WO2009087220A1 - Use of thiazoloimidazoles, thiazolotetrazoles and thiazolotriazoles as mglur5 antagonists - Google Patents

Use of thiazoloimidazoles, thiazolotetrazoles and thiazolotriazoles as mglur5 antagonists Download PDF

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Publication number
WO2009087220A1
WO2009087220A1 PCT/EP2009/050217 EP2009050217W WO2009087220A1 WO 2009087220 A1 WO2009087220 A1 WO 2009087220A1 EP 2009050217 W EP2009050217 W EP 2009050217W WO 2009087220 A1 WO2009087220 A1 WO 2009087220A1
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Prior art keywords
compound
methyl
thiazolo
triazol
ethyl
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PCT/EP2009/050217
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French (fr)
Inventor
Pier D'alessandro
Olivier Eric Lorthioir
Stephen Paul Watson
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Glaxo Group Limited
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Publication of WO2009087220A1 publication Critical patent/WO2009087220A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention relates to the use of thiazolotriazole, thiazoloimidazole and thiazolotetrazole derivatives in treating diseases and conditions for which antagonism of the mGluR5 receptor is beneficial, in particular substance related disorders.
  • the invention also relates to certain novel derivatives.
  • the invention relates to compositions containing the derivatives and processes for their preparation.
  • the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or condition for which antagonism of the mGluRs receptor is beneficial,
  • X is N or -C(R X )-;
  • Y is N or -C(RY)-;
  • R1 is H, halo, C-
  • R ⁇ and R ⁇ which may be the same or different, are H, C-
  • R 4 is 5- or 6-membered monocyclic heterocyclyl, phenyl or C3_gcycloalkyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-
  • R 4 is a fused bicyclic ring system optionally comprising one or two heteroatoms independently selected from O, N and S and optionally substituted by one or more substituents independently selected from halo, C-
  • R5 is H; or R ⁇ together with the N to which it is attached, forms a ring fused with R 4 , which ring is optionally substituted by one or more substitutents independently selected from the list: halo, C-
  • R x and RY which may be the same or different, are -(CH2) n R ⁇ ; wherein R ⁇ is H; halo; C-
  • R 1 a , R 1 b , R 4a , R 4b , R 6a and R 6b which may be the same or different, are H or
  • R 1 c , R 1 d , R 4c R 4d , R 6c and R 6d which may be the same or different, are H or
  • R ⁇ e , R 4e and R ⁇ e which may be the same or different, are C-
  • an alkyl substituent is a univalent radical derived by removal of a hydrogen atom from an acyclic alkane.
  • .galkyl refers to such an alkyl substituent containing 1 to 6 carbons.
  • alkyl substituents include methyl and ethyl, may be straight chain (i.e. n-propyl, n-butyl, n- pentyl and n-hexyl) or branched chain (for example, isopropyl, isobutyl, secbutyl, tert- butyl, isopentyl and neopentyl).
  • such an alkyl substituent is methyl, ethyl, n-propyl or isopropyl.
  • a halo substituent refers to fluoro, chloro, bromo and iodo radicals. In an embodiment unless otherwise indicated such a halo substituent is fluoro or chloro.
  • a haloalkyl substituent is an alkyl group substituted by one or more halo substituents, which halo substituents may be the same or different.
  • .ghaloalkyl refers to such a haloalkyl substituent containing 1 to 6 carbons.
  • Such haloalkyl substituents include monofluoromethyl, difluoromethyl, trifluoromethyl and 1-chloro-2-fluoroethyl.
  • such a haloalkyl substituent is monofluoromethyl, difluoromethyl or trifluoromethyl.
  • an alkoxy substituent is a group of formula "R-O-" where R is alkyl as defined above.
  • .galkoxy refers to such an alkoxy substituent containing 1 to 6 carbons.
  • alkoxy substituents include methoxy and ethoxy and may be straight chain (i.e. n-propoxy, n-butoxy, n- pentoxy and n-hexyloxy) or branched chain (for example, isopropoxy, isobutoxy, secbutoxy, tert-butoxy, isopentoxy and neopentoxy).
  • such an alkoxy substituent is methoxy, ethoxy, n-propoxy or isopropoxy.
  • an alkylthio substituent is a group of formula "R-S-" where R is alkyl as defined above.
  • R is alkyl as defined above.
  • .galkylthio refers to such an alkylthio substituent containing 1 to 6 carbons.
  • alkylthio substituents include methylthio and ethylthio and may be straight chain or branched chain.
  • such an alkylthio substituent is methylthio, ethylthio, n-propylthio or isopropylthio.
  • a haloalkoxy substituent is a group of formula "R-O-" where R is haloalkyl as defined above.
  • R is haloalkyl as defined above.
  • C- ⁇ ghaloalkoxy refers to such a haloalkoxy substituent containing 1 to 6 carbons.
  • Such haloalkoxy substituents include monofluoromethoxy, difluorom ethoxy, trifluoromethoxy and 1- chloro-2-fluoroethoxy and may be straight chain or branched chain.
  • such a haloalkoxy substituent is monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
  • a haloalkylthio substituent is a group of formula "R-S-" where R is haloalkyl as defined above.
  • _ghaloalkylthio refers to such a haloalkylthio substituent containing 1 to 6 carbons.
  • Such haloalkylthio substituents include monofluoromethylthio, difluoromethylthio, trifluoromethylthio and 1-chloro-2-fluoroethylthio and may be straight chain or branched chain.
  • such a haloalkylthio substituent is monofluoromethylthio, difluoromethylthio or trifluoromethylthio.
  • a cycloalkyl substituent is a univalent radical derived by removal of a hydrogen atom from a monocyclic cycloalkane, comprising from 5 to 6 carbons all interconnected to form a ring.
  • Examples of cycloalkyl substituents are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • the cycloalkyl substituent is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • a 5 to 6-membered monocyclic heterocyclyl substituent refers to a univalent radical derived by removal of a hydrogen atom from a 5 to 6-membered monocyclic heterocyclic ring; the heterocyclic ring containing one or more carbon atoms; one or more hydrogen atoms; and independently 1 to 4 heteroatoms such as nitrogen, oxygen and sulfur; the carbon and heteroatoms being interconnected to form a ring.
  • the monocyclic heterocyclyl substituent may be saturated, unsaturated or aromatic.
  • saturated monocyclic heterocyclyl substituents are pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino and piperazinyl.
  • unsaturated monocyclic heterocyclyl substituents are 2H-pyrrolyl, 2-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl and 2H- pyranyl, 4H-pyranyl.
  • aromatic monocyclic heterocyclyl substituents are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, azepinyl, oxazepinyl, thiazepinyl and diazepinyl.
  • a 3 to 6-membered saturated heterocyclyl substituent refers to a univalent radical derived by removal of a hydrogen atom from a 3 to 6-membered saturated heterocyclic ring; the heterocyclic ring containing, as appropriate, one or more carbon atoms; one or more hydrogen atoms; and independently 1 to 4 heteroatoms such as nitrogen, oxygen and sulfur; the carbon and heteroatoms being interconnected to form a ring.
  • the 3 to 6-membered saturated heterocyclyl is pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino and piperazinyl.
  • R ⁇ is halo, C-
  • R ⁇ is H and R ⁇ is C-
  • Racemic compounds may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilising methods known to those skilled in the art.
  • chiral intermediate compounds may be resolved and used to prepare chiral compounds of the invention.
  • the chiral compounds of the invention may be prepared by chiral synthesis.
  • R ⁇ is H and R 4 is 5- or 6-membered monocyclic heterocyclyl, phenyl or C3_gcycloalkyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-
  • R ⁇ is H and R 4 is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl or C3_gcycloalkyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-
  • R ⁇ is H and R 4 is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or phenyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-
  • R ⁇ is H and R 4 is pyridyl or phenyl, either of which is optionally substituted by one or more substituents independently selected from the list: halo; C-
  • R ⁇ is H and R 4 is pyridyl or phenyl, either of which is optionally substituted by one or more substituents independently selected from the list: halo; C-
  • R ⁇ is H and R 4 is pyridyl or phenyl, either of which is optionally substituted by one or more substituents independently selected from the list: halo; C-
  • X and Y are not both N. In an embodiment, when X is -C(R X )- and Y is -C(RY)- then at least one of R x and RY is H.
  • At least one of X and Y is N.
  • R x and RY which may be the same or different, are -(CH2)nR®; wherein R ⁇ is H; halo; C-
  • R x and RY which may be the same or different, are H, halo, C-
  • the compound of formula (I) has formula (Ia)
  • R1 is H, halo, C-
  • R3 is C-
  • R5 is H and R ⁇ is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or phenyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-
  • the compound of formula (I) is selected from the list consisting of: (+/-)1-(2-Cyclopropyl-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 1 );
  • (+/-)2-Methyl-1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)propyl phenylcarbamate (Compound 49); (+/-) 2,2,2-trifluoro-1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 50);
  • X is N or -C(R X )-;
  • Y is N or -C(RY)-;
  • R 1 is H, halo, C-
  • R2 and R ⁇ which may be the same or different, are H, C-
  • R 4 is 5- or 6-membered monocyclic heterocyclyl, phenyl or C3_gcycloalkyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-
  • 5-or 6-membered monocyclic heterocyclyl optionally substituted independently by one or more halo, C-
  • R 4 is a fused bicyclic ring system optionally comprising one or two heteroatoms independently selected from O, N and S and optionally substituted by one or more substituents independently selected from halo, C-
  • R5 is H; or R ⁇ together with the N to which it is attached, forms a ring fused with R 4 , which ring is optionally substituted by one or more substitutents independently selected from the list: halo, C- ⁇ galkyl, C- ⁇ galkoxy,
  • R x and RY which may be the same or different, are -(CH2)nR®; wherein R ⁇ is H; halo; C- ⁇ galkyl; C-
  • C3_gheterocyclyl comprising one heteroatom selected from O, N and S; cyano; -N(R 6a )(R 6b ); -C(O)N(R 6c )(R 6d ); -N(R 6c )C(O)R 6e ; -C(O)R 6e or
  • R 1 a , R 1 b , R 4a , R 4b , R 6a and R 6b which may be the same or different, are H or
  • R 1 C, RI cI 1 R4C R 4d, R 6c and R6d s which may be the same or different, are H or
  • R ⁇ e , R 4e and R ⁇ e which may be the same or different, are C-
  • the compounds of formula (I) as defined in the first or second aspects may contain a basic centre and may form non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, with carboxylic acids or with organo-sulfonic acids.
  • inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, with carboxylic acids or with organo-sulfonic acids.
  • Examples include the HCI, HBr, HI, sulfate or bisulfate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate and pamoate salts.
  • suitable pharmaceutical salts see Berge et al, J.
  • the salt is pharmaceutically acceptable.
  • pro-drugs examples include Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as “pro-moieties”, for example as described by H. Bundgaard in "Design of Prodrugs” (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within the compounds defined in the first or second aspects.
  • the invention provides a prodrug of a compound defined in the first aspect.
  • the compounds defined in the first or second aspects, their salts or prodrugs, may exist in solvated or hydrated form. Therefore, in a further aspect, the invention provides a solvate or hydrate of a compound defined in the first or second aspects or a salt thereof.
  • the compounds of formula (I) defined in the first or second aspects or their salts, or solvates or hydrates of either, may exist in one or more polymorphic form. Therefore, in a further aspect, the invention provides a polymorph of a compound of formula (I) defined in the first aspect or their salts, or a polymorph of a solvate or hydrate of a compound of formula (I) defined in the first or second aspects, or a salt thereof.
  • compounds of formula (I) as defined in the first or second aspects their salts and prodrugs; any solvates or hydrates of any salt or prodrug; and any polymorph of any compound, salt, solvate or hydrate are referred to as "compounds of the invention”.
  • the term “compounds of the invention” also includes all embodiments of the first or second aspects.
  • the compounds of the invention may exist in one or more tautomeric forms. All tautomers and mixtures thereof are included in the scope of the present invention. For example, a claim to 2-hydroxyquinolinyl would also cover its tautomeric form, ⁇ - quinolinonyl.
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 0, 31 P, 32 P, 35 S, 18 F and 36 CI, respectively.
  • isotopic variations of the invention for example, those in which a radioactive isotope such as 3 H or 14 C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • lsotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Experimental section hereafter using appropriate isotopic variations of suitable reagents.
  • Compounds of formula (I) may be prepared by reacting compounds of formula (II) with activated carbamoyl reagents generated in situ from amines of formula (III) and a reagent such as carbonyl diimidazole (CDI) according to reaction scheme 1.
  • Typical reaction conditions comprise reacting (III) with CDI in a sealed vessel in a microwave reactor at 80 degC in dry DCM for 20 minutes followed by addition of (II) and further heating at 80 degC for 20 minutes.
  • compounds of formula (Ib) may be prepared by reacting compounds of formula (II) with isocyanates of formula (IV) according to reaction scheme 2.
  • Typical reaction conditions comprise reacting (II) with (IV) in a sealed vessel in a microwave reactor at 80 degC in dry DCM for 20 minutes.
  • Alternative conditions comprise reacting compounds of formula (II) with sodium hydride in THF at room temperature followed by addition of (IV) at room temperature.
  • Compounds of formula (II) may be prepared by reacting compounds of formula (V) with an organometallic reagent, such as an organolithium or a Grignard reagent, according to reaction scheme 3.
  • Typical reaction conditions comprise reacting (V) with Grignard reagent R ⁇ MgX in THF at room temperature.
  • compounds of formula (Vb) i.e. compounds of formula (V) (see scheme 3) where X is C(R X ) and R ⁇ is H, may be prepared according to reaction scheme 6, by reacting compounds of formula (Vl) or their tautomers with ⁇ -halo- ⁇ - keto esters of formula (VIII) to give compounds of formula (IX). Reduction of (IX) with lithium aluminium hydride followed by oxidation with manganese dioxide gives compounds of formula (Vb).
  • Vb Compounds of formula (Via), i.e. compounds of formula (Vl) (see schemes 5 and 6) where X is -C(R X )- and Y is N, may be prepared according to reaction scheme 7 via compounds of formula (X).
  • Compounds of formula (X) may be prepared by reacting activated carboxylic acids (Xl) (such as acid chlorides and 1-hydroxybenzotriazole esters) with a thiosemicarbazide.
  • Typical reaction conditions comprise reacting compounds of formula (Xl) with the thiosemicarbazide in a sealed vessel in a microwave reactor at 80 degC in a suitable solvent (such as DCM or acetone) for 10 minutes with or without a tertiary amine base (such as triethylamine) to give (X).
  • Cyclisation of (X) to give (Via) may be achieved by reacting (X) in a sealed vessel in a microwave reactor at 150 degC in aqueous ethanolic sodium hydroxide for 10 minutes.
  • the compounds of the invention antagonise the mGluR5 receptor and may be used to treat diseases or conditions for which antagonism of the mGluRs receptor is beneficial. Therefore according to a further aspect, the invention provides a compound of the invention for use in treating a disease or condition.
  • the disease or condition is a human disease or condition.
  • the disease or condition is one for which antagonism of the mGluRs receptor is beneficial.
  • the disease or condition for which antagonism of the mGluRs receptor is beneficial is selected from the list consisting of: [the numbers in brackets after the listed diseases below refer to the classification code in Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM-IV) and/or the International Classification of Diseases, 10th Edition (ICD-10)]:
  • i) Psychotic disorders for example Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60)); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) (including the subtypes Bipolar Type and Depressive Type); Delusional Disorder (297.1) (including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type); Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder due to a General Medical Condition (including the subtypes with Delusions and with Hallucinations); Substance-Induced Psychotic Disorder (including the subtypes with Delusions (293.81 ) and with Hallucinations (293.82)); and Psychotic Disorder Not Otherwise Specified (298.9).
  • Depression and mood disorders for example Depressive Episodes (including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode); Depressive Disorders (including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (31 1 )); Bipolar Disorders (including Bipolar I Disorder, Bipolar Il Disorder (i.e.
  • Anxiety disorders for example Social Anxiety Disorder; Panic Attack; Agoraphobia, Panic Disorder; Agoraphobia Without History of Panic Disorder (300.22); Specific Phobia (300.29) (including the subtypes Animal Type, Natural Environment Type, Blood-lnjection-lnjury Type, Situational Type and Other Type); Social Phobia (300.23); Obsessive-Compulsive Disorder (300.3); Posttraumatic Stress Disorder (309.81 ); Acute Stress Disorder (308.3); Generalized Anxiety Disorder (300.02); Anxiety Disorder Due to a General Medical Condition (293.84); Substance-Induced Anxiety Disorder; and Anxiety Disorder Not Otherwise Specified (300.00).
  • Substance-related disorders for example Substance Use Disorders (including Substance Dependence, Substance Craving and Substance Abuse); Substance- Induced Disorders (including Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance-Induced Persisting Dementia, Substance- Induced Persisting Amnestic Disorder, Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder,
  • Substance Use Disorders including Substance Dependence, Substance Craving and Substance Abuse
  • Substance- Induced Disorders including Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance-Induced Persisting Dementia, Substance- Induced Persisting Amnestic Disorder, Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder,
  • Substance-Induced Sexual Dysfunction Substance-Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders (including Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81 ), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder, Alcohol-Induced Mood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-Induced Sleep Disorder and Alcohol-Related Disorder Not Otherwise Specified (291.9)); Amphetamine (or Amphetamine-I_ike)-Related Disorders (for example Amphetamine Dependence (304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89), Amphetamine Withdraw
  • Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, or Anxiolytic Intoxication Delirium, Sedative, Hypnotic, or Anxiolytic Withdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-Persisting Dementia, Sedative-, Hypnotic-, or Anxiolytic- Persisting Amnestic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Psychotic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Mood Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Anxiety Disorder Sedative-, Hypnotic-, or Anxiolytic-lnduced Sexual Dysfunction, Sedative-, Hypnotic-, or Anxiolytic-lnduced Sleep Disorder and Sedative-, Hypnotic-, or An
  • Sleep disorders for example primary sleep disorders such as Dyssomnias (including Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47)); primary sleep disorders such as Parasomnias (including Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47)); Sleep Disorders Related to Another Mental Disorder (including Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44)); Sleep Disorder Due to a General Medical
  • Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type.
  • Eating disorders such as Anorexia Nervosa (307.1 ) (including the subtypes Restricting Type and Binge-Eating/Purging Type); Bulimia Nervosa (307.51 )
  • Autism Spectrum Disorders including Autistic Disorder (299.00), Asperger's Disorder, Rett's Disorder, Childhood Disintegrative Disorder and Pervasive Developmental Disorder Not Otherwise Specified.
  • Attention-Deficit /Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention-Deficit/Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit/Hyperactivity Disorder Hyperactive-Impulse Type (314.01 ) and Attention-Deficit/Hyperactivity Disorder Not Otherwise Specified (314.9)); Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder (including the subtypes childhood- onset type (321.81 ), Adolescent-Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81 ) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23).
  • Enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e.g. Alzheimer's disease.
  • the disease or condition for which antagonism of the mGluRs receptor is beneficial is selected from the list consisting of: Parkinson's Disease, epilepsy, inflammatory pain, neuropathic pain, migraine, Down's Syndrome, gastroesophageal reflux disease.
  • the invention provides a compound of the invention for use as a neuroprotectant.
  • the disease or condition for which antagonism of the mGluRs receptor is beneficial is a substance-related disorder.
  • references herein to "treat”, “treating” or “treatment” extend to prophylaxis, prevention of recurrence and suppression or amelioration of symptoms (whether mild, moderate or severe) as well as the treatment of established conditions.
  • a compound of the invention for treating a disease or condition for which antagonism of the mGluRs receptor is beneficial is beneficial.
  • the disease or condition is a substance related disorder.
  • a method of treating a disease or condition for which antagonism of the mGluR5 receptor is beneficial in a human comprising administering an effective amount of a compound of the invention.
  • the disease or condition is a substance related disorder.
  • the compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient by an appropriate route. Accordingly, in another aspect, the invention provides pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically-acceptable excipients.
  • pharmaceutically-acceptable excipient means any pharmaceutically acceptable material present in the pharmaceutical composition or dosage form other than the compound or compounds of the invention. Typically the material gives form, consistency and performance to the pharmaceutical composition.
  • compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. In addition, the pharmaceutical compositions of the invention may comprise one or more additional pharmaceutically active compounds.
  • compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be dispensed and then given to the patient such as with powders or syrups.
  • the pharmaceutical compositions of the invention may be prepared and packaged as dosage forms wherein each physically discrete dosage form contains a safe and effective amount of a compound of the invention.
  • the invention provides dosage forms comprising pharmaceutical compositions of the invention. Each discrete dosage form typically contains from 0.1 mg to 100 mg of a compound of the invention.
  • compositions of the invention will typically be formulated into dosage forms which are adapted for administration to the patient by the desired route of administration.
  • dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration such as sterile solutions, suspensions, implants and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal and vaginal administration such as suppositories, pessaries and foams; (5) inhalation and intranasal such as dry powders, aerosols, suspensions and solutions (sprays and drops); (6) topical administration such as creams, ointments, lotions, solutions, pastes, drops, sprays, foams and gels; (7) ocular administration such as drops, ointment, sprays, suspensions and inserts; (8) buccal and sub
  • Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the release of the compound of the invention at the appropriate rate to treat the condition.
  • Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavouring agents, flavour masking agents, colouring agents, anticaking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, rate modifying agents, antioxidants, preservatives, stabilizers, surfactants and buffering agents.
  • excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavouring agents, flavour masking agents, colouring agents, anticaking agents, hume
  • Skilled artisans possess the knowledge and skill in the art to enable them to determine suitable pharmaceutically-acceptable excipients in appropriate amounts for use with the compounds of the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically- acceptable excipients and may be useful in selecting suitable pharmaceutically- acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • the pharmaceutical compositions of the invention may be prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include starches, crospovidone, sodium starch glycolate, cros- carmellose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and sodium dodecyl sulphate.
