WO2008116816A1 - Combinaison de ligand de cb2 et de paracetamol - Google Patents

Combinaison de ligand de cb2 et de paracetamol Download PDF

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WO2008116816A1
WO2008116816A1 PCT/EP2008/053354 EP2008053354W WO2008116816A1 WO 2008116816 A1 WO2008116816 A1 WO 2008116816A1 EP 2008053354 W EP2008053354 W EP 2008053354W WO 2008116816 A1 WO2008116816 A1 WO 2008116816A1
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alkyl
group
substituted
formula
hydrogen
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PCT/EP2008/053354
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Andrew Billinton
Nicholas Maughan Clayton
David Andrew Stevens
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Glaxo Group Limited
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/535—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to combinations of cannabinoid 2 modulators with paracetamol (acetaminophen), pharmaceutical compositions comprising these combinations and their use in the treatment of diseases, particularly pain.
  • Cannabinoids are a specific class of psychoactive compounds present in Indian cannabis (Cannabis sativa), including about sixty different molecules, the most representative being cannabinol, cannabidiol and several isomers of tetrahydrocannabinol.
  • Indian cannabis canbis sativa
  • cannabinol cannabidiol
  • isomers of tetrahydrocannabinol Knowledge of the therapeutic activity of cannabis dates back to the ancient dynasties of China, where, 5,000 years ago, cannabis was used for the treatment of asthma, migraine and some gynaecological disorders. These uses later became so established that, around 1850, cannabis extracts were included in the US Pharmacopaeia and remained there until 1947.
  • Cannabinoids are known to cause different effects on various systems and/or organs, the most important being on the central nervous system and on the cardiovascular system. These effects include alterations in memory and cognition, euphoria, and sedation. Cannabinoids also increase heart rate and vary systemic arterial pressure. Peripheral effects related to bronchial constriction, immunomodulation, and inflammation have also been observed. The capability of cannabinoids to reduce intraocular pressure and to affect respiratory and endocrine systems is also well documented. See e.g. L.E. Hollister, Health Aspects of Cannabis, Pharmacological Reviews, Vol. 38, pp. 1-20, (1986). More recently, it was found that cannabinoids suppress the cellular and humoral immune responses and exhibit anti-inflammatory properties. Wirth et al., Antiinflammatory Properties of Cannabichrome, Life Science. Vol. 26, pp. 1991-1995, (1980).
  • the total size of the patient population suffering from pain is vast (almost 300 million), dominated by those suffering from back pain, osteo-arthritic pain and post-operative pain.
  • Neuropathic pain associated with neuronal lesions such as those induced by diabetes, HIV, herpes infection, or stroke) occurs with lower, but still substantial prevalence, as does cancer pain.
  • the pathogenic mechanisms that give rise to pain symptoms can be grouped into two main categories:
  • Neuronal Pain those that result from a neuronal lesion of some form (Neuropathic Pain).
  • Chronic inflammatory pain consists predominantly of osteo-arthritis, chronic low back pain and rheumatoid arthritis. The pain results from acute and on-going injury and/or inflammation. There may be both spontaneous and provoked pain.
  • CB2 receptors are expressed on inflammatory cells (T cells, B cells, macrophages, mast cells) and mediate immune suppression through inhibition of cellular interaction/ inflammatory mediator release. CB2 receptors may also be expressed on sensory nerve terminals and therefore directly inhibit hyperalgesia.
  • compounds which are capable of selectively modulating the receptor for cannabinoids offer a unique approach toward the pharmacotherapy of immune disorders, inflammation, osteoporosis, renal ischemia and other pathophysiological conditions.
  • the present invention provides combinations comprising one or more cannabioid 2 modulators and paracetamol (acetaminophen), pharmaceutical compositions containing these combinations and their use.
  • the present invention provides a pharmaceutical composition comprising one or more cannabinoid 2 modulators and paracetamol.
  • the present invention provides a method of treating a human or animal subject suffering from a condition which is mediated by the activity of CB2 receptors which comprises administering to said subject a therapeutically effective combination of one or more CB2 modulators and paracetamol.
