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WO2008009935A1 - Compositions pharmaceutiques et leur utilisation - Google Patents

Compositions pharmaceutiques et leur utilisation Download PDF

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Publication number
WO2008009935A1
WO2008009935A1 PCT/GB2007/002722 GB2007002722W WO2008009935A1 WO 2008009935 A1 WO2008009935 A1 WO 2008009935A1 GB 2007002722 W GB2007002722 W GB 2007002722W WO 2008009935 A1 WO2008009935 A1 WO 2008009935A1
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het
alkyl
different
same
group
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PCT/GB2007/002722
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English (en)
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David Selwood
Dieter Riddal
Charmaine Griffiths
Robert Keynes
Tomas Bellamy
John Garthwaite
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Ucl Business Plc
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Publication of WO2008009935A1 publication Critical patent/WO2008009935A1/fr

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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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to phenothiazine derivatives and their use in treating or preventing diseases mediated by lipid peroxidation.
  • Lipid peroxidation is a key factor in numerous disease states where oxidative stress has been implicated, including neurodegenerative disorders, cardiovascular disease, asthma and diabetes.
  • Lipid peroxidation is initiated by radical species such as the hydroxyl radical (OH), which can abstract a hydrogen atom from unsaturated lipid, thus generating a lipid radical (L ' ) and H 2 O.
  • the lipid radical can combine with O 2 , generating the lipid 'peroxyl' radical (LOO ' ), which can further react with unsaturated lipid. If allowed to progress unchecked, a damaging, self-propagating cascade of peroxidation results.
  • Nitric oxide is known to bind peroxidising lipid at an almost diffusion- limited rate. This reaction has dual effects: firstly NO is consumed avidly in the reaction and secondly, given time, continuously released NO may act as a chain breaking inhibitor of lipid peroxidation.
  • the phenothiazine derivatives of formula (I) are capable of reducing or preventing lipid peroxidation.
  • the present invention therefore provides the use of a phenothiazine derivative which is (a) a compound of formula (I) or a tautomer thereof, or (b) a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in treating or preventing a disorder mediated by lipid peroxidation:
  • each R 2 is the same or different and represents a group of formula -Y 1 -A, -Y'-Het-A, -Y'-Het-A-A', -Y !
  • R 3 and R 4 are the same or different and represent a hydrogen or halogen atom or a group selected from Cj -4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, C 2 - 4 alkenyloxy, CM haloalkyl, C 2-4 haloalkenyl, Ci -4 haloalkoxy, C 2-4 haloalkenyloxy, hydroxyl, C 1-4 hydroxyalkyl, Ci- 4 alkylthio and C 2-4 alkenylthio, or a group of formula -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C 1-4 alkyl; or
  • R 1 together with R 3 or R 4 , forms a 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl group which is optionally fused to a phenyl,
  • R 3 and R 4 represents a hydrogen or halogen atom, a group selected from C 1-4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, C 2-4 alkenyloxy, Ci -4 haloalkyl, C 2-4 haloalkenyl, Ci -4 haloalkoxy, C 2-4 haloalkenyloxy, hydroxyl, C] -4 hydroxyalkyl, Ci -4 alkylthio and C 2-4 alkenylthio, or a group of formula -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl; each A and A' is the same or different and represents a phenyl, 5- to 10- membered heteroaryl, 5- to 10-membered heterocyclyl or C 3-6 carbocyclyl group which is optionally fused
  • the invention also provides a phenothiazine derivative which is (a) a compound of formula (I) described above or a tautomer thereof, or (b) a pharmaceutically acceptable salt thereof, for use in a method of treating the human or animal body. Further provided is a method of alleviating a condition mediated by lipid peroxidation in a patient, which method comprises administering to said patient an effective amount of a phenothiazine derivative as defined above.
  • a Cj -6 alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, for example a Cj -4 alkyl group or moiety containing from 1 to 4 carbon atoms.
  • Examples of C 1-4 alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.
  • the alkyl moieties may be the same or different.
  • two alkenyl moieties may be the same or different.
  • a Cj -6 alkyl ene group or moiety is a linear or branched alkylene group or moiety, for example a Ci -4 alkylene group or moiety.
  • Examples include methylene, n-ethylene, n-propylene and -C(CH 3 ) 2 - groups and moieties.
  • an alkylene group is a substituent on an A, A' or A" group, it is typically attached to 2 adj acent ring atoms on the A, A ' or A ".
  • a C 2-6 alkenylene group or moiety is a linear or branched alkenylene group or moiety, for example a C 2-4 alkenylene group or moiety.
  • a halogen is typically chlorine, fluorine, bromine or iodine and is preferably chlorine, bromine or fluorine.
  • a C 1-4 alkoxy group or C 2-4 alkenyloxy group is typically a said Ci -4 alkyl group or a C 2-4 alkenyl group respectively which is attached to an oxygen atom.
  • a haloalkyl, haloalkenyl, haloalkoxy or haloalkenyloxy group is typically a said alkyl, alkenyl, alkoxy or alkenyloxy group respectively which is substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms.
  • preferred haloalkoxy groups include methoxy groups substituted by 1 or 2 said halogen atoms, such as -OCH 2 F and -OCHF 2 , preferably -OCHF 2 .
  • Other preferred haloalkyl and haloalkoxy groups include perhaloalkyl and perhaloalkoxy groups such as -CX 3 and -OCX 3 wherein X is a said halogen atom, for example chlorine and fluorine.
  • Particularly preferred haloalkyl groups are -CF 3 and -CCl 3 , more preferably -CF 3 .
  • Ci -4 alkylthio or C 2-4 alkenylthio group is typically a said C] -4 alkyl group or a C 2-4 alkenyl group respectively which is attached to a sulphur atom, for example -S-CH 3 .
  • a Ci -4 hydroxyalkyl group is a C] -4 alkyl group substituted by one or more hydroxy groups. Typically, it is substituted by one, two or three hydroxy groups. Preferably, it is substituted by a single hydroxy group.
  • a preferred hydroxyalkyl group is -(CH 2 ) 2 -OH.
  • a 5- to 10- membered heteroaryl group or moiety is a monocyclic 5- to 10- membered aromatic ring, such as a 5- or 6- membered ring, containing at least one heteroatom, for example 1, 2, 3 or 4 heteroatoms, selected from O, S and N. When the ring contains 4 heteroatoms these are preferably all nitrogen atoms.
  • Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Furanyl, thienyl, pyridyl, imidazolyl, pyrazolyl, thiazolyl, isoisothiazolyl, thiadiazolyl, pyridazinyl, triazolyl, oxadiazolyl and tetrazolyl groups are preferred.
  • A is a 5- to 10- membered heteroaryl moiety fused to a phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or C 3-6 carbocyclyl group, it is typically fused to a phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C 3-6 carbocyclyl ring. More preferably, it is fused to a phenyl or C 3-6 carbocyclyl ring.
  • Preferred examples of a 5- to 10-membered heteroaryl moiety fused to a phenyl ring include indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl and quinazolinyl. Particularly preferred examples include benzothienyl, benzotriazolyl and benzothiazolyl.
  • Preferred examples of a 5- to 10-membered heteroaryl moiety fused to a C 3-6 carbocyclyl ring include pyrazolyl fused to a C 3-6 carbocyclyl ring, for example pyrazolyl fused to a cyclopentyl ring.
  • A' is a 5- to 10- membered heteroaryl moiety fused to a phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or C 3-6 carbocyclyl group, it is typically fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring. More preferably, it is fused to a phenyl ring.
  • Preferred examples of a 5- to 10-membered heteroaryl moiety fused to a phenyl ring include indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl and quinazolinyl. Particularly preferred examples include benzothienyl, benzotriazolyl and benzothiazolyl.
  • a or A' is a phenyl group fused to a further phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or C 3-6 carbocyclyl group, it is preferably fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring.
  • a or A' is a phenyl group it is a monocyclic moiety (i.e. it is non- fused).
  • a 5- to 10- membered heterocyclyl group or moiety is a monocyclic non-aromatic, saturated or unsaturated C 5 -C io carbocyclic ring in which one or more, for example 1, 2 or 3, of the carbon atoms are replaced with a moiety selected from N, O, S, S(O) and S(O) 2 , and wherein one or more of the remaining carbon atoms is optionally replaced by a group -C(O)- or -C(S)-.
  • the 5- to 10- membered heterocyclyl ring is a 5- to 6- membered ring.
  • Suitable heterocyclyl groups and moieties include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dioxolanyl, pyrazolidinyl, piperidyl, piperazinyl, thiomorpholinyl, S-oxo-thiomorpholinyl, S 5 S- dioxo-thiomorpholinyl, morpholinyl, 1,3 -dioxolanyl, 1 ,4-dioxolanyl, trioxolanyl, trithianyl, imidazolinyl, pyrazolinyl, thioxolanyl,
  • Preferred heterocyclyl groups are piperidinyl, pyrrolidinyl, piperazinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, imidazolinyl, thioxothiazolidinyl, oxopyrrolidinyl, oxothiazolidinyl and oxopyrazolidinyl groups. More preferred heterocyclyl groups are piperazinyl, piperidinyl, thioxothiazolidinyl, oxopyrrolidinyl, oxothiazolidinyl and oxopyrazolidinyl groups.
  • A, A ' or A" is a said 5- to 10- membered heterocyclyl moiety fused to a further phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or C 3-6 carbocyclyl group it is preferably fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring. More preferably, it is fused to a phenyl ring.
  • An example is 2-oxo-dihydroindolyl. o
  • a C 3-6 carbocyclic moiety is a monocyclic non-aromatic saturated or unsaturated hydrocarbon ring having from 3 to 6 carbon atoms. Preferably it is a saturated or mono-unsaturated hydrocarbon ring (i.e.
  • a cycloalkyl moiety or a cycloalkenyl moiety having from 3 to 6 carbon atoms.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and their mono-unsaturated variants.
  • a preferred saturated example is cyclopropyl.
  • a preferred mono-unsaturated example is cyclopentenyl (i.e. a cyclopentyl group containing one carbon-carbon double bond).