  • the oral solid dosage form may further comprise a glidant such as talc and colloidal silicon dioxide.
  • the oral solid dosage form may further comprise an outer coating which may have cosmetic or functional properties.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent psychotic disorders: i) antipsychotics; ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine).
  • the compounds of the invention may be used in combination with antidepressants to treat or prevent depression and mood disorders.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent bipolar disease: i) mood stabilisers; ii) antipsychotics; and iii) antidepressants.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants.
  • Antipsychotic drugs include Typical Antipsychotics (for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine); and Atypical Antipsychotics (for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone and amisulpride).
  • Typical Antipsychotics for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine
  • Atypical Antipsychotics for example clozapine, olanzapine, risperidone, quetiapine,
  • Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine, sertraline femoxetine, fluvoxamine, indalpine and zimeldine); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine and venlafaxine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).
  • Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.
  • Anxiolytics include benzodiazepines such as alprazolam and lorazepam.
  • hydrophobic cartridges Isolute Phase Separators
  • propylsulfonic acid functionalized silica cartridges IOLUTE SCX-2
  • a number of the compounds were purified using a Mass Directed Auto-Purification System (MDAP) incorporating HPLC techniques and an appropriate mass spectrometer such as the Waters® ZQ mass spectrometer.
  • MDAP Mass Directed Auto-Purification System
  • Microwave heating was performed using InitiatorTM and EmrysTM Optimizer microwave reactors from Biotage.
  • Phenyl isocyanate (commercially available from Aldrich) (0.340 ml, 3.1 1 mmol) was added to (+/-)1-(2-cyclopropyl-6-methyl-[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethanol (Intermediate 1 ) (0.62 mmole) in dry DCM (4ml). TEA (0.17 ml, 1.24 mmol) was added. The reaction mixture was heated in a microwave reactor for 20 minutes at 8O 0 C and evaporated to dryness.
  • (+/-)1-(6-Methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethanol (Intermediate 4) (183 mg, 1 mmol) and CDI (324 mg, 2.000 mmol) in dry DCM (5 ml) were heated in a microwave reactor at 80 0 C for 20 minutes. The mixture obtained was then added to a solution of cyclobutylamine hydrochloride (321 mg, 3.00 mmol) in dry DCM (5 ml) and TEA (418 ⁇ l, 3.00 mmol). The resulting mixture was heated in a microwave reactor at 80 0 C for 20 minutes.
  • racemic compounds which support the first aspect of the invention were purchased from Bionet-Key Organics Ltd.
  • the absolute configuration of Compound 32a was predicted with 91 % confidence by ab initio Vibrational Circular Dichroism (VCD).
  • VCD Vibrational Circular Dichroism
  • Solution-phase VCD and IR spectra were measured for samples in CDCI3 using a BioTools BOMEM ChiralirTM FT-VCD spectrometer operating at 4 cm "1 resolution.
  • Spectral data were acquired in the 2000-950 cm "1 region of the mid-infrared spectrum.
  • Absolute configurations were assigned by comparing the signs (+/-) predicted for a set of diagnostic marker bands in the VCD spectrum of a full structure model with (1 R)-absolute configuration to corresponding bands in the VCD spectra of the compounds.
  • racemic compounds of formula (Ie), i.e. compounds of general formula (I) where Y is C(R X ), X is N, R 1 is methyl, R 2 is methyl, R 3 is H and R 5 is H, (see Table 4) were prepared in a similar fashion to the preparation of Compound 40 replacing the Intermediate 19 with the starting materials indicated, and using the appropriate isocyanate.
  • Phenylisocyanate (0.070 ml_, 0.641 mmol) was added to a mixture of (+/-) 2,2,2- trifluoro-1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethanol (Intermediate 40) (38 mg, 0.160 mmol) in DCM (2 ml.) under argon. The reaction mixture was heated at 8O 0 C for 20 min in a microwave reactor. The reaction mixture was evaporated to dryness. The residue was dissolved in DCM (10ml) and water (10ml), and the organic phase was separated. The aqueous phase was extracted with DCM (10ml).
  • (+/-) 1-(5-Methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethanol (Intermediate 19) (54mg, 0.3mmol) was dissolved in THF (5ml) and NaH (60% in mineral oil, 15mg, 0.36mmol) was added. The mixture was stirred at room temperature for 30min and then 2- fluoro-phenylisocyanate (49mg, 0.36mmol, available from Alfa) was added. The resulting mixture was stirred at room temperature for another 16 hours. The residue was partitioned between water (20ml) and DCM (50ml).
  • (+/-) 1-(5-Methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethanol (Intermediate 19) (50mg, 0.27mmol) was dissolved in THF (5ml) and NaH (60% in mineral oil, 13mg, 0.33mmol) was added. The mixture was stirred at room temperature for 30min and then 3-chlorophenylisocyanate (83mg, 0.54mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. Water (15 ml) was added and the mixture was extracted with ethyl acetate (3 x15ml).
  • 3-Chloro-2,4-pentanedione (commercially available from Aldrich) (0.074 ml, 0.622 mmol) was added to a mixture of 5-cyclopropyl-1 ,2-dihydro-3H-1 ,2,4-triazole-3-thione (Intermediate 10) (0.088 g, 0.622 mmol) in ethanol (4 ml).
  • the reaction mixture was heated in a microwave reactor at 13O 0 C for 20min.
  • Sodium borohydride (0.024 g, 0.622 mmol) was added to the reaction mixture as a solution in water (1 ml) and the reaction mixture was stirred for approximately 4 hrs at room temperature.
  • racemic intermediates of formula (lie), i.e. intermediates of general formula (II) where X is C(R X ), R ⁇ is methyl, R ⁇ is methyl and R ⁇ is H, were prepared in a similar fashion to the preparation of Intermediate 1 from the starting material indicated.
  • the aqueous phase was extracted with ethyl acetate (2 x 30ml).
  • the organic phases were combined, dried with MgS ⁇ 4 and evaporated to dryness.
  • the residue was redissolved in ethanol (6 ml).
  • Sodium borohydride (89 mg, 2.362 mmol) was added and the reaction mixture was stirred at room temperature for 1 hr.
  • the reaction mixture was evaporated to dryness and the residue was dissolved in a mixture of ethyl acetate (20ml) and saturated aqueous sodium bicarbonate (20ml).
  • the organic phase was separated and the aqueous phase was extracted with ethyl acetate (2 x 20ml).
  • the organic phases were combined, dried with MgS ⁇ 4 and evaporated to dryness.
  • CHO cells containing human mGluR ⁇ receptors engineered with geneswitch expression control technology were prepared. These cells were induced with 0.1 nM mifepristone to enable expression and growth media was added.
  • the growth media comprised DMEM (Dulbeccos Modifies Eagle medium) 50OmIs (supplied by Gibco - catalogue number 31 166), 50 ml dialysed FCS (Foetal Calf Serum) (supplied by Gibco - catalogue number 26400-044), 0.02mg/ml proline, 0.25mg/ml hygromycin and 0.5mg/ml zeocin.
  • the cells in the growth media were then dispensed using a Multidrop (supplied by ThermoFisher) into 384-well black clear-bottom plates at a confluency of 10K cells/well in a volume of 50 ⁇ l.
  • the plates were incubated at 37 0 C to give a monolayer with a confluency of 80%.
  • the growth medium was aspirated using a power washer (supplied by Tecan) and 30 ⁇ l of loading buffer was added to the cells using a Multidrop.
  • the loading buffer comprised Hanks Balanced Salt Solution (HBSS) + 2.5M probenicid + 2 ⁇ M Fluo-4 (MDC) and 250 ⁇ M Brilliant Black (MDC).
  • HBSS Hanks Balanced Salt Solution
  • MDC 2 ⁇ M Fluo-4
  • MDC 250 ⁇ M Brilliant Black
  • test compounds in DMSO at a concentration of 1 OmM, were further diluted with DMSO using a Biomek FX (supplied by Beckman Coulter) into a 384-well compound plate (supplied by Greiner). Each dilution was then transferred in 1 ul aliquots to a further compound plate and assay buffer added to give a final volume of 50 ⁇ l, making a final assay concentration of 1 1.8 ⁇ M.
  • the assay buffer consisted of HBSS and 2.5M probenicid.
  • a 0.38M solution of glutamic acid in water was further diluted in DMSO to a concentration of 204 mM.
  • 16 x 1 1 point concentration response curves (CRCs) were prepared in DMSO with a top concentration of 204mM, making the final assay concentration 1 mM, diluted serially to 1 in 4. This was performed using the Biomek FX liquid handling device. 1 ⁇ l stampouts of the CRCs were prepared. 50 ⁇ l of compound buffer was added prior to use.
  • EC80 concentration of Glutamate endogenous liqand 50 ⁇ l of compound buffer was added to the glutamate CRC plate. This plate was added using the FLIPR to a plate of cells that had been loaded for 2 hrs. A fluorescent read was made. An EC80 concentration of glutamate was calculated by using 4x EC50 concentration generated. An EC80 concentration solution of glutamate was prepared in compound buffer and dispensed into 384-well plates, excluding column 18 where compound buffer alone was added.
  • test compounds 10 ⁇ l were added to the cell plates using a Cybiwell liquid handling device (supplied by Cybio). The cell plates were incubated at 37 0 C for 15 min, a FLIPR addition of the EC80 was made and a fluorescent read generated. Blocking of the receptor by test compound, in a dose dependent manner is evident from the calcium vs time profiles generated for each well. The data is analysed using XC50 software to produce CRCs, from which the potency and plC50 can be determined.
  • CHO cells containing human mGluR ⁇ receptors with Tet On expression control technology (supplied by Clontech) were prepared. These cells were grown in cell factories, induced with 10ng/ml doxycycline to enable expression, harvested and then cryo-preserved at -140 0 C in 1 ml aliquots for future use.
  • the cells were thawed, suspended in growth media and centrifuged at I OOOrpm for 5 min.
  • the growth media consisted of F12 Hams Nutrient mix (supplied by Gibco - catalogue number 21765) and 10% Tet approved FBS (supplied by Clontech - catalogue number 631 106). The cells were then re-suspended in growth media and incubated at 37°C for 1 hour in a spinner flask.
  • the cell suspension was centrifuged once more and resuspended at 2.5 x 10 ⁇ cells/ml in loading buffer consisting of HBSS, 0.1 % BSA (supplied by CalBiochem - catalogue number 126609) and 0.1 % Pluronic F68 (supplied by Gibco - catalogue number 24040-032).
  • the cells were loaded with coelentrazine (supplied by Invitrogen C - catalogue number 6780) to a concentration of 5 ⁇ M, wrapped in foil and loaded overnight with mixing.
  • the cells were diluted to 15 x 10 ⁇ cells/ml in dilution buffer consisting of HBSS and 0.1 % Pluronic F68.
  • Coelentrazine is the chromophore co-factor which activates the apo-protein, aequorin.
  • the protein has three high affinity binding sites for calcium.
  • agonism of the mGluR ⁇ receptor binding of calcium to the aequorin protein induces a conformational change resulting in an oxidative decarboxylation reaction producing coelenteramide and a flash luminescence signal. This signal was measured using the Lumilux (supplied by Perkin Elmer).
  • test compounds were prepared in DMSO at a concentration of 3mM. These solutions are serially diluted with DMSO to 1 in 4 using a Biomek FX liquid handling device (supplied by Beckman Coulter) in a 384-well compound plate (supplied by Greiner). Daughter plates of 0.5 ⁇ l/well were stamped-out from this master plate for use in the assay.
  • Glutamate Dose Response Curve Preparation A 10OmM solution of glutamic acid was prepared in water. This was further diluted with DMSO to a concentration of 1OmM. 16 x 11 point concentration response curves (CRC) were prepared in DMSO, making the final assay concentration 1.66 x10 ' ⁇ M, with 1 in 3 serial dilutions using the Biomek FX. 0.5 ⁇ l stamp-outs of this plate were generated for use in the assay.
  • CRC concentration response curves
  • the glutamate CRC plate was placed on the Lumilux where 20 ⁇ l/well of dilution buffer was added, followed by 10 ⁇ l/well of loaded cell suspension and a luminescence read was made.
  • An EC80 concentration of glutamate was calculated by using 4X EC50 generated.
  • the EC80 solution was prepared in dilution buffer and added to a reservoir within the Lumilux. Running the Assay
  • the supporting compounds were tested in assay a) and/or assay b).
  • assay b) compounds 1 to 17, 19 to 29, 31 to 38, 40, 40b, 41-56 gave a plC50 equal to or greater than 4.5.
  • assay a) compound 39 gave a plC50 of 5.0.

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Abstract

The invention relates to the use of thiazolotriazole, thiazoloimidazole and thiazolotetrazole derivatives of formula (I) in treating diseases and conditions for which antagonism of the mGluR5 receptor is beneficial, in particular substance related disorders. The invention also relates to certain novel derivatives. In addition, the invention relates to compositions containing the derivatives and processes for their preparation.

Description

USE OF THIAZOLOIMIDAZOLES, THIAZOLOTETRAZOLES AND THIAZOLOTRIAZOLES AS MGLUR5 ANTAGONISTS
The invention relates to the use of thiazolotriazole, thiazoloimidazole and thiazolotetrazole derivatives in treating diseases and conditions for which antagonism of the mGluR5 receptor is beneficial, in particular substance related disorders. The invention also relates to certain novel derivatives. In addition, the invention relates to compositions containing the derivatives and processes for their preparation.
According to a first aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or condition for which antagonism of the mGluRs receptor is beneficial,
Figure imgf000002_0001
(I) wherein
X is N or -C(RX)-; Y is N or -C(RY)-;
R1 is H, halo, C-|.galkyl, C-|.galkoxy, C-|.ghaloalkoxy, C-|.ghaloalkyl, C-|.galkylthio, C-|.ghaloalkylthio, cyclopropyl, cyano, -N(R1 a)(R1 b), -C(O)N(R1 c)(R1 d),
-N(R1 c)C(0)R1 e, -C(0)R1 e or -SO2R1 e;
R^ and R^, which may be the same or different, are H, C-|.galkyl, C-|.ghaloalkyl or cyclopropyl; or R^ and R^, together with the carbon to which they are attached, form a 3 to 6-membered saturated ring, optionally containing one heteroatom selected from O, N and S;
R4 is 5- or 6-membered monocyclic heterocyclyl, phenyl or C3_gcycloalkyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-|.galkyl; C-|.galkoxy; C-μghaloalkoxy; C-|.ghaloalkyl; C-μgalkylthio; C-|.ghaloalkylthio; cyclopropyl; cyano; -N(R4a)(R4b); -C(O)N(R4C)(R4Cl); -N(R4C)C(O)R4e; -C(0)R4e; -SO2R4e; 5-or 6-membered monocyclic heterocyclyl optionally substituted independently by one or more halo, C-|_3alkyl or C-|_3haloalkyl; phenyl optionally substituted independently by one or more halo, C-|_3alkyl or C-|. 3haloalkyl; and C3_gcycloalkyl optionally substituted independently by one or more halo, C-|_3alkyl or C-|_3haloalkyl; or R4 is a fused bicyclic ring system optionally comprising one or two heteroatoms independently selected from O, N and S and optionally substituted by one or more substituents independently selected from halo, C-|_3alkyl and C-|_3haloalkyl; and
R5 is H; or R^ together with the N to which it is attached, forms a ring fused with R4, which ring is optionally substituted by one or more substitutents independently selected from the list: halo, C-|.galkyl, C-|.galkoxy, C-|.ghaloalkoxy and C-|.ghaloalkyl; wherein
Rx and RY, which may be the same or different, are -(CH2)nR^; wherein R^ is H; halo; C-|.galkyl; C-|.galkoxy; C-|.ghaloalkoxy; C-|.ghaloalkyl; C-|.galkylthio;
C-|.ghaloalkylthio; C-|_3alkoxyC-|_3alkoxy; C3_gcycloalkyl; saturated C3_gheterocyclyl comprising one heteroatom selected from O, N and S; cyano; -N(R6a)(R6b); -C(O)N(R6c)(R6d); -N(R6c)C(O)R6e; -C(O)R6e or -SO2R6e; and n is 0, 1 or 2; wherein
R1 a, R1 b, R4a, R4b, R6a and R6b, which may be the same or different, are H or
C-i-galkyl; R1 c, R1 d, R4c R4d, R6c and R6d, which may be the same or different, are H or
C-|.galkyl; and R^ e, R4e and R^e, which may be the same or different, are C-|.galkyl or
C-|.ghaloalkyl; with the proviso that R^ , R^ and R^ are not all H.
As used herein unless otherwise indicated, an alkyl substituent is a univalent radical derived by removal of a hydrogen atom from an acyclic alkane. For example,
C-|.galkyl refers to such an alkyl substituent containing 1 to 6 carbons. Such alkyl substituents include methyl and ethyl, may be straight chain (i.e. n-propyl, n-butyl, n- pentyl and n-hexyl) or branched chain (for example, isopropyl, isobutyl, secbutyl, tert- butyl, isopentyl and neopentyl). In an embodiment unless otherwise indicated, such an alkyl substituent is methyl, ethyl, n-propyl or isopropyl. As used herein, a halo substituent refers to fluoro, chloro, bromo and iodo radicals. In an embodiment unless otherwise indicated such a halo substituent is fluoro or chloro.
As used herein unless otherwise indicated, a haloalkyl substituent is an alkyl group substituted by one or more halo substituents, which halo substituents may be the same or different. For example, C-|.ghaloalkyl refers to such a haloalkyl substituent containing 1 to 6 carbons. Such haloalkyl substituents include monofluoromethyl, difluoromethyl, trifluoromethyl and 1-chloro-2-fluoroethyl. In an embodiment unless otherwise indicated such a haloalkyl substituent is monofluoromethyl, difluoromethyl or trifluoromethyl.
As used herein unless otherwise indicated, an alkoxy substituent is a group of formula "R-O-" where R is alkyl as defined above. For example, C-|.galkoxy refers to such an alkoxy substituent containing 1 to 6 carbons. Such alkoxy substituents include methoxy and ethoxy and may be straight chain (i.e. n-propoxy, n-butoxy, n- pentoxy and n-hexyloxy) or branched chain (for example, isopropoxy, isobutoxy, secbutoxy, tert-butoxy, isopentoxy and neopentoxy). In an embodiment unless otherwise indicated, such an alkoxy substituent is methoxy, ethoxy, n-propoxy or isopropoxy.
As used herein unless otherwise indicated, an alkylthio substituent is a group of formula "R-S-" where R is alkyl as defined above. For example, C-|.galkylthio refers to such an alkylthio substituent containing 1 to 6 carbons. Such alkylthio substituents include methylthio and ethylthio and may be straight chain or branched chain. In an embodiment unless otherwise indicated, such an alkylthio substituent is methylthio, ethylthio, n-propylthio or isopropylthio.
As used herein unless otherwise indicated, a haloalkoxy substituent is a group of formula "R-O-" where R is haloalkyl as defined above. For example, C-μghaloalkoxy refers to such a haloalkoxy substituent containing 1 to 6 carbons. Such haloalkoxy substituents include monofluoromethoxy, difluorom ethoxy, trifluoromethoxy and 1- chloro-2-fluoroethoxy and may be straight chain or branched chain. In an embodiment unless otherwise indicated, such a haloalkoxy substituent is monofluoromethoxy, difluoromethoxy or trifluoromethoxy. As used herein unless otherwise indicated, a haloalkylthio substituent is a group of formula "R-S-" where R is haloalkyl as defined above. For example, C-|_ghaloalkylthio refers to such a haloalkylthio substituent containing 1 to 6 carbons. Such haloalkylthio substituents include monofluoromethylthio, difluoromethylthio, trifluoromethylthio and 1-chloro-2-fluoroethylthio and may be straight chain or branched chain. In an embodiment unless otherwise indicated, such a haloalkylthio substituent is monofluoromethylthio, difluoromethylthio or trifluoromethylthio.
As used herein unless otherwise indicated, a cycloalkyl substituent is a univalent radical derived by removal of a hydrogen atom from a monocyclic cycloalkane, comprising from 5 to 6 carbons all interconnected to form a ring. Examples of cycloalkyl substituents are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In an embodiment, the cycloalkyl substituent is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
As used herein, unless otherwise indicated, a 5 to 6-membered monocyclic heterocyclyl substituent refers to a univalent radical derived by removal of a hydrogen atom from a 5 to 6-membered monocyclic heterocyclic ring; the heterocyclic ring containing one or more carbon atoms; one or more hydrogen atoms; and independently 1 to 4 heteroatoms such as nitrogen, oxygen and sulfur; the carbon and heteroatoms being interconnected to form a ring. The monocyclic heterocyclyl substituent may be saturated, unsaturated or aromatic. Examples of saturated monocyclic heterocyclyl substituents are pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino and piperazinyl. Examples of unsaturated monocyclic heterocyclyl substituents are 2H-pyrrolyl, 2-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl and 2H- pyranyl, 4H-pyranyl. Examples of aromatic monocyclic heterocyclyl substituents are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, azepinyl, oxazepinyl, thiazepinyl and diazepinyl.
As used herein, unless otherwise indicated, a 3 to 6-membered saturated heterocyclyl substituent refers to a univalent radical derived by removal of a hydrogen atom from a 3 to 6-membered saturated heterocyclic ring; the heterocyclic ring containing, as appropriate, one or more carbon atoms; one or more hydrogen atoms; and independently 1 to 4 heteroatoms such as nitrogen, oxygen and sulfur; the carbon and heteroatoms being interconnected to form a ring. In an embodiment, the 3 to 6-membered saturated heterocyclyl is pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino and piperazinyl.
In an embodiment, R^ is halo, C-|.galkyl, C-μgalkoxy, C-|.ghaloalkoxy, C-μghaloalkyl, C-|.galkylthio, C-|.ghaloalkylthio, cyclopropyl or cyano. In a further embodiment R^ is halo or C-|.galkyl.