  • the present invention provides a combination of one or more cannabinoid 2 modulators and paracetamol for use as a medicament.
  • the present invention provides the use of a combination of one or more CB2 modulators and paracetamol in the treatment of a disease mediated by CB2 receptors.
  • the present invention provides the use of a combination of one or more CB2 modulators and paracetamol in the manufacture of a medicament for treating a disease mediated by CB2 receptors.
  • the combination comprises one or more cannabinoid 2 modulators as described in any of the following patent specifications whose disclosures are incorporated herein by reference: International Patent Applications WO 04/018433, WO 04/018434, WO 04/029027, WO 04/029026, WO 05/075440, WO05/075464, WO05/080350, WO 05/080345, WO05/080349, and WO05/121140, and co-pending unpublished International Patent Applications
  • Y is phenyl, optionally substituted with one, two or three substituents
  • R 1 is selected from hydrogen, Ci_ 6 alkyl, C 3 _ 6 cycloalkyl and halosubstitutedCi_ 6 alkyl;
  • R 2 is (CH 2 ) m R 3 where m is 0 or 1 ; or R 1 and R 2 together with N to which they are attached form an optionally substituted 4- to 8- membered non-aromatic heterocyclyl ring;
  • R 3 is an optionally substituted 4- to 8- membered non-aromatic heterocyclyl group, an optionally substituted C 3 . 8 cycloalkyl group, an optionally substituted straight or branched Ci 40 alkyl, an optionally substituted C 5 . 7 cycloalkenyl or R 5 ;
  • R 4 is selected from hydrogen, Ci -6 alkyl, C 3 _ 6 cycloalkyl, or halosubstitutedCi_ 6 alkyl, COCH 3 , and SO 2 Me;
  • R 5 is
  • R 6 is methyl, chloro or CHxFn wherein n is 1 , 2, or 3, x is 0, 1 or 2 and n and x add up to
  • R 7 is OH, Ci -6 alkoxy, NR 8a R 8b , NHCOR 9 , NHSO 2 R 9 , SOqR 9 ;
  • R 8a is H or Ci. 6 alkyl
  • R 8b is H or Q.galkyl
  • R 9 is C U6 alkyl
  • q is O, 1 or 2.
  • Y is a substituted phenyl.
  • Y is substituted by 1 or 2 substituents. If mono-substituted, in one particular embodiment the substituent is in the 3 position. If di-substituted, in one particular embodiment the substituents are in the 2- and 4- positions.
  • the substituent or substituents are preferably selected from Ci_ 6 alkyl, halosubstitutedCi. 6 alkyl, Ci_ 6 alkoxy, a hydroxy group, a cyano group, halo, a Ci. salkylsulfonyl group, -CONH 2 , -NHCOCH 3 , -COOH, halosubstitutedCi_ 6 alkoxy, SCi.
  • Y is substituted by chloro, fluoro, bromo, cyano, CF 3 , methyl, CF 3 O- or SCH 3 and methoxy; more particularly halo, cyano or methoxy.
  • the compound of formula (I) is a compound of formula (Ia)
  • R 1 is selected from hydrogen, Ci_ 6 alkyl, C 3 . 6 cycloalkyl and halosubstitutedCi_ 6 alkyl;
  • R 3 is 2- or 3- azetidinyl, oxetanyl, thioxetanyl, thioxetanyl-s-oxide, thioxetanyl-s,s-dioxide, dioxalanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiomorpholinyl, thiomorpholinyl-s,s- dioxide, tetrahydropyridinyl, azapine, oxapine, azacyclooctanyl, azaoxacyclooctanyl, azathiacyclooctanyl, oxacylcooctanyl, thiacyclooctanyl, a C 3 .g cycl
  • R 10 is selected from Ci 6 alkyl, halosubstitutedCi 6 alkyl, Ci 6 alkoxy, a hydroxy group, a cyano group, halo, a Ci_ 6 alkyl sulfonyl group, -CONH 2 , -NHCOCH 3, -COOH, halosubstitutedCi_ 6 alkoxy, SCi -6 alkyl and SO 2 NR 8a R 8b ;
  • R 4 is selected from hydrogen, Ci -6 alkyl, C 3 _6 cycloalkyl, or halosubstitutedCi.6 alkyl, COCH 3 and SO 2 Me;
  • R 5 is
  • R 6 is methyl, chloro or CHxFn wherein n is 1 , 2, or 3, x is 0, 1 or 2 and n and x add up to 3;
  • R 7 is OH, Ci.ealkoxy, NR 8a R 8b , NHCOR 9 , NHSO 2 R 9 , SOqR 9 ;
  • R 8a is H or Ci. 6 alkyl;
  • R 8b is H or Ci.ealkyl;
  • R 9 is Cusalkyl;
  • q is 0, 1 or 2; and
  • d is O, 1, 2 or 3.
