alkylaryl, NC 0-6 alkylheteroaryl,C 0-6 alkylOaryl, C 0-6 alkylOheteroaryl, C 0-6 alkylNaryl, C 0-6 alkylNheteroaryl, OC 0-6 alkylOaryl, OC 0-6 alkylOheteroaryl, OC 0-6 alkylNaryl, 0-6 alkylNheter
• ii) selected from the group consisting of benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, pyridonyl, pyridazinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl and purinyl; and
• R 4 is selected from the group consisting of hydrogen, hydroxy, C 0-6 alkylcyano, ⁇ NR 5 , ⁇ NOR 5 , C 1-4 alkylhalo, halo, C 1-6 alkyl, OC 1-4 alkyl, OC 0-6 alkylaryl, O(CO)C 1-4 alkyl, C 0-4 alkyl(S)C 0-4 alkyl, C 1-4 alkyl(SO)C 0-4 alkyl, C 1-4 alkyl(SO 2 )C 0-4 alkyl, (SO)C 0-4 alkyl, (SO 2 )C 0-4 alkyl, C 1-4 alkylOR 5 , C 0-4 alkylNR 5 R 6 and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O and S, which ring may optionally be fused with a 5- or 6-membered ring containing one or more atoms independently selected from the group consisting of
• R 5 and R 6 are independently selected from the group consisting of hydrogen and C 1-6 alkyl
• any C 1-6 alkyl defined under R 1 , R 2 and R 4 may be substituted by one or more A;
• A is selected from the group consisting of hydrogen, hydroxy, halo, nitro, oxo, C 0-6 alkylcyano, C 0-4 alkylC 3-6 cycloalkyl, C 1-6 alkyl, C 1-6 alkylhalo, OC 1-6 alkylhalo, C -6 alkenyl, C 0-3 alkylaryl, C 0-6 alkylOR 5 , OC 2-6 alkylOR 5 , C 1-6 alkylSR 5 , OC 2-6 alkylSR 5 , (CO)R 5 , O(CO)R 5 , OC 2-6 alkylcyano, OC 1-6 alkylC 0-2 R 5 , O(CO)OR 5 , OC 1-6 alkyl(CO)R 5 , C 1-6 alkyl(CO)R 5 , NR 5 OR 6 , OC 2-6 alkylNR 5 R 6 , C 0-6 alkyl(CO)NR 5 R 6 ,
• m1 is selected from 0, 1, 2, 3 and 4;
• m2 is selected from 0, 1, 2 and 3;
• n is selected from 0, 1 and 2;
• t is 0 or 1
• the compound is not 5-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-thiophen-3-yl-[1,2,4]oxadiazole.
• compositions comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier.
• a pharmaceutical formulation including a compound of formula I for use in the treatment of mGluR5 receptor-mediated disorders, and particularly neurological disorders, psychiatric disorders, acute and chronic pain.
• a compound of formula I for use in therapy for the treatment of mGluR5 receptor-mediated disorders, and particularly neurological disorders, psychiatric disorders, acute and chronic pain.
• C 1-6 means a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms.
• C means 1 cabon atom.
• alkyl includes both straight and branched chain alkyl groups and may be 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.
• C 1-3 alkyl refers to an alkyl group having 1, 2 or 3 carbon atoms, and may be methyl, ethyl, n-propyl and i-propyl.
• cycloalkyl refers to an optionally substituted, saturated cyclic hydrocarbon ring system.
• C 3-7 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
• alkenyl includes both straight and branched chain alkenyl groups.
• C 2-6 alkenyl refers to an alkenyl group having 2 to 6 carbon atoms and one or two double bonds, and may be, but is not limited to vinyl, allyl, propenyl, i-propenyl, butenyl, i-butenyl, crotyl, pentenyl, i-pentenyl and hexenyl.
• alkynyl includes both straight and branched chain alkynyl groups.
• 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.
• heteroaryl refers to an optionally substituted monocyclic or bicyclic unsaturated, aromatic ring system containing at least one heteroatom selected independently from N, O or S.
• 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
• alkylaryl refers to a substituent that is attached via the alkyl group to an aryl, heteroaryl and cycloalkyl group.
• a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S includes aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated.
• 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, tetrahydropyranyl, thiomorpholinyl, phenyl, cyclohexyl, cyclopentyl and cyclohexenyl.