In an embodiment, R^ is H and R^ is C-|.galkyl, C-|.ghaloalkyl or cyclopropyl. In a further embodiment, R^ is H and R^ is C-|.galkyl. In a still further embodiment R^ is H and R^ is methyl. It will appreciated that in these latter embodiments, the carbon atom to which R2 and R^ are attached is chiral. The scope of the present invention includes individual enantiomers and mixtures of each enantiomer including racemic mixtures. In an embodiment, the compound of formula (I) has formula (Ia)
Figure imgf000006_0001
(Ia)
Racemic compounds may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilising methods known to those skilled in the art. In addition, chiral intermediate compounds may be resolved and used to prepare chiral compounds of the invention. In addition, the chiral compounds of the invention may be prepared by chiral synthesis.
In an embodiment, R^ is H and R4 is 5- or 6-membered monocyclic heterocyclyl, phenyl or C3_gcycloalkyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-|.galkyl; C-|.galkoxy; C-|. ghaloalkoxy; C-|.ghaloalkyl; C-|.galkylthio; C-|.ghaloalkylthio; cyclopropyl; cyano; -N(R4a)(R4b); -C(O)N(R4C)(R4d); _N(R4C)C(O)R4e; -C(O)R4e; and -SO2R4e; wherein R4a and R4^, which may be the same or different, are H or C-|.galkyl; R4c and R4^, which may be the same or different, are H or C-|.galkyl; and R4e is C-|. galkyl or C-|.ghaloalkyl.
In a further embodiment, R^ is H and R4 is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl or C3_gcycloalkyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-| .galkyl; C-|.galkoxy; C-|. ghaloalkoxy; C-|.ghaloalkyl; C-|.galkylthio; C-|.ghaloalkylthio; cyclopropyl; cyano; -N(R4a)(R4b); -C(O)N(R4c)(R4d); -N(R4c)C(O)R4e; -C(O)R4e; and -SO2R4e; wherein R4a and R4b, which may be the same or different, are H or C-| .galkyl; R4c and R4^, which may be the same or different, are H or C-| .galkyl; and R4e is C-|. galkyl or C-|.ghaloalkyl.
In a still further embodiment, R^ is H and R4 is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or phenyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-| .galkyl; C-|.galkoxy; C-μ ghaloalkoxy; C-μghaloalkyl; C-|.galkylthio and C-|.ghaloalkylthio.
In a further embodiment, R^ is H and R4 is pyridyl or phenyl, either of which is optionally substituted by one or more substituents independently selected from the list: halo; C-|.galkyl; C-μgalkoxy; C-| .ghaloalkoxy; C-μghaloalkyl; C-|.galkylthio; C-|.ghaloalkylthio; cyclopropyl; cyano; -N(R4a)(R4b); -C(O)N(R4c)(R4d); -N(R4c)C(O)R4e; -C(O)R4e; and -SO2R4e; wherein R4a and R4b, which may be the same or different, are H or C-| .galkyl; R4c and R4d, which may be the same or different, are H or C-| .galkyl; and R4e is C-| .galkyl or C-μghaloalkyl.
In a still further embodiment, R^ is H and R4 is pyridyl or phenyl, either of which is optionally substituted by one or more substituents independently selected from the list: halo; C-|.galkyl; C-μgalkoxy; C-| .ghaloalkoxy; C-μghaloalkyl; C-|.galkylthio and C-|.ghaloalkylthio.
In a still further embodiment, R^ is H and R4 is pyridyl or phenyl, either of which is optionally substituted by one or more substituents independently selected from the list: halo; C-|.galkyl and C-μgalkoxy.
In an embodiment, X and Y are not both N. In an embodiment, when X is -C(RX)- and Y is -C(RY)- then at least one of Rx and RY is H.
In an embodiment, at least one of X and Y is N.
In an embodiment, Rx and RY, which may be the same or different, are -(CH2)nR®; wherein R^ is H; halo; C-|.galkyl; C-|.galkoxy; C-μghaloalkoxy; C-|.ghaloalkyl; C-μ galkylthio; C-|.ghaloalkylthio; C-|_3alkoxyC-|_3alkoxy; C3_gcycloalkyl; saturated C3_gheterocyclyl comprising one heteroatom selected from O, N and S; cyano; - N(R6a)(R6b); -C(O)N(R6c)(R6d); -N(R6c)C(O)R6e; -C(O)R6e or -SO2R6e; and n is 0 or 1.
In an embodiment, Rx and RY, which may be the same or different, are H, halo, C-|. galkyl, C-|.ghaloalkyl, C3_gcycloalkyl, saturated C3_gheterocyclyl, C3. gcycloalkylmethyl or saturated C3_gheterocyclylmethyl, wherein either C3. gheterocyclyl comprises one heteroatom selected from O, N and S.
In a further embodiment, the compound of formula (I) has formula (Ia)
Figure imgf000008_0001
(Ia) wherein one of X and Y is N and the other X or Y is -C(RX)- or -C(RY)-; wherein Rx or RY is
H, halo, C-|.galkyl, C-μghaloalkyl, C3_gcycloalkyl, saturated C3_gheterocyclyl, C3. gcycloalkylmethyl or saturated C3_gheterocyclylmethyl, wherein either C3. gheterocyclyl comprises one heteroatom selected from O, N and S; R1 is H, halo, C-|.galkyl, C-|.galkoxy, C-|.ghaloalkoxy, C-|.ghaloalkyl, C-|.galkylthio,
C-|.ghaloalkylthio, cyclopropyl or cyano;
R3 is C-|.galkyl, C-|.ghaloalkyl or cyclopropyl; and
R5 is H and R^ is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or phenyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-|.galkyl; C-|.galkoxy; C-|.ghaloalkoxy; C-|.ghaloalkyl; C-|.galkylthio and C-|.ghaloalkylthio.
In an embodiment, the compound of formula (I) is selected from the list consisting of: (+/-)1-(2-Cyclopropyl-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 1 );
1-(2-Cyclopropyl-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate
(Compound 1 b) (faster eluting enantiomer);
(+/-) 1-[2-(cyclopropylmethyl)-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl]ethyl phenylcarbamate (Compound 2);
(+/-) 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl [2-
(methyloxy)phenyl]carbamate (Compound 6);
(+/-) 1-(3-methylimidazo[2,1-b][1 ,3]thiazol-2-yl)ethyl phenylcarbamate (Compound 7);
(+/-) 1-(3-methylimidazo[2,1-b][1 ,3]th iazol-2-y I )ethy I (3-chlorophenyl)carbamate (Compound 8);
(+/-) 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (3-fluorophenyl)carbamate
(Compound 10);
(+/-) 1-(3-methylimidazo[2,1-b][1 ,3]th iazol-2-y I )ethy I (3-fluorophenyl)carbamate
(Compound 1 1 ); 1-[6-methyl-2-(tetrahydro-3-furanyl)[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl]ethyl phenylcarbamate (Compound 12);
1 -(+/-) [6-methyl-2-(trifluoromethyl)[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl]ethyl phenylcarbamate (Compound 13);
(+/-) 1-(2,6-dimethyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 14);
(+/-) 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (3-bromophenyl)carbamate
(Compound 20);
(+/-)1-(6-Methyl-[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl [3- (methyloxy)phenyl]carbamate (Compound 27); 1-(6-Methyl-[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl [3-
(methyloxy)phenyl]carbamate (Compound 27b) (slower eluting enantiomer);
(+/-) 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (3-chlorophenyl)carbamate (Compound 31 ); (+/-) 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 32);
(1 R)-1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate: (Compound 32a); (+/-) 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (3- methylphenyl)carbamate (Compound 33);
(+/-)1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl phenylcarbamate (Compound 40);
1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl phenylcarbamate (Compound 40b) (faster eluting enantiomer);
(+/-) 1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl (3-fluorophenyl)carbamate
(Compound 42);
1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl (3-fluorophenyl)carbamate
(Compound 42a) (slower eluting enantiomer); (+/-) 1-(3,5-dimethyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl (3- fluorophenyl)carbamate (Compound 43);
(+/-) 1-(3-chloro-5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl phenylcarbamate
(Compound 46);
(+/-) 1-(3-bromo-5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl phenylcarbamate (Compound 47);
(+/-)1-(6-Methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)propyl phenylcarbamate
(Compound 48);
(+/-)2-Methyl-1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)propyl phenylcarbamate (Compound 49); (+/-) 2,2,2-trifluoro-1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 50);
(+/-)1-(2-Chloro-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl cyclobutylcarbamate (Compound 51 );
(+/-) 1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl (3-chlorophenyl)carbamate (Compound 53);
1-Methyl-1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate
(Compound 54); and
(+/-) 1-(2-Chloro-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate
(Compound 55); or a salt of any of the above. According to a second aspect, the invention provides a compound of formula (I) or a salt thereof
Figure imgf000011_0001
(I) wherein
X is N or -C(RX)-; Y is N or -C(RY)-;
R1 is H, halo, C-|.galkyl, C-|.galkoxy, C-|.ghaloalkoxy, C-|.ghaloalkyl, C-|.galkylthio, C-|.ghaloalkylthio, cyclopropyl, cyano, -N(R1a)(R1b), -C(O)N(R1C)(RId)1
-N(R1 C)C(O)R1 e, -C(O)R1 e or -SO2R1 e;
R2 and R^, which may be the same or different, are H, C-|.galkyl, C-|.ghaloalkyl or cyclopropyl; or R^ and Rβ, together with the carbon to which they are attached, form a 3 to 6-membered saturated ring, optionally containing one heteroatom selected from O, N and S;
R4 is 5- or 6-membered monocyclic heterocyclyl, phenyl or C3_gcycloalkyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-|.galkyl; C-|.galkoxy; C-μghaloalkoxy; C-|.ghaloalkyl; C-μgalkylthio; C-|.ghaloalkylthio; cyclopropyl; cyano; -N(R4a)(R4b); -C(O)N(R4c)(R4d); -N(R4C)C(O)R4e; -C(O)R4e; -SO2R4e;
5-or 6-membered monocyclic heterocyclyl optionally substituted independently by one or more halo, C-|_3alkyl or C-|_3haloalkyl; phenyl optionally substituted independently by one or more halo, C-|_3alkyl or C-|. βhaloalkyl; and C3_gcycloalkyl optionally substituted independently by one or more halo, C-|_3alkyl or C-|_3haloalkyl; or R4 is a fused bicyclic ring system optionally comprising one or two heteroatoms independently selected from O, N and S and optionally substituted by one or more substituents independently selected from halo, C-|_3alkyl and C-|_3haloalkyl; and
R5 is H; or R^ together with the N to which it is attached, forms a ring fused with R4, which ring is optionally substituted by one or more substitutents independently selected from the list: halo, C-μgalkyl, C-μgalkoxy,
C-|.ghaloalkoxy and C-|.ghaloalkyl; wherein
Rx and RY, which may be the same or different, are -(CH2)nR®; wherein R^ is H; halo; C-μgalkyl; C-|.galkoxy; C-μghaloalkoxy; C-|.ghaloalkyl; C-|.galkylthio;
C-|.ghaloalkylthio; C-|_3alkoxyC-|_3alkoxy; C3_gcycloalkyl; saturated
C3_gheterocyclyl comprising one heteroatom selected from O, N and S; cyano; -N(R6a)(R6b); -C(O)N(R6c)(R6d); -N(R6c)C(O)R6e; -C(O)R6e or
-SO2R6e; and n is 0, 1 or 2; wherein
R1 a, R1 b, R4a, R4b, R6a and R6b, which may be the same or different, are H or
C-|.galkyl; R1C, RI cI1 R4C R4d, R6c and R6ds which may be the same or different, are H or
C-|.galkyl; and R^ e, R4e and R^e, which may be the same or different, are C-|.galkyl or
C-|.ghaloalkyl; with the proviso that R-I , R2 and R^ are not all H; wherein the compound of formula (I) is not
1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (3-chlorophenyl)carbamate (Compound 31 );
1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 32);
1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (3-methylphenyl)carbamate (Compound 33); 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (4-methylphenyl)carbamate (Compound 34);
1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl [3- (trifluoromethyl)phenyl]carbamate (Compound 35);
1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (4-fluorophenyl)carbamate (Compound 36);
1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (4-chlorophenyl)carbamate (Compound 37);
1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (3,4-dichlorophenyl)carbamate (Compound 38); or 1-(3-methylimidazo[2,1-b][1 ,3]thiazol-2-yl)ethyl (4-chlorophenyl)carbamate (Compound 39). It will be appreciated that the embodiments described for the first aspect extend to the second aspect also.
The compounds of formula (I) as defined in the first or second aspects may contain a basic centre and may form non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, with carboxylic acids or with organo-sulfonic acids. Examples include the HCI, HBr, HI, sulfate or bisulfate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate and pamoate salts. For reviews on suitable pharmaceutical salts see Berge et al, J. Pharm, ScL, 66, 1-19, 1977; P L Gould, International Journal of Pharmaceutics, 33 (1986), 201-217; and Bighley et al, Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc, New York 1996, Volume 13, page 453-497. In an embodiment, the salt is pharmaceutically acceptable.
It will be appreciated by those skilled in the art that certain protected derivatives of the compounds of formula (I) as defined in the first or second aspects, which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds defined in the first or second aspects which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All protected derivatives and prodrugs of compounds defined in the first or second aspects are included within the scope of the invention. Examples of suitable pro-drugs for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro-moieties", for example as described by H. Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within the compounds defined in the first or second aspects. Therefore, in a further aspect, the invention provides a prodrug of a compound defined in the first aspect. The compounds defined in the first or second aspects, their salts or prodrugs, may exist in solvated or hydrated form. Therefore, in a further aspect, the invention provides a solvate or hydrate of a compound defined in the first or second aspects or a salt thereof.
The compounds of formula (I) defined in the first or second aspects or their salts, or solvates or hydrates of either, may exist in one or more polymorphic form. Therefore, in a further aspect, the invention provides a polymorph of a compound of formula (I) defined in the first aspect or their salts, or a polymorph of a solvate or hydrate of a compound of formula (I) defined in the first or second aspects, or a salt thereof.
Hereinafter, compounds of formula (I) as defined in the first or second aspects, their salts and prodrugs; any solvates or hydrates of any salt or prodrug; and any polymorph of any compound, salt, solvate or hydrate are referred to as "compounds of the invention". The term "compounds of the invention" also includes all embodiments of the first or second aspects.
The compounds of the invention may exist in one or more tautomeric forms. All tautomers and mixtures thereof are included in the scope of the present invention. For example, a claim to 2-hydroxyquinolinyl would also cover its tautomeric form, α- quinolinonyl.
The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2H, 3H, 11C, 13C, 14C, 15N, 17O, 180, 31P, 32P, 35S, 18F and 36CI, respectively. Certain isotopic variations of the invention, for example, those in which a radioactive isotope such as 3H or 14C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances, lsotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Experimental section hereafter using appropriate isotopic variations of suitable reagents.
Compounds of the invention may be prepared in a variety of ways. In the following reaction schemes and hereafter, unless otherwise stated R^ to R^, X, Y, n etc are as defined in the first aspect. These processes form further aspects of the invention.
Throughout the specification, general formulae are designated by Roman numerals (I), (II), (III), (IV) etc. Subsets of these general formulae are defined as (Ia), (Ib), (Ic) etc .... (IVa), (IVb), (IVc) etc.
Compounds of formula (I) may be prepared by reacting compounds of formula (II) with activated carbamoyl reagents generated in situ from amines of formula (III) and a reagent such as carbonyl diimidazole (CDI) according to reaction scheme 1.
Typical reaction conditions comprise reacting (III) with CDI in a sealed vessel in a microwave reactor at 80 degC in dry DCM for 20 minutes followed by addition of (II) and further heating at 80 degC for 20 minutes.
Scheme 1
Figure imgf000015_0001
(N) (I)
Alternatively, compounds of formula (Ib), i.e. compounds of formula I where R^ is H, may be prepared by reacting compounds of formula (II) with isocyanates of formula (IV) according to reaction scheme 2. Typical reaction conditions comprise reacting (II) with (IV) in a sealed vessel in a microwave reactor at 80 degC in dry DCM for 20 minutes. Alternative conditions comprise reacting compounds of formula (II) with sodium hydride in THF at room temperature followed by addition of (IV) at room temperature. Scheme 2
Figure imgf000016_0001
(II) (Ib)
Compounds of formula (II) may be prepared by reacting compounds of formula (V) with an organometallic reagent, such as an organolithium or a Grignard reagent, according to reaction scheme 3. Typical reaction conditions comprise reacting (V) with Grignard reagent R^MgX in THF at room temperature.
Scheme 3
Figure imgf000016_0002
(V) (II)
Compounds of formula (Na), i.e. compounds of general formula (II) where R^ is H, may be prepared by reduction of compounds of formula (V) according to reaction scheme 4. Typical reaction conditions comprise sodium borohydride in ethanol at room temperature.
Scheme 4
Reduction
Figure imgf000016_0003
Figure imgf000016_0004
(V) (Na) Compounds of formula (Va), i.e. compounds of formula (V) where X is C(RX), may be prepared by reacting compounds of formula (Vl) or their tautomers with compounds of formula (VII) according to reaction scheme 5. Typical reaction conditions comprise reacting (Vl) with (VII) in a sealed vessel in a microwave reactor at 130 degC in ethanol for 20 minutes with or without a tertiary amine base (such as triethylamine).
Scheme 5
Figure imgf000017_0001
Alternatively, compounds of formula (Vb), i.e. compounds of formula (V) (see scheme 3) where X is C(RX) and R^ is H, may be prepared according to reaction scheme 6, by reacting compounds of formula (Vl) or their tautomers with α-halo-β- keto esters of formula (VIII) to give compounds of formula (IX). Reduction of (IX) with lithium aluminium hydride followed by oxidation with manganese dioxide gives compounds of formula (Vb).
Scheme 6
Figure imgf000017_0002
(Vl)
(IX)
Figure imgf000017_0003
(Vb) Compounds of formula (Via), i.e. compounds of formula (Vl) (see schemes 5 and 6) where X is -C(RX)- and Y is N, may be prepared according to reaction scheme 7 via compounds of formula (X). Compounds of formula (X) may be prepared by reacting activated carboxylic acids (Xl) (such as acid chlorides and 1-hydroxybenzotriazole esters) with a thiosemicarbazide. Typical reaction conditions comprise reacting compounds of formula (Xl) with the thiosemicarbazide in a sealed vessel in a microwave reactor at 80 degC in a suitable solvent (such as DCM or acetone) for 10 minutes with or without a tertiary amine base (such as triethylamine) to give (X). Cyclisation of (X) to give (Via) may be achieved by reacting (X) in a sealed vessel in a microwave reactor at 150 degC in aqueous ethanolic sodium hydroxide for 10 minutes.
Scheme 7
Figure imgf000018_0001
(Xl) (X)
Figure imgf000018_0002
(Via)
Compounds of formula (VIb), i.e. compounds of formula (Vl) (see schemes 5 and 6) where X is -C(RX)- and Y is -C(RY)- , may be prepared according to reaction scheme 8, via reaction of a hydrochloride salt of the corresponding aminoketone (XII) with potassium isothiocyanate for example in water at 90 deg C for 4 hours.
Scheme 8
Figure imgf000018_0003
(XIl) (VIb) Compounds of formula (lib), i.e. compounds of general formula (II) where X is N and Y is -C(RY)-, may be prepared according to reaction scheme 9. Firstly compounds of formula (XIII) may be reacted with compounds of formula (VII) to give compounds of formula (XIV). Typical reaction conditions comprise reacting (XIII) with (VII) in a sealed vessel in a microwave reactor at 130 degC in ethanol for 20 minutes with or without a tertiary amine base (such as triethylamine). Compounds of formula (XIV) may then be cyclised using polyphosphoric acid to compounds of formula (XV). Reduction of compounds of formula (XV) with sodium borohydride gives compounds of formula (lib).
Scheme 9
Figure imgf000019_0001
(XIV)
Figure imgf000019_0002
(XV) (lib)
It will be appreciated by the skilled chemist that compounds of formula (I) may be converted to other compounds of formula (I) by methods known in the art.
