US20040152699A1 - Compounds - Google Patents

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Publication number
US20040152699A1
US20040152699A1 US10/637,012 US63701203A US2004152699A1 US 20040152699 A1 US20040152699 A1 US 20040152699A1 US 63701203 A US63701203 A US 63701203A US 2004152699 A1 US2004152699 A1 US 2004152699A1
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United States
Prior art keywords
triazol
phenyl
methyl
chloro
oxadiazol
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Abandoned
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US10/637,012
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English (en)
Inventor
Jalaj Arora
Louise Edwards
Methvin Isaac
Donald McLeod
Abdelmalik Slassi
Tomislav Stefanac
Thomas Stormann
David Wensbo
Tao Xin
Helena Gyback
Martin Johansson
Annika Kers
John Malmberg
Alexander Minidis
Karin Oscarsson
Mangus Waldman
Ulrika Yngve
Christoffer Osterwall
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AstraZeneca AB
Original Assignee
ASTRAZENECA AND NPS PHARMACEUTICALS Inc
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Priority to US10/637,012 priority Critical patent/US20040152699A1/en
Assigned to ASTRAZENECA AB, NPS PHARMACEUTICAL reassignment ASTRAZENECA AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MCLEOD, DONALD A., EDWARDS, LOUISE, ARORA, JALAJ, ISAAC, METHVIN, GYBANK, HELENA, JOHANSSON, MARTIN, KERS, ANNIKA, MALMBERG, JOHN, MINIDIS, ALEXANDER, OSCARSSON, KARIN, OSTERWALL, CHRISTOFFER, SLASSI, ABDELMALIK, STEFANAC, TOMISLAV, STORMANN, THOMAS M., WALDMAN, MANGUS, WENSBO, DAVID, XIN, TAO, YNGVE, ULRIKA
Publication of US20040152699A1 publication Critical patent/US20040152699A1/en
Priority to US11/274,611 priority patent/US7456200B2/en
Assigned to ASTRAZENECA AB reassignment ASTRAZENECA AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ASTRAZENECA AB, NPS PHARMACEUTICALS, INC.
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—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
    • 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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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050288347A1 (en) * 2004-03-26 2005-12-29 Hodge Carl N Certain triazole-based compounds, compositions, and uses thereof
US20060116515A1 (en) * 2004-12-01 2006-06-01 Kalypsys, Inc. Inducible nitric oxide synthase dimerization inhibitors
US20070197609A1 (en) * 2005-11-28 2007-08-23 Kalypsys, Inc. Salts of inducible nitric oxide synthase dimerization inhibitors
EP1958631A1 (en) * 2007-02-14 2008-08-20 AEterna Zentaris GmbH Novel triazole derivatives as ligands of G-protein coupled receptors
US20110144049A1 (en) * 2009-10-21 2011-06-16 Serebruany Victor L Treating Cardiac Arrhythmias, Heart Failure, Peripheral Artery Disease and Stroke with Cyclopentyl-Triazolo-Pyrimidine or Derivative Thereof
US8686007B2 (en) 2011-04-22 2014-04-01 Cytokinetics, Inc. Certain heterocycles, compositions thereof, and methods for their use
US9604965B2 (en) 2010-04-23 2017-03-28 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US9730886B2 (en) 2010-04-23 2017-08-15 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US9994528B2 (en) 2010-04-23 2018-06-12 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
US9994559B2 (en) 2014-12-17 2018-06-12 King's College London Bicycloheteroaryl-heteroaryl-benzoic acid compounds as retinoic acid receptor beta (RARβ) agonists
US10220027B2 (en) 2011-07-13 2019-03-05 Gilead Sciences, Inc. FXR (NR1H4) binding and activity modulating compounds
US10329286B2 (en) 2016-06-13 2019-06-25 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US10421730B2 (en) 2016-06-13 2019-09-24 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US10870644B2 (en) 2016-06-22 2020-12-22 King's College London Crystalline forms of 4-(5-(4,7-dimethylbenzofuran-2-yl)-l,2,4-oxadiazol-3-yl)benzoic acid and processes for their preparation
US10933052B2 (en) 2017-11-17 2021-03-02 Cellix Bio Private Limited Compositions and methods for the treatment of eye disorders
US11225473B2 (en) 2019-01-15 2022-01-18 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US11524005B2 (en) 2019-02-19 2022-12-13 Gilead Sciences, Inc. Solid forms of FXR agonists
US11833150B2 (en) 2017-03-28 2023-12-05 Gilead Sciences, Inc. Methods of treating liver disease

Families Citing this family (68)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR0313265A (pt) * 2002-08-09 2005-07-05 Astrazeneca Ab Compostos e respectivos processos de preparação, uso e formulações farmacêuticas e métodos de prevenção e/ou tratamento de distúrbios mediados por receptor mglur5 e de inbição da ativação de receptores mglu r5.