  • R 1 is hydrogen.
  • R 4 is Ci_ 6 alkyl or hydrogen, more preferably methyl or hydrogen even more preferably hydrogen.
  • R 1 and R 2 together with N to which they are attached form an optionally substituted 5- or 6- membered non-aromatic heterocyclyl ring.
  • R 6 is CHxFn, for example CF 3 , CHF 2 , CH 2 F ; more preferably
  • R 5 is
  • R 7 is OH.
  • R 3 is an optionally substituted 4- to 8- membered non- aromatic heterocyclyl group, an optionally substituted C 3 . 8 cycloalkyl group, an optionally substituted straight or branched Ci 40 alkyl or R 5 .
  • R 3 is an optionally substituted C 3 .gcycloalkyl group or an optionally substituted 4- to 8- membered nonaromatic heterocyclyl, m is 1.
  • R 3 is an optionally substituted C 3 . 6 cycloalkyl group or an optionally substituted 4- or 6- membered nonaromatic heterocyclyl.
  • R 1 and R 2 together with N to which they are attached form a 4- to 8- membered non-aromatic heterocyclyl ring which is selected from pyrrolidinyl, morpholinyl, piperizinyl, piperidinyl and tetrahydropyridinyl.
  • R 3 is nonaromatic heterocyclyl it is selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiomorpholinyl, thiomorpholinyl-s,s-dioxide, tetrahydropyridinyl.
  • the compound of formula (I) is a compound of formula (Ib)
  • R 10 is selected from chloro, fluoro, bromo, cyano, CF 3 , methyl, CF 3 O- or SCH 3 and methoxy;
  • R 4 is selected from hydrogen or methyl;
  • R 8a is H or Ci. 6 alkyl;
  • R 8b is H or Ci.galkyl;
  • m is 1. hi one particular embodiment the compound of formula (I) is a compound of formula (Ic)
  • R 10 is selected from chloro, fluoro, bromo, cyano, CF 3 , methyl, CF 3 O- or SCH 3 and methoxy;
  • R 4 is hydrogen or methyl;
  • R 8a is H or Ci -6 alkyl;
  • R 8b is H or Ci -6 alkyl;
  • d is O, 1, 2 or 3.
  • halogen or halo' are used to represent fluorine, chlorine, bromine or iodine.
  • alkyl' as a group or part of a group means a straight or branched chain alkyl group or combinations thereof, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, pentyl, hexyl, 1,1-dimethylethyl, or combinations thereof.
  • 'alkoxy' as a group or as part of a group means a straight, branched or cyclic chain alkyl group having an oxygen atom attached to the chain, for example a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy group, pentoxy, hexyloxy group, cyclopentoxy or cyclohexyloxy group.
  • 'cycloalkyF means a closed 3- to 7- membered non-aromatic ring, for example cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl
  • 'aryl' means a 5- or 6- membered aromatic ring, for example phenyl, or a 7- to 12- membered bicyclic ring system where at least one of the rings is aromatic, for example naphthyl.
  • R 3 is an optionally substituted aromatic heterocyclyl group
  • the ring may contain 1, 2, 3, or 4 hetero atoms.
  • the hetero atoms are selected from oxygen, nitrogen or sulphur.
  • 5- membered heterocyclyl groups in this instance include furanyl, dioxalanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazinyl, isothiazolyl, isoxazolyl, thienyl, pyrazolyl or tetrazolyl.