  • A, A' or A" is a said C 3-6 carbocyclyl group fused to a further phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or C 3-6 carbocyclyl group, it is preferably fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring.
  • A, A ' or A" is a C 3-6 carbocyclyl group it is a monocyclic moiety (i.e. it is non-fused).
  • phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties are substituted by two or three substituents, it is preferred that not more than two substituents are selected from C 1-4 alkylene, cyano and nitro. More preferably, not more than one substituent is selected from Ci -4 alkylene, cyano and nitro. Furthermore, when the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties are substituted by two or three substituents, it is preferred that not more than one substituent is selected from -X-A'".
  • the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A, A' and A" groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and- are selected from halogen atoms and C 1-4 alkyl, Ci -4 alkylene, C 2-4 alkenyl, Ci -4 alkoxy, CM haloalkyl, C ]-4 haloalkoxy, hydroxyl, nitro, Q -4 hydroxyalkyl, Cj -4 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl, and -X-A'" wherein X represents a bond or Ci -4 alkylene, and A'" represents furanyl or thienyl.
  • substituents are themselves unsubstituted.
  • the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A, A' and A" groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C 1-2 alkyl, C 1-4 alkylene, C 2-3 alkenyl, Ci -2 alkoxy, Ci -2 haloalkyl, Ci -2 haloalkoxy, hydroxyl, nitro, C 1-2 hydroxyalkyl, Ci -2 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Cj -2 alkyl, and -X-A'" wherein X represents a bond or Ci -2 alkylene, and A'" represents furanyl or thienyl.
  • the L and L' groups are unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and hydroxyl, cyano, -CO 2 R 5 -SO 2 OR and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or C 1-4 alkyl. More preferably the L and I/ groups are unsubstituted or substituted by 1 or 2 groups selected from hydroxyl, cyano, -CO 2 R and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci -2 alkyl. More preferably each R, R' and R" is the same or different and represents hydrogen or methyl.
  • R is hydrogen.
  • R' and R" is methyl and the other is hydrogen or methyl.
  • the L and I/ groups are unsubstituted or substituted by 1 group described above.
  • each A is the same or different and is a phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C 3-6 carbocyclyl group which is optionally fused to a further phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C 3-6 carbocyclyl group.
  • each A is the same or different and is a non-fused phenyl, 5- to 6- membered heteroaryl, 5- to 6-membered heterocyclyl or C 3-6 carbocyclyl group or is a 5- to 6- membered heteroaryl ring fused to a further phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C 3-6 carbocyclyl group.
  • each A is the same or different and is a non-fused phenyl, 5- to 6- membered heteroaryl, 5- to 6-membered heterocyclyl or C 3-6 carbocyclyl group or is a 5- to 6- membered heteroaryl ring fused to a further phenyl or C 3-6 carbocyclyl ring.
  • A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Triazolyl furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred.
  • A is a fused heteroaryl group it is preferably a 5- to 6-membered heteroaryl group fused to a further phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C 3-6 carbocyclyl group. More preferably it is a 5- to 6- membered heteroaryl group fused to a further phenyl ring or C 3-6 carbocyclyl group.
  • Preferred examples include indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinazolinyl and pyrazolyl rings fused to a C 3-6 carbocyclyl group.
  • Particularly preferred examples of a heteroaryl group fused to a phenyl ring include benzothienyl, benzotriazolyl and benzothiazolyl.
  • Particularly preferred examples of a heteroaryl group fused to a C 3-6 carbocyclyl group include a pyrazolyl ring fused to a cyclopentyl group.
  • A is a non-fused heterocyclyl group it is preferably selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dioxolanyl, pyrazolidinyl, piperidyl, piperazinyl, thiomorpholinyl, S-oxo- thiomorpholinyl, S,S-dioxo-thiomorpholinyl, morpholinyl, 1,3 -dioxolanyl, 1,4- dioxolanyl, trioxolanyl, trithianyl, imidazolinyl, pyrazolinyl, thiox
  • it is selected from piperidinyl, pyrrolidinyl, piperazinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, imidazolinyl, thioxothiazolidinyl, oxopyrrolidinyl, oxothiazolidinyl and oxopyrazolidinyl groups. More preferably it is selected from piperazinyl, piperidinyl thioxothiazolidinyl groups.
  • A is a non-fused carbocyclyl group it is preferably a monocyclic non- aromatic saturated or unsaturated hydrocarbon ring having from 3 to 6 carbon atoms. Preferably it is a saturated hydrocarbon ring (i.e. a cycloalkyl moiety) having from 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. A preferred example is cyclopropyl.
  • the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A groups are unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and C 1-4 alkyl, C 1-4 alkylene, C 2-4 alkenyl, C 1-4 alkoxy, C 1-4 haloalkyl, Ci -4 haloalkoxy, hydroxyl, nitro, C 1-4 hydroxyalkyl, C 1-4 alkylfhio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl, and -X-A'" wherein X represents a bond or Ci -4 alkylene, and A"' represents furanyl or thienyl.
  • each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -2 alkyl, Ci -4 alkylene, C 2-3 alkenyl, C 1-2 alkoxy, Ci -2 haloalkyl, C] -2 haloalkoxy, hydroxyl, nitro, C] -2 hydroxyalkyl, Ci -2 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -2 alkyl, and -X-A'" wherein X represents a bond or Ci -2 alkylene, and A"' represents furanyl or thienyl.
  • X represents a bond or -CH 2 -.
  • A' is furanyl.
  • a substituent is a Ci -4 alkylene group it is preferably a -C(CH 3 ) 2 - group which is attached to two adjacent carbon atoms on the A ring.
  • A is preferably a heterocyclyl or carbocyclyl group or is a phenyl, heteroaryl, heterocyclyl or carbocyclyl group fused to a heterocyclyl or carbocyclyl group to which the Ci -4 alkylene group is bonded.
  • each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -2 alkyl, C 3-4 alkylene, C 2-3 alkenyl, Ci -2 haloalkyl, hydroxyl, nitro, C 1-2 hydroxyalkyl, Ci -2 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -2 alkyl, and -X-A'" wherein X represents a bond or C] -2 alkylene, and A'" represents furanyl.
  • each A' is the same or different and represents a phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C 3-6 carbocyclyl group which is optionally fused to a further phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C 3-6 carbocyclyl group.
  • each A is the same or different and is a phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C 3-6 carbocyclyl group which is optionally fused to a further phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group.
  • each A' is the same or different and represents a non-fused phenyl, 5- to 6-membered heteroaryl or 5- to 6- membered heterocyclyl group. More preferably each A' is the same or different and represents a non- fused phenyl or 5- to 6- membered heteroaryl group.
  • A' is a 5- to 6- membered heteroaryl group it preferably represents pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl are preferred. Most preferred are pyridyl, pyrimidinyl, pyridazinyl and thiazolyl.
  • the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, Cj -4 haloalkyl, Cj -4 haloalkoxy, hydroxyl, Ci -4 hydroxyalkyl, Ci -4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl.
  • the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Cj -2 alkyl, Ci -2 alkoxy, Cj -2 haloalkyl, Ci -2 haloalkoxy, hydroxyl and Ci -2 alkylthio.
  • the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C] -2 alkyl and Cj -2 alkoxy groups. More preferably the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A' groups are unsubstituted or substituted by 1 or 2 or 3 substituents described above.
  • each A" is the same or different and represents a 5- to 6- membered heterocyclyl or C 3-6 carbocyclyl group which is optionally fused to a further phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C 3-6 carbocyclyl group.
  • each A" is the same or different and is a 5- to 6- membered heterocyclyl or C 3-6 carbocyclyl group which is optionally fused to a further phenyl, 5- to 6- membered heterocyclyl or 5- to 6- membered heteroaryl.
  • each A" is the same or different and is a non-fused 5- to 6- membered heterocyclyl or C 3-6 carbocyclyl group or is a 5- to 6- membered heterocyclyl fused to a further phenyl ring. More preferably each A" is the same or different and is a non-fused 5- to 6- membered heterocyclyl or is a 5- to 6- membered heterocyclyl fused to a phenyl ring.
  • A" is a non-fused heterocyclyl group, preferably at least one carbon in the heterocyclyl ring is replaced by -C(O)- or -C(S)-, more preferably one carbon atom is replaced by -C(O)- or -C(S)-.
  • Particularly preferred are lH-pyrazol-5(4H)-onyl, l,3,4-thiazol-2(3H)-thionyl, oxopyrrolidinyl, oxothiazolidinyl and oxopyrazolidinyl groups, more preferably lH-pyrazol-5(4H)-onyl.
  • A" is a fused heterocyclyl group it is preferably a 2-oxo-dihydroindolyl group.
  • each A" is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, Ci -4 haloalkyl, C] -4 haloalkoxy, hydroxyl, C] -4 hydroxyalkyl, Ci -4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl.
  • each A" is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -2 alkyl, Ci -2 alkoxy, Ci -2 haloalkyl, Ci -2 haloalkoxy, hydroxyl and Ci -2 alkylthio. More preferably each A" group is unsubstituted or substituted by 1 or 2 Cj -2 alkyl groups, more preferably by 1 Ci -2 alkyl group, more preferably methyl.
  • each Z is the same or different and represents CR'" wherein R'" represents hydrogen, Ci -2 alkyl or a group -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -2 alkyl.
  • R"' represents Ci -2 alkyl, it is preferably methyl.
  • R'" represents -NR 'R
  • each R' and R" is the same or different and represents hydrogen or methyl, more preferably each R' and R" represents hydrogen.
  • each Het is the same or different and represents -O- or -NR'- wherein R' is hydrogen or Ci -2 alkyl.
  • R' is hydrogen or Ci -2 alkyl.
  • R' is hydrogen or methyl, more preferably hydrogen.
  • the left hand end of the Y 2 group is attached to the phenothiazine group or is closer to the phenothiazine group than the right hand end of the Y 2 group.
  • each Het is the same or different and represents -0-, -S- or -NR'- wherein R' is hydrogen or Ci -2 alkyl.