• a 3- to 8-membered ring containing one or more atoms independently selected from C, N, O or S includes aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated.
• rings may be, but are not limited to imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl or thiomorpholinyl, tetrahydrothiopyranyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, oxazolyl, oxazolidinonyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, triazolyl, phenyl, cyclopropyl, aziridinyl, cyclobutyl, azetidinyl, cyclopent
• a 3- to 8-membered ring containing one or more atoms independently selected from C, N, O or S, which group may optionally be fused with a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, includes aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated.
• rings may be, but are not limited to naphthyl, norcaryl, chromyl, isochromyl, indanyl, benzoimidazol or tetralinyl, benzooxazolyl, benzothiazolyl, benzofuryl, benzothienyl, benzotriazolyl, indolyl, azaindolyl, indazolyl, indolinyl, isoindolinyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, quinolinyl, quinoxalinyl and benzotriazolyl.
• ⁇ NR 5 and ⁇ NOR 5 include imino- and oximogroups carrying an R 5 substituent and may be, or be part of, groups including, but not limited to iminoalkyl, iminohydroxy, iminoalkoxy, amidine, hydroxyamidine and alkoxyamidine.
• halo may be fluoro, chloro, bromo or iodo.
• alkylhalo means an alkyl group as defined above, substituted with one or more halo.
• C 1-6 alkylhalo may include, but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and bromopropyl.
• OC 1-6 alkylhalo may include, but is not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy and difluoroethoxy.
• P may be hydrogen or C 3-7 alkyl or P may be a 3- to 8-membered ring containing one or more atoms selected from C, N, O or S said ring may be optionally fused with a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O, or S.
• P is selected from 5 and 6 membered aromatic and heteroaromatic rings.
• P is selected from thiophene, pyridyl, thiazolyl, furyl, pyrrolyl and phenyl, whereby the phenyl ring is substituted on position 3 or disubstituted on positions 2 and 5.
• P is phenyl substituted on position 3 or disubstituted on positions 2 and 5.
• P is optionally substituted via a carbon atom with 0, 1, 2, 3 or 4 groups R 1 , wherein the number of R 1 substituents on the P ring is designated by the term m1.
• m1 is 1 or 2.
• m1 is 1.
• R 1 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C 1-6 alkylhalo, OC 1-6 alkylhalo, C 1-6 alkyl, OC 1-6 alkyl, C 2-6 alkenyl, OC 2-6 alkenyl, C 2-6 alkynyl, OC 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, OC 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, OC 0-6 alkylaryl, CHO, (CO)R 5 , O(CO)R 5 , O(CO)OR 5 , O(CN)OR 5 , C 1-6 alkylOR 5 , OC 2-6 alkylOR 5 , C 1-6 alkyl(CO)R 5 , OC 1-6 alkyl(CO)R 5 , C 0-6 alkylCO 2 R 5 , OC 1-6 1-6
• R 1 is selected from hydrogen, hydroxy, halo, nitro, C 1-6 alkylhalo, OC 1-6 alkylhalo, C 1-6 alkyl, OC 1-6 alkyl, C 2-6 alkenyl, C 0-6 alkylC 3-6 cycloalkyl, C 1-6 alkylOR 5 , C 1-6 alkyl(CO)R 5 , C 0-6 alkylCO 2 R 5 , C 0-6 alkylcyano, C 0-6 alkylNR 5 R 6 , C 0-6 alkylSR 5 and a 5- or 6-membered ring containing one or more atoms independently selected from the group consisting of C and O.
• Any C 1-6 alkyl defined under R 1 may be substituted by one or more A.
• R 1 is ethyl and A is hydroxyl.
• R 1 is selected from hydrogen, methyl, ethyl, cyclopropyl, hydroxy, methoxy, cyano, flouro, chloro, bromo, iodo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, amino, nitro, dimethylamino, methylsulfanyl, vinyl, acetyl, formic acid methyl ester, methoxymethyl, ethanol and furyl.