  • 6-membered heterocyclyl groups are pyridinyl, pyrizinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl.
  • Y is phenyl, substituted with one, two or three substituents
  • R 1 is selected from hydrogen, Ci -6 alkyl, C 3 . 8 cycloalkyl, and halosubstitutedCi_ 6 alkyl;
  • R 2 is C(R 7 ) 2 R 3 ;
  • R 3 is an optionally substituted 5- to 6- membered aromatic heterocyclyl group, or group A:
  • R 4 is selected from hydrogen, Ci -6 alkyl, C 3 . 7 cycloalkyl, and halosubstitutedCi_ 6 alkyl, COCH 3, or SO 2 Me;
  • R 6 is methyl, chloro or CHxFn wherein n is 1 , 2, or 3, x is 0, 1 or 2 and n and x add up to
  • Ra can be independently selected from hydrogen, fluoro, chloro or trifluoromethyl
  • Rb can be independently be selected from hydrogen, Ci -6 alkyl, Ci -6 alkoxy, haloCi -6 alkoxy, hydroxy, cyano, halo, sulfonyl, CONH 2 , COOH or NHCOOC i -6 alkyl; and
  • R 7 can be independently hydrogen or Ci -6 alkyl, with the proviso that the compound is not 2-(4-terf-butyl-phenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid benzylamide; 2-(4-tert-butyl-phenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid benzyl-methyl- amide;
  • Y is substituted by 1 or 2 substituents. If mono- substituted, in one particular embodiment the substituents is in the 3 position; if disubstituted, in one particular embodiment, the substituents are in the 2,4- positions.
  • Substituents for Y are selected from: Cue alkyl, halosubstitutedCu ⁇ alkyl, Cue alkoxy, hydroxy group, cyano group, halo, Ci_ 6 alkyl sulfonyl group, COOH, halosubstituted Cue alkoxy,
  • Y is substituted by halo, cyano or methoxy.
  • R 1 is hydrogen or Ci_ 6 alkyl, more preferably hydrogen.
  • R 4 is Cu 6 alkyl or hydrogen, more preferably methyl or hydrogen, even more preferably hydrogen.
  • R is CH 2 R .
  • R 3 is group A, pyridinyl, or pyrimidinyl, any of which can be optionally substituted.
  • halo is fluoro.
  • substituents when R 3 is an 5- to 6- membered aromatic heterocyclyl group are halo, methoxy, and cyano.
  • Rb is selected from hydrogen, halo, methoxy, and cyano.
  • R 6 is CHxFn, more preferably CF 3
  • halogen or halo' are used to represent fluorine, chlorine, bromine or iodine.
  • alkyl' as a group or part of a group means a straight or branched chain alkyl group or combinations thereof, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, pentyl, hexyl, 1,1-dimethylethyl, or combinations thereof.
  • 'alkoxy' as a group or as part of a group means a straight, branched or cyclic chain alkyl group having an oxygen atom attached to the chain, for example a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy group, pentoxy, hexyloxy group, cyclopentoxy or cyclohexyloxy group.
  • 'cycloalkyl' means a closed non-aromatic ring, for example cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or cyclooctyl.
  • the ring may optionally contain 1 , 2, 3 or 4 further heteroatoms.
  • the ring may be saturated or unsaturated.
  • the further heteroatoms are selected from oxygen, nitrogen or sulphur.
  • An example of a 4- membered heterocyclyl ring is azetidinyl.
  • Examples of 5- membered heterocyclyl rings include pyrrolidinyl.
  • Examples of 6-membered heterocyclyl rings are morpholinyl, piperizinyl or piperidinyl.
  • An additional example is tetrahydropyridinyl.
  • Examples of a 7- membered heterocyclyl ring are azapine or oxapine.
  • Examples of 8-membered heterocyclyl rings are azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl.
  • R 3 is an optionally substituted non-aromatic heterocyclyl group
  • the ring may contain 1, 2, 3, or 4 heteroatoms.
  • the heteroatoms are selected from oxygen, nitrogen or sulphur.