The compounds of the invention antagonise the mGluR5 receptor and may be used to treat diseases or conditions for which antagonism of the mGluRs receptor is beneficial. Therefore according to a further aspect, the invention provides a compound of the invention for use in treating a disease or condition. In an embodiment the disease or condition is a human disease or condition. In an embodiment the disease or condition is one for which antagonism of the mGluRs receptor is beneficial. In an embodiment the disease or condition for which antagonism of the mGluRs receptor is beneficial is selected from the list consisting of: [the numbers in brackets after the listed diseases below refer to the classification code in Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM-IV) and/or the International Classification of Diseases, 10th Edition (ICD-10)]:
i) Psychotic disorders for example Schizophrenia (including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60)); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) (including the subtypes Bipolar Type and Depressive Type); Delusional Disorder (297.1) (including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type); Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder due to a General Medical Condition (including the subtypes with Delusions and with Hallucinations); Substance-Induced Psychotic Disorder (including the subtypes with Delusions (293.81 ) and with Hallucinations (293.82)); and Psychotic Disorder Not Otherwise Specified (298.9).
ii) Depression and mood disorders for example Depressive Episodes (including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode); Depressive Disorders (including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (31 1 )); Bipolar Disorders (including Bipolar I Disorder, Bipolar Il Disorder (i.e. Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80)); Other Mood Disorders (including Mood Disorder due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features); Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features); and Mood Disorder Not Otherwise Specified (296.90). iii) Anxiety disorders for example Social Anxiety Disorder; Panic Attack; Agoraphobia, Panic Disorder; Agoraphobia Without History of Panic Disorder (300.22); Specific Phobia (300.29) (including the subtypes Animal Type, Natural Environment Type, Blood-lnjection-lnjury Type, Situational Type and Other Type); Social Phobia (300.23); Obsessive-Compulsive Disorder (300.3); Posttraumatic Stress Disorder (309.81 ); Acute Stress Disorder (308.3); Generalized Anxiety Disorder (300.02); Anxiety Disorder Due to a General Medical Condition (293.84); Substance-Induced Anxiety Disorder; and Anxiety Disorder Not Otherwise Specified (300.00).
iv) Substance-related disorders for example Substance Use Disorders (including Substance Dependence, Substance Craving and Substance Abuse); Substance- Induced Disorders (including Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance-Induced Persisting Dementia, Substance- Induced Persisting Amnestic Disorder, Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder,
Substance-Induced Sexual Dysfunction, Substance-Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders (including Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81 ), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder, Alcohol-Induced Mood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-Induced Sleep Disorder and Alcohol-Related Disorder Not Otherwise Specified (291.9)); Amphetamine (or Amphetamine-I_ike)-Related Disorders (for example Amphetamine Dependence (304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89), Amphetamine Withdrawal (292.0), Amphetamine Intoxication Delirium, Amphetamine Induced Psychotic Disorder, Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder, Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder and Amphetamine-Related Disorder Not Otherwise Specified (292.9)); Caffeine
Related Disorders (including Caffeine Intoxication (305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder and Caffeine-Related Disorder Not Otherwise Specified (292.9)); Cannabis-Related Disorders (including Cannabis Dependence (304.30), Cannabis Abuse (305.20), Cannabis Intoxication (292.89), Cannabis Intoxication Delirium, Cannabis-lnduced Psychotic Disorder, Cannabis- lnduced Anxiety Disorder and Cannabis-Related Disorder Not Otherwise Specified (292.9)); Cocaine-Related Disorders (including Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder, Cocaine- Induced Mood Disorder, Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder Not Otherwise Specified (292.9)); Hallucinogen-Related Disorders (including Hallucinogen Dependence (304.50), Hallucinogen Abuse (305.30), Hallucinogen Intoxication (292.89), Hallucinogen Persisting Perception Disorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium, Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-Related Disorder Not Otherwise Specified (292.9)); Inhalant-Related Disorders (including Inhalant Dependence (304.60), Inhalant Abuse (305.90), Inhalant Intoxication (292.89), Inhalant Intoxication Delirium, Inhalant- Induced Persisting Dementia, Inhalant-Induced Psychotic Disorder, Inhalant-Induced Mood Disorder, Inhalant-Induced Anxiety Disorder and Inhalant-Related Disorder Not Otherwise Specified (292.9)); Nicotine-Related Disorders (including Nicotine Dependence (305.1 ), Nicotine Withdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified (292.9)); Opioid-Related Disorders (including Opioid Dependence (304.00), Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal (292.0), Opioid Intoxication Delirium, Opioid-lnduced Psychotic Disorder, Opioid-lnduced Mood Disorder, Opioid-lnduced Sexual Dysfunction, Opioid-lnduced Sleep Disorder and Opioid-Related Disorder Not Otherwise Specified (292.9)); Phencyclidine (or Phencyclidine-Like)-Related Disorders (including Phencyclidine Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication (292.89), Phencyclidine Intoxication Delirium, Phencyclidine-lnduced Psychotic Disorder, Phencyclidine-lnduced Mood Disorder, Phencyclidine-lnduced Anxiety Disorder and Phencyclidine-Related Disorder Not Otherwise Specified (292.9)); Sedative-, Hypnotic-, or Anxiolytic-Related Disorders (including Sedative, Hypnotic, or Anxiolytic Dependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40), Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative, Hypnotic, or
Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, or Anxiolytic Intoxication Delirium, Sedative, Hypnotic, or Anxiolytic Withdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-Persisting Dementia, Sedative-, Hypnotic-, or Anxiolytic- Persisting Amnestic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Psychotic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Mood Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Anxiety Disorder Sedative-, Hypnotic-, or Anxiolytic-lnduced Sexual Dysfunction, Sedative-, Hypnotic-, or Anxiolytic-lnduced Sleep Disorder and Sedative-, Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise Specified (292.9)); Polysubstance-Related Disorder (including Polysubstance Dependence (304.80)); and Other (or Unknown) Substance-Related Disorders (including Anabolic Steroids, Nitrate Inhalants and Nitrous Oxide).
v) Sleep disorders for example primary sleep disorders such as Dyssomnias (including Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47)); primary sleep disorders such as Parasomnias (including Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47)); Sleep Disorders Related to Another Mental Disorder (including Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44)); Sleep Disorder Due to a General Medical
Condition; and Substance-Induced Sleep Disorder (including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type).
vi) Eating disorders such as Anorexia Nervosa (307.1 ) (including the subtypes Restricting Type and Binge-Eating/Purging Type); Bulimia Nervosa (307.51 )
(including the subtypes Purging Type and Nonpurging Type); Obesity; Compulsive Eating Disorder; Binge Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50).
vii) Autism Spectrum Disorders including Autistic Disorder (299.00), Asperger's Disorder, Rett's Disorder, Childhood Disintegrative Disorder and Pervasive Developmental Disorder Not Otherwise Specified.
viii) Attention-Deficit /Hyperactivity Disorder (including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention-Deficit/Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit/Hyperactivity Disorder Hyperactive-Impulse Type (314.01 ) and Attention-Deficit/Hyperactivity Disorder Not Otherwise Specified (314.9)); Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder (including the subtypes childhood- onset type (321.81 ), Adolescent-Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81 ) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23).
ix) Enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e.g. Alzheimer's disease.
In an embodiment the disease or condition for which antagonism of the mGluRs receptor is beneficial is selected from the list consisting of: Parkinson's Disease, epilepsy, inflammatory pain, neuropathic pain, migraine, Down's Syndrome, gastroesophageal reflux disease.
In a further embodiment, the invention provides a compound of the invention for use as a neuroprotectant.
In an embodiment the disease or condition for which antagonism of the mGluRs receptor is beneficial is a substance-related disorder.
It will be appreciated that references herein to "treat", "treating" or "treatment" extend to prophylaxis, prevention of recurrence and suppression or amelioration of symptoms (whether mild, moderate or severe) as well as the treatment of established conditions.
It will be appreciated that the invention includes the following further aspects. The diseases and conditions described above extend, where appropriate, to these further aspects.
i) A compound of the invention for treating a disease or condition for which antagonism of the mGluRs receptor is beneficial. In an embodiment the disease or condition is a substance related disorder.
ii) A method of treating a disease or condition for which antagonism of the mGluR5 receptor is beneficial in a human comprising administering an effective amount of a compound of the invention. In an embodiment the disease or condition is a substance related disorder. The compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient by an appropriate route. Accordingly, in another aspect, the invention provides pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically-acceptable excipients.
As used herein, "pharmaceutically-acceptable excipient" means any pharmaceutically acceptable material present in the pharmaceutical composition or dosage form other than the compound or compounds of the invention. Typically the material gives form, consistency and performance to the pharmaceutical composition.
The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. In addition, the pharmaceutical compositions of the invention may comprise one or more additional pharmaceutically active compounds.
Such pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be dispensed and then given to the patient such as with powders or syrups. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged as dosage forms wherein each physically discrete dosage form contains a safe and effective amount of a compound of the invention. Accordingly, in another aspect, the invention provides dosage forms comprising pharmaceutical compositions of the invention. Each discrete dosage form typically contains from 0.1 mg to 100 mg of a compound of the invention.
The compositions of the invention will typically be formulated into dosage forms which are adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration such as sterile solutions, suspensions, implants and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal and vaginal administration such as suppositories, pessaries and foams; (5) inhalation and intranasal such as dry powders, aerosols, suspensions and solutions (sprays and drops); (6) topical administration such as creams, ointments, lotions, solutions, pastes, drops, sprays, foams and gels; (7) ocular administration such as drops, ointment, sprays, suspensions and inserts; (8) buccal and sublingual administration such as lozenges, patches, sprays, drops, chewing gums and tablets.
Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the release of the compound of the invention at the appropriate rate to treat the condition.
Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavouring agents, flavour masking agents, colouring agents, anticaking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, rate modifying agents, antioxidants, preservatives, stabilizers, surfactants and buffering agents. The skilled artisan will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
Skilled artisans possess the knowledge and skill in the art to enable them to determine suitable pharmaceutically-acceptable excipients in appropriate amounts for use with the compounds of the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically- acceptable excipients and may be useful in selecting suitable pharmaceutically- acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press). The pharmaceutical compositions of the invention may be prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch and pre- gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. hydroxypropyl methyl cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include starches, crospovidone, sodium starch glycolate, cros- carmellose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and sodium dodecyl sulphate. The oral solid dosage form may further comprise a glidant such as talc and colloidal silicon dioxide. The oral solid dosage form may further comprise an outer coating which may have cosmetic or functional properties.
The compounds of the invention may be used in combination with the following agents to treat or prevent psychotic disorders: i) antipsychotics; ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine). The compounds of the invention may be used in combination with antidepressants to treat or prevent depression and mood disorders.
The compounds of the invention may be used in combination with the following agents to treat or prevent bipolar disease: i) mood stabilisers; ii) antipsychotics; and iii) antidepressants.
The compounds of the invention may be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants.
Antipsychotic drugs include Typical Antipsychotics (for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine); and Atypical Antipsychotics (for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone and amisulpride).
Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine, sertraline femoxetine, fluvoxamine, indalpine and zimeldine); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine and venlafaxine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).
Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.
Anxiolytics include benzodiazepines such as alprazolam and lorazepam.
It will be appreciated that the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially. All publications, including, but not limited to, patents and patent applications cited in this specification, are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
Supporting Compounds
The preparation of a number of the compounds of the invention are described below.
In the procedures that follow, after each starting material, reference to an intermediate is typically provided. This is provided merely for assistance to the skilled chemist. The starting material may not necessarily have been prepared from the batch referred to.
Compounds of the invention and intermediates are named using ACD/Name PRO 6.02 chemical naming software (Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada).
Abbreviations
AIBN 2,2 -Azobιs(2-methylpropιonιtrιle)
CDI - 1 ,1 '-(oxomethanediyl)bis-1 H-imidazole
Cmp - Compound
DCM - Dichloromethane
DIC - N,N'-bis(1-methylethyl)carbodiimide
DMAP - N,N-dimethyl-4-pyridinamine
DMSO - Dimethylsulphoxide
EA Ethyl acetate
HOBT - 1-H-1 ,2,3-benzotriazol-1 -ol
HPLC - High Performance Liquid Chromatography lnt - Intermediate
LCMS - Mass Spec Coupled High Performance Liquid
Chromatography
MDAP - Mass Spec. Directed Preparative HPLC purification
MeCN - Acetonitrile
MW - Microwave reactor
NBS - N-Bromosuccinimide
NCS - N-Chlorosuccinimide
NMR - Nuclear Magnetic Resonance
PE - Petroleum ether PPA - Polyphosphoric acid
RT. - Chromatographic retention time
TEA - Triethylamine
THF - Tetrahydrofuran
TLC Thin layer chromatography
Physical Characterisation
1 H NMR spectra were run on a Bruker Avance 400MHz instrument with a 5mm QNP probe at 27 0C. Data were recorded at 400 MHz in deuterio-chloroform with tetramethylsilane as an internal reference and calibrated to 0.00 ppm or in D4-deuterio- methanol. Chemical shifts given in parts per million (ppm) are centred about the given value. Multiplicities are designated as s (singlet), d (doublet), t (triplet), dd (double doublet), ddd (double-double-doublet), dt (double triplet), m (multiplet).
Analytical LCMS characterization was performed using one of three: LCMS A, LCMS B and LCMS C. The equipment and conditions are as follows:
Figure imgf000030_0001
Figure imgf000031_0002
LCMS C
Agilent LC/MSD 1 100 Mass Spectrometer, operating in ESI(+) ionization mode coupled with HPLC instrument Agilent 1 100 Series [LC/MS-ESI(+): analysis performed on a Supelcosil ABZ+Plus (33x4.6 mm, 3 μm) (mobile phase: from 10%[CH3CN+0.05%TFA] to 90 %[CH3CN+0.05%TFA] and 10% [water] in 2.2 min, under these conditions for 2.8 min. T= 45 0C, flux = 0.9 mL/min.).
Purification
Where appropriate TLC preparative plates (Silica gel on glass, 1000μm, 20x20 cm)
(commercially available from Aldrich) were used for compound purification.
Where appropriate hydrophobic cartridges (Isolute Phase Separators) or propylsulfonic acid functionalized silica cartridges (ISOLUTE SCX-2) purchased from Biotage were used for reaction work-up and compound purification.
A number of the compounds were purified using a Mass Directed Auto-Purification System (MDAP) incorporating HPLC techniques and an appropriate mass spectrometer such as the Waters® ZQ mass spectrometer.
Microwave heating was performed using Initiator™ and Emrys™ Optimizer microwave reactors from Biotage.
Compound 1 : (+/-)1 -(2-Cvclopropyl-6-methviri ,31thiazolo[3,2-biri ,2,41triazol-5- vDethyl phenylcarbamate
Figure imgf000031_0001
Phenyl isocyanate (commercially available from Aldrich) (0.340 ml, 3.1 1 mmol) was added to (+/-)1-(2-cyclopropyl-6-methyl-[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethanol (Intermediate 1 ) (0.62 mmole) in dry DCM (4ml). TEA (0.17 ml, 1.24 mmol) was added. The reaction mixture was heated in a microwave reactor for 20 minutes at 8O0C and evaporated to dryness. The crude material was purified using MDAP to give the title compound (60mg, 28% yield); MS: ES+ m/z: 343 [MH+] at r.t 3.5 min. Ci7H18N4O2S requires 342 (analysed by LCMS A); 1H NMR (400 MHz, MeOD): δ 0.98-1.04 (4H, m), 1.66 (3H,d), 2.07-2.12 (1 H m), 2.57 (3H,s), 6.20 (1 H, q), 7.00 (1 H,t), 7.24 (2H,t), 7.40 (2H,d). Racemic Compound 1 was subjected to chiral preparative HPLC using a Chiralpak IC column (250mm x 5 mm, 5μm particle size, mobile phase Heptane : Absolute Ethanol 90:10 v/v pump-mixed, Flow rate = 17.0mls/min Isocratic, Run time = 15.0 minutes) to give two enantiomers:
Compound 1 a: (slower eluting enantiomer) Analysed by chiral analytical HPLC using a Chiralpak IC column (250mm x 4.6 mm, 5μm particle size, mobile phase Heptane : Absolute Ethanol 70:30 v/v pump-mixed, Flow rate = 1.0mls/min Isocratic, Run time = 6.0 minutes), retention time 4.32 min; MS: ES+ m/z: 343.9 [MH+] at R.T 3. min. C17H18N4O2S requires 343 (analysed by LCMS C); and
Compound 1 b: (faster eluting enantiomer) Analysed by chiral analytical HPLC using a Chiralpak IC column (250mm x 4.6 mm, 5μm particle size, mobile phase Heptane : Absolute Ethanol 70:30 v/v pump-mixed, Flow rate = 1.0mls/min Isocratic, Run time = 6.0 minutes), retention time 4.84 min; MS: ES+ m/z: 343.9 [MH+] at R.T 3. min. C17H18N4O2S requires 343 (analysed by LCMS C).
The following racemic compounds of formula (Ic), i.e. compounds of general formula (I) where X is C(RX), R1 is methyl, R2 is methyl, R3 is H and R5 is H, (see Table 1 ) were prepared in a similar fashion to the preparation of Compound 1 replacing Intermediate 1 with the starting materials indicated and the appropriate isocyanate.
Figure imgf000033_0001
Table 1
Figure imgf000033_0002
Figure imgf000034_0002
The preparations of Compounds 10, 11 and 15 were performed without addition of
TEA.
The preparation of Compound 13 required pre purification by Silica Chromatography
The preparation of Compound 14 required further purification, first via preparative
TLC (1 :1 ethyl acetate/cyclohexane as the eluent) then via MDAP purification.
Compounds 12 and 15 were isolated as a mixture of diastereomers.
Examples analysed via LCMS A
* Examples analysed via LCMS B
* Examples analysed via LCMS C
Compound 17: (+/-)1-n ,3lthiazolor3,2-biri ,2,4ltriazol-5-ylethyl phenylcarbamate
Figure imgf000034_0001
The title compound was prepared in similar fashion to Compound 1 replacing Intermediate 1 with (+/-)1-[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-ylethanol (Intermediate 8); (80mg, 61 % yield); MS: ES+ m/z: 289 [MH+] at RT 2.1 min. C13H12N4O2S requires 288 (analysed by LCMS C);1H NMR (400 MHz, MeOD): δ 1.74 (3H, d), 6.1 1 (1 H, q), 7.02 (1 H,t), 7.26 (2H, t), 7.43 (2H,d), 8.18 (1 H,s), 8.21 (1 H,s).
Compound 18: (6-MethylM .31thiazolor3.2-biπ .2.41triazol-5-vnmethyl phenylcarbamate
Figure imgf000035_0001
The title compound was prepared in similar fashion to Compound 1 replacing Intermediate 1 with (6-methyl[1 ,3]thiazolo[3,2-fe][1 ,2,4]triazol-5-yl)methanol (Intermediate 32); (16mg, 79% yield); MS: ES+ m/z: 289 [MH+] at RT 2.14 min. C13H12N4O2S requires 288 (analysed by LCMS C);1H NMR (400 MHz, CDCI3): δ 2.64 (3H, s), 5.31 (2H, s), 7.10 (1 H,t), 7.28-7.43 (4H, m), 8.14 (1 H,s).
Compound 19: (+M1-(6-Methviri .3lthiazolor3.2-biπ .2.4ltriazol-5-vnethyl 3- pyridinylcarbamate
Figure imgf000035_0002
3-Pyridinamine (28mg, 0.3mmole) and CDI (54mg, 0.33mmole) in dry DCM (1 ml) were heated in a microwave reactor at 8O0C for 20 minutes. The mixture obtained was then added to a solution of (+/-)1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5- yl)ethanol (Intermediate 4) (18mg, 0.1 mmole) in dry DCM (1 ml) and TEA (28μl,
0.2mmole). The resulting mixture was heated in a microwave reactor at 8O0C for 20 minutes. The crude material obtained after solvent removal was purified using MDAP to give the title compound (15mg 50% yield); MS: ES+ m/z: 304 [MH+] at RT 1.9 min. Ci3H13N5O2S requires 303 (analysed by LCMS A); 1H NMR (400 MHz, MeOD): δ 1.72 (3H,d), 2.65 (3H,s), 6.28 (1 H,q), 7.35-7.38 (1 H,m) 7.99 (1 H,d), 8.19-8.21 (1 H,dd), 8.21 (1 H,s) 8.60 (1 H,d).
The following racemic compounds of formula (Id), i.e. compounds of general formula (I) where X is CH, Y is N, R1 is methyl, R2 is methyl, R3 is H and R5 is H, (see Table 2) were prepared in a similar fashion to the preparation of Compound 19 replacing 3- pyridinamine with the appropriate amine.
Figure imgf000036_0001
(Id)
Table 2
Figure imgf000036_0003
analysed via LCMS A
Compound 22: (+/-)1-(6-methviri .31thiazolor3.2-biri .2.41triazol-5-yl)ethyl (5-fluoro-3- pyridinvDcarbamate
Figure imgf000036_0002
The title compound was prepared in similar fashion to Compound 19 replacing the 3- pyridinamine with 5-fluoro-3-pyridinamine (available from Apollo Scientific Ltd.)
(19mg, 12% yield); 1H NMR (400 MHz, MeOD): δ 1.71 (3H, d), 2.64 (3H,s), 6.29 (1 H, q), 7.93 (1 H,d), 8.10 (1 H, d), 8.20 (1 H,s), 8.35-8.36 (1 H,m).
Compound 23: (+/-)1-(6-methviri .31thiazolor3.2-biri .2.41triazol-5-yl)ethyl [5- (methyloxy)-3-pyridinyl1carbamate
Figure imgf000037_0001
The title compound was prepared in similar fashion to Compound 19 replacing the 3- pyridinamine with 5-(methyloxy)-3-pyridinamine (available from J&W PharmLab, LLC) (21 mg, 13% yield); 1H NMR (400 MHz, MeOD): δ 1.70 (3H, d), 2.64 (3H,s), 3.84 (3H,s), 6.24 (1 H, q), 7.65 (1 H,s), 7.89 (1 H, d), 8.14 (1 H,d), 8.20 (1 H,s).
Compound 24: (+/-)1-(6-methviri .31thiazolor3.2-biri .2.41triazol-5-yl)ethyl (5-bromo-3- pyridinvDcarbamate
Figure imgf000037_0002
The title compound was prepared in similar fashion to Compound 19 replacing the 3- pyridinamine with 5-bromo-3-pyridinamine (available from Sigma Aldrich) (The precipitate obtained after the second irradiation was discarded by filtration) (20mg, 11 % yield); 1H NMR (400 MHz, MeOD): δ 1.71 (3H, d), 2.64 (3H,s), 6.28 (1 H, q), 8.20 (1 H, s), 8.23-8.28 (2H,m), 8.49-8.51 (1 H,m).
Compound 25: (+/-)1-(6-methviri .31thiazolor3.2-biri .2.41triazol-5-yl)ethyl (5-methyl-3- pyridinvDcarbamate
Figure imgf000037_0003
The title compound was prepared in similar fashion to Compound 19 replacing the 3- pyridinamine with 5-methyl-3-pyridinamine (available from Apollo Scientific Ltd.) (22mg, 7% yield); 1 H NMR (400 MHz, MeOD): δ 1.69 (3H, d), 2.32 (3H,s), 2.64 (3H,s), 6.26 (1 H, q), 7.81 (1 H, s), 8.03 (1 H,s), 8.20 (1 H,s), 8.39 (1 H,s). Compound 26: (+/-)1-(6-methviri .31thiazolor3.2-biri .2.41triazol-5-yl)ethyl (2-methyl-4- pyrimidinvDcarbamate
Figure imgf000038_0001
The title compound was prepared in similar fashion to Compound 19 replacing the 3- pyridinamine with 2-methyl-4-pyrimidinamine (available from Specs, Kluyverweg 6, 2629 HT, Delft, The Netherlands) (8mg, 3% yield); 1H NMR (400 MHz, MeOD): δ 1.52 (3H,d), 2.48 (3H,s), 2.51 (3H,s), 5.22 (1 H, q), 6.51 (1 H,d), 7.99 (1 H, d), 8.16 (1 H,s), 8.32 (1 H, broad s).