• P is selected from the group consisting of thiophene, pyridyl, thiazolyl, furyl, pyrrolyl or phenyl, whereby the phenyl ring is substituted on position 3 or disubstituted on positions 2 and 5 and R 1 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C 1-6 alkylhalo, OC 1-6 alkylhalo, C 1-6 alkyl, OC 1-6 alkyl, C 2-6 alkenyl, C 0-6 alkylC 3-6 cycloalkyl, C 1-6 alkylOR 5 , C 1-6 alkyl(CO)R 5 , C 0-6 alkylCO 2 R 5 , C 0-6 alkylcyano, C 0-6 alkylNR 5 R 6 , C 0-6 alkylSR 5 and a 5-membered ring containing one or more atoms independently selected from the group consisting of thiophene, pyrid
• P is phenyl substituted on position 3 or disubstituted on positions 2 and 5 and R 1 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C 1-6 alkylhalo, OC 1-6 alkylhalo, C 1-6 alkyl, OC 1-6 alkyl, C 2-6 alkenyl, C 0-6 alkylC 3-6 cycloalkyl, C 1-6 alkylOR 5 , C 1-6 alkyl(CO)R 5 , C 0-6 alkylCO 2 R 5 , C 0-6 alkylcyano, C 0-6 alkylNR 5 R 6 , C 0-6 alkylSR 5 and a 5-membered ring containing one or more atoms independently selected from the group consisting of C and O.
• the ring P is connected to the core ring by M 1 , wherein M 1 can be a bond directly joining P to the core ring.
• M 1 can also be a linker C 1-3 alkyl.
• M 1 is a bond.
• M 1 When M 1 is not a direct bond M 1 can be further substituted with 0, 1, 2 or 3 substituents R 2 wherein the number of substituents R 2 is designated by the term n.
• the substituents R 2 may be selected from hydrogen, hydroxy, oxo, C 1-4 alkylhalo, halo and C 1-4 alkyl. In a preferred embodiment of the invention n is 0.
• X 1 is selected from the group consisting of C, CO, N, O and S.
• X 2 is selected from the group consisting of C, N, O and S.
• X 3 is selected from the group consisting of N, O and S, or X 3 is selected from N, O, S, and C when X 2 is selected from N, O, or S, and when X 3 is C the substituent R on X 3 is H.
• X 1 , X 2 and X 3 can be further substituted with 0, 1 or 2 substituents R wherein the number of substituents R is designated by the term t.
• the substituent R may be selected from the group consisting of hydrogen, C 0-3 alkyl, halo, C 0-3 alkylOR 5 , C 0-3 alkylNR 5 R 6 , C 0-3 alkyl(CO)OR 5 , C 0-3 alkylNR 5 R 6 and C 0-3 alkylaryl.
• R is selected from the group consisting of hydrogen, C 0-3 alkyl and halo.
• X 1 is C, N or O and R is selected from hydrogen, C 0-3 alkyl and halo. In one embodiment R is selected from hydrogen, chloro or methyl.
• X 1 is N.
• X 2 is selected from N, O and S, and R is hydrogen.
• X 3 is N, O or S.
• X 1 is O and one of X 2 and X 3 is O and the other is N.
• X 1 is N and one of X 2 and X 3 is O and the other is N.
• X 1 is C or CR and one of X 2 and X 3 is O and the other is N.
• X 2 is O and X 3 is N, and in yet another preferred embodiment of the invention X 2 is N and X 3 is O.
• X 1 is O and X 2 and X 3 are N.
• the ring containing X 1 , X 2 and X 3 forms an oxadiazole, isoxazole, oxazole, chloro-isoxazole or a methyl-isoxazole.
• the ring containing X 1 , X 2 and X 3 forms an oxadiazole. In another preferred embodiment of the invention the ring containing X 1 , X 2 and X 3 forms an isoxazole.
• M 2 may be a direct bond from the core ring to the variable X 4 or M 2 may be selected from the group consisting of bond, C 1-3 alkyl, C 2-3 alkynyl, C 0-4 alkyl(CO)C 0-4 alkyl, C 0-3 alkylOC 0-3 alkyl, C 0-3 alkylNR 5 C 1-3 alkyl, C 0-3 alkyl(CO)NR 5 , C 0-4 alkylNR 5 , C 0-3 alkyl(SO)C 0-3 alkyl and C 0-3 alkyl(SO 2 )C 0-3 alkyl.
• M 2 is a bond or C 1-3 alkyl. In further preferred embodiments of the invention M 2 is C 1-3 alkyl, preferably methyl or ethyl.
• M 2 When M 2 is not a direct bond M 2 may be further substituted with 0, 1 or 2 R 3 groups wherein the number of substituents R 3 is designated by the term n. In one embodiment of the invention n is 1 or 2. In another embodiment of the invention n is 0.