  • 4- membered groups are 2- or 3- azetidinyl, oxetanyl, thioxetanyl, thioxetanyl-s-oxide, thioxetanyl-s,s-dioxide.
  • Examples of 5- membered heterocyclyl groups in this instance include dioxalanyl, pyrrolidinyl or tetrahydrofuranyl or tetrahydrothiophenyl.
  • 6-membered heterocyclyl groups are morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiomorpholinyl or thiomorpholinyl-s,s-dioxide.
  • An additional example is tetrahydropyridinyl.
  • Examples of a 7- membered heterocyclyl ring are azapine or oxapine.
  • Examples of 8- membered groups are azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl, oxacylcooctanyl, or thiacyclooctanyl.
  • R 1 Y is phenyl, substituted with one, two or three substituents
  • R 1 is selected from hydrogen, Ci 6 alkyl, C 3 7 cycloalkyl, or halosubstitutedCi 6 alkyl;
  • R 2 is (CH 2 )InR 3 ,
  • R 3 is an unsubstituted or substituted 5- to 6- membered aromatic heterocyclyl group, or group A:
  • R 4 is selected from hydrogen, Ci 6 alkyl, C3 7 cycloalkyl, or halosubstitutedCi ⁇ alkyl, COCH 3 and SO 2 Me;
  • R 6 is unsubstituted or substituted (Ci ⁇ )alkyl or chloro and R 10 is hydrogen or R 10 is unsubstituted or substituted (Ci ⁇ )alkyl or chloro and R 6 is hydrogen;
  • Ra can be independently selected from hydrogen, fluoro, chloro or trifluoromethyl
  • Rb can independently be selected from hydrogen, Ci 6 alkyl, Ci 5 alkoxy, halo substituted Ci 6 alkoxy, hydroxy, cyano, halo, sulfonyl, CONH 2 , COOH, SO 2 CH 3 , NHCOCH 3 , NHSO 2 CH 3 and CONHCH 3
  • m is 1 or 2.
  • Y is substituted by 1 or 2 substituents. If mono- substituted, m one particular embodiment, the substituent is in the 3 position.
  • Substituents for Y are selected from: Ci 6 alkyl, halosubstitutedCi 6 alkyl, Ci 6 alkoxy, hydroxy, cyano, halo, Ci 6 alkylsulfonyl, COOH, halosubstitutedCi 6 alkoxy, CONH 2 , NHCOCH 3 , Ci 6 alkynyl, C 1 6 alkyenyl SO 2 NR 8a R 8b wherein R 8a and R 8b are independently selected from H and Ci 6 alkyl.
  • Y is substituted by halo, cyano, methoxy, methyl, trifluoromethyl or trifluoromethoxy.
  • R 2 is CH 2 R 3 .
  • the compound of formula (III) is a compound of formula
  • R 1 is selected from hydrogen, Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, or halosubstitutedCi. 6 alkyl;
  • R 3 is furanyl, dioxalanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazinyl, isothiazolyl, isoxazolyl, thienyl, pyrazolyl, tetrazolyl, pyridyl, pyrizinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl which can be unsubstituted or substituted with 1, 2 or 3 substitutents selected from Ci_ 6 alkyl, Ci_ 6 alkoxy, halosubstitutedCi_ 6 alkoxy, halosubstitutedCi_ 6 alkyl, hydroxy, cyano, halo, sulfonyl, CONH 2 and COOH , or R 3 is group A:
  • R 4 is selected from hydrogen, Ci_ 6 alkyl, C 3 . 7 cycloalkyl, or halosubstitutedCi_ 6 alkyl, COCH 3, and SO 2 Me;
  • R 6 is unsubstituted or substituted (Ci_ 6 )alkyl, chloro and R 10 is hydrogen or R 10 is unsubstituted or substituted (Ci_ 6 )alkyl or chloro and R 6 is hydrogen;
  • Ra can be independently selected from hydrogen, fluoro, chloro or trifluoromethyl
  • Rb can independently be selected from hydrogen, Ci ⁇ alkyl, Ci s alkoxy, halosubstitutedCi 6 alkoxy, hydroxy, cyano, halo, sulfonyl, CONH 2 , COOH, SO 2 CH 3 , NHCOCH 3 , NHSO 2 CH 3 and CONHCH 3 ;
  • R 11 is Ci_6 alkyl, halosubstitutedCi_ 6 alkyl, Ci_ 6 alkoxy, hydroxy, cyano, halo, Ci. 6alkylsulfonyl, CONH 2 , NHCOCH 3 , COOH, halosubstitutedCi_ 6 alkoxy, Q.galkynyl, Ci. 6 alkynyl, SO 2 NR 8a R 8b ; d is 1, 2, or 3: m is 1 or 2; and
  • R 8a and R 8b are independently selected from hydrogen or Ci_ 6 alkyl.