  • R' is hydrogen or methyl.
  • each Het' is the same or different and represents -O- or -NR'- wherein R' is hydrogen or Ci -2 alkyl.
  • R' is hydrogen or Ci -2 alkyl.
  • R' is hydrogen or methyl, more preferably hydrogen.
  • each L is the same or different and represents a Ci -4 alkylene or C 2-4 alkenylene group.
  • L represents a Ci -4 alkylene group it is preferably a -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH 2 -CH(CH 3 )- or -CH 2 -CH(CH 3 )-CH 2 - group.
  • non-symmetrical L groups is attached to the phenothiazine group or is closer to the phenothiazine group than the right hand end of the L group.
  • an L group bears 2 substituents, preferably at most there is 1 substituent selected from -C(O)R, -CO 2 R', -S(O)R, -SO 2 R' and -NR 'R".
  • each L group is unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and hydroxyl, cyano, -CO 2 R, -SO 2 OR and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci -4 alkyl. More preferably each L group is unsubstituted or substituted by 1 or 2 groups selected from hydroxyl, cyano, -CO 2 R and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci -2 alkyl. More preferably each R, R' and R' ' is the same or different and represents hydrogen or methyl.
  • each L group is unsubstituted or substituted by 1 group described above.
  • each I/ is the same or different and represents a Ci -4 alkyl group, more preferably a Ci -3 alkyl group. More preferably each I/ is the same or different and represents methyl, ethyl, -CH 2 -CH 2 -CH 3 or -CH(CH 3 ) 2 . Most preferably each L/ is the same or different and represents methyl or -CH(CH 3 ) 2 .
  • each I/ group is unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and hydroxyl, cyano, -CO 2 R, -SO 2 OR and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or C] -4 alkyl. More preferably each L' group is unsubstituted or substituted by 1 or 2 groups selected from hydroxyl, cyano, -CO 2 R and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or C] -2 alkyl. More preferably each R, R' and R" is the same or different and represents hydrogen or methyl.
  • each I/ group is unsubstituted or substituted by 1 group described above. More preferably each I/ group is unsubstituted.
  • the group S ' preferably represents -S- or -SO-. More preferably S ' represents -S-.
  • R 2 is a group of formula -Y'-A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A, -Y'-A-A', -Y'-L-A-A', -Y'-L-A-Het-A', -Y'-A-Het-A', -Y'-L-Het-A, -Y'-Het-L-A, -Y'-L-Het-A-A', -Y'-Het-L-A-A', -Y'-L-Het-A-A', -Y'-Het-L-A-A', -Y'-L-Het-A-A', -Y'-Het-A-Y'-A', -Y'-Het-A-
  • R 2 is a group of formula -Y'-A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A, -Y'-A-A', -Y'-L-A-A', -Y'-L-A-Het-A', -Y'-A-Het-A', -Y'-L-Het-A, -Y'-Het-L-A, -Y'-L-Het-A-A', -Y'-Het-L-A-A', -Y'-L-Het-A-Y'-A', -Y'-Het-A-Y'-A', -Y'-Het-A-Y'-Het'-A', -Y'-A-Het-A-Y-Het'-A', -Y'-A-Het-Y-Het-A', -Y'-L-Het-
  • each Z is the same or different and represents CR'" wherein R'" represents hydrogen, Ci -2 alkyl or a group -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C 1-2 alkyl.
  • R'" represents hydrogen or Cj -2 alkyl.
  • R'" represents Ci -2 alkyl, it is preferably methyl.
  • Het is preferably -NR'- wherein R' is hydrogen or Ci -2 alkyl, more preferably wherein R' is hydrogen or methyl, most preferably hydrogen.
  • preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups.
  • A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Triazolyl furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred, with pyrimidinyl most preferred.
  • each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, Ci -4 haloalkyl, Ci -4 haloalkoxy, hydroxyl, nitro, Ci -4 hydroxyalkyl, Cj -4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C 1-4 alkyl.
  • each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from Ci -2 alkyl, hydroxyl, nitro and C] -4 haloalkyl.
  • Preferred Ci -2 substituents are methyl groups.
  • Preferred haloalkyl substituents are Ci -2 alkyl groups which are substituted by one or more said halogen atoms. Typically, they are substituted by 1 , 2 or 3 said halogen atoms.
  • Particularly preferred Ci -2 haloalkyl substituents are perhaloalkyl substituents, in particular -CF 3 .
  • each Z is the same or different and represents CR'" wherein R'" represents hydrogen, Ci -2 alkyl or a group -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -2 alkyl.
  • R'" represents hydrogen or Ci -2 alkyl, more preferably R'" represents hydrogen or methyl, more preferably methyl.
  • Het is preferably -NR'- wherein R' is hydrogen or Ci -2 alkyl, more preferably wherein R' is hydrogen or methyl, most preferably hydrogen.
  • R 2 is -Y 2 -Y'-A
  • a preferred Y 1 group is -SO 2 -.
  • preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused phenyl rings.
  • each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, Ci -4 haloalkyl, Ci -4 haloalkoxy, hydroxyl, nitro, Ci -4 hydroxyalkyl, Ci -4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl.
  • Particularly preferred substituents are halogen atoms, in particular bromine atoms.
  • preferred Het groups include -O-.
  • preferred L groups include Cj -4 alkylene groups, for example Ci -3 alkylene groups, more preferably -CH 2 -CH 2 -CH 2 - groups.
  • the L groups are unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and hydroxyl, cyano, -CO 2 R, -SO 2 OR and -NR'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or C 1-4 alkyl.
  • each L group is unsubstituted or substituted by 1 or 2 groups selected from hydroxyl, cyano, -CO 2 R and -NR'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci -2 alkyl. More preferably each L is unsubstituted or substituted by 1 or 2 hydroxyl groups, more preferably it is substituted by one hydroxyl group.
  • R 2 is -Het-L-Het'-A-Het'-A'
  • preferred Het' groups include -O- and -NR'- wherein R' is hydrogen or Ci -2 alkyl.
  • Het' represents -NR'-, then preferably R' is hydrogen or methyl, more preferably hydrogen.
  • the Het' groups are the same or different, and preferably one is -O- and the other is -NR'- as defined above. More preferably the Het' group bonded to the L and A groups is -O- and the Het' group bonded to the A and A' groups is -NR'-.
  • preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused phenyl rings.
  • each A is unsubstituted or substituted by I 5 2 or 3 substituents which are the same or different and are selected from halogen atoms and C 1-4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, Ci -4 haloalkyl, C 1-4 haloalkoxy, hydroxyl, nitro, Ci -4 hydroxyalkyl, Ci -4 alkylthio and -NR'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl. More preferably each A is unsubstituted.
  • preferred A' groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused phenyl rings.
  • the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C 1-4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, Ci -4 haloalkyl, C ]-4 haloalkoxy, hydroxyl, C 1-4 hydroxyalkyl, Cj -4 alkylthio and -NR'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl. More preferably the A' groups are unsubstituted.
  • preferred R groups include 5- to 6- membered heterocyclyl or C 3-6 carbocyclyl group which is optionally fused to a further phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C 3-6 carbocyclyl group.
  • each A" is the same or different and is a 5- to 6- membered heterocyclyl or C 3-6 carbocyclyl group which is optionally fused to a further phenyl, 5- to 6- membered heterocyclyl or 5- to 6- membered heteroaryl.
  • each A" is the same or different and is a non-fused 5- to 6- membered heterocyclyl or C 3-6 carbocyclyl group or is a 5- to 6- membered heterocyclyl fused to a further phenyl ring. More preferably each A" is the same or different and is a non-fused 5- to 6- membered heterocyclyl.
  • Suitable non-fused heterocyclyl groups include lH-pyrazol- 5(4H)-onyl, l,3,4-thiazol-2(3H)-thionyl, oxopyrrolidinyl, oxothiazolidinyl and oxopyrazolidinyl groups, more preferably lH-pyrazol-5(4H)-onyl.
  • each A" is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, Ci -4 haloalkyl, Cj -4 haloalkoxy, hydroxyl, Cj -4 hydroxyalkyl, C 1-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C i -4 alkyl. More preferably each A " is unsubstituted or substituted by 1 or 2 Cj -2 alkyl groups, more preferably by one methyl group.
  • preferred R groups include hydrogen and Ci -2 alkyl, more preferably hydrogen or methyl, more preferably methyl.
  • preferred A" groups include 5- to 6- membered heterocyclyl or C 3-6 carbocyclyl groups optionally fused to a further phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group. More preferably A" is a 5- to 6- membered heterocyclyl fused to a further phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group, most preferably a 5- to 6- membered heterocyclyl fused to a further phenyl ring.
  • a suitable fused group is 2-oxo- dihydroindolyl.
  • each A" is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, Cj -4 haloalkyl, C 1-4 haloalkoxy, hydroxyl, Ci -4 hydroxyalkyl, Cj -4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Cj -4 alkyl.
  • each A" is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -2 alkyl, Cj -2 alkoxy, C 1-2 haloalkyl, Ci -2 haloalkoxy, hydroxyl and Cj -2 alkylthio. More preferably each A" is unsubstituted.
  • R 1 represents a hydrogen atom or a group selected from Ci -4 alkyl, C 2-4 alkenyl, Cj -4 haloalkyl, C 2-4 haloalkenyl and Ci -4 hydroxyalkyl
  • R 1 represents a hydrogen atom or a group selected from Ci -4 alkyl, C 2-4 alkenyl, Cj -4 haloalkyl, C 2-4 haloalkenyl and Ci -4 hydroxyalkyl
  • R 1 represents a group of formula -Y 1 -A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A, -Y'-A-A', -Y'-L-A-A', -Y'-L-A-Het-A', -Y'-A-Het-A', -Y'-L-Het-A, -Y'-Het-L-A, -Y'-L-Het-A-A', -Y'-Het-L-A-A', -Y'-L-Het-A-Y'-A', -Y'-Het-A-Y'-A', -Y'-Het-A-Y'-Het'-A', -Y'-A-Het-A-Y'-Het'-A', -Y'-A-Het-A-Y'-Het'-A', -Y'
  • R 5 groups include halogen atoms and groups selected from Ci -4 alkyl, Ci -4 alkoxy, Ci -4 haloalkyl, Ci -4 alkylthio, or from a group of formula -C(O)R or -S(O)R wherein each R is the same or different and represents hydrogen or Cj -4 alkyl.