• R 3 is selected from the group consisting of R 3 is selected from a group consisting of hydroxy, C 0-6 alkylcyano, oxo, ⁇ NR 5 , ⁇ NOR 5 , C 1-4 alkylhalo, halo, C 1-4 alkyl, O(CO)C 1-4 alkyl, C 1-4 alkyl(SO)C 0-4 alkyl, C 1-4 alkyl(SO 2 )C 0-4 alkyl, (SO)C 0-4 alkyl, (SO 2 )C 0-4 alkyl, OC 1-4 alkyl, C 1-4 alkylOR 5 and C 0-4 alkylNR 5 R 6 .
• R 3 is selected from hydrogen and C 1-4 alkyl, preferably methyl or dimethyl.
• M 2 may be selected from the group consisting of a bond, C 1-3 alkyl, C 2-3 alkynyl, C 0-4 alkyl(CO)C 0-4 alkyl, C 0-3 alkylOC 0-3 alkyl, C 0-3 alkylNR 5 C 1-3 alkyl, C 0-3 alkyl(CO)NR 5 , C 0-4 alkylNR 5 , C 0-3 alkyl(SO)C 0-3 alkyl and C 0-3 alkyl(SO 2 )C 0-3 alkyl and R 3 is selected from hydrogen and C 1-4 alkyl.
• M 2 is a bond or C 1-3 alkyl and R 3 is hydrogen, methyl or dimethyl.
• M 2 may be selected from the group consisting of a bond, methyl and ethyl and R 3 is hydrogen, methyl or dimethyl.
• M 2 is nitrogen. In yet a further embodiment of the invention M 2 is oxygen.
• X 4 is selected from the group consisting of C 0-4 alkylR 5 R 6 , C 3-7 cycloalkyl, C 1-4 alkyl(NR 5 R 6 ), NR 5 , C 0-4 alkyl(NR 5 R 6 ) ⁇ N, NR 5 C 0-4 alkyl(NR 5 R 6 ) ⁇ N, NOC 0-4 alkyl, C 1-4 alkylhalo, O, SO, SO 2 and S, and wherein the bond between M 2 and X 4 is a single bond.
• X 4 is selected from the group consisting of C 0-4 alkylR 5 R 6 , C 3-7 cycloalkyl, NR 5 , O, SO, SO 2 and S and R 5 and R 6 are independently selected from hydrogen and C 1-6 alkyl.
• X 4 is selected from the group consisting of CH 2 , CHCH 3 , CH(CH 3 ) 2 and NR 5 .
• X 4 is NR 5 and R 5 is selected from hydrogen and C 1-6 alkyl.
• R 5 is methyl or hydrogen and R 6 is hydrogen.
• X 4 is O. In yet another preferred embodiment of the invention X 4 is S.
• Embodiments of the present invention include those wherein Q is a 5- or 6-membered ring.
• Q is selected from the group consisting of the group consisting of triazolyl, imidazolyl, oxadiazolyl, imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl and thiadiazolyl, and wherein any substitutable nitrogen atom in the ring is substituted with R 4 on such nitrogen atom.
• the 5 membered ring Q is selected from the group consisting of triazolyl and thiadiazolyl. In another embodiment the 5 membered ring Q is selected from the group consisting of tetrazolyl and oxadiazolyl. In a further embodiment the 5 membered ring Q is imidazolyl.
• Q is selected from the group consisting of benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, pyridonyl, pyridazinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl and purinyl.
• the 6 membered ring Q is selected from the group consisting of pyridonyl, tetrahydrotriazolopyridyl and tetrahydrotriazolopyrimidinyl.
• the 6 membered ring Q is pyridazinyl.
• the 6 membered ring Q is selected from the group consisting of benzoimidazolyl, benzooxazolyl and imidazopyridyl.
• Q can be further substituted with 0, 1, 2 or 3 substituents R 4 , wherein the number of R 4 substituents is designated by the term m2.
• m2 is 1 or 2.