EP1644363B1 (en) 2003-05-30 2012-02-22 Gemin X Pharmaceuticals Canada Inc. Triheterocyclic compounds, compositions, and methods for treating cancer
WO2005077345A1 (en) * 2004-02-03 2005-08-25 Astrazeneca Ab Compounds for the treatment of gastro-esophageal reflux disease
JP2007523178A (ja) * 2004-02-18 2007-08-16 アストラゼネカ アクチボラグ 代謝型グルタメート受容体アンタゴニストとしてのトリアゾール化合物およびそれらの使用
US7585881B2 (en) * 2004-02-18 2009-09-08 Astrazeneca Ab Additional heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
TW200538108A (en) 2004-02-19 2005-12-01 Astrazeneca Ab Fused heterocyclic compounds and their use as metabotropic glutamate receptor antagonists
PT2060570E (pt) * 2004-02-23 2012-05-07 Glaxo Group Ltd Derivados de azabiciclo(3.1.0)-hexano úteis como moduladores dos receptores d3 da dopamina
CA2580409C (en) 2004-09-16 2013-08-13 Astellas Pharma Inc. Triazole derivative or salt thereof
JP4557685B2 (ja) 2004-11-15 2010-10-06 独立行政法人理化学研究所 蛍光蛋白質
JP4966866B2 (ja) * 2005-01-14 2012-07-04 エフ．ホフマン−ラ ロシュ アーゲー ｍＧｌｕＲ５アンタゴニストとしてのチアゾール−４−カルボキサミド誘導体
JPWO2006080533A1 (ja) * 2005-01-31 2008-06-19 持田製薬株式会社 ３−アミノ−１，２，４−トリアゾール誘導体
GB0510139D0 (en) * 2005-05-18 2005-06-22 Addex Pharmaceuticals Sa Novel compounds B1
GB0510142D0 (en) * 2005-05-18 2005-06-22 Addex Pharmaceuticals Sa Novel compounds A1
TW200804345A (en) 2005-08-30 2008-01-16 Novartis Ag Substituted benzimidazoles and methods of preparation
UY29796A1 (es) * 2005-09-29 2007-04-30 Astrazeneca Ab Nuevos compuestos para el tratamiento de trastornos neurológicos, psiquiátricos o del dolor
TW200811157A (en) 2006-05-05 2008-03-01 Astrazeneca Ab mGluR5 modulators I
AU2007296964B2 (en) 2006-09-11 2012-05-31 Novartis Ag Nicotinic acid derivatives as modulators of metabotropic glutanate receptors
TW200821305A (en) * 2006-10-05 2008-05-16 Astrazeneca Ab MGluR5 modulators
US20110207704A1 (en) * 2006-12-15 2011-08-25 Abbott Laboratories Novel Oxadiazole Compounds
JP2010513283A (ja) * 2006-12-15 2010-04-30 アボット・ラボラトリーズ 新規なオキサジアゾール化合物
CA2696016A1 (en) 2007-07-13 2009-01-22 Addex Pharma S.A. Novel heteroaromatic derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors
TWI558320B (zh) 2007-08-13 2016-11-21 孟山都科技有限責任公司 控制植物寄生性線蟲的化合物及方法以及被覆有該化合物之種子
US20100227845A1 (en) * 2007-10-18 2010-09-09 Zhicai Wu Substituted 1,2,4-oxadiazoles and analogs thereof as cb2 receptor modulators, useful in the treatment of pain, respiratory and non-respiratory diseases
MX2010004272A (es) 2007-10-19 2010-04-30 Astrazeneca Ab Derivados de tetrazol como moduladores de receptores de glutamato metabotropicos (mglurs).