  • R 5 is a halogen atom it is preferably a chlorine, fluorine or bromine atom, more preferably a chlorine atom.
  • R 5 is a Ci -4 alkyl group it is preferably a C] -2 alkyl group.
  • R 5 is a Ci -4 alkoxy group it is preferably a Ci -2 alkoxy group, more preferably methoxy.
  • R 5 is a Ci -4 haloalkyl group it is preferably a C ]-2 haloalkyl group, more preferably a Cj -2 perhaloalkyl group, most preferably trifluoromethyl.
  • R 5 is a C ⁇ alkylthio group it is preferably a Cj -2 alkylthio group, more preferably methylthio.
  • R 5 is a group of formula -C(O)R then R is preferably a Ci -2 alkyl group, more preferably methyl.
  • R 5 is a group of formula -S(O)R then R is preferably a Ci -2 alkyl group, more preferably methyl.
  • the R 5 groups are the same or different and represent chlorine, fluorine or bromine atoms and groups selected from Ci -2 alkoxy, Ci -2 haloalkyl, Ci -2 alkylthio, or from a group of formula -C(O)R or -S(O)R wherein each R is the same or different and represents a C] -2 alkyl.
  • R 5 groups denote the number of R 5 groups present on the phenyl rings which form part of the central phenothiazine group.
  • p and q are independently zero, one or two.
  • one of p and q is one and the other is zero.
  • preferred R 5 groups include halogen atoms and groups selected from C] -4 alkoxy, Ci -4 haloalkyl, -C(O)R and -S(O)R wherein each R is the same or different and represents Ci -4 alkyl, in particular -Cl, -0-CH 3 , -SO-CH 3 , -CF 3 and -CO-CH 3 .
  • both p and q are one.
  • each R 5 group represents a halogen atom, more preferably each R 5 group represents chlorine atom.
  • m is one, it is preferred that p is zero.
  • n is one, it is preferred that q is zero.
  • both m and n are zero, preferably both p and q are zero.
  • preferred R 1 groups include hydrogen, Ci -4 alkyl and groups of formula -Y'-A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A, -Y'-A-A', -Y'-L-Het-A, -Y'-Het-L-A, -Y'-L-Het-A-A', -Y'-L-Het-Y'-A, -Y'-Het-A-Y'-Het'-A', -Y*-Y 2 -A, -Y'-L-Y 3 -Het-L', -Y'-L-Y 4 , -A-Het-A', -L-A-A', -L-Y'-Het-L-A and -L-Y 1 -Y 2 - A-A', more preferably from
  • preferred R 1 groups include hydrogen and groups of formula -Y'-A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A, -Y'-A-A', -Y'-L-Het-A, -Y'-Het-L-A, -Y'-L-Het-A-A', -Y'-L-Het-Y'-A, -Y'-Het-A-Y'-Het'-A', -Y'-Y 2 -A, -Y'-L-Y 3 -Het-L ⁇ -A-Het-A', -L-A-A', -L-Y'-Het-L-A and -L-Y'-Y 2 -A-A ⁇
  • preferred R 1 groups include -Y'-A, -Y'-Het-A, -Y'-Het-A-A', -Y'-Het-A
  • R 1 is Ci -4 alkyl it is preferably a C] -2 alkyl group, more preferably a methyl group.
  • Y is other than -CO- and/or A is attached to Y via a C atom.
  • preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl rings, and 5- to 6- membered heteroaryl rings fused to a phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C 3-6 carbocyclyl ring.
  • Preferred 5- to 6- membered heteroaryl rings include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Preferred fused 5- to 6- membered heteroaryl rings include 5- to 6- membered heteroaryl rings fused to a phenyl ring or to a C 3-6 carbocyclyl ring.
  • Examples of a 5- to 6- membered heteroaryl ring fused to a phenyl ring include indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl and quinazolinyl, more preferably benzothienyl, benzotriazolyl and benzothiazolyl, most preferably benzothienyl.
  • Examples of a 5- to 6- membered heteroaryl ring fused to a C 3- 6 carbocyclyl ring include pyrazolyl fused to a C 3-6 carbocyclyl ring, more preferably pyrazolyl fused to a cyclopentyl ring.
  • each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, Ci -4 alkylene, C 2-4 alkenyl, Ci -4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, hydroxyl, nitro, CM hydroxyalkyl, C 1-4 alkylthio, -NR'R' r wherein each R' and R" is the same or different and represents hydrogen or C 1-4 alkyl, and -X-A"' wherein X represents a bond or CM alkylene, and A'" represents furanyl or thienyl.
  • each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -2 alkyl, Ci -4 alkylene, Ci -2 alkoxy, Q -2 haloalkyl, Ci -2 haloalkoxy, hydroxyl, nitro, C ]-2 hydroxyalkyl, C ]-2 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -2 alkyl.
  • each A is unsubstituted or substituted by 1 or 2 substituents selected from halogen atoms, Ci -2 alkyl and C 3-4 alkylene groups.
  • halogen atoms are chlorine or bromine atoms.
  • substituent is a Cj -2 alkyl group it is preferably methyl.
  • substituent is a C 3-4 alkylene it is preferably -C(CH 3 ) 2 -.
  • an alkylene substituent is preferably, preferably only one such alkylene group is present.
  • R 1 When R 1 is -Y'-Het-A, a preferred Y 1 group is -CO-.
  • preferred Het groups include -S- and -NR'- where R' is hydrogen or C] -2 alkyl, more preferably where R' is hydrogen.
  • preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups.
  • A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Triazolyl furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred. Triazolyl and imidazolyl are most preferred.
  • each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, Cj -4 alkoxy, Ci -4 haloalkyl, Cj -4 haloalkoxy, hydroxyl, nitro, C] -4 hydroxyalkyl, Ci -4 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C 1-4 alkyl, and -X-A'" wherein X represents a bond or C 1-4 alkylene, and A'" represents furanyl or thienyl.
  • each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -2 alkyl, C 2-3 alkenyl, Cj -2 alkoxy, Ci -2 haloalkyl, Ci -2 haloalkoxy, hydroxyl, nitro, Ci -2 hydroxyalkyl, Ci -2 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -2 alkyl, and -X-A'" wherein X represents a bond or Ci -2 alkylene, and A"' represents furanyl or thienyl.
  • each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -2 alkyl, Ci -2 alkoxy, Cj -2 haloalkyl, Ci -2 haloalkoxy, hydroxyl, nitro, d- 2 hydroxyalkyl, C ]-2 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -2 alkyl.
  • each A is unsubstituted or substituted by 1 or 2 substituents selected from Cj -2 alkyl groups. When the substituent is a C] -2 alkyl group it is preferably methyl.
  • R 1 When R 1 is -Y'-Het-A-A', a preferred Y 1 group is -CO-. When R 1 is -Y'-Het-A-A', a most preferred Het group is-S-. When R 1 is -Y'-Het-A-A', preferred A groups include non-fused phenyl, 5- to 6- membered heteroaryl and 5- to 6- membered heterocyclyl groups.
  • A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Triazolyl furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred. Oxadiazolyl groups are most preferred.
  • A is a non-fused 5- to 6- membered heterocyclyl group it is preferably selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dioxolanyl, pyrazolidinyl, piperidyl, piperazinyl, thiomorpholinyl, S-oxo-thiomorpholinyl, S 5 S- dioxo-thiomorpholinyl, morpholinyl, 1,3 -dioxolanyl, 1,4-dioxolanyl, trioxolanyl, trithianyl, imidazolinyl, pyrazolinyl
  • Preferred heterocyclyl groups are piperidinyl, pyrrolidinyl, piperazinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, imidazolinyl, thioxothiazolidinyl, oxopyrrolidinyl, oxothiazolidinyl and oxopyrazolidinyl groups, most preferably thioxothiazolidinyl.
  • R 1 is -Y'-Het-A-A'
  • each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, hydroxyl, nitro, C i- 4 hydroxyalkyl, Ci -4 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl, and -X-A'" wherein X represents a bond or C] -4 alkylene, and A'" represents furanyl or thienyl.
  • each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and C 1-2 alkyl, C 2-3 alkenyl, Ci -2 alkoxy, Ci -2 haloalkyl, Ci -2 haloalkoxy, hydroxyl, nitro, Ci -2 hydroxyalkyl, Ci -2 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -2 alkyl. More preferably each A is unsubstituted.
  • T 1 is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and C 1-2 alkyl, C 2-3 alkenyl, Ci -2 alkoxy, Ci -2 haloalkyl, Ci -2 haloalkoxy, hydroxyl, nitro, Ci -2 hydroxyalkyl, Ci -2 alkylthi
  • A' typically represents a non-fused phenyl or 5- to 6- membered heteroaryl group, most preferably a non-fused phenyl group.
  • A' is a non-fused 5- to 6- membered heteroaryl group it preferably represents pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl are preferred.
  • R 1 is -Y'-Het-A-A'
  • A' groups are unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, Cj -4 alkoxy, Cj -4 haloalkyl, C 1-4 haloalkoxy, hydroxyl, Ci -4 hydroxyalkyl, Cj -4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Cj -4 alkyl.
  • A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -2 alkyl, Ci -2 alkoxy, Cj -2 haloalkyl, Ci -2 haloalkoxy, hydroxyl and Ci -2 alkylthio. More preferably the A' groups are unsubstituted or substituted by 1 or 2 unsubstituted Ci -2 alkyl groups, in particular methyl.
  • R 1 When R 1 is -Y 1 -L-A, a preferred Y 1 group is -CO-.
  • preferred L groups include Ci -4 alkylene and C 2-4 alkenylene groups.
  • L represents a Ci -4 alkylene group it is preferably a Ci -2 alkylene group, more preferably a -CH 2 - group.