• the substituent R 4 is selected from the group consisting of C 0-6 alkylcyano, ⁇ NC 1-4 alkyl, ⁇ NOR 5 , C 1-4 alkylhalo, halo, C 1-6 alkyl, OC 1-4 alkyl, C 2-4 alkenyl, C 0-2 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, OC 0-6 alkylaryl, OC 0-6 alkylheteroaryl, NC 0-6 alkylaryl, NC 0-6 alkylheteroaryl, C 0-6 alkylOaryl, C 0-6 alkylOheteroaryl, C 0-6 alkylNaryl, C 0-6 alkylNheteroaryl, OC 0-6 alkylOaryl, OC 0-6 alkylOheteroaryl, OC 0-6 alkylOheteroaryl, OC
• R 4 on the 5 membered Q ring is selected from the group consisting of C 1-4 alkylhalo, C 1-6 alkyl, C 2-4 alkenyl, C 0-2 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, OC 0-6 alkylaryl, OC 0-6 alkylheteroaryl, NC 0-6 alkylaryl, NC 0-6 alkylheteroaryl, C 0-6 alkylOaryl, C 0-6 alkylOheteroaryl, C 0-6 alkylNaryl, C 0-6 alkylNheteroaryl, OC 0-6 alkylOaryl, OC 0-6 alkylOheteroaryl, OC 0-6 alkylNaryl, OC 0-6 alkylNheteroaryl, NC 0-6 alkylOaryl,
• Q is selected from the group consisting of triazolyl, imidazolyl, oxadiazolyl, imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl and thiadiazolyl, and wherein any substitutable nitrogen atom in the ring is substituted with R 4 on such nitrogen atom and R 4 is selected from the group consisting of C 1-4 alkylhalo, C 1-6 alkyl, C 2-4 alkenyl, C 0-2 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, OC 0-6 alkylaryl, OC 0-6 alkylheteroaryl, NC 0-6 alkylaryl, NC 0-6 alkylheteroaryl,C 0-6 alkylOaryl, C 0-6 alkylOheteroaryl, C 0-6 alkylN
• Q selected from the group consisting of triazolyl, imidazolyl, oxadiazolyl, tetrazolyl and thiadiazolyl, and wherein any substitutable nitrogen atom in the ring is substituted with R 4 on such nitrogen atom and R 4 is selected from the group consisting of C 1-4 alkylhalo, C 1-6 alkyl, C 2-4 alkenyl, C 0-2 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, OC 0-6 alkylaryl, OC 0-6 alkylheteroaryl, NC 0-6 alkylaryl, NC 0-6 alkylheteroaryl,C 0-6 alkylOaryl, C 0-6 alkylOheteroaryl, C 0-6 alkylNaryl, C 0-6 alkylNheteroaryl, OC 0-6 alkylO0-6 alkylO
• the substituent R 4 is selected from the group consisting of hydrogen, hydroxy, C 0-6 alkylcyano, ⁇ NR 5 , ⁇ NOR 5 , C 1-4 alkylhalo, halo, C 1-6 alkyl, OC 1-4 alkyl, OC 0-6 alkylaryl, O(CO)C 1-4 alkyl, C 0-4 alkyl(S)C 0-4 alkyl, C 1-4 alkyl(SO)C 0-4 alkyl, C 1-4 alkyl(SO 2 )C 0-4 alkyl, (SO)C 0-4 alkyl, (SO 2 )C 0-4 alkyl, C 1-4 alkylOR 5 , C 0-4 alkylNR 5 R 6 and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O and S, which ring may optionally be fused with a 5- or 6-membered ring containing
• R 4 on the 6 membered Q ring is selected from hydrogen and C 1-6 alkyl.
• R 4 is hydrogen, methyl, ethyl, propyl, butyl or hexyl.
• Q selected from the group consisting of benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, pyridonyl, pyridazinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl and purinyl and R 4 is hydrogen or C 1-6 alkyl.
• Q selected from the group consisting of benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, pyridonyl, pyridazinyl and imidazopyridyl, and R 4 is hydrogen or C 1-6 alkyl.
• R 4 is selected from the group consisting of benzo[b]thiophenyl, benzodioxolyl, bromo, bromofuryl, butoxyphenyl, chloromethoxypyridyl, chlorophenyl, chlorophenylmethanol, chloropyridyl, chlorothiophene, cyanophenyl, cyclohexyl, cyclopentyl, dichloro-phenyl, dichloropyridyl, difluorophenyl, dimethylthiazolyl, ethanol, ethoxymethyl, fluoromethylphenyl, fluorophenyl, formic acid methyl ester, furyl, hydrogen, hydroxyphenoxymethyl, hydroxyphenyl, imidazolyl, methoxyethyl, methoxymethyl, methoxyphenoxymethyl, methoxyphenyl, methoxyphenylethyl, methoxypyridazinyl,
• Ring Q may be substituted by one or more R 4 on a carbon and/or a nitrogen atom in the ring.