  • R 1 is hydrogen or more particularly hydrogen.
  • R 4 is hydrogen or methyl, more particularly hydrogen.
  • R 3 is pyridinyl, pyrimidinyl, imidazoyl, oxadiazoyl, triazolyl or pyrazinyl any of which can be unsubstituted or substituted or is group A, In one particular embodiment R 3 is group A, pyridinyl or pyrimidinyl. In a further particular embodiment R 3 is group A or pyridinyl
  • R 3 is a substituted 5- to 6- membered aromatic heterocyclyl group
  • the substituent or substituents is/are preferably selected from: Ci -6 alkyl, Ci -6 alkoxy, halosubstituted Ci -6 alkoxy, hydroxy, cyano, halo, sulfonyl, CONH 2 , and COOH.
  • the halo is fluoro.
  • the substituents are halo, methoxy, and cyano.
  • R 6 or R 10 When R 6 or R 10 are substituted alkyl groups, they can be substituted with 1 , 2 or 3 substitutents selected from hydroxy, C ⁇ alkyloxy, cyano, halo, NR 8a R 8b , CONR 8a R 8b , SO 2 NR 8a R 8b , NR 8a COR 8b or NR 8a SO 2 R 8b , preferably hydroxy or fluorine.
  • R 6 is a substituted or unsubstituted (Ci -6 )alkyl, chloro or CHxFn wherein n is 1, 2, or 3, x is O, 1 or 2 and n and x add up to 3 and R 10 is hydrogen or R 10 is a substituted or unsubstituted (Ci -6 )alkyl, chloro or CHxFn wherein n is 1, 2, or 3, x is O, 1 or 2 and n and x add up to 3 and R 6 is hydrogen hi one particular embodiment R 6 is Z-butyl, isopropyl or CHxFn, more preferably R 6 is isopropyl or CHxFn even more preferably isopropyl or CF 3 and R 10 is hydrogen or R 10 is f-butyl, isopropyl or CHxFn, more preferably R 10 is isopropyl or CHxFn, more preferably isopropyl or CF 3 and R 6 is hydrogen
  • Rb is selected from halo, methoxy, and cyano.
  • R 6 is (Ci -6 )alkyl, chloro or CHxFn wherein n is 1, 2, or 3, x is
  • Y is phenyl, substituted with one, two or three substituents
  • R 1 is selected from hydrogen, Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, or halosubstitutedCi_ 6 alkyl;
  • R 2 is CH 2 R 3 ;
  • R 3 is an optionally substituted 5- to 6- membered aromatic heterocyclyl group, or group A:
  • R 4 is selected from hydrogen, Ci -6 alkyl, C 3 . 7 cycloalkyl, or halosubstitutedCi. 6 alkyl, COCH 3 , or SO 2 Me;
  • R 6 is (Ci_ 6 )alkyl, chloro or CHxFn wherein n is 1, 2, or 3, x is 0, 1 or 2 and n and x add up to 3 and R 10 is hydrogen or R 10 is (Ci_ 6 )alkyl, chloro or CHxFn wherein n is 1, 2, or 3, x is 0, 1 or 2 and n and x add up to 3 and R 6 is hydrogen;
  • Ra can be independently selected from hydrogen, fluoro, chloro or trifluoromethyl; and Rb can independently be selected from hydrogen, Ci_ 6 alkyl, Ci -6 alkoxy, haloCi_ 6 alkoxy, a hydroxy group, a cyano group, halo, a sulfonyl group, CONH 2 , or COOH.