  • each L group is unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and hydroxyl, cyano, -CO 2 R, -SO 2 OR and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci -4 alkyl. More preferably each L group is unsubstituted or substituted by 1 or 2 groups selected from hydroxyl, cyano, -CO 2 R and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Cj -2 alkyl. More preferably each R, R' and R" is the same or different and represents hydrogen or methyl. More preferably each L group is unsubstituted or substituted by 1 or 2 cyano groups, for example by 1 cyano group.
  • preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups.
  • A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Triazolyl furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred, most preferably pyrazolyl and triazolyl.
  • each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, C] -4 alkoxy, Cj -4 haloalkyl, C 1-4 haloalkoxy, hydroxyl, nitro, C 1-4 hydroxyalkyl, Ci -4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl.
  • each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -2 alkyl, C 2-3 alkenyl, Ci -2 alkoxy, Ci -2 haloalkyl, Ci -2 haloalkoxy, hydroxyl, nitro, Ci -2 hydroxyalkyl, Ci -2 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C 1-2 alkyl. More preferably each A is unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from C 1-2 alkyl, nitro, C 1-2 haloalkoxy. When a substituent is Ci -2 alkyl it is preferably methyl. When the substituent is Ci -2 haloalkoxy it is preferably -0-CHF 2 .
  • R 1 When R 1 is -Y 1 -A-A', a preferred Y 1 group is -CO-.
  • preferred A groups include non-fused phenyl, 5- to 6- membered heteroaryl and 5- to 6- membered heterocyclyl groups, more preferably 5- to 6- membered heterocyclyl groups.
  • A is a non-fused heterocyclyl group it is preferably selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dioxolanyl, pyrazolidinyl, piperidyl, piperazinyl, thiomorpholinyl, S-oxo- thiomorpholinyl, S,S-dioxo-thiomorpholinyl, morpholinyl, 1,3 -dioxolanyl, 1,4- dioxolanyl, trioxolanyl, trithianyl, imidazolinyl, pyrazolinyl and thiox
  • Preferably it is selected from piperidinyl, pyrrolidinyl, piperazinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl and imidazolinyl groups. More preferably it is selected from piperazinyl and piperidinyl groups, most preferably from piperazinyl groups.
  • each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, Ci -4 haloalkyl, Ci -4 haloalkoxy, hydroxyl, nitro, Q -4 hydroxyalkyl, Ci -4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl.
  • each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C) -2 alkyl, C 2-3 alkenyl, C 1-2 alkoxy, C 1-2 haloalkyl, Ci -2 haloalkoxy, hydroxyl, nitro, Ci -2 hydroxyalkyl, Ci -2 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -2 alkyl. Most preferably each A is unsubstituted.
  • preferred A' groups include non-fused phenyl and 5- to 6- membered heteroaryl groups.
  • A' is a 5- to 6- membered heteroaryl group it preferably represents pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl are preferred. Most preferred are pyridyl, pyrimidinyl, pyridazinyl and thiazolyl, more preferably pyridyl.
  • each A' is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C 1-4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, Cj -4 haloalkyl, C 1-4 haloalkoxy, hydroxyl, Ci -4 hydroxyalkyl, C 1-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl.
  • the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A' groups are unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -2 alkyl, Ci -2 alkoxy, Ci -2 haloalkyl, Ci -2 haloalkoxy, hydroxyl and Ci -2 alkylthio.
  • the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -2 alkyl and Ci -2 alkoxy groups. Most preferably each A' is unsubstituted.
  • R 1 When R 1 is -Y'-L-Het-A, a preferred Y 1 group is -CO-.
  • preferred L groups include Ci -4 alkylene groups, more preferably Ci -2 alkylene groups, most preferably -CH 2 -. Preferably the L groups are unsubstituted.
  • preferred Het groups include -O- and -S-.
  • preferred A groups include non-fused phenyl, 5- to 6- membered heteroaryl, 5- to 6-membered heterocyclyl and C 3-6 carbocyclyl groups and 5- to 6- membered heteroaryl rings fused to a phenyl ring. More preferably each A group is a non-fused 5- to 6- membered heteroaryl group or a 5- to 6- membered heteroaryl group fused to a phenyl ring.
  • A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Triazolyl furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred. Most preferred are triazolyl, imidazolyl, pyrimidinyl, thiadiazolyl and pyridyl.
  • A is a 5- to 6-membered heteroaryl group fused to a phenyl ring it is preferably selected from indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl and quinazolinyl.
  • Particularly preferred examples include benzothienyl, benzotriazolyl and benzothiazolyl, with benzotriazolyl and benzothiazolyl being most preferred.
  • R 1 is -Y'-L-Het-A
  • each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, Cj -4 alkoxy, Ci -4 haloalkyl, Ci -4 haloalkoxy, hydroxyl, nitro, Ci -4 hydroxyalkyl, Ci -4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Cj -4 alkyl.
  • each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Cj -2 alkyl, C 2-3 alkenyl, Cj -2 alkoxy, Ci -2 haloalkyl, Ci -2 haloalkoxy, hydroxyl, nitro, Ci -2 hydroxyalkyl, Ci -2 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C] -2 alkyl.
  • each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from Ci -2 alkyl, nitro and -NR 'R " wherein each R' and R" is the same or different and represents hydrogen or Cj -2 alkyl.
  • Preferred Cj -2 substituents include methyl, for example an A group may be substituted by one or two methyl groups.
  • Preferred -NR 'R" substituents include -NH 2 , for example an A group may be substituted by one -NH 2 group.
  • R 1 When R 1 is -Y'-Het-L-A, a preferred Y 1 group is -CO-.
  • R 1 When R 1 is -Y'-Het-L-A, a preferred Het group is -NR'- where R' is hydrogen or Ci -4 alkyl, more preferably where R' is hydrogen.
  • preferred L groups include Ci -4 alkylene or C 2-4 alkenylene groups, more preferably Ci -4 alkylene groups.
  • L represents a Cj -4 alkylene group it is preferably a -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH 2 -CH(CH 3 )- or -CH 2 -CH(CH 3 )-CH 2 - group, more preferably a -CH 2 -CH 2 -CH 2 - group.
  • each L group is unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and hydroxyl, cyano, -CO 2 R, -SO 2 OR and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci -4 alkyl. More preferably each L group is unsubstituted or substituted by 1 or 2 groups selected from hydroxyl, cyano, -CO 2 R and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci -2 alkyl. More preferably each R, R' and R" is the same or different and represents hydrogen or methyl. More preferably each L is unsubstituted or substituted by one -CO 2 R group. Most preferably R is hydrogen.
  • R 1 When R 1 is -Y'-Het-L-A, preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups. Preferably the A groups are non-fused phenyl rings.
  • R 1 When R 1 is -Y'-Het-L-A, typically each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C] -4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, C] -4 haloalkyl, Ci -4 haloalkoxy, hydroxyl, nitro, Ci -4 hydroxyalkyl, Ci -4 alkyl thio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl. More preferably each A is unsubstituted.
  • R' is -Y'-L-Het-A-A'
  • a preferred Y 1 group is -CO-.
  • preferred L groups include Ci -4 alkylene groups, in particular Cj -2 alkylene groups, most preferably -CH 2 -.
  • R 1 is -Y'-L-Het-A-A'
  • a preferred Het group is -S-.
  • preferred A groups include non- fused phenyl and 5- to 6- membered heteroaryl rings, most preferably non-fused 5- to 6- membered heteroaryl rings.
  • A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Triazolyl furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred, with triazolyl and oxadiazolyl being most preferred.
  • each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, Ci -4 haloalkyl, Ci -4 haloalkoxy, hydroxyl, nitro, Ci -4 hydroxyalkyl, C] -4 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl and -X-A'" wherein X represents a bond or Ci -4 alkylene, and A'" represents furanyl or thienyl.
  • each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and C 1-2 alkyl, C 2-3 alkenyl, Ci -2 alkoxy, Ci -2 haloalkyl, Ci -2 haloalkoxy, hydroxyl, nitro, C 1-2 hydroxyalkyl, Ci -2 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -2 alkyl, and -X-A'" wherein X represents a bond or Ci -2 alkylene, and A'" represents furanyl or thienyl.
  • each A is unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from C 2-3 alkenyl and -X-A'" wherein X represents a bond or Cj -2 alkylene, and A'" represents furanyl or thienyl.
  • substituents which are the same or different and are selected from C 2-3 alkenyl and -X-A'" wherein X represents a bond or Cj -2 alkylene, and A'" represents furanyl or thienyl.
  • the substiruent is -X-A'" preferably X represents a bond or -CH 2 -.
  • substituent is -X-A'" preferably A'" is furanyl.
  • R 1 is -Y'-L-Het-A-A'
  • preferred A' groups include non-fused pheny
  • A' is a non-fused 5- to 6- membered heteroaryl group it preferably represents pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl are preferred. Most preferred are pyridyl groups.
  • R 1 is -Y'-L-Het-A-A'
  • A' groups are unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, Ci -4 haloalkyl, Ci -4 haloalkoxy, hydroxyl, Ci -4 hydroxyalkyl, Cj -4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C 1-4 alkyl.
  • the A' groups are unsubstituted or substituted with 1 or 2 halogen atoms, preferably with 1 or 2 fluorine atoms, more preferably by one fluorine atom.
  • R 1 is -Y'-L-Het-Y'-A
  • a preferred Y 1 group is -CO-.
  • preferred L groups include Ci -4 alkylene groups, more preferably C] -2 alkylene groups, most preferably a -CH 2 - group.
  • each L group is unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and hydroxyl, cyano, -CO 2 R, -SO 2 OR and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci -4 alkyl. More preferably each L group is unsubstituted.
  • R 1 is -Y'-L-Het-Y'-A
  • preferred Het groups include -0-.
  • preferred A groups include non-fused C 3-6 carbocyclyl groups, preferably a monocyclic non-aromatic saturated or unsaturated hydrocarbon ring having from 3 to 6 carbon atoms. Preferably it is a saturated hydrocarbon ring (i.e. a cycloalkyl moiety) having from 3 to 6 carbon atoms, more preferably cyclopropyl.