WO2009054785A1 (en) * 2007-10-26 2009-04-30 Astrazeneca Ab 1,2,4-triazole ether derivatives as modulators of mglur5
AU2009241656A1 (en) * 2008-04-28 2009-11-05 Astrazeneca Ab Methods of preparing substituted heterocycles
WO2009147189A1 (en) 2008-06-05 2009-12-10 Glaxo Group Limited Novel compounds
JP5502077B2 (ja) 2008-06-05 2014-05-28 グラクソ グループ リミテッド 新規な化合物
US8658635B2 (en) 2008-06-05 2014-02-25 Glaxosmithkline Intellectual Property Development Limited Benzpyrazol derivatives as inhibitors of PI3 kinases
EP2288607B1 (en) 2008-06-09 2014-09-24 Sanofi Sulfonamides with heterocycle and oxadiazolone headgroup, processes for their preparation and their use as pharmaceuticals
EP2320892A2 (en) 2008-06-30 2011-05-18 Novartis AG Combination products
BRPI0914121B8 (pt) 2008-07-03 2021-05-25 Astellas Pharma Inc derivado de triazol ou sal do mesmo
DE102008057364A1 (de) 2008-11-14 2010-05-20 Bayer Schering Pharma Aktiengesellschaft Substituierte Aryl-Verbindungen und ihre Verwendung
DE102008057344A1 (de) 2008-11-14 2010-05-20 Bayer Schering Pharma Aktiengesellschaft Aminoalkyl-substituierte Aryl-Verbindungen und ihre Verwendung
DE102008057343A1 (de) 2008-11-14 2010-05-20 Bayer Schering Pharma Aktiengesellschaft Heterocyclisch substituierte Aryl-Verbindungen und ihre Verwendung
DE102009041242A1 (de) 2009-09-11 2011-12-15 Bayer Schering Pharma Aktiengesellschaft Heterocyclisch substituierte Aryl-Verbindungen und ihre Verwendung
DE102009041241A1 (de) 2009-09-11 2011-08-04 Bayer Schering Pharma Aktiengesellschaft, 13353 Substituierte Aryl-Verbindungen und ihre Verwendung
JP2012512867A (ja) * 2008-12-18 2012-06-07 アストラゼネカ・アクチエボラーグ １−［５−（３−クロロ−フェニル）−イソオキサゾール−３−イル］−エタノン及び（ｒ）−１−［５−（３−クロロ−フェニル）−イソオキサゾール−３−イル］−エタノールの新しい製造方法
ES2542551T3 (es) 2009-03-09 2015-08-06 Glaxo Group Limited 4-Oxadiazol-2-il-indazoles como inhibidores de PI3 cinasas
EP3260453B1 (en) 2009-04-30 2021-03-31 Glaxo Group Limited Oxazole substituted indazoles as pi3-kinase inhibitors
CN102725281A (zh) * 2009-06-05 2012-10-10 奥斯陆大学医院公司 作为wtn通路抑制剂的氮杂茂类衍生物
TWI481607B (zh) * 2009-12-17 2015-04-21 Lundbeck & Co As H 作為ｐｄｅ１０ａ酵素抑制劑的２－芳基咪唑衍生物
EP2519521B1 (en) * 2009-12-29 2013-11-20 Eli Lilly and Company Tetrahydrotriazolopyridine compounds as selective mglu5 receptor potentiators useful for the treatment of schizophrenia
ES2586231T3 (es) * 2010-03-03 2016-10-13 Probiodrug Ag Inhibidores de glutaminil ciclasa
PE20130213A1 (es) 2010-04-30 2013-03-19 Novartis Ag Marcadores predictivos utiles en el tratamiento del sindrome fragil x (fxs)
WO2012006760A1 (en) * 2010-07-14 2012-01-19 Merck Sharp & Dohme Corp. Tricyclic compounds as allosteric modulators of metabotropic glutamate receptors
UA112418C2 (uk) 2010-09-07 2016-09-12 Астеллас Фарма Інк. Терапевтичний болезаспокійливий засіб
GB201018124D0 (en) 2010-10-27 2010-12-08 Glaxo Group Ltd Polymorphs and salts
US20130203735A1 (en) * 2010-10-28 2013-08-08 John T. Sisko Caprolactam mglur5 receptor modulators
EP2649063A1 (en) 2010-12-08 2013-10-16 Oslo University Hospital HF Triazole derivatives as wnt signaling pathway inhibitors
US9139576B2 (en) 2011-05-03 2015-09-22 Merck Sharp & Dohme Corp. Aminomethyl biaryl benzotriazole derivatives
US8592423B2 (en) 2011-06-21 2013-11-26 Bristol-Myers Squibb Company Inhibitors of PDE10
WO2013131981A1 (en) 2012-03-08 2013-09-12 Novartis Ag Predictive markers useful in the diagnosis and treatment of fragile x syndrome (fxs)
US8889854B2 (en) 2012-05-07 2014-11-18 Bristol-Myers Squibb Company C-17 bicyclic amines of triterpenoids with HIV maturation inhibitory activity