Compound 27: (+/-)1-(6-Methyl-ri ,3lthiazolor3,2-biri ,2,4ltriazol-5-yl)ethyl [3- (methyloxy)phenyllcarbamate
Figure imgf000038_0002
m-Methoxyaniline (0.056 ml, 0.5 mmol) was added to a mixture of CDI (4.0 eq.; 324 mg, 2.00 mmol) and DMAP (6 mg, 0.050 mmol) in acetonitrile (2 ml). The reaction mixture was heated at 12O0C for 20min in a microwave reactor. (+/-)1-(6-
Methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethanol (Intermediate 4) (92 mg, 0.50 mmol) was added to the reaction mixture which was heated at 120 0C for 20min in a microwave reactor then evaporated to dryness to give a solid. The solid was dissolved in DCM (4ml). The organic solution was washed with 2N HCI (4ml). The organic solution was filtered through a phase separator cartridge and evaporated to dryness to give a solid (147mg). The solid was purified by MDAP followed by trituration with diethyl ether to give the title compound (42mg, 25% yield); MS: ES+ m/z: 333 [MH+] at RT 3.2 min. Ci5H16N4O3S requires 332 (analysed by LCMS A).
Racemic Compound 27 was subjected to chiral preparative HPLC using a Chiralpak IC column (250mm x 20 mm, 5μm particle size, mobile phase Heptane : Absolute Ethanol 50:50 v/v pump-mixed, Flow rate = 17.0mls/min Isocratic, Run time = 12.0 minutes) followed by purification via MDAP, to give two enantiomers: Compound 27a (the faster eluting enantiomer): Analysed by chiral analytical HPLC using a Chiralpak IC column (250 x 4.6 mm, 5μm particle size, mobile phase Heptane : Absolute Ethanol 50:50 v/v pump-mixed, Flow rate = 1.0mls/min Isocratic, Run time = 20.0 minutes), retention time 6.34 min; MS: ES+ m/z: 333 [MH+] at RT 2.2 min. Ci5H16N4O3S requires 332 (analysed by LCMS C ); and
Compound 27b (the slower eluting enantiomer): Analysed by chiral analytical HPLC using a Chiralpak IC column (250 x 4.6 mm, 5μm particle size, mobile phase Heptane : Absolute Ethanol 70:30 v/v pump-mixed, Flow rate = 1.Omls/min Isocratic, Run time = 6.0 minutes), retention time 8.79 min; MS: ES+ m/z: 333.0 [MH+] at RT 2.2 min. C15H16N4O3S requires 332 (analysed by LCMS C ).
Compound 28: (+/-)1-(6-methyl[1 ,3lthiazolo[3,2-bl[1 ,2,41triazol-5-yl)ethyl cvclobutylcarbamate
Figure imgf000039_0001
(+/-)1-(6-Methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethanol (Intermediate 4) (183 mg, 1 mmol) and CDI (324 mg, 2.000 mmol) in dry DCM (5 ml) were heated in a microwave reactor at 80 0C for 20 minutes. The mixture obtained was then added to a solution of cyclobutylamine hydrochloride (321 mg, 3.00 mmol) in dry DCM (5 ml) and TEA (418μl, 3.00 mmol). The resulting mixture was heated in a microwave reactor at 80 0C for 20 minutes. The crude material obtained after solvent removal was purified using MDAP to give the title compound (72.5mg 25% yield); MS: ES+ m/z: 281 [MH+] at RT 2.87 min. C12H16N4O2S requires 280 (analysed by LCMS A); 1H NMR (400 MHz, MeOD): δ 1.62 (3H,d), 1.64-1.71 (2H,m), 1.87-2.00 (2H,m), 2.17- 2.30 (2H,m), 2.59 (3H,s), 4.00-4.08 (1 H,m), 6.07-6.12 (1 H,q), 8.21 (1 H,s).
Compound 29: (+M1-(6-methviri .3lthiazolor3.2-biπ .2.4ltriazol-5-vnethyl 3.4-dihvdro- 1 (2H)-quinolinecarboxylate
Figure imgf000040_0001
The title compound was prepared in similar fashion to Compound 28 replacing the cyclobutylamine hydrochloride with 1 ,2,3,4-tetrahydroquinoline (available from Sigma Aldrich) (151 mg, 88% yield); 1H NMR (400 MHz, MeOD): δ 1.68 (3H, d), 2.58 (3H,s), 2.78-2.88 (2H,m), 3.60-3.75 (2H, m), 4.51-4.67 (2H, m), 6.19 (1 H,q), 7.06-7.19 (4H,m), 8.18 (1 H,s).
Compound 30: (+/-) 1-(6-methviri .31thiazolor3.2-biri .2.41triazol-5-yl)ethyl (1-methyl- 4-piperidinyl)carbamate
Figure imgf000040_0002
The title compound was prepared in similar fashion to Compound 28 replacing the cyclobutylamine hydrochloride with 1-methyl-4-piperidinamine (available from Apollo Scientific Ltd.) (1 1 mg, 3% yield); 1H NMR (400 MHz, MeOD): δ 1.63 (3H, d), 1.68- 1.85 (2H,m), 2.00-2.17 (2H,m), 2.60 (3H,s), 2.81 (3H,s), 3.00-3.16 (2H, m), 3.35-3.47 (2H, m), 3.62-3.72 (1 H, m), 6.13 (1 H,q), 8.21 (1 H,s), 8.40-8.50 (1 H,bs).
The following racemic compounds which support the first aspect of the invention were purchased from Bionet-Key Organics Ltd.
Table 3
Figure imgf000040_0003
6
Figure imgf000041_0001
Figure imgf000042_0001
Racemic Compound 32 was subjected to chiral preparative HPLC using a Chiralpak IC (250mm x 20 mm, 5μm particle size, mobile phase Heptane : Absolute Ethanol 90:10 v/v pump-mixed, Flow rate = 17.0mls/min Isocratic, Run time = 16.0 minutes) followed by trituration with Diethyl Ether : Iso-Hexane 25:75, to give two enantiomers.
Compound 32a: (1 R)-1-(6-methyl[1.31thiazolor3.2-b1M .2.41triazol-5-yl)ethyl phenylcarbamate:
Figure imgf000042_0002
Analysed by chiral analytical HPLC using a Chiralpak column (250mm x 4.6 mm, 5μm particle size, mobile phase Heptane : Absolute Ethanol 90:10 v/v pump-mixed, Flow rate = 1.0mls/min Isocratic, Run time = 15.0 minutes), retention time 12.05 min; MS: ES+ m/z: 303 [MH+] at RT 2.2 min. C14 H14 N4 O2 S requires 302 (analysed by LCMS C); and
Compound 32b: (1 S)-1-(6-methviri .31thiazolor3.2-biπ .2.41triazol-5-vnethyl phenylcarbamate: Analysed via chiral analytical HPLC using a Chiralpak IC column (250mm x 4.6 mm, 5μm particle size, mobile phase Heptane : Absolute Ethanol 90:10 v/v pump-mixed, Flow rate = 1.0mls/min Isocratic, Run time = 15.0 minutes), retention time 10.20 min; MS: ES+ m/z: 303 [MH+] at RT 2.2 min. C14 H14 N4 O2 S requires 302 (analysed by LCMS C).
The absolute configuration of Compound 32a was predicted with 91 % confidence by ab initio Vibrational Circular Dichroism (VCD). Solution-phase VCD and IR spectra were measured for samples in CDCI3 using a BioTools BOMEM ChiralirTM FT-VCD spectrometer operating at 4 cm"1 resolution. Spectral data were acquired in the 2000-950 cm"1 region of the mid-infrared spectrum. Absolute configurations were assigned by comparing the signs (+/-) predicted for a set of diagnostic marker bands in the VCD spectrum of a full structure model with (1 R)-absolute configuration to corresponding bands in the VCD spectra of the compounds.
Compound 40: (+/-)1-(5-methyl[1 ,3lthiazolo[2,3-cl[1.2.41triazol-6-yl)ethyl phenylcarbamate
Figure imgf000043_0001
To a solution of (+/-)1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethanol (Intermediate 19) (120mg, 0.248mmol) in anhydrous DCM (1OmL) was added phenyl isocyanate (30mg, 0.25mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The obtained crude product was purified by column chromatography (DCM/MeOH= 50/1 ) to give the title compound (40mg, yield 40.4%); mass Spectrum (ESI) m/z calcd for Ci4Hi4N4θ2S 302.1 , found 303 (MH +) at r.t 1.2 min (analysed by LCMS C); 1HNMR (CHCI3-d6): 58.56(1 H, b), 7.65(1 H, s), 7.42-7.44(2H, m), 7.30-7.31 (2H, m), 7.06(1 H, m), 6.1 1 (1 H, q), 2.54(3H, s), 1.63(3H,t). Racemic Compound 40 was subjected to chiral preparative HPLC using a Chiralpak IC column (250mm x 20 mm, 5μm particle size, mobile phase Heptane : Absolute Ethanol 50:50 v/v pump-mixed, Flow rate = 17.0mls/min Isocratic, Run time = 15.0 minutes), to give two enantiomers:
Compound 40a (slower eluting enantiomer). Analysed by chiral analytical HPLC using a Chiralpak IC column (250mm x 4.6 mm, 5μm particle size, mobile phase Heptane : Absolute Ethanol 50:50 v/v pump-mixed, Flow rate = 1.0mls/min Isocratic, Run time = 12.5 minutes), retention time 10.88 min; MS: ES+ m/z: 303 [MH+] at RT 1.9 min. C14 H14 N4 O2 S requires 302 (analysed by LCMS C); and
Compound 40b (faster eluting enantiomer): analysed by chiral analytical HPLC using a Chiralpak IC column (250mm x 4.6 mm, 5μm particle size, mobile phase Heptane : Absolute Ethanol 50:50 v/v pump-mixed, Flow rate = 1.0mls/min Isocratic, Run time = 12.5 minutes), retention time 8.22 min; MS: ES+ m/z: 303 [MH+] at RT 1.9 min. C14 H14 N4 O2 S requires 302 (analysed by LCMS C).
The following racemic compounds of formula (Ie), i.e. compounds of general formula (I) where Y is C(RX), X is N, R1 is methyl, R2 is methyl, R3 is H and R5 is H, (see Table 4) were prepared in a similar fashion to the preparation of Compound 40 replacing the Intermediate 19 with the starting materials indicated, and using the appropriate isocyanate.
Figure imgf000044_0001
(Ie)
Table 4
Figure imgf000044_0002
Figure imgf000045_0001
* LCMS C
Racemic Compound 42 was subjected to chiral preparative HPLC using a Chiralcel OJ column (250mm x 20 mm, 10μm particle size, mobile phase Heptane : Absolute Ethanol 50:50 v/v pump-mixed, Flow rate = 17.0mls/min Isocratic, Run time = 12.0 minutes) to give two enantiomers:
Compound 42a (the slower eluting enantiomer): Analysed by chiral analytical HPLC using a Chiralcel OJ column (250 x 4.6 mm, 10μm particle size, mobile phase Heptane : Absolute Ethanol 50:50 v/v pump-mixed, Flow rate = 1.0mls/min Isocratic, Run time = 15.0 minutes), retention time 8.73 min; and
Compound 42b (the faster eluting enantiomer): Analysed by chiral analytical HPLC using a Chiralcel OJ column (250 x 4.6 mm, 10μm particle size, mobile phase Heptane : Absolute Ethanol 50:50 v/v pump-mixed, Flow rate = 1.Omls/min Isocratic, Run time = 15.0 minutes), retention time 6.42 min; MS: ES+ m/z: 321.1 [MH+] at RT 2.0 min. C14 H13 F N4 O2 S requires 320 (analysed by LCMS C ).
Compound 48: (+/-) 1-(6-MethylM .31thiazolor3.2-b1M .2.41triazol-5-yl)propyl phenylcarbamate
Figure imgf000046_0001
To a solution of (+/-)1-(6-methyl[1 ,3]thiazolo[3,2-fe][1 ,2,4]triazol-5-yl)propan-1-ol (Intermediate 29) (40mg, 0.2mmol) in anhydrous THF (5ml) was added NaH (12mg, 0.3mmol) at O0C. The mixture was stirred at this temperature for 30min, then phenylisocyanate (48mg, 0.4mmol) was added and mixture was stirred at r.t. overnight. The solvent was evaporated in vacuum and the residue was purified by column chromatography on silica gel (EA/PE=1/10 to 1/2) to give the title compound (8mg, yield 12.7%); mass spectrum (ESI) m/z calcd for Ci5H16N4O2S 316.38, found 317 (MH+). at r.t 1.62 min (LCMS C); 1HNMR (30OmHz, CDCI3): δ8.12(1 H, s), 7.27- 7.37 (4H, m), 7.07( 1 H, dd), 6.89 (1 H, s), 5.95(1 H, t), 2.65(3H, s), 2.04-2.11 (1 H, m), 1.87-1.94(1 H, m), 1.01 (3H,t).
Compound 49: (+/-) 2-Methyl-1-(6-methviri .31thiazolor3.2--3iπ .2.41triazol-5-yl)propyl phenylcarbamate
Figure imgf000046_0002
The title compound was prepared from (+/-) 2-methyl-1-(6-methyl[1 ,3]thiazolo[3,2- fe][1 ,2,4]triazol-5-yl)-1-propanol (Intermediate 30) by a simliar process to the preparation of Compound 48; mass spectrum (ESI) m/z calcd for C16H18N4O2S 330.40, found 331.0(MH+) at r.t 1.68 min (LCMS C); 1HNMR (30OmHz, CDCI3): δ8.115(1 H, s), 7.27-7.36 (4H, m), 7.07( 1 H, dd), 6.69 (1 H, s), 5.67(1 H, d), 2.64(3H, s), 2.13-2.21 (1 H, m), 1.15(3H, d), 0.94(3H,d).
Compound 50: (+/-) 2.2.2-trifluoro-1-(6-methviri .3lthiazolor3.2-biπ .2.4ltriazol-5- vDethyl phenylcarbamate
Figure imgf000047_0001
Phenylisocyanate (0.070 ml_, 0.641 mmol) was added to a mixture of (+/-) 2,2,2- trifluoro-1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethanol (Intermediate 40) (38 mg, 0.160 mmol) in DCM (2 ml.) under argon. The reaction mixture was heated at 8O0C for 20 min in a microwave reactor. The reaction mixture was evaporated to dryness. The residue was dissolved in DCM (10ml) and water (10ml), and the organic phase was separated. The aqueous phase was extracted with DCM (10ml). The organic phases were combined, filtered using a phase separator cartridge and evaporated to dryness to obtain a solid which was purified by flash chromatography using a gradient of 0% ethyl acetate/isohexane to 20% ethyl acetate/isohexane and than via MDAP to give the title compound; MS: ES+ m/z: 357; [MH+] at RT 2.6 min. C14H11F3N4O2S requires 356 (analysed by LCMS C).
Compound 51 : (+M1-(2-Chloro-6-methviπ ,31thiazolor3.2-biπ ,2.41triazol-5-vnethyl cvclobutylcarbamate
Figure imgf000047_0002
A solution of (+/-)1-(2-chloro-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethanol (Intermediate 35) (99 mg, 0.455 mmol) in DCM (5ml) was added to CDI. The reaction mixture was heated at 8O0C for 20 minutes in a microwave reactor. Cyclobutylamine (0.155 ml_, 1.819 mmol) was added to the reaction mixture. The reaction mixture was heated in a microwave reactor at 8O0C for 20 minutes. DCM (10ml) and water (10ml) were added to the reaction mixture. The organic phase was separated, washed with brine (10ml), filtered via a phase separator cartridge, evaporated to dryness and purified via MDAP to obtain the title compound (50mg, 35% yield); MS: ES+ m/z: 315 [MH+] at RT 2.5 min. C12 H15 Cl N4 O2 S requires 314 (analysed by LCMS C).
Compound 52: (+M1-(5-methviri .3lthiazolor2.3-ciπ .2.4ltriazol-6-vnethyl (2- fluorophenvDcarbamate
Figure imgf000048_0001
(+/-) 1-(5-Methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethanol (Intermediate 19) (54mg, 0.3mmol) was dissolved in THF (5ml) and NaH (60% in mineral oil, 15mg, 0.36mmol) was added. The mixture was stirred at room temperature for 30min and then 2- fluoro-phenylisocyanate (49mg, 0.36mmol, available from Alfa) was added. The resulting mixture was stirred at room temperature for another 16 hours. The residue was partitioned between water (20ml) and DCM (50ml). The organic layer was concentrated and purified by column chromatography on silica gel (petroleum etheπEA = 75:25) to give the title compound (15mg, yield 16%) as a white solid; LC/MS [m/z] calcd. For C14H13FN4O2S 320.34 (M), found 320.9 (MH +); 1HNMR (DMSO):δ 8.477 (s, 1 H), 7.916-7.946 (b, 1 H), 6.944-7.070 (m, 3H), 6.830 (s, 1 H), 6.023-6.070 (m, 1 H), 2.494 (s, 3H), 1.614 (d, 3H).
Compound 53: (+/-) 1-(5-methviri .31thiazolor2.3-ciri .2.41triazol-6-yl)ethyl (3- chlorophenvDcarbamate
Figure imgf000048_0002
(+/-) 1-(5-Methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethanol (Intermediate 19) (50mg, 0.27mmol) was dissolved in THF (5ml) and NaH (60% in mineral oil, 13mg, 0.33mmol) was added. The mixture was stirred at room temperature for 30min and then 3-chlorophenylisocyanate (83mg, 0.54mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. Water (15 ml) was added and the mixture was extracted with ethyl acetate (3 x15ml). The combined organic phases were washed with brine (50ml), dried and concentrated under reduced pressure. The obtained crude product was purified by prep-HPLC to give the title compound as a white solid (30mg); LC/MS [m/z] calcd. For C14H13CIN4O2S 336.04 (M), found 337.0 (MH +); 1HNMR (CDCI3):δ 8.565 (s, 1 H), 7.560 (s, 1 H), 7.451 (s, 1 H), 7.18-7.22 (m, 2H), 7.029-7.047 (d, 1 H), 6.083-6.133 (q, 1 H), 2.557 (s, 3H), 1.637-1.653 (d, 3H).
Compound 54: 1-Methyl-1-(6-methviri .3lthiazolor3.2-άiπ .2.4ltriazol-5-vnethyl phenylcarbamate
Figure imgf000049_0001
2-(6-Methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)-2-propanol (Intermediate 34) (80mg, 0.41 mmol) was dissolved in anhydrous THF (1OmL) and NaH (60% in mineral oil, 24mg, 0.61 mmol) was added. The reaction mixture was stirred at r.t. for 2.5h and then phenylisocyanate (72mg, 0.61 mmol) was added. The reaction mixture was stirred at r.t. overnight. The mixture was quenched with ice-water (2ml) and extracted with DCM (3 x 4OmL). The combined organic layers were dried over Na2SC>4, filtered and concentrated to afford a light yellow oil. The oil was purified by column chromatography (DCM/MeOH=100/1 ) on silica gel to give the title compound (30mg, yield 23%) as a grey solid; LC/MS [m/z] calcd. For C15 H16N4O2S 316.38 (M), 317.0 (MH +) at r.t 1.39min (analysed by LCMS C); 1HNMR (DMSO):δ 8.08 (s, 1 H), 7.28- 7.34 (m, 4H), 7.07 (d, 1 H), 6.71 (s, 1 H), 2.64 (s, 3H), 1.94 (s, 6H).
Compound 55: (+/-) 1-(2-Chloro-6-methviri .31thiazolor3.2-biπ .2.41triazol-5-vnethyl phenylcarbamate
Figure imgf000049_0002
A solution of (+/-) 1-(2-chloro-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethanol (Intermediate 35) (18 mg, 0.083 mmol) and phenylisocyanate (0.045 ml, 0.413 mmol) in DCM (1 ml) was heated in a microwave reactor for 20 minutes at 800C then evaporated to dryness to give a solid. The solid was purified via MDAP to give the title compound (14mg, 50% yield); MS: ES+ m/z: 337 [MH+] at R.T 2.7 min. C14 H13 Cl N4 O2 S requires 336 (analysed by LCMS C). Compound 56: (+/-) 1-(2-Cvano-6-methviri .31thiazolor3.2-biri .2.41triazol-5-yl)ethyl phenylcarbamate
Figure imgf000050_0001
60% Sodium hydride in mineral oil (5.92 mg, 0.148 mmol) was added to a solution of (+/-) 5-(1 -hydroxyethyl)-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazole-2-carbonitrile (Intermediate 38) (28 mg, 0.134 mmol) in THF (1.4 ml). DMF (0.3 ml) was added and the reaction mixture was stirred at room temperature for 20 minutes. Phenyl isocyanate (0.037 ml, 0.336 mmol) was added and the reaction mixture was stirred at room temperature for 40 minutes. Methanol (1 ml) was added and the reaction mixture was evaporated to obtain a yellow oil which was dissolved in DCM (20ml) and NaHCO3 saturated solution (15ml). The organic phase was separated, evaporated and purified via flash chromatography on silica column using gradient elution from 0% ethyl acetate/iso-hexane to 70% ethyl acetate/iso-Hexane and then via MDAP to give the title compound; MS: ES+ m/z: 328 [MH+] at RT 2.7 min. C15H13N5O2 requires 327 (analysed by LCMS C).