• R 4 is selected from benzo[b]thiophenyl, benzodioxolyl, bromo, bromofuryl, butoxyphenyl, chloromethoxypyridyl, chlorophenyl, chlorophenylmethanol, chloropyridyl, chlorothiophene, cyanophenyl, cyclohexyl, cyclopentyl, dichloro-phenyl, dichloropyridyl, difluorophenyl, dimethylthiazolyl, ethanol, ethoxymethyl, fluoromethylphenyl, fluorophenyl, formic acid methyl ester, furyl, hydrogen, hydroxyphenoxymethyl, hydroxyphenyl, imidazolyl, methoxyethyl, methoxymethyl, methoxyphenoxymethyl, methoxymethyl, methoxymethyl, methoxy
• R 4 is selected from acetic acid methylester, allyl, amino, benzyl, cyclopropyl, cyclopropylmethyl, ethyl, flourobenzyl, fluoroethyl, furylmethyl, hydroxyethyl, isobutyl, methoxyethyl, methyl, methylbenzyl, methylbutyl, methylsulfanylpropyl, n-butyl, n-hexyl, n-propyl, tetrahydrofurylmethyl, thiophenylmethyl and trifluoroethyl.
• R 4 is a ring
• R 4 can be substituted with one or more substituents A, wherein A is selected from hydrogen, hydroxy, halo, nitro, oxo, C 0-6 alkylcyano, C 0-4 alkylC 3-6 cycloalkyl, C 1-6 alkyl, C 1-6 alkylhalo, OC 1-6 alkylhalo, C 2-6 alkenyl, C 0-3 alkylaryl, C 0-6 alkylOR 5 , OC 2-6 alkylOR 5 , C 1-6 alkylSR 5 , OC 2-6 alkylSR 5 , (CO)R 5 , O(CO)R 5 , OC 2-6 alkylcyano, OC 1-6 alkylCO 2 R 5 , O(CO)OR 5 , OC 1-6 alkyl(CO)R 5 , C 1-6 alkyl(CO)R 5 , NR 5 OR 6 , OC 2-6 alkylNR 5 R 6
• A is selected from hydroxy, halo, nitro, oxo, C 0-6 alkylcyano, C 1-6 alkyl, C 2-6 alkenyl, C 0-3 alkylaryl, C 0-6 alkylOR 5 and a 5-membered ring containing one or more atoms independently selected from the group consisting of C and O.
• P is selected from the group consisting of hydrogen, C 3-7 alkyl and a 3- to 8-membered ring containing one or more atoms independently selected from the group consisting of C, N, O and S, which ring may optionally be fused with a 5- or 6-membered ring containing one or more atoms independently selected from the group consisting of C, N, O and S;
• R 1 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C 1-6 alkylhalo, OC 1-6 alkylhalo, C 1-6 alkyl, OC 1-6 alkyl, C 2-6 alkenyl, OC 2-6 alkenyl, C 2-6 alkynyl, OC 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, OC 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, OC 0-6 alkylaryl, CHO, (CO)R 5 , O(CO)R 5 , O(CO)OR 5 , O(CN)OR 5 , C 1-6 alkylOR 5 , OC 2-6 alkylOR 5 , C 1-6 alkyl(CO)R 5 , OC 1-6 alkyl(CO)R 5 , C 0-6 alkylCO 2 R 5 , OC 1-6 alkylCO 2 R 5 ,
• M 1 is selected from the group consisting of a bond, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 0-4 alkyl(CO)C 0-4 alkyl, C 0-3 alkylOC 0-3 alkyl, C 0-3 alkyl(CO)NR 5 , C 0-3 alkyl(CO)NR 5 C 0-3 alkyl, C 0-4 alkylNR 5 , C 0-3 alkylSC 0-3 alkyl, C 0-3 alkyl(SO)C 0-3 alkyl and C 0-3 alkyl(SO 2 )C 0-3 alkyl;
• R 2 is selected from the group consisting of hydrogen, hydroxy, C 0-6 alkylcyano, oxo, ⁇ NR 5 , ⁇ NOR 5 , C 1-4 alkylhalo, halo, C 1-4 alkyl, O(CO)C 1-4 alkyl, C 1-4 alkyl(SO)C 0-4 alkyl, C 1-4 alkyl(SO 2 )C 0-4 alkyl, (SO)C 0-4 alkyl, (SO 2 )C 0-4 alkyl, OC 1-4 alkyl, , C 1-4 alkylOR 5 and C 0-4 alkylNR 5 R 6 ;