  • R 1 is -Y'-L-Het-Y'-A
  • each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, Ci -4 haloalkyl, Ci -4 haloalkoxy, hydroxyl, nitro, C 1-4 hydroxyalkyl, Ci -4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl.
  • each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -2 alkyl, C 2-3 alkenyl, Ci -2 alkoxy, Ci -2 haloalkyl, Ci -2 haloalkoxy, hydroxyl, nitro, C ⁇ 2 hydroxyalkyl, Ci -2 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -2 alkyl. More preferably each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -2 alkyl groups. Preferred halogen atoms are chlorine atoms.
  • Preferred Ci -2 alkyl groups are methyl groups.
  • the Y 1 groups may be the same or different, preferably one is -CO- and the other is -SO 2 -. More preferably the first Y 1 group, which is bonded to the phenothiazine ring, is -CO- and the other Y 1 group, between the A and Het' groups, is -SO 2 -.
  • preferred Het groups include -NR'- where R' is hydrogen or Ci -4 alkyl, preferably where R' is hydrogen or C ] -2 alkyl, more preferably where R' is hydrogen.
  • preferred Het' groups include -NR'- where R' is hydrogen or Ci -4 alkyl, preferably where R' is hydrogen or Ci -2 alkyl, more preferably where R' is hydrogen.
  • R 1 When R 1 is -Y'-Het-A-Y'-Het'-A', preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused phenyl rings.
  • R 1 When R 1 is -Y ⁇ Het-A-Y'-Het'-A', typically each A is unsubstituted or substituted by I 5 2 or 3 substituents which are the same or different and are selected from halogen atoms and C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, Ci -4 haloalkyl, Ci -4 haloalkoxy, hydroxyl, nitro, Ci -4 hydroxyalkyl, C] -4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Q -4 alkyl. More preferably each A is unsubstituted.
  • preferred A' groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused 5- to 6- membered heteroaryl groups.
  • A' is a non-fused 5- to 6- membered heteroaryl group it preferably represents pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl are preferred. Most preferred are pyridyl, pyrimidinyl, pyridazinyl and thiazolyl, more preferably pyrimidinyl and thiazolyl
  • R 1 is -Y ⁇ Het-A-Y'-Het'-A'
  • A' groups are unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, C] -4 alkoxy, Cj -4 haloalkyl, Ci -4 haloalkoxy, hydroxyl, Ci -4 hydroxyalkyl, Ci -4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C 1-4 alkyl.
  • the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C 1-2 alkyl, Ci -2 alkoxy, C 1-2 haloalkyl, Cj -2 haloalkoxy, hydroxyl and Ci -2 alkylthio. More preferably the A' groups are unsubstituted or substituted by 1, 2 or 3 unsubstituted Ci -2 alkyl substituents. When the substituents are Ci -2 alkyl substituents they are preferably methyl groups.
  • a preferred Y 1 group is -CO-.
  • each Z is the same or different and represents CR'" wherein R'" represents hydrogen, C 1-2 alkyl or a group -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Cj -2 alkyl.
  • each R' and R" is the same or different and represents hydrogen or methyl, more preferably each R' and R" represents hydrogen.
  • each Het" is -O-.
  • preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably 5- to 6- raembered heteroaryl groups.
  • A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Triazolyl furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred, with pyridyl most preferred.
  • each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, C] -4 alkoxy, Ci -4 haloalkyl, Cj -4 haloalkoxy, hydroxyl, nitro, Ci -4 hydroxyalkyl, Cj -4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl. More preferably each A is unsubstituted.
  • R 1 is -Y'-L-Y ⁇ Het-L', a preferred Y 1 group is -CO-.
  • preferred L groups include Ci -4 alkylene, more preferably C 1-2 alkylene, most preferably -CH 2 -. Preferably each L group is unsubstituted.
  • preferred Het groups include -O-.
  • preferred I/ groups include Ci -4 alkyl groups, more preferably Cj -3 alkyl groups. More preferably each L' is the same or different and represents methyl, ethyl, -CH 2 -CH 2 -CH 3 or -CH(CH 3 ) 2 . Most preferably each I/ is the same or different and represents methyl or -CH(CH 3 ) 2 .
  • each I/ group is unsubstituted.
  • a preferred Y 1 group is -CO-.
  • preferred L groups include C 1-4 alkylene groups, more preferably C 1-2 alkylene groups, most preferably -CH 2 -. Preferably the L groups are unsubstituted.
  • preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused 5- to 6- membered heteroaryl rings.
  • A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Triazolyl furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred, with pyridyl most preferred.
  • each A is unsubstituted ⁇
  • substituents which are the same or different and are selected from halogen atoms and C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, C 1-4 haloalkyl, Cj -4 haloalkoxy, hydroxyl, nitro, Ci -4 hydroxyalkyl, Ci -4 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C ]-4 alkyl, and -X-A'" wherein X represents a bond or C] -4 alkylene, and A" ' represents furanyl or thienyl.
  • each A is unsubstituted or substituted by 1, 2 or 3 halogen substituents.
  • Preferred halogen substituents include fluorine and chlorine, for example each A group may be substituted by one chlorine atom and two fluorine atoms.
  • preferred Het groups include -NR'- wherein R' is hydrogen or Ci -4 alkyl, more preferably wherein R' is hydrogen or Ci -2 alkyl, more preferably wherein R' is hydrogen.
  • preferred A' groups include non- fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused phenyl rings.
  • the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, Ci -4 haloalkyl, C] -4 haloalkoxy, hydroxyl, Ci -4 hydroxyalkyl, Cj -4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Cj -4 alkyl. More preferably the A' groups are unsubstituted or substituted by 1 or 2 or 3 unsubstituted Ci -2 alkyl substituents. More preferably the A' groups are substituted by 1 or 2 unsubstituted C 1-2 substituents, such as methyl substituents.
  • preferred L groups include C] -4 alkylene groups, more preferably Cj -2 alkylene groups, most preferably -CH 2 - groups.
  • the L groups are preferably unsubstituted.
  • preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused 5- to 6- membered heteroaryl groups.
  • A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Triazolyl furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred, with triazolyl being most preferred.
  • each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, Ci -4 haloalkyl, C 1-4 haloalkoxy, hydroxyl, nitro, C 1-4 hydroxyalkyl, Ci -4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Cj -4 alkyl.
  • Preferred C 1-4 alkylthio substituents are Cj -2 alkylthio substituents, in particular -S-CH 3 substituents. More preferably each A is unsubstituted or substituted by one -S-CH 3 substituent, most preferably it is substituted by one -S-CH 3 substituent.
  • preferred A' groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused phenyl rings.
  • the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, Cj -4 haloalkyl, C 1-4 haloalkoxy, hydroxyl, C 1-4 hydroxyalkyl, C 1-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C J-4 alkyl.
  • the A' groups are unsubstituted or substituted by 1, 2 or 3 halogen substituents, for example by a single halogen substituent.
  • Preferred halogen atoms are chlorine atoms.
  • preferred L groups include C] -4 alkylene groups, for example Ci -2 alkylene groups, preferably -CH 2 - and -CH 2 -CH 2 -. Where there is more than one L group, the L groups are the same or different. For example, one L group may be -CH 2 - and the other may be -CH 2 -CH 2 -.
  • the L group bonded to the phenothiazine ring is -CH 2 -CH 2 - and the L group bonded to the Het and A groups is -CH 2 -.
  • the L groups are unsubstituted.
  • a preferred Y 1 group is -CO-.
  • a preferred Het group is -O-.
  • preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused phenyl rings.
  • each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, C] -4 alkoxy, Ci -4 haloalkyl, Ci -4 haloalkoxy, hydroxyl, nitro, C] -4 hydroxyalkyl, Cj -4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Cj -4 alkyl. More preferably each A is unsubstituted or substituted by 1, 2 or 3 halogen substituents, for example by 2 halogen atoms.
  • Preferred halogen atoms include fluorine and chlorine atoms. For example each A may be substituted by one chlorine atom and one fluorine atom.
  • preferred L groups include Ci -4 alkylene groups, preferably Ci -2 alkylene groups, more preferably -CH 2 -.
  • a preferred Y 1 group is -CO-.
  • each Z is the same or different and represents CR'" wherein R'" represents hydrogen, Ci -2 alkyl or a group -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -2 alkyl.
  • R'" represents hydrogen or C ⁇ 2 alkyl, more preferably R'" represents hydrogen.
  • Het represents -NR'- wherein R' is hydrogen or C 1-2 alkyl, more preferably R' is hydrogen or methyl, most preferably hydrogen.
  • preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused 5- to 6- membered heteroaryl groups.
  • A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Triazolyl furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred, with pyrazolyl most preferred.
  • each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, Cj -4 haloalkyl, C] -4 haloalkoxy, hydroxyl, nitro, Ci -4 hydroxyalkyl, Cj -4 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl, and -X-A'" wherein X represents abond or Cj -4 alkylene, and A'" represents furanyl or thienyl.
  • each A is unsubstituted or substituted by 1, 2 or 3 substituents which are of formula -X-A'" wherein X represents a bond or Ci -2 alkylene, and A'" represents furanyl or thienyl.
  • substituents which are of formula -X-A'" wherein X represents a bond or Ci -2 alkylene, and A'" represents furanyl or thienyl.
  • preferred A' groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused phenyl rings.
  • the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, Ci -4 haloalkyl, Ci -4 haloalkoxy, hydroxyl, C 1-4 hydroxyalkyl, Ci -4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C 1-4 alkyl. More preferably the A' groups are unsubstituted.
  • R 3 and R 4 are preferably selected from hydrogen and halogen atoms, and groups selected from Ci -2 alkyl, Ci -2 alkoxy, Ci -2 haloalkyl, Ci -2 haloalkoxy, hydroxyl, Ci -2 hydroxyalkyl, Ci -2 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -2 alkyl. More preferably, when R 3 and R do not form a fused group with R 1 , then R 3 and R 4 are selected from hydrogen and halogen atoms, with preferred halogen atoms being chlorine atoms. When one of R 3 and R 4 does not form a fused group with R 1 , then preferably R 3 and R 4 are the same, more preferably R 3 and R 4 are both either hydrogen or chlorine.