  • halogen or halo' are used to represent fluorine, chlorine, bromine or iodine.
  • 'alkyl' as a group or part of a group means a straight or branched chain alkyl group or combinations thereof, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, pentyl, hexyl, 1,1-dimethylethyl, or combinations thereof.
  • 'alkoxy' as a group or as part of a group means a straight, branched or cyclic chain alkyl group having an oxygen atom attached to the chain, for example a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy group, pentoxy, hexyloxy group, cyclopentoxy or cyclohexyloxy group.
  • 'cycloalkyl' means a closed 3- to 7- membered non-aromatic ring, for example cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl
  • 'cycloalkenyP means a closed non-aromatic carbon ring containing 1 or more double bonds, for example cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, or cyclooctenyl.
  • 'alkynyP as a group or part of a group means a straight or branched chain carbon chain or combinations containing 1 or more triple carbon bonds for example a ethynyl, propynyl, butynyl, pentynyl, hexynyl or combinations thereof.
  • 'aryl' means a 5- or 6- membered aromatic ring, for example phenyl, or a 7- to 12- membered bicyclic ring system where at least one of the rings is aromatic, for example naphthyl.
  • R 3 is an aromatic heterocyclyl group
  • the ring may contain 1, 2, 3, or 4 hetero atoms.
  • the hetero atoms are selected from oxygen, nitrogen or sulphur.
  • 5- membered heterocyclyl groups in this instance include furanyl, dioxalanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazinyl, isothiazolyl, isoxazolyl, thienyl, pyrazolyl or tetrazolyl.
  • 6-membered heterocyclyl groups are pyridyl, pyrizinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl.
  • Y is phenyl, unsubstituted or substituted with one, two or three substituents;
  • R 1 is selected from hydrogen, Ci_ 6 alkyl, C 3 . 6 cycloalkyl, or halosubstitutedCi. 6 alkyl;
  • R is (CH 2 ) m R where m is 0 or 1 ; or R 1 and R 2 together with N to which they are attached form an optionally substituted 4- to
  • R 3 is a 4- to 8- membered non-aromatic heterocyclyl group, a C 3 _ 8 cycloalkyl group, a straight or branched C M0 alkyl, a C 2 .ioalkenyl, a C 3 . 8 cycloalkenyl, a C 2 _i 0 alkynyl, or a C 3 . gcycloalkynyl any of which can be unsubtituted or substituted or R 5 ;
  • R 4 is selected from hydrogen, Ci_ 6 alkyl, C 3 . 6 cycloalkyl, or halosubstitutedCi_ 6 alkyl,
  • R 5 is
  • p is 0, 1 or 2
  • X is CH 2; O, or S;
  • R 6 is a substituted or unsubstituted (Ci_ 6 )alkyl or chloro and R 10 is hydrogen or R 10 is a substituted or unsubstituted (Ci_ 6 )alkyl or chloro and R 6 is hydrogen;
  • R 7 is OH, d. 6 alkoxy, NR 8a R 8b , NHCOR 9 , NHSO 2 R 9 or SOqR 9 ;
  • R 8a is H or Ci. 6 alkyl;
  • R 8b is H or Ci.galkyl;
  • R 9 is C U6 alkyl; and
  • q is O, l or 2.
  • Y is a substituted phenyl. In one particular embodiment Y is substituted by 1 or 2 substituents. If mono- substituted, in one particular embodiment, the substituents is in the 3 position.
  • the substituent or substituents are preferably selected from: Ci_ 6 alkyl, halosubstitutedCi. 6 alkyl, Ci_ 6 alkoxy, a hydroxy group, a cyano group, halo, a Ci. salkylsulfonyl group, -CONH 2 , -NHCOCH 3, -COOH, Ci -6 alkynyl, halosubstitutedCi_ 6 alkoxy, or SO 2 NR 8a R 8b wherein R 8a and R 8b are as defined above.
  • Y is substituted by halo, cyano, methoxy, trifluoromethoxy or methyl.