• X 1 , X 2 and X 3 are independently selected from the group consisting of CR, CO, N, NR, O and S;
• R is selected from the group consisting of hydrogen, C 0-3 alkyl, halo, C 0-3 alkylOR 5 , C 0-3 alkylNR 5 R 6 , C 0-3 alkyl(CO)OR 5 , C 0-3 alkylNR 5 R 6 and C 0-3 alkylaryl;
• M 2 is selected from the group consisting of a bond, C 1-3 alkyl, C 3-7 cycloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 0-4 alkyl(CO)C 0-4 alkyl, C 0-3 alkylOC 0-3 alkyl, C 0-3 alkylNR 5 C 1-3 alkyl, C 0-3 alkyl(CO)NR 5 , C 0-4 alkylNR 5 , C 0-3 alkylSC 0-3 alkyl, C 0-3 alkyl(SO)C 0-3 alkyl and C 0-3 alkyl(SO 2 )C 0-3 alkyl;
• R 3 is selected from the group consisting of hydrogen, hydroxy, C 0-6 alkylcyano, oxo, ⁇ NR 5 , ⁇ NOR 5 , C 1-4 alkylhalo, halo, C 1-4 alkyl, O(CO)C 1-4 alkyl, C 1-4 alkyl(SO)C 0-4 alkyl, C 1-4 alkyl(SO 2 )C 0-4 alkyl, (SO)C 0-4 alkyl, (SO 2 )C 0-4 alkyl, OC 1-4 alkyl, C 1-4 alkylOR 5 and C 0-4 alkylNR 5 R 6 ;
• X 4 is selected from the group consisting of C 0-4 alkylR 5 , C 0-4 alkyl(NR 5 R 6 ), C 0-4 alkyl(N 5 R 6 ) ⁇ N, NR 5 C 0-4 alkyl(NR 5 R 6 ) ⁇ N, NOC 0-4 alkyl, C 1-4 alkylhalo, C, O, SO, SO 2 and S;
• Q is a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O and S, which group may optionally be fused with a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O and S and which fused ring may be substituted by one or more A;
• R 4 is selected from the group consisting of hydrogen, hydroxy, C 0-6 alkylcyano, oxo, ⁇ NR 5 , ⁇ NOR 5 , C 1-4 alkylhalo, halo, C 1-4 alkyl, OC 1-4 alkyl, OC 0-6 alkylaryl, O(CO)C 1-4 alkyl, C 0-4 alkyl(S)C 0-4 alkyl, C 1-4 alkyl(SO)C 0-4 alkyl, C 1-4 alkyl(SO 2 )C 0-4 alkyl, (SO)C 0-4 alkyl, (SO 2 )C 0-4 alkyl, C 1-4 alkylOR 5 , C 0-4 alkylNR 5 R 6 and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O and S, wherein said ring may be substituted by one or more A;
• R 5 and R 6 are independently selected from the group consisting of hydrogen, hydroxy, C 1-6 alkyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O and S, and wherein R 5 and R 6 may together form a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O and S;
• any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl and C 0-6 alkylheteroaryl defined under R 1 , R 2 , R 3 , R 4 , R 5 and R 6 may be substituted by one or more A;
• A is selected from the group consisting of hydrogen, hydroxy, oxo, halo, nitro, C 0-6 alkylcyano, C 1-4 alkyl, C 0-4 alkylC 3-6 cycloalkyl, C 1-6 alkylhalo, OC 1-6 alkylhalo, C 2-6 alkenyl, OC 1-6 alkyl, C 0-3 alkylaryl, C 0-6 alkylOR 5 , OC 2-6 alkylOR 5 , C 1-6 alkylSR 5 , OC 2-6 alkylSR 5 , (CO)R 5 , O(CO)R 5 , OC 2-6 alkylcyano, C 0-6 alkylCO 2 R 5 , OC 1-6 alkylCO 2 R 5 , O(CO)OR 5 , OC 1-6 alkyl(CO)R 5 , C 1-6 alkyl(CO)R 5 , NR 5 OR 6 , C 0-6 alkylNR 5 R 6
• m is selected from 0, 1, 2, 3 and 4;
• n is selected from 0, 1, 2 and 3,
• the present invention relates to the use of compounds of formula I and IA as hereinbefore defined as well as to the salts thereof.