  • R 1 forms a fused group with one of R 3 and R 4
  • the other of R 3 and R 4 is preferably selected from hydrogen and halogen atoms, unsubstituted groups selected from Ci- 2 alkyl, Ci -2 alkoxy, C 1-2 haloalkyl, Ci -2 haloalkoxy, hydroxyl, Ci -2 hydroxyalkyl, Ci -2 alkylthio and -NR r R" wherein each R' and R" is the same or different and represents hydrogen or C 1-2 alkyl.
  • R 1 forms a fused group with one of R 3 and R 4
  • the other of R 3 and R 4 is selected from hydrogen and halogen atoms, with preferred halogen atoms being chlorine atoms. More preferably, when R 1 forms a fused group with one of R 3 and R 4 , then the other of R 3 and R 4 is hydrogen.
  • R 1 forms a fused groups with one of R 3 and R 4 then the fused group is preferably 5- to 6- membered heterocyclyl ring which is optionally fused to a further phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C 3-6 carbocyclyl group.
  • the group formed by R 1 and R 3 or R 4 is more preferably a non- fused 5- to 6- membered heterocyclyl ring or a 5- to 6- membered heterocyclyl ring fused to a C 3-6 carbocyclyl group.
  • R 1 forms a fused groups with one of R 3 and R 4 then the group so formed is preferably unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2 . 4 alkenyl, Ci -4 alkoxy, Cj -4 haloalkyl, Ci -4 haloalkoxy, hydroxyl, Ci -4 hydroxyalkyl, Ci -4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl.
  • R 1 and R 3 or R 4 When the group formed by R 1 and R 3 or R 4 is a non-fused 5- to 6- membered heterocyclyl ring it is preferably selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, tetrahydroforanyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dioxolanyl, pyrazolidinyl, piperidyl, piperazinyl, thiomorpholinyl, S-oxo-thiomorpholinyl, S, S- dioxo-thiomo ⁇ holinyl, morpholinyl, 1,3 -dioxolanyl, 1 ,4-dioxolanyl, trio
  • R 1 and R 3 or R 4 When the group formed by R 1 and R 3 or R 4 is a non-fused 5- to 6- membered heterocyclyl it is preferably unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, Ci -4 haloalkyl, Cj -4 haloalkoxy, hydroxyl, Ci -4 hydroxyalkyl, Ci -4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C] -4 alkyl.
  • Ci -2 haloalkyl groups More preferably it is unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from Ci -2 haloalkyl and hydroxyl groups. Most preferably it is substituted by 1 hydroxyl group and 1 Ci -2 haloalkyl group.
  • Preferred Ci -2 haloalkyl groups include -CF 3 .
  • R 1 and R 3 or R 4 When the group formed by R 1 and R 3 or R 4 is a 5- to 6- membered heterocyclyl ring fused to a C 3-6 carbocyclyl group it is preferably an azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dioxolanyl, pyrazolidinyl, piperidyl, piperazinyl, thiomorpholinyl, S-oxo-thiomorpholinyl, S, S- dioxo-thiomorpholinyl, morpholinyl, 1,3 -dioxolanyl, 1 ,4-diox
  • the C 3-6 carbocyclyl ring is preferably a monocyclic non-aromatic saturated or unsaturated hydrocarbon ring having from 3 to 6 carbon atoms.
  • it is a saturated or mono-unsaturated hydrocarbon ring (i.e. a cycloalkyl moiety or a cycloalkenyl moiety) having from 3 to 6 carbon atoms.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and their mono-unsaturated variants, with cyclopentenyl being preferred.
  • R 1 and R 3 or R 4 are a 5- to 6- membered heterocyclyl ring fused to a C 3-6 carbocyclyl group, it is a piperidinyl group fused to a mono-unsaturated cyclopentenyl group.
  • R 1 and R 3 or R 4 When the group formed by R 1 and R 3 or R 4 is a 5- to 6- membered heterocyclyl ring fused to a C 3-6 carbocyclyl group it is preferably unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, C 1-4 haloalkyl, Cj -4 haloalkoxy, hydroxyl, Cj -4 hydroxyalkyl, C 1-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C 1-4 alkyl.
  • Preferred compounds of the invention are phenothiazine derivatives which are (a) compounds of formula (I) above or a tautomer thereof, or (b) a pharmaceutically acceptable salt thereof, wherein:
  • R 3 and R 4 are the same or different and represent hydrogen or halogen, or a group selected from C 1-2 alkyl, Cj -2 alkoxy, C 1-2 haloalkyl, Ci -2 haloalkoxy, hydroxyl, Ci -2 hydroxyalkyl, Ci -2 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Cj -2 alkyl; or
  • phenothiazine derivatives which are (a) compounds of formula (I) above or a tautomer thereof, or (b) a pharmaceutically acceptable salt thereof, wherein: S' represents -S-, -SO- or -SO 2 -;
  • R 1 represents hydrogen or Ci -4 alkyl when m or n is 1 , and otherwise represents hydrogen, Ci -4 alkyl or a group of formula -Y'-A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A, -Y'-A-A', -Y'-L-Het-A, -Y'-Het-L-A, -Y'-L-Het-A-A', -Y'-L-Het-Y'-A, -Y'-Het-A-Y'-Het'-A', -Y'-Y 2 -A, -Y ] -L-Y 3 -Het-L', -Y 1 -L-Y 4 , -A-Het-A', -L-A-A', -L-Y ! -Het-L-A and
  • R 3 and R 4 are the same or different and represent hydrogen or halogen atoms; or (ii) R 1 , together with R 3 or R 4 , forms a non-fused 5- to 6- membered heterocyclyl ring or a 5- to 6- membered heterocyclyl ring fused to a C 3-6 carbocyclyl group wherein the fused group formed by R 1 and R 3 or R 4 is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -2 alkyl, Ci -2 alkoxy, Ci -2 haloalkyl, C] -2 haloalkoxy, hydroxyl and Ci -2 alkylthio, and the other of R 3 and R 4 represents a hydrogen or halogen atom; - each A is the same or different and is a non-fused phenyl, 5- to 6- membered heteroaryl
  • carbocyclyl moieties in the A groups are unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -2 alkyl, C 2-3 alkenyl, Ci -2 alkoxy, Ci -2 haloalkyl, Q -2 haloalkoxy, hydroxyl, nitro, Ci -2 hydroxyalkyl, Cj -2 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or
  • each A' is the same or different and represents a non-fused phenyl or 5- to 6- membered heteroaryl group, and wherein the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci -2 alkyl and Ci -2 alkoxy groups; each A" is the same or different and represents a non-fused 5- to 6- membered heterocyclyl or C 3-6 carbocyclyl group or is a 5- to 6- membered heterocyclyl fused to a further phenyl ring, and wherein each A" is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same
  • phenothiazine derivatives which are (a) compounds of formula (I) above or a tautomer thereof, or (b) a pharmaceutically acceptable salt thereof, wherein: S ' represents -S-, -SO- or -SO 2 -;
  • R 1 represents hydrogen or C 1-4 alkyl when m or n is 1, and otherwise represents hydrogen, Ci -4 alkyl or a group of formula -Y 1 -A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A, -Y 1 -A-A', -Y'-L-Het-A, -Y'-Het-L-A, -Y'-L-Het-A-A', -Y'-L-Het-Y'-A, -Y'-Het-A-Y'-A, -Y'-Het-A-Y'-Het'-A', -Y !
  • R 3 and R 4 are the same or different and represent hydrogen or halogen atoms; or (ii) R 1 , together with R 3 or R 4 , forms a non-fused 5- to 6- membered heterocyclyl ring or a 5- to 6- membered heterocyclyl ring fused to a C 3-6 carbocyclyl group wherein the group formed by R 1 and R 3 and R 4 is unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from C 1-2 haloalkyl and hydroxyl groups, and the other of R 3 and R 4 represents a hydrogen atom; each A is the same or different and is a non-fused phenyl, 5- to 6- membered heteroaryl, 5- to 6-membered heterocyclyl or C 3-6 carbocyclyl group or is a
  • Particularly preferred compounds of formula (I) include: 1. (3,6-Dichloro-benzo[b]thiophen-2-yl)-phenothiazin-l O-yl-methanone; 2. 2-(4-Furan-2-ylmethyl-5-pyridin-3-yl-4H-[ 1 ,2,4]triazol-3-ylsulfanyl)-l - phenothiazin- 10-yl-ethanone;
  • R 1 is other than hydrogen. More preferably R 1 is a substituent other than hydrogen or Ci -4 alkyl.
  • These antioxidant compounds are highly potent, of low molecular weight (an advantage for blood brain barrier permeability) and have other drug-like chemical characteristics. They may thus prove of significant value in the treatment of neurodegenerative conditions and also of the host of conditions involving oxidative stress outside the central nervous system.
  • Compounds of formula (I) containing one or more chiral centre may be used in enantiomerically or diastereoisomerically pure form, or in the form of a mixture of isomers.
  • the compounds of formula (I) can, if desired, be used in the form of solvates. Further, for the avoidance of doubt, the compounds of the invention may be used in any tautomeric form.
  • a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.
  • Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or ⁇ -toluenesulphonic acid.
  • Preferred pharmaceutically acceptable salts are maleate and besylate salts (i.e. salts of maleic acid an benzenesulphonic acid respectively).
  • Pharmaceutically acceptable bases include alkali metal (e.g.
  • alkali earth metal e.g. calcium or magnesium
  • alkyl amines e.g. calcium or magnesium
  • alkyl amines e.g. sodium or potassium
  • alkali earth metal e.g. calcium or magnesium
  • organic bases such as alkyl amines, aralkyl amines and heterocyclic amines.
  • the compounds of formula (I) are useful in the manufacture of medicaments for use in the treatment of the numerous disease states where lipid peroxidation has been implicated.