Intermediate 1 : (+/-) 1-(2-Cvclopropyl-6-methyl-ri ,3lthiazolor3,2-biπ ,2,4ltriazol-5- vDethanol
Figure imgf000050_0002
3-Chloro-2,4-pentanedione (commercially available from Aldrich) (0.074 ml, 0.622 mmol) was added to a mixture of 5-cyclopropyl-1 ,2-dihydro-3H-1 ,2,4-triazole-3-thione (Intermediate 10) (0.088 g, 0.622 mmol) in ethanol (4 ml). The reaction mixture was heated in a microwave reactor at 13O0C for 20min. Sodium borohydride (0.024 g, 0.622 mmol) was added to the reaction mixture as a solution in water (1 ml) and the reaction mixture was stirred for approximately 4 hrs at room temperature. After dilution with water the reaction mixture was acidified with aqueous HCI 5M then basified with aqueous NaOH (2M). Extraction with DCM and solvent removal under vacuum gave the title compound; MS: ES+ m/z: 224 [MH+] at R. T 2.4 min. C10H13N3OS requires 223 (analysed by LCMS A).
The following racemic intermediates of formula (lie), i.e. intermediates of general formula (II) where X is C(RX), R^ is methyl, R^ is methyl and R^ is H, were prepared in a similar fashion to the preparation of Intermediate 1 from the starting material indicated.
Figure imgf000051_0001
(lie)
Figure imgf000051_0002
Intermediate 8: (+/-) 1-M .31thiazolor3.2-b1M .2.41triazol-5-ylethanol
Figure imgf000052_0001
To 1 ,2-dihydro-3H-1 ,2,4-triazole-3-thione (Intermediate 12) (506 mg, 5 mmol) in MeCN (15 ml) was added chloropropanedial (available from Acros Organics) (533 mg, 5.00 mmol) and the reaction mixture was heated in a microwave reactor at 130 degC for 20min. The content of the vessel was transferred to a round bottom flask and the vessel was washed with acetonitrile, diethyl ether, DCM, THF and toluene. All the washings were combined with the reaction mixture and the solvent removed. To this crude material under argon at 0 degC was added THF (20 ml) then methylmagnesium bromide (5.36 ml, 7.50 mmol) (1.4M in Toluene/THF 3/1 ). The reaction mixture was allowed to warm to room temperature and stirred for 45min. Saturated aqueous ammonium chloride (10ml) was then added, followed by DCM (25ml) and water (25ml). After vigorous shaking and phase separation the organic phase was evaporated to dryness. The material was purified by silica gel chromatography (Biotage SP4) to give the title compound as a white crystalline solid.
Intermediate 9: 1-r6-methyl-2-(tetrahvdro-2-furanyl)ri ,31thiazolo[3,2-biri ,2,41triazol-5- yllethanol (diastereomeric mixture)
Figure imgf000052_0002
A mixture of (+/-) 5-(tetrahydro-2-furanyl)-1 ,2-dihydro-3H-1 ,2,4-triazole-3-thione (Intermediate 18) (337 mg, 1.968 mmol) and 3-chloro-2,4-pentanedione (commercially available from Aldrich) (0.223 ml, 1.968 mmol) in ethanol (11 ml) was heated in a microwave reactor at 150 degC for 20min. The reaction mixture was evaporated to dryness and the solid obtained was dissolved in a mixture of ethyl acetate (25ml) and aqueous 2M NaOH (20ml). The organic phase was separated. The aqueous phase was extracted with ethyl acetate (2 x 30ml). The organic phases were combined, dried with MgSθ4 and evaporated to dryness. The residue was redissolved in ethanol (6 ml). Sodium borohydride (89 mg, 2.362 mmol) was added and the reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was evaporated to dryness and the residue was dissolved in a mixture of ethyl acetate (20ml) and saturated aqueous sodium bicarbonate (20ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2 x 20ml). The organic phases were combined, dried with MgSθ4 and evaporated to dryness. The residue was purified by MDAP to give the title compound (26.0mg, 5.2% yield) as a mixture of diastereomers; MS: ES+ m/z: 254 [MH+] at RT 2.23 min. C11 H15N3O2S requires 253 (analysed by LCMS A).
Intermediate 10: 5-Cvclopropyl-i ,2-dihvdro-3H-1 ,2,4-triazole-3-thione
Figure imgf000053_0001
Hydrazinecarbothioamide (91 mg, 1.00 mmol) was added to cyclopropanecarbonyl chloride (0.09 ml, 1 mmol) in acetone (5 ml). The reaction mixture was heated in a microwave reactor at 800C for 10 minutes, then evaporated to dryness. Ethanol (1 ml) was added, then aqueous NaOH 2M (4ml). The reaction mixture obtained was heated in a microwave reactor at 15O0C for 10 minutes. The reaction mixture was diluted with water and acidified, then extracted with ethyl acetate. The organic phases were combined and evaporated to dryness to give the title compound; MS: ES+ m/z: 142 [MH+] at RT 1.0 min. C5H7N3S requires 141 (analysed by LCMS A).
Intermediate 11 : 5-(Cvclopropylmethyl)-1 ,2-dihvdro-3H-1 ,2,4-triazole-3-thione
Figure imgf000053_0002
HOBT (77 mg, 0.500 mmol) and DIC (0.078 ml, 0.500 mmol) were added to cyclopropylacetic acid (50.1 mg, 0.5 mmol) in tetrahydrofuran (5 ml). After about 5 minutes hydrazinecarbothioamide (45 mg, 0.500 mmol) was added and the reaction mixture was heated in a microwave reactor at 100°C for 5 minutes. The reaction mixture was evaporated to dryness. Ethanol (2 ml) and sodium hydroxide (2 ml, 4.00 mmol) were added to the crude material. The reaction mixture was heated in a microwave reactor at 15O0C for 10 minutes. After dilution with water and addition of aqueous HCI (5M), the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and dried over MgSC>4 then evaporated to dryness to give the title compound; MS: ES+ m/z: 156 [MH+] at RT 1.7 min. C6H9N3S requires 155 (analysed by LCMS A).
Intermediate 12: 1 ,2-Dihvdro-3H-1 ,2,4-triazole-3-thione
Figure imgf000054_0001
Commercially available from Lancaster.
Intermediate 13: 1 ,3-Dihydro-2H-imidazole-2-thione
Figure imgf000054_0002
Commercially available from Lancaster.
Intermediate 14: (+/-) 5-(Tetrahvdro-3-furanylV1.2-dihvdro-3H-1.2.4-triazole-3-thione
Figure imgf000054_0003
The title intermediate was prepared in similar fashion to Intermediate 1 1 replacing the cyclopropylacetic acid with the (+/-) tetrahydro-3-furancarboxylic acid (commercially available from Aldrich); MS: ES+ m/z: 172 [MH+] at RT 0.9 min. C6H9N3OS requires 171 (analysed by LCMS A).
Intermediate 15: 5-(trifluoromethyl)-1 ,2-dihvdro-3H-1 ,2,4-triazole-3-thione
Figure imgf000055_0001
Commercially available from FluoroChem Ltd.
Intermediate 16: 1-(6-methyl[1 ,31thiazolor3.2-άiπ ,2.41triazol-5-vnethanone
Figure imgf000055_0002
1 ,2-Dihydro-3H-1 ,2,4-triazole-3-thione (506mg, 5mmol, Alfa) and 3-chloropenatane- 2.4-dione (808mg, 6mmol, Aldrich) were dissolved in ethanol (15OmL) and the resulting mixture was stirred under reflux overnight. The solvent was removed to give the title compound (815mg, yield 90%) as green-yellow solid; LC/MS [m/z] calcd. For C7H7N3OS 181.22(M), found 182.0 (MH +).
Intermediate 17: 5-methyl-1 ,2-dihvdro-3H-1 ,2,4-triazole-3-thione
Figure imgf000055_0003
The title intermediate was prepared in similar fashion to Intermediate 1 1 replacing the cyclopropylacetic acid with acetic acid; MS: ES+ m/z: 116 [MH+] at RT 0.45 min. C3H5N3S requires 115 (analysed by LCMS A).
Intermediate 18: (+/-) 5-(tetrahvdro-2-furanyl)-1 ,2-dihvdro-3H-1 ,2,4-triazole-3-thione
Figure imgf000055_0004
The title intermediate was prepared in similar fashion to Intermediate 1 1 replacing the cyclopropylacetic acid with tetrahydro-2-furancarboxylic acid (available from Sigma-Aldrich). After the second microwave irradiation, the crude material was evaporated to dryness then redissolved in a mixture of DCM (20ml) and 5M HCI (15ml). The organic phase was separated. The aqueous phase was extracted with DCM (2 X 20ml). The organic phases were combined, dried with MgSC>4 and evaporated to dryness to give the title compound; MS: ES+ m/z: 172 [MH+] at RT 1.10 min. C6H9N3OS requires 171 (analysed by LCMS A).
Intermediate 19: (+/-) 1-(5-methviri .3lthiazolor2.3-ciπ .2.4ltriazol-6-vnethanol
Figure imgf000056_0001
To a solution of 1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethanone (Intermediate 21 ) (490mg, 2.71 mmol) in THF (8OmL) was added NaBH4 (1020mg, 27.10mmol) at O 0C. Then the mixture was stirred for 30min at room temperature and the resulting suspension was filtered. The solvent was concentrated under reduced pressure to give a crude product which was purified by column chromatography on silica gel (DCM: MeOH= 20: 1 ) to give the title compound (120mg, yield 25%); LC/MS [m/z] calcd. For C7H9N3OS 183.1 , found 184 (MH +) at r.t 1.03 min (analysed by LCMS C).
Intermediate 20: (+/-) 1-(3.5-dimethviri .3lthiazolor2.3-ciπ .2.4ltriazol-6-vnethanol
Figure imgf000056_0002
The title compound was prepared from 1-(3,5-dimethyl[1 ,3]thiazolo[2,3- c][1 ,2,4]triazol-6-yl)ethanone (Intermediate 22) via a simliar process to the preparation of Intermediate 19; LC/MS [m/z] calcd. For C8H11N3OS 197.1 , found 184 (MH +) at r.t 1.07 min (analysed by LCMS C).
Intermediate 21 : 1-(5-methyl[1 ,31thiazolor2.3-clH .2.41triazol-6-vnethanone
Figure imgf000057_0001
/V-(5-Acetyl-4-methyl-1 ,3-thiazol-2-yl)formic hydrazide (Intermediate 23) (450mg, 2.26mmol) was dissolved in PPA (3OmL) and the mixture was stirred for 4 hrs at 140 0C. Water (30 ml.) was added and the reaction mixture was adjusted with sodium bicarbonate to pH7. The mixture was extracted with ethyl acetate (3 x 5OmL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to give the title compound (250mg, yield 61%); LC/MS [m/z] calcd. For C7H7N3OS 181.1 , found 182 (MH +) at r.t 0.85 min (analysed by LCMS C).
Intermediate 22: 1-(3,5-dimethylH ,31thiazolo[2,3-ciri ,2,41triazol-6-yl)ethanone
Figure imgf000057_0002
The title compound was prepared from /V-(5-acetyl-4-methyl-1 ,3-thiazol-2- yl)acetohydrazide (Intermediate 24) by a simliar process to the preparation of Intermediate 21 ; mass spectrum m/z calcd for C8H9N3OS 195.05, found 196.1 (MH+).
Intermediate 23: /V-(5-Acetyl-4-methyl-1 ,3-thiazol-2-yl)formic hvdrazide
Figure imgf000057_0003
To a solution of 2-formylhydrazinecarbothioamide (Intermediate 25) (500mg, 4.20mmol) in methanol (4OmL) were added 3-chloropenatane-2.4-dione (565mg, 4.20mmol) and pyridine (0.4OmL). The mixture was stirred at 2O0C overnight. Water (2OmL) was added and the mixture was extracted with ethyl acetate (3 x 3OmL). The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH= 20/1 ) to give the title compound (450mg, yield 52%); LC/MS [m/z] calcd. For C7H9N3O2S 199.25, found 200 (MH +).
Intermediate 24: /V-(5-Acetyl-4-methyl-1 ,3-thiazol-2-yl)acetohvdrazide
Figure imgf000058_0001
The title compound was prepared from 2-acetylhydrazinecarbothioamide (Intermediate 26) by a simliar process to the preparation of Intermediate 23; mass spectrum (ESI) m/z calcd for C8H11N3OS 213.06, found 214.1 (MH+).
Intermediate 25: 2-Formylhvdrazinecarbothioamide
Figure imgf000058_0002
Thiosemicarbazide (3Og, 0.329mol) was dissolved in formic acid (10OmL) and the mixture was heated at reflux for 2hs. The reaction mixture was cooled to O0C to give a white solid. The solid was recrystallized from ethanol to give the title compound (18g, yield 50%); LC/MS [m/z] calcd. For C2H5N3OS 119.02, found 120 (MH +) at r.t 0.30 min (analysed by LCMS C).
Intermediate 26: 2-Acetylhvdrazinecarbothioamide
Figure imgf000058_0003
To a solution of thiosemicarbazide (9.1 Og, O.I Omol) in anhydrous THF (100ml) was added acetyl chloride (8.64g, 0.11 mol) at O0C slowly. The mixture was heated to reflux for 3hs. After cooling, water (100 mL) was added and the mixture was extracted with ethyl acetate (3 x 10OmL). The organic phase was washed with brine, dried and concentrated under reduced pressure. Purification by column chromatography (MeOH/DCM=1/1 ) gave the title compound (8.64g, 65% yield); mass spectrum (ESI) m/z calcd for C3H7N3OS 133.03, found 134.0 (MH+). Intermediate 27: (+/-) 1-(3-chloro-5-methyiri .31thiazolor2.3-ciri .2.41triazol-6- vDethanol
Figure imgf000059_0001
A mixture of (+/-) 1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethanol
(Intermediate 19) (183.00mg, 1 mmol) and NCS (665.00mg, 5mmol) in anhydrous chloroform (20 ml.) was stirred at room temperature for 3 hours. The solvent was concentrated under reduced pressure. Purification by column chromatography (DCM/MeOH=50/1 ) gave the title compound (86.80mg, yield 40%); mass spectrum (ESI) m/z calcd for C7H8CIN3OS 217.68, found 218.0 (MH+).
Intermediate 28: (+/-) 1-(3-bromo-5-methviri ,3lthiazolor2,3-ciπ ,2,4ltriazol-6- vDethanol
Figure imgf000059_0002
To a solution of (+/-) 1 -(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethanol
(Intermediate 19) (400mg, 2.18mmol) in chloroform (3OmL) were added NBS (1.17g, 6.56mmol) and AIBN (107mg, 0.65mmol). The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. Purification by column chromatography (DCM/MeOH=30/1 ) gave the title compound (170mg, yield 90%).
Intermediate 29: (+/-) 1-(6-methviri ,3lthiazolor3,2-biπ ,2,4ltriazol-5-yl)propan-1-ol
Figure imgf000059_0003
To a solution of 6-methyl[1 ,3]thiazolo[3,2-b][1,2,4]triazole-5-carbaldehyde (Intermediate 31 ) (100mg, O.ΘOmmol) in anhydrous THF (5ml_) was added CH3CH2MgCI (0.36ml, 0.72mmol, Aldrich) dropwise at -780 C. The mixture was stirred for 1 hour at -780C and allowed to stir at r. t. for 2 hours. Then the mixture was quenched with water (10 ml_) and extracted with ethyl acetate (3x1 OmL). The combined organic phases were dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel (EA/PE=1/5 to 2/1 ) to give the title compound (40mg, yield 33.9%); mass spectrum (ESI) m/z calcd for C8H11N3OS 197.26, found 198.0 (MH+).
Intermediate 30: (+/-) 2-Methyl-1-(6-methviri ,3lthiazolor3,2-άiπ,2,4ltriazol-5-yl)-1- propanol
Figure imgf000060_0001
The title compound was prepared from 6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazole-5- carbaldehyde (Intermediate 31 ) by a simliar process to preparation of Intermediate 29; mass spectrum (ESI) m/z calcd for C9H13N3OS 211.28, found 212.0 (MH+).
Intermediate 31 : 6-MethylM ,31thiazolor3.2-άiπ ,2.41triazole-5-carbaldehvde
Figure imgf000060_0002
To a solution of (6-methyl[1 ,3]thiazolo[3,2-fe][1 ,2,4]triazol-5-yl)methanol (Intermediate 32) (600mg, 3.55mmol) in chloroform (5OmL) was added MnO2 (3.09g,
35.50mmol, Aldrich). The reaction mixture was stirred at room temperature overnight.
The mixture was filtered and the solvent was evaporated under reduced pressure to give the title compound (450mg, yield 75.9%); mass spectrum (ESI) m/z calcd for
C6H5N3OS 167.19, found 168.0 (MH+).
Intermediate 32: (6-Methviri .31thiazolor3.2-άiπ.2.41triazol-5-vnmethanol
Figure imgf000061_0001
To a solution of ethyl 6-methyl[1 ,3]thiazolo[3,2-ιb][1 ,2,4]triazole-5-carboxylate (Intermediate 33) (1.0Og, 4.74mmol) in methanol (3OmL) was added NaBH4 (0.72g, 19mmol) and the mixture was stirred at room temperature for 3 hours. Water (10OmL) was added and the reaction mixture was extracted with ethyl acetate (2 x 10OmL). The organic phase was washed with brine, dried over Na2S04 and concentrated to give the title compound (800mg, yield 80%); mass spectrum (ESI) m/z calcd for C6H7N3OS 169.20, found 170.0 (MH+).
Intermediate 33: Ethyl 6-methviri .31thiazolor3.2-άiri .2.41triazole-5-carboxylate
Figure imgf000061_0002
To a solution of 1 ,2-dihydro-3H-1 ,2,4-triazole-3-thione (5g, 49.50mmol, Alfa) in ethanol (30OmL) was added ethyl-2-chloroacetoacetate (9.8Og, 59.80mmol). The mixture was stirred at 750C for 3 days. Then Na2CC"3 (6.34g, 59.80mmol) was added and the mixture was heated to 750C for 6 hours. The mixture was concentrated under reduced pressure and purified by column chromatography (PE/EA=10/1 ) to afford the title compound (LOOg, yield 10%).
Intermediate 34: 2-(6-Methyl[1 ,31thiazolo[3,2-airi ,2,41triazol-5-yl)-2-propanol
Figure imgf000061_0003
1-(6-Methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethanone (Intermediate 16) (181 mg, 1 mmol) was dissolved in anhydrous THF (2OmL) and cooled to -78°C. Methyl magnesium bromide (1.7OmL, 3.00M in THF, 5.10mmol) was added dropwise. After the addition, the reaction mixture was stirred at -78°C for 5 hours and monitored by LC-MS. The mixture was quenched by saturated NH4CI and the solvent removed. The residue was extracted with Ethyl acetate (3 x 5OmL). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford a light yellow oil which was purified by column chromatography (DCIWMeOH=I 00/1 ) to give the title product (120mg, yield 61 %); LC/MS [m/z] calcd. For C8H11N3OS 197.26 (M), found 198.1 (MH+).
Intermediate 35: (+/-) 1-(2-Chloro-6-methviri .3lthiazolor3.2-biπ .2.4ltriazol-5- vDethanol
Figure imgf000062_0001
A mixture of 1-(2-chloro-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethanone (Intermediate 36) (294 mg, 1.363 mmol) and sodium borohydride (51.6 mg, 1.363 mmol) in ethanol (15 ml_) was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness. DCM (35ml) and saturated sodium bicarbonate solution (35ml) were added. The organic phase was separated. The aqueous phase was extracted with DCM (35ml). The organic phases were combined, dried with magnesium sulfate and evaporated to obtain the title compound as a yellow oil
(295mg, 100% yield); MS: ES+ m/z: 218 [MH+] at RT 1.5 min. C7H8CIN3OS requires 217 (analysed by LCMS C).
Intermediate 36: 1-(2-Chloro-6-methviri ,3lthiazolor3,2-biπ ,2,4ltriazol-5-yl)ethanone
Figure imgf000062_0002
lsoamyl nitrite (0.961 ml, 7.13 mmol) was added to a mixture of 1-(2-amino-6- methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethanone (Intermediate 37) (700 mg, 3.57 mmol) and copper(ll) chloride (538 mg, 3.92 mmol) in acetonitrile (35 ml) at -150C. The reaction mixture was stirred for 5 minutes at -150C. Acetonitrile (20 ml) was added then the reaction mixture was stirred at -130C for 30 minutes. The reaction mixture was allowed to reached room temperature and stirred for 20 minutes. The reaction mixture was heated at 780C for 75 minutes then allowed to cool down at room temperature. The mixture was placed in a ice bath and NaOH (2M) (1 1 ml) and DCM (12ml) were added. The reaction mixture was allowed to reach room temperature and was stirred at room temperature for 15 minutes. DCM (45ml) and water (40 ml) were added. The organic phase was separated. The aqueous phase was extracted with DCM (55 ml). The organic phases were combined, dried with MgSO4 and evaporated to dryness to give the title compound (540mg, 70% yield); MS: ES+ m/z: 216 [MH+] at RT 1.5 min. C7H6CIN3OS requires 215 (analysed by LCMS C).
Intermediate 37: 1-(2-Amino-6-methviri .3lthiazolor3.2-biri .2.4ltriazol-5-yl)ethanone
Figure imgf000063_0001
Three separate reaction mixtures each containing 5-amino-1 ,2-dihydro-3H-1 ,2,4- triazole-3-thione (commercially available from Aldrich) (697 mg, 6 mmol) and 3- chloro-2,4-pentanedione (commercially available from Aldrich) (807 mg, 6.00 mmol) in ethanol (20 ml) were heated in a microwave reactor at 15O0C for 20 minutes. The three reaction mixtures were combined and evaporated to dryness to give a solid. Trituration with diethyl ether gave the title compound (3.2 g, 90% yield); MS: ES+ m/z: 197 [MH+] at RT 1.1 min. C7H8N4OS requires 196 (analysed by LCMS C).