US8729263B2 (en) 2012-08-13 2014-05-20 Novartis Ag 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions
US9073875B2 (en) 2012-11-20 2015-07-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of indoleamine 2,3-dioxygenase
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PL3027600T3 (pl) 2013-07-31 2022-08-08 Novartis Ag 1,4-dwupodstawione pochodne pirydazyny i ich zastosowanie do leczenia stanów związanych z niedoborem smn
GB201506658D0 (en) 2015-04-20 2015-06-03 Cellcentric Ltd Pharmaceutical compounds
GB201506660D0 (en) 2015-04-20 2015-06-03 Cellcentric Ltd Pharmaceutical compounds
EP3159332A1 (en) 2015-10-23 2017-04-26 Ludwig-Maximilians-Universität München 5,5'-bis(2,4,6-trinitrophenyl)-2,2'-bi(1,3,4-oxadiazole) and bis(2,4,6-trinitrobenzoyl)oxalohydrazide
CN111094255B (zh) 2017-09-14 2023-10-03 第一三共株式会社 具有环状结构的化合物
CN113329754A (zh) 2018-11-20 2021-08-31 麻雀制药股份有限公司 用于施用皮质类固醇的方法
EP3771711A1 (en) 2019-07-29 2021-02-03 Bayer Animal Health GmbH Pyrazole derivatives for controlling arthropods
CN111362934A (zh) * 2020-04-21 2020-07-03 南开大学 一类异噻唑联噁二唑衍生物及其制备方法和用途
IL316907A (en) 2022-05-16 2025-01-01 Sparrow Pharmaceuticals Inc METHODS AND COMPOSITIONS FOR TREATING GLUCOCORTICOD EXCESS
IL316898A (en) 2022-05-19 2025-01-01 Astrazeneca Ab Heteroaromatic amido compounds are useful in the treatment of liver diseases
CN115716822B (zh) * 2022-11-14 2025-05-16 徐州医科大学 苯并咪唑基异噁唑类化合物在制备与多发性骨髓瘤有关药物方面的应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3740434A (en) * 1966-12-23 1973-06-19 American Cyanamid Co Substituted nitroimidazolylthiadiazoles and oxadiazoles as antiprotozoal agents
US3816426A (en) * 1970-10-27 1974-06-11 Abbott Lab 1-(5-phenyl-4-oxo-2-oxazolin-2-yl)piperazines
US5140034A (en) * 1989-03-14 1992-08-18 Merck Sharp & Dohme Ltd. Five-membered ring systems with bonded imidazolyl ring substituents
US5631269A (en) * 1992-10-23 1997-05-20 Merck Sharp & Dohme Limited Dopamine receptor subtype ligands

Family Cites Families (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56127364A (en) 1980-03-01 1981-10-06 Mitsui Toatsu Chem Inc Novel piperazine compound, its preparation and utilization
JP3003148B2 (ja) 1989-01-05 2000-01-24 藤沢薬品工業株式会社 チアゾール化合物、その製造法およびそれを含有する医薬組成物
US4914207A (en) * 1989-05-09 1990-04-03 Pfizer Inc. Arylthiazolylimidazoles
DE3929673A1 (de) * 1989-09-07 1991-03-14 Bayer Ag Substituierte carbamoyltriazole
IL96891A0 (en) 1990-01-17 1992-03-29 Merck Sharp & Dohme Indole-substituted five-membered heteroaromatic compounds,their preparation and pharmaceutical compositions containing them
DE19643037A1 (de) * 1996-10-18 1998-04-23 Boehringer Ingelheim Kg Neue Oxadiazole, Verfahren zu ihrer Herstellung sowie deren Verwendung als Arzneimittel
DE19725450A1 (de) 1997-06-16 1998-12-17 Hoechst Schering Agrevo Gmbh 4-Haloalkyl-3-heterocyclylpyridine und 4-Haloalkyl-5-heterocyclylpyrimidine, Verfahren zu ihrer Herstellung, sie enthaltende Mittel und ihre Verwendung als Schädlingsbekämpfungsmittel
DE19858193A1 (de) * 1998-12-17 2000-06-21 Aventis Cropscience Gmbh 4-Trifluormethyl-3-oxadiazolylpyridine, Verfahren zu ihrer Herstellung, sie enthaltende Mittel und ihre Verwendung als Schädlingsbekämpfungsmittel
EP1037878A2 (en) * 1997-11-21 2000-09-27 Nps Pharmaceuticals, Inc. Metabotropic glutamate receptor antagonists for treating central nervous system diseases
DE19858191A1 (de) 1998-12-17 2000-06-21 Aventis Cropscience Gmbh 4-Haloalkyl-3-heterocyclylpyridine und 4-Haloalkyl-5-heterocyclyl-pyrimidine und ihre Verwendung als Repellentien
DE19858192A1 (de) * 1998-12-17 2000-06-21 Aventis Cropscience Gmbh 4-Trifluormethyl-3-oxazolylpyridine, Verfahren zu ihrer Herstellung, sie enthaltende Mittel und ihre Verwendung als Schädlingsbekämpfungsmittel