  • Such disease states include neurodegenerative disorders; cardiovascular disease including ischaemia, in particular stroke (cerebral ischaemia); asthma and diabetes.
  • Neurodegenerative disorders which can be treated include Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, Huntington disease, Kennedy's disease, Krabbe disease, Lewy body dementia, Machado- Joseph disease (Spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis,
  • the compounds of formula (I) can also be used in the manufacture of medicaments for anti- ex citotoxic treatments, for example in the treatment of reperfusion injury.
  • the compounds of formula (I) can also be used in the manufacture of medicaments for the prevention of deafness due to excessive sound levels, or which delay the onset of or slow the progression of deafness due to excessive sound levels.
  • the compounds of formula (I) can also be used in the manufacture of medicaments for the treatment of traumatic CNS injury.
  • Medicaments produced in the invention are pharmaceutical compositions which typically contain up to 85 wt% of a compound of the invention. More typically, they contain up to 50 wt% of a compound of the invention.
  • Preferred pharmaceutical compositions are sterile and pyrogen free. Further, the pharmaceutical compositions typically contain a compound of the invention which is a substantially pure optical isomer.
  • the medicaments of the invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules.
  • the medicaments of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques.
  • the medicaments may also be administered as suppositories.
  • solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arable gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g.
  • diluents e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch
  • lubricants e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols
  • binding agents e.g. starches, arable gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrroli
  • Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes.
  • Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
  • the syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
  • Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
  • Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
  • the compounds used in the present invention may be used in conjunction with known neuroprotective agents.
  • the medicaments comprising the compounds of formula (I) therefore typically further comprise a neuroprotective agent.
  • the present invention provides a pharmaceutical composition comprising:
  • a neuroprotective agent for separate, simultaneous or sequential use in the treatment of the human or animal body.
  • the present invention also provides the use of a phenothiazine derivative of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating a disorder mediated by lipid peroxidation by co-administration with a said neuroprotective agent. Also provided is the use of a said neuroprotective agent, in the manufacture of a medicament for use in treating a disorder mediated by lipid peroxidation, by co-administration with a phenothiazine derivative of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof.
  • a therapeutically effective amount of the compounds used in the invention is administered to a patient.
  • a typical dose is from about 0.01 to 100 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration.
  • daily dosage levels are from 0.05 to 16 mg per kg of body weight, more preferably, from 0.05 to 1.25 mg per kg of body weight.
  • Haemoglobin beads (12-16 mg/ml) were triple washed in Tris buffer (20 mM) before reduction by exposure to freshly prepared sodium dithionate (10 mM) for 20 min in air. Following a further 2 washes in Tris, the beads were kept as a working stock at 1.2 mg/ml on ice until used.
  • TBARS thiobarbituric acid-reactive species
  • the supernatant was added to a mixture of thiobarbituric acid (0.67 % w/v) and butylated hydroxytoluene (10 % w/v) and was then heated to 90 °C for 30 min. After cooling to room temperature, the absorbance of the solution was measured at 510 nm and 532 nm and the absorbance ratio (532 nm — 510 nm)/510 nm was calculated. The concentration was determined by reference to malondialdehyde standards.
  • Acute cerebellar cell suspensions (20 x 10 6 cells/ml; 1.25 mg protein/ml) were prepared from 8-day-old Sprague Dawley rats according to published procedures except that the pups were not pre-treated with hydroxyurea.
  • the cell incubation medium contained (mM): NaCl (130), KCl (3), CaCl 2 (1.5), MgSO 4 (1.2), Na 2 HPO 4 (1.2), Tris- HCl (15) and glucose (11) adjusted to pH 7.4 at 37 0 C.
  • NO consumption by the cell suspension was studied following the addition of the NO donor diethylenetriamine/NO adduct DET A/NO (200 ⁇ M) (Alexis, Nottingham, U.K.) which was made in 10 mM NaOH and kept on ice until use.
  • NO donor diethylenetriamine/NO adduct DET A/NO 200 ⁇ M
  • ISO-NO World Precision Instruments, Stevenage, Herts, U.K.
  • SOD superoxide dismutase
  • Other stock solutions (from Sigma, Poole, Dorset, U.K.) were made up at 1000 x concentration in DMSO so that the final DMSO concentration did not exceed 0.1 %.
  • Culture inserts were incubated in 6-well plates with 1 ml media consisting of minimal essential medium (50%), heat-inactivated horse serum (25%), Hank's balanced salt solution (25%), and penicillin/streptomycin (as above), buffered to pH 7.3 with Tris (5 mM) and NaHCO 3 (0.35 g/1). Cultures were incubated at 37 0 C in 5% CO 2 for 4 days and subsequently at 33 0 C in 5% CO 2 until use at 12-14 days in vitro. Inserts were transferred to fresh media after 1, 4, 7, and 10 days.
  • Hippocampal slice cultures (12-14 days old) were incubated in serum-free medium (SFM) consisting of: minimal essential medium without HEPES (74 %), Hank's balanced salt solution (24 %), B27 supplement without antioxidants (2 %) penicillin/streptomycin (as above) and glucose (0.5 g/1) for 2 h before exposure to freshly prepared ascorbate (500 ⁇ M) and FeSO 4 (10 - 1000 ⁇ M).
  • SFM serum-free medium
  • Alternatively cultures were exposed to ABAP (0.3 - 3 mM).
  • Stock compounds Trolox and compound 26 were prepared at 1000 X final concentration in DMSO and were present in the SFM throughout the experiment when used. Neuronal damage was assessed by propidium iodide staining after 24 h.
  • a modified oxyhaemoglobin assay was used to screen for compounds that inhibit NO consuming activity.
  • the ability of test compounds to inhibit NO consumption was determined after 25 min and compared to the effect of the calcium chelator EGTA (which gave 100% inhibition).
  • Figure 1 shows representative traces (A) and (B) and summary of the data (C) of NO consumption after addition of the NO donor DETA/NO (200 ⁇ M) to buffer or cerebellar cells (20 x 106 cells/ml; 1.25 mg protein/ml) in the absence or presence of compound numbers 24, 25, 10, 12, 14 and 28.
  • Example 3 Comparison with established antioxidants A number of phenothiazine compounds (compounds 12, 14, 24, 25, 48 and 56) were tested alongside a range of potent NO consumption inhibitors as well as the antioxidant Trolox and a clinically approved free radical scavenger Edaravone.
  • the 'Azo' initiator ABAP 0.3 - 3 mM was administered to slice cultures for 24 h and death measured as above. Treatment with this compound elicited slice toxicity more selectively in CAl.
  • Compound 24 is based upon a phenothiazine structure. The ability of this and related compounds to inhibit NO consumption was tested using the oxyhaemoglobin bead assay. Compounds inhibited NO consumption with the following ICs 0 S: compound 24, 80 ⁇ 8 nM; phenothiazine, 105 ⁇ 2 nM; iminostilbene 243 ⁇ 33 nM and phenoxazine, 19 ⁇ 3 nM ( Figures 4A to 4D).

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Abstract

L'invention concerne l'utilisation d'un dérivé de phénotiazine qui est (a) un composé de formule (I) ou un tautomère de celui-ci, ou (b) un sel pharmaceutiquement acceptable de celui-ci, pour la fabrication d'un médicament destiné à être utilisé dans le traitement d'un trouble par la médiation d'une peroxydation de lipide, où R1, R2, R3, R4, R5, S', m, n, p et q sont tels que définis présentement.
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CN102573762A (zh) * 2009-09-04 2012-07-11 株式会社资生堂 高粘度o/w乳膏的制备方法
WO2014126076A1 (fr) * 2013-02-12 2014-08-21 国立大学法人九州大学 Composé, matière électroluminescente et élément électroluminescent organique
CN104109134A (zh) * 2014-06-26 2014-10-22 陕西科技大学 一种n-酰基吩噻嗪及其制备方法
WO2014191632A1 (fr) * 2013-05-31 2014-12-04 Medeia Therapeutics Ltd Utilisation de dérivés de benzo[b]thiazine en tant qu'agents cytoprotecteurs
US9187439B2 (en) 2011-09-21 2015-11-17 Inception Orion, Inc. Tricyclic compounds useful as neurogenic and neuroprotective agents
CN107043345A (zh) * 2017-06-20 2017-08-15 齐鲁工业大学 联苯乙酮腙‑吲哚啉‑2,3‑二酮西弗碱的制备、结构和用途
US11084807B2 (en) 2016-08-18 2021-08-10 Vidac Pharama Ltd. Piperazine derivatives, pharmaceutical compositions and methods of use thereof

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US9187439B2 (en) 2011-09-21 2015-11-17 Inception Orion, Inc. Tricyclic compounds useful as neurogenic and neuroprotective agents
WO2014126076A1 (fr) * 2013-02-12 2014-08-21 国立大学法人九州大学 Composé, matière électroluminescente et élément électroluminescent organique
WO2014191632A1 (fr) * 2013-05-31 2014-12-04 Medeia Therapeutics Ltd Utilisation de dérivés de benzo[b]thiazine en tant qu'agents cytoprotecteurs
US9827249B2 (en) 2013-05-31 2017-11-28 Aranda Pharma Ltd Use of condensed benzo[B]thiazine derivatives as cytoprotectants
CN104109134A (zh) * 2014-06-26 2014-10-22 陕西科技大学 一种n-酰基吩噻嗪及其制备方法
US11084807B2 (en) 2016-08-18 2021-08-10 Vidac Pharama Ltd. Piperazine derivatives, pharmaceutical compositions and methods of use thereof
US12162868B2 (en) 2016-08-18 2024-12-10 Vidac Pharma Ltd.. Piperazine derivatives, pharmaceutical compositions and methods of use thereof
CN107043345A (zh) * 2017-06-20 2017-08-15 齐鲁工业大学 联苯乙酮腙‑吲哚啉‑2,3‑二酮西弗碱的制备、结构和用途
CN107043345B (zh) * 2017-06-20 2019-07-05 齐鲁工业大学 联苯乙酮腙-吲哚啉-2,3-二酮西弗碱的制备、结构和用途

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