Intermediate 38: (+/-) 5-(1-Hvdroxyethvn-6-methviri .3lthiazolor3.2-biπ .2.4ltriazole-2- carbonitrile
Figure imgf000063_0002
The title intermediate was prepared in a similar fashion to preparation of Intermediate 35 replacing the Intermediate 36 with 5-acetyl-6-methyl[1 ,3]thiazolo[3,2- b][1 ,2,4]triazole-2-carbonitrile (Intermediate 39); MS: ES+ m/z: 209 [MH+] at RT 1.7 min. C8H8N4OS requires 208 (analysed by LCMS C). Intermediate 39: 5-Acetyl-6-methyiri ,31thiazolo[3,2-b1M ,2,41triazole-2-carbonitrile
Figure imgf000064_0001
lsoamyl nitrite (0.921 ml_, 6.56 mmol) was added to a mixture of 1-(2-amino-6- methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethanone (Intermediate 37) (920 mg, 4.69 mmol) and copper (I) cyanide (462 mg, 5.16 mmol) in acetonitrile (80 ml_) at -1 O0C. The reaction mixture was stirred at -1 O0C for 30 minutes. The reaction mixture was allowed warm up to room temperature and than heated at reflux with stirring for 105 minutes. Acetonitrile (50 ml) was added, the reaction mixture was heated at reflux for 1.5 hours and then cooled to room temperature. The reaction mixture was cooled in an ice bath and NaOH (2M) (20ml) was added followed by saturated sodium bicarbonate solution (300ml), followed by DCM (350ml). The mixture was filtered through cotton wool and the organic phase was separated. The organic phase was washed with brine (250ml), dried with MgSC>4 and evaporated to obtain a green/brown oil which was purified by flash chromatography on silica gel using a gradient: from 0% ethyl acetate / iso-hexane to 100% ethyl acetate / iso-hexane to obtain the title compound as a white solid; MS: ES+ m/z: 207 [MH+] at RT 1.9 min. C8H6N4OS requires 206 (analysed by LCMS C).
Intermediate 40: (+/-) 2,2,2-trifluoro-1-(6-methyl[1 ,3lthiazolo[3,2-bl[1 ,2,4ltriazol-5- vDethanol
Figure imgf000064_0002
The title intermediate was prepared in a similar fashion to the preparation of Intermediate 1 replacing the 3-chloro-2,4-pentanedione with 3-chloro-1 ,1 ,1 -trifluoro- 2,4-pentanedione (commercially available from Fluorochem) and Intermediate 10 with 1 ,2-dihydro-3H-1 ,2,4-triazole-3-thione (Intermediate 12) (85mg, 12% yield); MS: ES+ m/z: 238 [MH+] at RT 1.59 min. C7H6F3N3OS requires 237 (analysed by LCMS C). The supporting compounds were tested in one of the following calcium mobilisation assays.
a) FLIPR Assay Cell Preparation
24hrs prior to running the assay, Chinese hamster overy (CHO) cells containing human mGluRδ receptors engineered with geneswitch expression control technology (supplied by Invitrogen) were prepared. These cells were induced with 0.1 nM mifepristone to enable expression and growth media was added. The growth media comprised DMEM (Dulbeccos Modifies Eagle medium) 50OmIs (supplied by Gibco - catalogue number 31 166), 50 ml dialysed FCS (Foetal Calf Serum) (supplied by Gibco - catalogue number 26400-044), 0.02mg/ml proline, 0.25mg/ml hygromycin and 0.5mg/ml zeocin. The cells in the growth media were then dispensed using a Multidrop (supplied by ThermoFisher) into 384-well black clear-bottom plates at a confluency of 10K cells/well in a volume of 50μl. The plates were incubated at 370C to give a monolayer with a confluency of 80%.
On the day of the assay, the growth medium was aspirated using a power washer (supplied by Tecan) and 30μl of loading buffer was added to the cells using a Multidrop. The loading buffer comprised Hanks Balanced Salt Solution (HBSS) + 2.5M probenicid + 2μM Fluo-4 (MDC) and 250μM Brilliant Black (MDC). The cells were incubated at 370C for 2 hours (This allows uptake of the dye Fluo-4 AM into the cell cytosol where it becomes trapped when natural esterases cleave the AM region of the Fluo-4. In the event of a response to ligand at the mGluRδ receptors, calcium will move from the internal stores in the endoplasmic reticulum into the cytosol where it will bind to the Fluo-4 dye and fluoresce when excited by laser light).
Compound Preparation
The test compounds, in DMSO at a concentration of 1 OmM, were further diluted with DMSO using a Biomek FX (supplied by Beckman Coulter) into a 384-well compound plate (supplied by Greiner). Each dilution was then transferred in 1 ul aliquots to a further compound plate and assay buffer added to give a final volume of 50μl, making a final assay concentration of 1 1.8μM. The assay buffer consisted of HBSS and 2.5M probenicid. Glutamate Dose Response Curve Preparation
A 0.38M solution of glutamic acid in water, was further diluted in DMSO to a concentration of 204 mM. 16 x 1 1 point concentration response curves (CRCs) were prepared in DMSO with a top concentration of 204mM, making the final assay concentration 1 mM, diluted serially to 1 in 4. This was performed using the Biomek FX liquid handling device. 1 μl stampouts of the CRCs were prepared. 50 μl of compound buffer was added prior to use.
Estimation of EC80 concentration of Glutamate (endogenous liqand) 50μl of compound buffer was added to the glutamate CRC plate. This plate was added using the FLIPR to a plate of cells that had been loaded for 2 hrs. A fluorescent read was made. An EC80 concentration of glutamate was calculated by using 4x EC50 concentration generated. An EC80 concentration solution of glutamate was prepared in compound buffer and dispensed into 384-well plates, excluding column 18 where compound buffer alone was added.
Running the Assay
10μl of test compounds were added to the cell plates using a Cybiwell liquid handling device (supplied by Cybio). The cell plates were incubated at 370C for 15 min, a FLIPR addition of the EC80 was made and a fluorescent read generated. Blocking of the receptor by test compound, in a dose dependent manner is evident from the calcium vs time profiles generated for each well. The data is analysed using XC50 software to produce CRCs, from which the potency and plC50 can be determined.
b) mGluRδ Aequorin Assay Cell Preparation
CHO cells containing human mGluRδ receptors with Tet On expression control technology (supplied by Clontech) were prepared. These cells were grown in cell factories, induced with 10ng/ml doxycycline to enable expression, harvested and then cryo-preserved at -1400C in 1 ml aliquots for future use.
On the afternoon prior to the assay, the cells were thawed, suspended in growth media and centrifuged at I OOOrpm for 5 min. The growth media consisted of F12 Hams Nutrient mix (supplied by Gibco - catalogue number 21765) and 10% Tet approved FBS (supplied by Clontech - catalogue number 631 106). The cells were then re-suspended in growth media and incubated at 37°C for 1 hour in a spinner flask. After this post thaw recovery period, the cell suspension was centrifuged once more and resuspended at 2.5 x 10^ cells/ml in loading buffer consisting of HBSS, 0.1 % BSA (supplied by CalBiochem - catalogue number 126609) and 0.1 % Pluronic F68 (supplied by Gibco - catalogue number 24040-032). The cells were loaded with coelentrazine (supplied by Invitrogen C - catalogue number 6780) to a concentration of 5μM, wrapped in foil and loaded overnight with mixing. Immediately prior to the assay, the cells were diluted to 15 x 10^ cells/ml in dilution buffer consisting of HBSS and 0.1 % Pluronic F68.
Coelentrazine is the chromophore co-factor which activates the apo-protein, aequorin. The protein has three high affinity binding sites for calcium. Upon agonism of the mGluRδ receptor, binding of calcium to the aequorin protein induces a conformational change resulting in an oxidative decarboxylation reaction producing coelenteramide and a flash luminescence signal. This signal was measured using the Lumilux (supplied by Perkin Elmer).
Compound Preparation
The test compounds were prepared in DMSO at a concentration of 3mM. These solutions are serially diluted with DMSO to 1 in 4 using a Biomek FX liquid handling device (supplied by Beckman Coulter) in a 384-well compound plate (supplied by Greiner). Daughter plates of 0.5μl/well were stamped-out from this master plate for use in the assay.
Glutamate Dose Response Curve Preparation A 10OmM solution of glutamic acid was prepared in water. This was further diluted with DMSO to a concentration of 1OmM. 16 x 11 point concentration response curves (CRC) were prepared in DMSO, making the final assay concentration 1.66 x10'^M, with 1 in 3 serial dilutions using the Biomek FX. 0.5μl stamp-outs of this plate were generated for use in the assay.
Estimation of EC80 concentration of Glutamate
The glutamate CRC plate was placed on the Lumilux where 20μl/well of dilution buffer was added, followed by 10μl/well of loaded cell suspension and a luminescence read was made. An EC80 concentration of glutamate was calculated by using 4X EC50 generated. The EC80 solution was prepared in dilution buffer and added to a reservoir within the Lumilux. Running the Assay
20μl/well of buffer and 10μl/well of cell suspension were added to the test compounds using the lumilux. These plates were incubated at room temperature for 15 mins, 10μl/well of EC80 solution added and a luminescence read made. Blocking of the receptor by test compound in a dose dependent manner was evident from the luminescence vs time profiles generated for each well. The data was analysed using XC50 software to produce CRCs, from which the potency and plC50 can be determined.
The supporting compounds were tested in assay a) and/or assay b). Using assay b) compounds 1 to 17, 19 to 29, 31 to 38, 40, 40b, 41-56 gave a plC50 equal to or greater than 4.5. Using assay a) compound 39 gave a plC50 of 5.0.

Claims

Claims
1. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or condition for which antagonism of the mGluRs receptor is beneficial,
Figure imgf000069_0001
(I) wherein X is N or -C(RX)-; Y is N or -C(RY)-; R1 is H, halo, C-|.galkyl, C-|.galkoxy, C-|.ghaloalkoxy, C-|.ghaloalkyl, C-|.galkylthio,
C-|.ghaloalkylthio, cyclopropyl, cyano, -N(R1a)(R1b), -C(O)N(R1C)(RId)1
-N(R1 C)C(O)R1 e, -C(O)R1 e or -SO2R1 e; R^ and R^, which may be the same or different, are H, C-|.galkyl, C-|.ghaloalkyl or cyclopropyl; or R^ and R^, together with the carbon to which they are attached, form a 3 to 6-membered saturated ring, optionally containing one heteroatom selected from O, N and S;
R4 is 5- or 6-membered monocyclic heterocyclyl, phenyl or C3_gcycloalkyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-|.galkyl; C-|.galkoxy; C-|.ghaloalkoxy;
C-|.ghaloalkyl; C-|.galkylthio; C-|.ghaloalkylthio; cyclopropyl; cyano;
-N(R4a)(R4b); -C(O)N(R4c)(R4d); -N(R4c)C(O)R4e; -C(O)R4e; -SO2R4e;
5-or 6-membered monocyclic heterocyclyl optionally substituted independently by one or more halo, C-|_3alkyl or C-|_3haloalkyl; phenyl optionally substituted independently by one or more halo, C-|_3alkyl or C-|. βhaloalkyl; and C3_gcycloalkyl optionally substituted independently by one or more halo, C-|_3alkyl or C-|_3haloalkyl; or R4 is a fused bicyclic ring system optionally comprising one or two heteroatoms independently selected from O, N and S and optionally substituted by one or more substituents independently selected from halo, C-|_3alkyl and C-|_3haloalkyl; and R5 is H; or R^ together with the N to which it is attached, forms a ring fused with R^, which ring is optionally substituted by one or more substitutents independently selected from the list: halo, C-μgalkyl, C-μgalkoxy,
C-|_ghaloalkoxy and C-|.ghaloalkyl; wherein Rx and RY, which may be the same or different, are -(CH2)nR®; wherein R^ is H; halo; C-μgalkyl; C-|.galkoxy; C-μghaloalkoxy; C-|.ghaloalkyl; C-μgalkylthio; C-|.ghaloalkylthio; C-|_3alkoxyC-|_3alkoxy; C3_gcycloalkyl; saturated
C3_gheterocyclyl comprising one heteroatom selected from O, N and S; cyano; -N(R6a)(R6b); -C(O)N(R6c)(R6d); -N(R6c)C(O)R6e; -C(O)R6e or
-SO2R6e; and n is 0, 1 or 2; wherein R1 a, R1 b, R4aj R4b] R6a and φb; which may be the same or different, are H or
C-|.galkyl; R1C, RI cI1 R4C R4d; R6c and RBd1 which may be the same or different, are H or
C-|.galkyl; and
R1 e, R^e and Ftβe, which may be the same or different, are C-|.galkyl or C-|.ghaloalkyl; with the proviso that R1 , R^ and R^ are not all H.
2. The use according to claim 1 wherein R1 is halo, C-|.galkyl, C-|.galkoxy, C-μ ghaloalkoxy, C-|.ghaloalkyl, C-|.galkylthio, C-μghaloalkylthio, cyclopropyl or cyano.
3. The use according to any preceding claim wherein R1 is halo or C-|.galkyl.
4. The use according to any preceding claim wherein R^ is H and R^ is C-μ galkyl, C-|.ghaloalkyl or cyclopropyl.
5. The use according to any preceding claim wherein R^ is H and R^ is C-μ galkyl.
6. The use according to any preceding claim wherein R2 is H and R^ is methyl.
7. The use according to any preceding claim wherein the compound of formula (I) has formula (Ia)
Figure imgf000071_0001
(Ia)
8. The use according to any preceding claim wherein, R^ is H and R4 is 5- or 6- membered monocyclic heterocyclyl, phenyl or C3_gcycloalkyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-|.galkyl; C-|.galkoxy; C-|.ghaloalkoxy; C-|.ghaloalkyl; C-|.galkylthio; C-|. ghaloalkylthio; cyclopropyl; cyano; -N(R4a)(R4b); -C(O)N(R4C)(R4Cl); _ N(R4C)C(O)R4e; -C(O)R4e; and -SO2R4e; wherein R4a and R4b, which may be the same or different, are H or C-|.galkyl; R4c and R4^, which may be the same or different, are H or C-|.galkyl; and R4e is C-|.galkyl or C-|.ghaloalkyl.
9. The use according to any preceding claim wherein, R^ is H and R4 is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl or C3_gcycloalkyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-|.galkyl; C-μgalkoxy; C-|.ghaloalkoxy; C-μghaloalkyl; C-|.galkylthio; C-μ ghaloalkylthio; cyclopropyl; cyano; -N(R4a)(R4b); -C(O)N(R4c)(R4d); - N(R4c)C(O)R4e; -C(O)R4e; and -SO2R4e; wherein R4a and R4b, which may be the same or different, are H or C-|.galkyl; R4c and R4^, which may be the same or different, are H or C-|.galkyl; and R4e is C-|.galkyl or C-μghaloalkyl.
10. The use according to any preceding claim wherein R^ is H and R4 is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or phenyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-μgalkyl; C-μ galkoxy; C-|.ghaloalkoxy; C-μghaloalkyl; C-|.galkylthio and C-|.ghaloalkylthio.
11. The use according to any preceding claim wherein, R^ is H and R^ is pyridyl, pyrimidinyl or phenyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-|.galkyl and C-|.galkoxy.
12. The use according to any preceding claim wherein X and Y are not both N.
13. The use according to any preceding claim wherein when X is -C(RX)- and Y is -C(RY)- then at least one of Rx and RY is H.
14. The use according to any preceding claim wherein at least one of X and Y is N.
15. The use according to any preceding claim wherein, Rx and RY, which may be the same or different, are -(CH2)nR^; wherein R6 is H; halo; C-|.galkyl; C-|.galkoxy; C-|.ghaloalkoxy; C-|.ghaloalkyl; C-|.galkylthio; C-|.ghaloalkylthio; C-|_3alkoxyC-|_ 3alkoxy; C3_gcycloalkyl; saturated C3_gheterocyclyl comprising one heteroatom selected from O, N and S; cyano; -N(R6a)(R6b); -C(O)N(R6c)(R6d);
-N(R6c)C(O)R6e; -C(O)R6e or -SO2R6e; and n is 0 or 1.
16. The use according to any preceding claim wherein Rx and RY, which may be the same or different, are H, halo, C-|.galkyl, C-|.ghaloalkyl, C3_gcycloalkyl, saturated C3_gheterocyclyl, C3_gcycloalkylmethyl or saturated C3_gheterocyclylmethyl, wherein either C3_gheterocyclyl comprises one heteroatom selected from O, N and S.
17. The use according to claim 1 wherein the compound of formula (I) has formula (Ia)
Figure imgf000072_0001
(Ia) wherein one of X and Y is N and the other X or Y is -C(RX)- or -C(RY)-; wherein Rx or RY is H, halo, C-|.galkyl, C-μghaloalkyl, C3_gcycloalkyl, saturated C3_gheterocyclyl, C3. gcycloalkylmethyl or saturated C3_gheterocyclylmethyl, wherein either C3. gheterocyclyl comprises one heteroatom selected from O, N and S; R1 is H, halo, C-|.galkyl, C-μgalkoxy, C-μghaloalkoxy, C-|.ghaloalkyl, C-μgalkylthio, C-|.ghaloalkylthio, cyclopropyl or cyano; R3 is C-|.galkyl, C-|.ghaloalkyl or cyclopropyl; and
R5 is H and R^ is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or phenyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-|.galkyl; C-μgalkoxy; C-|.ghaloalkoxy; C-μghaloalkyl; C-|.galkylthio and C-|.ghaloalkylthio.
18. The use according to claim 1 wherein, the compound of formula (I) is selected from the list consisting of: (+/-)1-(2-Cyclopropyl-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 1 );
1-(2-Cyclopropyl-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate
(Compound 1 b) (faster eluting enantiomer);
(+/-) 1-[2-(cyclopropylmethyl)-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl]ethyl phenylcarbamate (Compound 2);
(+/-) 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl [2-
(methyloxy)phenyl]carbamate (Compound 6);
(+/-) 1-(3-methylimidazo[2,1-b][1 ,3]thiazol-2-yl)ethyl phenylcarbamate (Compound 7);
(+/-) 1-(3-methylimidazo[2,1-b][1 ,3]thiazol-2-yl)ethyl (3-chlorophenyl)carbamate (Compound 8);
(+/-) 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (3-fluorophenyl)carbamate
(Compound 10);
(+/-) 1-(3-methylimidazo[2,1-b][1 ,3]thiazol-2-yl)ethyl (3-fluorophenyl)carbamate
(Compound 1 1 ); 1-[6-methyl-2-(tetrahydro-3-furanyl)[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl]ethyl phenylcarbamate (Compound 12);
1 -(+/-) [6-methyl-2-(trifluoromethyl)[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl]ethyl phenylcarbamate (Compound 13);
(+/-) 1-(2,6-dimethyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 14); (+/-) 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (3-bromophenyl)carbamate (Compound 20);
(+/-)1-(6-Methyl-[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl [3- (methyloxy)phenyl]carbamate (Compound 27); 1-(6-Methyl-[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl [3-
(methyloxy)phenyl]carbamate (Compound 27b) (slower eluting enantiomer);
(+/-) 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (3-chlorophenyl)carbamate (Compound 31 );
(+/-) 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 32);
(1 R)-1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate: (Compound 32a);
(+/-) 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (3- methylphenyl)carbamate (Compound 33); (+/-)1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl phenylcarbamate (Compound 40);
1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl phenylcarbamate (Compound
40b) (faster eluting enantiomer);
(+/-) 1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl (3-fluorophenyl)carbamate (Compound 42);
1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl (3-fluorophenyl)carbamate
(Compound 42a) (slower eluting enantiomer);
(+/-) 1-(3,5-dimethyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl (3- fluorophenyl)carbamate (Compound 43); (+/-) 1-(3-chloro-5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl phenylcarbamate
(Compound 46);
(+/-) 1-(3-bromo-5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl phenylcarbamate
(Compound 47);
(+/-)1-(6-Methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)propyl phenylcarbamate (Compound 48);
(+/-)2-Methyl-1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)propyl phenylcarbamate (Compound 49);
(+/-) 2,2,2-trifluoro-1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 50); (+/-)1-(2-Chloro-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl cyclobutylcarbamate (Compound 51 );
(+/-) 1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl (3-chlorophenyl)carbamate (Compound 53); 1-Methyl-1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 54); and
(+/-) 1-(2-Chloro-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 55); or a salt of any of the above.
19. The use according to any preceding claim wherein the disease or condition is a substance-related disorder.
20. A method of treating a disease or condition for which antagonism of the mGluR5 receptor is beneficial in a human comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof
Figure imgf000075_0001
(I) wherein
X is N or -C(RX)-; Y is N or -C(RY)-;
R1 is H, halo, C-|.galkyl, C-|.galkoxy, C-|.ghaloalkoxy, C-|.ghaloalkyl, C-|.galkylthio, C-i.ghaloalkylthio, cyclopropyl, cyano, -N(R1 a)(R1 b), -C(O)N(R1 c)(R1 d), -N(R1 C)C(O)R1 e, -C(O)R1 e or -SO2R1 e;
R2 and R^, which may be the same or different, are H, C-|.galkyl, C-|.ghaloalkyl or cyclopropyl; or R2 and R^, together with the carbon to which they are attached, form a 3 to 6-membered saturated ring, optionally containing one heteroatom selected from O, N and S; R^ is 5- or 6-membered monocyclic heterocyclyl, phenyl or C3_gcycloalkyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-|.galkyl; C-|.galkoxy; C-|.ghaloalkoxy; C-|.ghaloalkyl; C-μgalkylthio; C-|.ghaloalkylthio; cyclopropyl; cyano; -N(R4a)(R4b); -C(O)N(R4C)(R4d); -N(R4C)C(O)R4e; -C(O)R4e; -SO2R4e; 5-or 6-membered monocyclic heterocyclyl optionally substituted independently by one or more halo, C-|_3alkyl or C-|_3haloalkyl; phenyl optionally substituted independently by one or more halo, C-|_3alkyl or C-|.