CO5170501A1 (es) 1999-04-14 2002-06-27 Novartis Ag AZOLES SUSTITUIDOS UTILES PARA EL TRATAMIENTO DE ENFERMEDADES MEDIADAS POR TNFa eIL-1 Y ENFERMEDADES DEL METABOLISMO OSEO
DE60023318T2 (de) 1999-08-19 2006-07-20 NPS Pharmaceuticals, Inc., Salt Lake City Heteropolycyclische verbindungen und ihre verwendung als antagonisten von metabotropen glutamatrezeptoren
EP1223932A4 (en) * 1999-10-01 2003-01-15 Smithkline Beecham Corp COMPOUNDS AND METHODS
TWI292316B (en) 1999-10-11 2008-01-11 Sod Conseils Rech Applic Pharmaceutical composition of thiazole derivatives intended to inhibit mao and/or lipidic peroxidation and/or to act as modulators of sodium channels and the use thereof
DE19962901A1 (de) 1999-12-23 2001-07-05 Aventis Cropscience Gmbh Azolylalkalylazol-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Schädlingsbekämpfungsmittel
ES2242767T3 (es) 2000-09-21 2005-11-16 Smithkline Beecham Plc Derivados de imidazol como inhibidores de quinasa raf.
RS43903A (en) 2000-12-04 2006-12-15 F.Hoffmann-La Roche Ag. Phenylethenyl or phenylethinyl derivatives as glutamate receptor antagonists
NZ530705A (en) 2001-07-19 2005-08-26 Cv Therapeutics Inc Substituted piperazine compounds and their use as fatty acid oxidation inhibitors
BR0313265A (pt) * 2002-08-09 2005-07-05 Astrazeneca Ab Compostos e respectivos processos de preparação, uso e formulações farmacêuticas e métodos de prevenção e/ou tratamento de distúrbios mediados por receptor mglur5 e de inbição da ativação de receptores mglu r5.
WO2005077345A1 (en) 2004-02-03 2005-08-25 Astrazeneca Ab Compounds for the treatment of gastro-esophageal reflux disease
ATE402935T1 (de) 2004-02-18 2008-08-15 Astrazeneca Ab Kondensierte heterocyclische verbindungen und deren verwendung als antagonisten des metabotropen rezeptors zur behandlung von gastrointestinalen erkrankungen
US7585881B2 (en) * 2004-02-18 2009-09-08 Astrazeneca Ab Additional heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
UY29796A1 (es) * 2005-09-29 2007-04-30 Astrazeneca Ab Nuevos compuestos para el tratamiento de trastornos neurológicos, psiquiátricos o del dolor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3740434A (en) * 1966-12-23 1973-06-19 American Cyanamid Co Substituted nitroimidazolylthiadiazoles and oxadiazoles as antiprotozoal agents
US3816426A (en) * 1970-10-27 1974-06-11 Abbott Lab 1-(5-phenyl-4-oxo-2-oxazolin-2-yl)piperazines
US5140034A (en) * 1989-03-14 1992-08-18 Merck Sharp & Dohme Ltd. Five-membered ring systems with bonded imidazolyl ring substituents
US5631269A (en) * 1992-10-23 1997-05-20 Merck Sharp & Dohme Limited Dopamine receptor subtype ligands

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050288347A1 (en) * 2004-03-26 2005-12-29 Hodge Carl N Certain triazole-based compounds, compositions, and uses thereof
US20060116515A1 (en) * 2004-12-01 2006-06-01 Kalypsys, Inc. Inducible nitric oxide synthase dimerization inhibitors
US7825256B2 (en) 2004-12-01 2010-11-02 Kalypsys, Inc. Inducible nitric oxide synthase dimerization inhibitors
US20070197609A1 (en) * 2005-11-28 2007-08-23 Kalypsys, Inc. Salts of inducible nitric oxide synthase dimerization inhibitors
EP1958631A1 (en) * 2007-02-14 2008-08-20 AEterna Zentaris GmbH Novel triazole derivatives as ligands of G-protein coupled receptors
WO2008098977A1 (en) * 2007-02-14 2008-08-21 Æterna Zentaris Gmbh Novel triazole derivatives as ligands of g-protein coupled receptors