• Salts for use in pharmaceutical formulations will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula I and Ia.
• Examples of pharmaceutically acceptable salts may be, but are not limited to hydrochloride, 4-aminobenzoate, anthranilate, 4-aminosalicylate, 4-hydroxybenzoate, 3,4-dihydroxybenzoate, 3-hydroxy-2-naphthoate, nitrate and trifluoroacetate.
• Other pharmaceutically acceptable salts and methods of preparing these salts may be found in, for example, Remington's Pharmaceutical Sciences (18 th Edition, Mack Publishing Co.).
• Some compounds of formula I may have chiral centres and/or geometric isomeric centres (E- and Z-isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers.
• the invention relates to any and all tautomeric forms of the compounds of formula I.
• the invention relates to the following compounds, which may be used as intermediates in the preparation of a compound of formula I;
• a pharmaceutical formulation comprising a compound of formula I, or salt thereof, for use in the prevention and/or treatment of metabotropic glutamate receptor subtype 5 receptor (mGluR5) mediated disorders and any disorder listed below.
• mGluR5 metabotropic glutamate receptor subtype 5 receptor
• composition may be in a form suitable for oral administration, for example as a tablet, pill, syrup, powder, granule or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment, patch or cream or for rectal administration as a suppository.
• parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
• a sterile solution, suspension or emulsion for topical administration as an ointment, patch or cream or for rectal administration as a suppository.
• compositions may be prepared in a conventional manner using one or more conventional excipients, pharmaceutical diluents and/or inert carriers.
• a pharmaceutical formulation comprising as active ingredient a therapeutically effective amount of a compound of formula I in association with one or more pharmaceutically acceptable diluent, excipients and/or inert carrier.
• Suitable daily doses of the compounds of formula I in the treatment of a mammal, including man are approximately 0.01 to 250 mg/kg body weight at peroral administration and about 0.001 to 250 mg/kg body weight at parenteral administration.
• the typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician.
• the compounds according to the present invention exhibit a high degree of potency and selectivity for individual metabotropic glutamate receptor (mGluR) subtypes.
• mGluR metabotropic glutamate receptor
• the compounds according to the present invention that are potent and selective for the mGluR Group I receptor and more particularly for mGluR5.
• the compounds of the present invention are expected to be useful in the prevention and/or treatment of conditions associated with excitatory activation of an mGluR Group I receptor and for inhibiting neuronal damage caused by excitatory activation of an mGluR Group I receptor, specifically when the mGluR Group I receptor is mGluR5.
• the compounds may be used to produce an inhibitory effect of mGluR Group I, especially mGluR5, in mammals, including man.
• mGluR5 is highly expressed in the central and peripheral nervous system and in other tissues.
• the compounds of the invention are well suited for the prevention and/or treatment of mGluR5 receptor-mediated disorders such as acute and chronic neurological and psychiatric disorders and chronic and acute pain disorders.
• Further disorders are Alzheimer's disease senile dementia, AIDS-induced dementia, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's Chorea, migraine, epilepsy, schizophrenia, depression, anxiety, acute anxiety, obsessive compulsive disorder, ophthalmological disorders such as retinopathies, diabetic retinopathies, glaucoma, auditory neuropathic disorders such as tinnitus, chemotherapy induced neuropathies, post-herpetic neuralgia and trigeminal neuralgia, tolerance, dependency, addiction and craving disorders, neurodevelopmental disorders including Fragile X, autism, mental retardation, schizophrenia and Down's Syndrome.
• the compounds are also well suited for the prevention and/or treatment of pain related to migraine, inflammatory pain, neuropathic pain disorders such as diabetic neuropathies, arthritis and rheumatitiod diseases, low back pain, post-operative pain and pain associated with various conditions including angina, renal or billiary colic, menstruation, migraine and gout.
• the dose required for the therapeutic or preventive treatment of a particular disorder will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.
• the invention relates to compounds of formula I as defined hereinbefore, for use in therapy.
• the invention relates to compounds of formula I as defined hereinbefore, for use in prevention and/or treatment of neurological disorders.

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