3haloalkyl; and C3_gcycloalkyl optionally substituted independently by one or more halo, C-|_3alkyl or C-|_3haloalkyl; or R4 is a fused bicyclic ring system optionally comprising one or two heteroatoms independently selected from O, N and S and optionally substituted by one or more substituents independently selected from halo, C-|_3alkyl and C-|_3haloalkyl; and
R5 is H; or R^ together with the N to which it is attached, forms a ring fused with R4, which ring is optionally substituted by one or more substitutents independently selected from the list: halo, C-μgalkyl, C-μgalkoxy, C-|.ghaloalkoxy and C-|.ghaloalkyl; wherein
Rx and RY, which may be the same or different, are -(CH2)nR^; wherein R^ is H; halo; C-μgalkyl; C-|.galkoxy; C-μghaloalkoxy; C-|.ghaloalkyl; C-μgalkylthio; C-|.ghaloalkylthio; C-|_3alkoxyC-|_3alkoxy; C3_gcycloalkyl; saturated C3_gheterocyclyl comprising one heteroatom selected from O, N and S; cyano; -N(R6a)(R6b); -C(O)N(R6c)(R6d); -N(R6c)C(O)R6e; -C(O)R6e or
-Sθ2R6e; and n is 0, 1 or 2; wherein R1 a, R1 b, R4a, R4b, R6a and R6b, which may be the same or different, are H or
C-i-galkyl; R1 c, R1 d, R4c R4d, R6c and R6d, which may be the same or different, are H or
C-|.galkyl; and R1 e, R4e and R^e, which may be the same or different, are C-|.galkyl or
C-|.ghaloalkyl; with the proviso that R^ , R^ and R^ are not all H.
21. The method according to claim 20 wherein R^ is halo, C-|.galkyl, C-μgalkoxy, C-|.ghaloalkoxy, C-|.ghaloalkyl, C-|.galkylthio, C-|.ghaloalkylthio, cyclopropyl or cyano.
22. The method according to claim 21 wherein R^ is halo or C-|.galkyl.
23. The method according to any one of claims 20 to 22 wherein R^ is H and R^ is C-|.galkyl, C-|.ghaloalkyl or cyclopropyl.
24. The method according to any one of claims 20 to 23 wherein R^ is H and R^ is C-|.galkyl.
25. The method according to any one of claims 20 to 24 wherein R^ is H and R^ is methyl.
26. The method according to any one of claims 20 to 25 wherein the compound of formula (I) has formula (Ia)
Figure imgf000077_0001
27. The method according to any one of claims 20 to 26 wherein, R^ is H and R4 is 5- or 6-membered monocyclic heterocyclyl, phenyl or C3_gcycloalkyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-|.galkyl; C-|.galkoxy; C-|.ghaloalkoxy; C-|.ghaloalkyl; C-|_galkylthio; C-|_ghaloalkylthio; cyclopropyl; cyano; -N(R4a)(R4b); -C(O)N(R4c)(R4d); -N(R4c)C(O)R4e; -C(O)R4e; and -SO2R4e; wherein R4a and R4^, which may be the same or different, are H or C-μgalkyl; R4c and R4^, which may be the same or different, are H or C-|.galkyl; and R4e is C-|.galkyl or C-|.ghaloalkyl.
28. The method according to any one of claims 20 to 27 wherein, R^ is H and R4 is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl or C3_gcycloalkyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-|.galkyl; C-μgalkoxy; C-|.ghaloalkoxy; C-μghaloalkyl; C-|.galkylthio; C-μ ghaloalkylthio; cyclopropyl; cyano; -N(R4a)(R4b); -C(O)N(R4C)(R4Cl); _ N(R4C)C(O)R4e; -C(O)R4e; and -SO2R4e; wherein R4a and R4b, which may be the same or different, are H or C-|.galkyl; R^c and R^d, which may be the same or different, are H or C-|.galkyl; and R^e js C-|.galkyl or C-μghaloalkyl.
29. The method according to any one of claims 20 to 28 wherein R^ is H and R^ is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or phenyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-|.galkyl; C-|.galkoxy; C-μghaloalkoxy; C-|.ghaloalkyl; C-μgalkylthio and C-|. ghaloalkylthio.
30. The method according to any one of claims 20 to 29 wherein, R^ is H and R^ is pyridyl, pyrimidinyl or phenyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-|.galkyl and C-μ galkoxy.
31. The method according to any one of claims 20 to 30 wherein X and Y are not both N.
32. The method according to any one of claims 20 to 31 wherein when X is - C(RX)- and Y is -C(RY)- then at least one of Rx and RY is H.
33. The method according to any one of claims 20 to 32 wherein at least one of X and Y is N.
34. The method according to any one of claims 20 to 33 wherein, Rx and RY, which may be the same or different, are -(CH2)nR®; wherein R^ is H; halo; C-|. galkyl; C-|.galkoxy; C-μghaloalkoxy; C-|.ghaloalkyl; C-μgalkylthio; C-|.ghaloalkylthio; C-|_3alkoxyC-|_3alkoxy; C3_gcycloalkyl; saturated C3_gheterocyclyl comprising one heteroatom selected from O, N and S; cyano; -N(R6a)(R6b); -C(O)N(R6c)(R6d); -N(R6c)C(O)R6e; -C(O)R6e or -SO2R6e; and n is 0 or 1.
35. The method according to any one of claims 30 to 34 wherein Rx and RY, which may be the same or different, are H, halo, C-| .galkyl, C-μghaloalkyl, C3. gcycloalkyl, saturated C3_gheterocyclyl, C3_gcycloalkylmethyl or saturated C3_gheterocyclylmethyl, wherein either C3_gheterocyclyl comprises one heteroatom selected from O, N and S.
36. The method according to claim 20 wherein the compound of formula (I) has formula (Ia)
Figure imgf000079_0001
(Ia) wherein one of X and Y is N and the other X or Y is -C(RX)- or -C(RY)-; wherein Rx or RY is
H, halo, C-|.galkyl, C-|.ghaloalkyl, C3_gcycloalkyl, saturated C3_gheterocyclyl, C3. gcycloalkylmethyl or saturated C3_gheterocyclylmethyl, wherein either C3. gheterocyclyl comprises one heteroatom selected from O, N and S;
R1 is H, halo, C-|.galkyl, C-|.galkoxy, C-|.ghaloalkoxy, C-|.ghaloalkyl, C-|.galkylthio, C-|.ghaloalkylthio, cyclopropyl or cyano;
R3 is C-|.galkyl, C-|.ghaloalkyl or cyclopropyl; and
R5 is H and R^ is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or phenyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-|.galkyl; C-|.galkoxy; C-|.ghaloalkoxy; C-|.ghaloalkyl; C-|.galkylthio and C-|_ghaloalkylthio.
37. The method according to claim 20 wherein, the compound of formula (I) is selected from the list consisting of:
(+/-)1-(2-Cyclopropyl-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 1 );
1-(2-Cyclopropyl-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 1 b) (faster eluting enantiomer);
(+/-) 1-[2-(cyclopropylmethyl)-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl]ethyl phenylcarbamate (Compound 2); (+/-) 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl [2- (methyloxy)phenyl]carbamate (Compound 6);
(+/-) 1-(3-methylimidazo[2,1-b][1 ,3]thiazol-2-yl)ethyl phenylcarbamate (Compound 7); (+/-) 1-(3-methylimidazo[2,1-b][1 ,3]thiazol-2-yl)ethyl (3-chlorophenyl)carbamate (Compound 8); (+/-) 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (3-fluorophenyl)carbamate (Compound 10);
(+/-) 1-(3-methylimidazo[2,1-b][1 ,3]th iazol-2-y I )ethy I (3-fluorophenyl)carbamate (Compound 1 1 ); 1-[6-methyl-2-(tetrahydro-3-furanyl)[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl]ethyl phenylcarbamate (Compound 12);
1 -(+/-) [6-methyl-2-(trifluoromethyl)[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl]ethyl phenylcarbamate (Compound 13);
(+/-) 1-(2,6-dimethyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 14);
(+/-) 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (3-bromophenyl)carbamate (Compound 20);
(+/-)1-(6-Methyl-[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl [3- (methyloxy)phenyl]carbamate (Compound 27); 1-(6-Methyl-[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl [3-
(methyloxy)phenyl]carbamate (Compound 27b) (slower eluting enantiomer);
(+/-) 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (3-chlorophenyl)carbamate (Compound 31 );
(+/-) 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 32);
(1 R)-1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate: (Compound 32a);
(+/-) 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (3- methylphenyl)carbamate (Compound 33); (+/-)1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl phenylcarbamate (Compound 40);
1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl phenylcarbamate (Compound 40b) (faster eluting enantiomer);
(+/-) 1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl (3-fluorophenyl)carbamate (Compound 42);
1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl (3-fluorophenyl)carbamate (Compound 42a) (slower eluting enantiomer); (+/-) 1-(3,5-dimethyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl (3- fluorophenyl)carbamate (Compound 43); (+/-) 1-(3-chloro-5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl phenylcarbamate
(Compound 46);
(+/-) 1-(3-bromo-5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl phenylcarbamate
(Compound 47); (+/-)1-(6-Methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)propyl phenylcarbamate
(Compound 48);
(+/-)2-Methyl-1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)propyl phenylcarbamate (Compound 49);
(+/-) 2,2,2-trifluoro-1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 50);
(+/-)1-(2-Chloro-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl cyclobutylcarbamate (Compound 51 );
(+/-) 1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl (3-chlorophenyl)carbamate
(Compound 53); 1-Methyl-1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate
(Compound 54); and
(+/-) 1-(2-Chloro-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate
(Compound 55); or a salt of any of the above.
38. The method according to any one of claims 20 - 37 wherein the disease or condition is a substance-related disorder.
39. A compound of formula (I) or a salt thereof
Figure imgf000081_0001
(I) wherein
X is N or -C(RX)-; Y is N or -C(RY)-; R1 is H, halo, C-|.galkyl, C-|.galkoxy, C-μghaloalkoxy, C-|.ghaloalkyl, C-|.galkylthio, C-i.ghaloalkylthio, cyclopropyl, cyano, -N(R1a)(R1b), -C(O)N(R1C)(RId)1 -N(R1 c)C(O)R1 e, -C(O)R1 e or -SO2R1 e;
R^ and R^, which may be the same or different, are H, C-|.galkyl, C-|.ghaloalkyl or cyclopropyl; or R^ and R^, together with the carbon to which they are attached, form a 3 to 6-membered saturated ring, optionally containing one heteroatom selected from O, N and S; R4 is 5- or 6-membered monocyclic heterocyclyl, phenyl or C3_gcycloalkyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-μgalkyl; C-|.galkoxy; C-μghaloalkoxy;
C-|.ghaloalkyl; C-μgalkylthio; C-|.ghaloalkylthio; cyclopropyl; cyano; -N(R4a)(R4b); -C(O)N(R4C)(R4d); -N(R4C)C(O)R4e; -C(O)R4e; -SO2R4e; 5-or 6-membered monocyclic heterocyclyl optionally substituted independently by one or more halo, C-|_3alkyl or C-|_3haloalkyl; phenyl optionally substituted independently by one or more halo, C-|_3alkyl or C-|. βhaloalkyl; and C3_gcycloalkyl optionally substituted independently by one or more halo, C-|_3alkyl or C-|_3haloalkyl; or R4 is a fused bicyclic ring system optionally comprising one or two heteroatoms independently selected from O, N and S and optionally substituted by one or more substituents independently selected from halo, C-|_3alkyl and C-|_3haloalkyl; and
R5 is H; or R^ together with the N to which it is attached, forms a ring fused with R4, which ring is optionally substituted by one or more substitutents independently selected from the list: halo, C-μgalkyl, C-μgalkoxy, C-|.ghaloalkoxy and C-|.ghaloalkyl; wherein
Rx and RY, which may be the same or different, are -(CH2)nR^; wherein R^ is H; halo; C-μgalkyl; C-|.galkoxy; C-μghaloalkoxy; C-|.ghaloalkyl; C-μgalkylthio; C-|.ghaloalkylthio; C-|_3alkoxyC-|_3alkoxy; C3_gcycloalkyl; saturated C3_gheterocyclyl comprising one heteroatom selected from O, N and S; cyano; -N(R6a)(R6b); -C(O)N(R6c)(R6d); -N(R6c)C(O)R6e; -C(O)R6e or
-Sθ2R6e; and n is 0, 1 or 2; wherein R1 a, R1 b, R4a, R4b, R6a and R6b, which may be the same or different, are H or
C-|_galkyl; R1 c, R1 d, R4c R4d, R6c and R6d, which may be the same or different, are H or C-|.galkyl; and R1 e, R4s and R^e, which may be the same or different, are C-|.galkyl or C-|.ghaloalkyl; with the proviso that R^ , R^ and R^ are not all H; wherein the compound of formula (I) is not 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (3-chlorophenyl)carbamate
(Compound 31 );
1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound
32);
1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (3-methylphenyl)carbamate (Compound 33);
1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (4-methylphenyl)carbamate
(Compound 34);
1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl [3-
(trifluoromethyl)phenyl]carbamate (Compound 35); 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (4-fluorophenyl)carbamate
(Compound 36);
1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (4-chlorophenyl)carbamate
(Compound 37);
1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (3,4-dichlorophenyl)carbamate (Compound 38); or
1-(3-methylimidazo[2,1-b][1 ,3]thiazol-2-yl)ethyl (4-chlorophenyl)carbamate
(Compound 39).
40. The compound according to claim 39 or a salt thereof wherein R^ is halo, C-| . galkyl, C-|.galkoxy, C-μghaloalkoxy, C-|.ghaloalkyl, C-μgalkylthio, C-|.ghaloalkylthio, cyclopropyl or cyano.
41. The compound according to claim 40 or a salt thereof wherein R^ is halo or C-|.galkyl.
42. The compound according to any one of claims 39 to 41 or a salt thereof wherein R2 is H and R^ is C-|.galkyl, C-μghaloalkyl or cyclopropyl.
43. The compound according to any one of claims 39 to 42 or a salt thereof wherein R^ is H and R^ is C-|.galkyl.
44. The compound according to any one of claims 39 to 43 or a salt thereof wherein R2 is H and R^ is methyl.
45. The compound according to any one of claims 39 to 44 or a salt thereof wherein the compound of formula (I) has formula (Ia)
Figure imgf000084_0001
46. The compound according to any one of claims 39 to 45 or a salt thereof wherein, R^ is H and R4 is 5- or 6-membered monocyclic heterocyclyl, phenyl or C3. gcycloalkyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-μgalkyl; C-μgalkoxy; C-μghaloalkoxy; C-|.ghaloalkyl; C-μgalkylthio; C-|.ghaloalkylthio; cyclopropyl; cyano; -N(R4a)(R4b); -C(O)N(R4c)(R4d); -N(R4c)C(O)R4e; -C(O)R4e; and -SO2R4e; wherein R4a and R4^1 which may be the same or different, are H or C-μgalkyl; R4c and R4^, which may be the same or different, are H or C-|.galkyl; and R4e is C-|.galkyl or C-|.ghaloalkyl.
47. The compound according to any one of claims 39 to 46 or a salt thereof wherein, R^ is H and R4 is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl or C3. gcycloalkyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-μgalkyl; C-μgalkoxy; C-μghaloalkoxy; C-|.ghaloalkyl; C-μgalkylthio; C-|.ghaloalkylthio; cyclopropyl; cyano; -N(R4a)(R4b); -C(O)N(R4C)(R4Cl); -N(R4C)C(O)R4e; -C(O)R4e; and -SO2R4e; wherein R4a and R4b, which may be the same or different, are H or C-μgalkyl; R4c and R4^, which may be the same or different, are H or C-|.galkyl; and R4e is C-|.galkyl or C-|.ghaloalkyl.
48. The compound according to any one of claims 39 to 47 or a salt thereof wherein R^ is H and R4 is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or phenyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-|.galkyl; C-μgalkoxy; C-|.ghaloalkoxy; C-μghaloalkyl; C-|.galkylthio and C-μghaloalkylthio.
49. The compound according to any one of claims 39 to 48 or a salt thereof wherein, R^ is H and R^ is pyridyl, pyrimidinyl or phenyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-|.galkyl and C-μgalkoxy.
50. The compound according to any one of claims 39 to 49 or a salt thereof wherein X and Y are not both N.
51. The compound according to any one of claims 39 to 50 or a salt thereof wherein when X is -C(RX)- and Y is -C(RY)- then at least one of Rx and RY is H.
52. The compound acccording to any one of claims 39 to 51 or a salt thereof wherein at least one of X and Y is N.
53. The compound according to any one of claims 39 to 52 or a salt thereof wherein, Rx and RY, which may be the same or different, are -(CH2)nR^; wherein R^ is H; halo; C-|.galkyl; C-μgalkoxy; C-|.ghaloalkoxy; C-μghaloalkyl; C-|.galkylthio; C-|. ghaloalkylthio; C-|_3alkoxyC-|_3alkoxy; C3_gcycloalkyl; saturated C3_gheterocyclyl comprising one heteroatom selected from O, N and S; cyano; -N(R^a)(R6b)j -C(O)N(R6c)(R6d); -N(R6c)C(O)R6e; -C(O)R6e or -SO2R6e; and n is 0 or 1.
54. The compound according to any one of claims 39 to 53 or a salt thereof wherein Rx and RY, which may be the same or different, are H, halo, C-|.galkyl, C-|. ghaloalkyl, C3_gcycloalkyl, saturated C3_gheterocyclyl, C3_gcycloalkylmethyl or saturated C3_gheterocyclylmethyl, wherein either C3_gheterocyclyl comprises one heteroatom selected from O, N and S.
55. The compound according to claim 39 or a salt thereof wherein the compound of formula (I) has formula (Ia)
Figure imgf000086_0001
(Ia) wherein one of X and Y is N and the other X or Y is -C(RX)- or -C(RY)-; wherein Rx or RY is H, halo, C-|.galkyl, C-μghaloalkyl, C3_gcycloalkyl, saturated C3_gheterocyclyl, C3. gcycloalkylmethyl or saturated C3_gheterocyclylmethyl, wherein either C3. gheterocyclyl comprises one heteroatom selected from O, N and S; R1 is H, halo, C-|.galkyl, C-|.galkoxy, C-|.ghaloalkoxy, C-|.ghaloalkyl, C-|.galkylthio, C-|.ghaloalkylthio, cyclopropyl or cyano; R3 is C-|.galkyl, C-|.ghaloalkyl or cyclopropyl; and R5 is H and R^ is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or phenyl, each of which is optionally substituted by one or more substituents independently selected from the list: halo; C-|.galkyl; C-|.galkoxy; C-|.ghaloalkoxy; C-|.ghaloalkyl; C-|.galkylthio and C-|.ghaloalkylthio.
56. The compound according to claim 39 wherein, the compound of formula (I) is selected from the list consisting of:
(+/-)1-(2-Cyclopropyl-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 1 );
1-(2-Cyclopropyl-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 1 b) (faster eluting enantiomer);
(+/-) 1-[2-(cyclopropylmethyl)-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl]ethyl phenylcarbamate (Compound 2);
(+/-) 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl [2-
(methyloxy)phenyl]carbamate (Compound 6); (+/-) 1-(3-methylimidazo[2,1-b][1 ,3]thiazol-2-yl)ethyl phenylcarbamate (Compound 7);
(+/-) 1-(3-methylimidazo[2,1-b][1 ,3]thiazol-2-yl)ethyl (3-chlorophenyl)carbamate
(Compound 8);
(+/-) 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (3-fluorophenyl)carbamate
(Compound 10); (+/-) 1-(3-methylimidazo[2,1-b][1 ,3]th iazol-2-y I )ethy I (3-fluorophenyl)carbamate (Compound 1 1 );
1-[6-methyl-2-(tetrahydro-3-furanyl)[1 !3]thiazolo[3!2-b][1 !2,4]triazol-5-yl]ethyl phenylcarbamate (Compound 12); 1 -(+/-) [6-methyl-2-(trifluoromethyl)[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl]ethyl phenylcarbamate (Compound 13);
(+/-) 1-(2,6-dimethyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 14);
(+/-) 1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl (3-bromophenyl)carbamate (Compound 20);
(+/-)1-(6-Methyl-[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl [3- (methyloxy)phenyl]carbamate (Compound 27);
1-(6-Methyl-[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl [3- (methyloxy)phenyl]carbamate (Compound 27b) (slower eluting enantiomer); (+/-)1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl phenylcarbamate (Compound 40);
1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl phenylcarbamate (Compound
40b) (faster eluting enantiomer);
(+/-) 1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl (3-fluorophenyl)carbamate (Compound 42);
1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl (3-fluorophenyl)carbamate
(Compound 42a) (slower eluting enantiomer);
(+/-) 1-(3,5-dimethyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl (3- fluorophenyl)carbamate (Compound 43); (+/-) 1-(3-chloro-5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl phenylcarbamate
(Compound 46);
(+/-) 1-(3-bromo-5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl phenylcarbamate
(Compound 47);
(+/-)1-(6-Methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)propyl phenylcarbamate (Compound 48);
(+/-)2-Methyl-1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)propyl phenylcarbamate (Compound 49);
(+/-) 2,2,2-trifluoro-1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 50); (+/-)1-(2-Chloro-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl cyclobutylcarbamate (Compound 51 );
(+/-) 1-(5-methyl[1 ,3]thiazolo[2,3-c][1 ,2,4]triazol-6-yl)ethyl (3-chlorophenyl)carbamate (Compound 53); 1-Methyl-1-(6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 54); and
(+/-) 1-(2-Chloro-6-methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethyl phenylcarbamate (Compound 55); or a salt of any of the above.
57. A pharmaceutical composition comprising a) a compound as defined in any one of claims 39 to 56 or a pharmaceutically acceptable salt thereof, and b) one or more pharmaceutically acceptable excipients.
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