US20110144049A1 (en) * 2009-10-21 2011-06-16 Serebruany Victor L Treating Cardiac Arrhythmias, Heart Failure, Peripheral Artery Disease and Stroke with Cyclopentyl-Triazolo-Pyrimidine or Derivative Thereof
US9994528B2 (en) 2010-04-23 2018-06-12 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
US9604965B2 (en) 2010-04-23 2017-03-28 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US9730886B2 (en) 2010-04-23 2017-08-15 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US11369565B2 (en) 2010-04-23 2022-06-28 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US10076519B2 (en) 2010-04-23 2018-09-18 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US10272030B2 (en) 2010-04-23 2019-04-30 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US10765624B2 (en) 2010-04-23 2020-09-08 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US8759380B2 (en) 2011-04-22 2014-06-24 Cytokinetics, Inc. Certain heterocycles, compositions thereof, and methods for their use
US9278962B2 (en) 2011-04-22 2016-03-08 Cytokinetics, Inc. Certain heterocycles, compositions thereof, and methods for their use
US8686007B2 (en) 2011-04-22 2014-04-01 Cytokinetics, Inc. Certain heterocycles, compositions thereof, and methods for their use
US10485795B2 (en) 2011-07-13 2019-11-26 Gilead Sciences, Inc. FXR (NR1H4) binding and activity modulating compounds
US10220027B2 (en) 2011-07-13 2019-03-05 Gilead Sciences, Inc. FXR (NR1H4) binding and activity modulating compounds
US10385044B2 (en) 2014-12-17 2019-08-20 King's College London Bicycloheteroaryl-heteroaryl-benzoic acid compounds as retinoic acid receptor beta (RARβ) agonists
US11401265B2 (en) 2014-12-17 2022-08-02 King's College London Bicycloheteroaryl-heteroaryl-benzoic acid compounds as retinoic acid receptor beta (RARβ) agonists
US10752616B2 (en) 2014-12-17 2020-08-25 King's College London Bicycloheteroaryl-heteroaryl-benzoic acid compounds as retinoic acid receptor beta (RARβ) agonists
US9994559B2 (en) 2014-12-17 2018-06-12 King's College London Bicycloheteroaryl-heteroaryl-benzoic acid compounds as retinoic acid receptor beta (RARβ) agonists
US10329286B2 (en) 2016-06-13 2019-06-25 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US10774054B2 (en) 2016-06-13 2020-09-15 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US10421730B2 (en) 2016-06-13 2019-09-24 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US12358903B2 (en) 2016-06-13 2025-07-15 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US10981881B2 (en) 2016-06-13 2021-04-20 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US11739065B2 (en) 2016-06-13 2023-08-29 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US11247986B2 (en) 2016-06-13 2022-02-15 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US10870644B2 (en) 2016-06-22 2020-12-22 King's College London Crystalline forms of 4-(5-(4,7-dimethylbenzofuran-2-yl)-l,2,4-oxadiazol-3-yl)benzoic acid and processes for their preparation
US11584741B2 (en) 2016-06-22 2023-02-21 King's College London Crystalline forms of 4-(5-(4,7-dimethylbenzofuran-2-yl)-1,2,4-oxadiazol-3-yl)benzoic acid and processes for their preparation
US11833150B2 (en) 2017-03-28 2023-12-05 Gilead Sciences, Inc. Methods of treating liver disease
US10933052B2 (en) 2017-11-17 2021-03-02 Cellix Bio Private Limited Compositions and methods for the treatment of eye disorders
US11225473B2 (en) 2019-01-15 2022-01-18 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US11524005B2 (en) 2019-02-19 2022-12-13 Gilead Sciences, Inc. Solid forms of FXR agonists
US12102625B2 (en) 2019-02-19 2024-10-01 Gilead Sciences, Inc. Solid forms of FXR agonists

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