  • the compound of formula (IV) is a compound of formula
  • R 1 is selected from hydrogen, Ci -6 alkyl, C 3 . 6 cycloalkyl, or halosubstitutedCi_ 6 alkyl;
  • R 3 is 2- or 3- azetidinyl, oxetanyl, thioxetanyl, thioxetanyl-s-oxide, thioxetanyl-s,s-dioxide, dioxalanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl-s,s-dioxide, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiomorpholinyl, thiomorpholinyl-s,s-dioxide, tetrahydropyridinyl, dioxanyl, tetrahydro-thiopyran 1,1 dioxide, azapine, oxapine, azacyclooctanyl, azaoxacyclooctanyl
  • R 4 is selected from hydrogen, Ci -6 alkyl, C 3 . 6 cycloalkyl, or halosubstitutedCi_ 6 alkyl, COCH 3i or SO 2 Me;
  • R 5 is
  • p is O, 1 or 2
  • X is CH 2 , 0 or S
  • R 6 is a substituted or unsubstituted or chloro and R 10 is hydrogen or R 10 is a substituted or unsubstituted or chloro and R 6 is hydrogen;
  • R 7 is OH, Ci. 6 alkoxy, NR 8a R 8b , NHCOR 9 , NHSO 2 R 9 or SOqR 9 ;
  • R 8a is H or Ci. 6 alkyl;
  • R 8b is H or d-galkyl;
  • R 9 is Ci -6 alkyl;
  • R 11 is Ci -6 alkyl, halosubstitutedCi_ 6 alkyl, Ci -6 alkoxy, hydroxy, cyano, halo, Ci-
  • R 6 or R 10 When R 6 or R 10 are substituted alkyl groups, they can be substituted with 1 , 2 or 3 substitutents selected from hydroxy, Q.galkyoxy, cyano, halo, NR 8a R 8b , CONR 8a R 8b , SO 2 NR 8a R 8b , NR 8a COR 8b orNR 8a SO 2 R 8b , preferably hydroxy or fluorine.
  • R 1 and R 2 together with the N to which they are attached form an optionally substituted 5-or 6- membered non-aromatic heterocyclyl ring.
  • R 6 is a substituted or unsubstituted (Ci_ 6 )alkyl, chloro or CHxFn wherein n is 1, 2, or 3, x is O, 1 or 2 and n and x add up to 3 and R 10 is hydrogen or R 10 is a substituted or unsubstituted (Ci_ 6 )alkyl, chloro or CHxFn wherein n is 1, 2, or 3, x is O, 1 or 2 and n and x add up to 3 and R 6 is hydrogen hi one particular embodiment R 6 is ?-butyl, isopropyl or CHxFn, more preferably R 6 is isopropyl or CHxFn even more preferably isopropyl or CF 3 and R 10 is hydrogen or R 10 is Z-butyl, isopropyl or CHxFn, more preferably R 10 is isopropyl or CHxFn, more preferably isopropyl or CF 3 and R 6 is hydrogen hi one particular embodiment R 10 is hydrogen
  • R 3 is an optionally substituted C 3 . 8 cycloalkyl group or an optionally substituted 4- to 8- membered nonaromatic heterocyclyl
  • m is 1.
  • R 3 is an optionally substituted C 3 . 6 cycloalkyl group or an optionally substituted 4- or 6- membered nonaromatic heterocyclyl.
  • the ring may be selected from pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl and tetrahydropyridinyl.
  • R 3 is an optionally substituted non-aromatic heterocyclyl group selected from dioxalanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl-s,s-dioxide, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxanyl, thiomorpholinyl, dioxanyl, thiomorpholinyl-s,s-dioxide and tetrahydropyridinyl.
  • non-aromatic heterocyclyl group selected from dioxalanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl-s,s-dioxide, morpholinyl, piperidinyl, piperazin
  • R 1 is selected from hydrogen;
  • R 3 is dioxalanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl-s,s-dioxide, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiomorpholinyl, thiomorpholinyl-s,s-dioxide, dioxanyl, tetrahydropyridinyl, a C 3 _ 8 cycloalkyl group, a straight or branched Ci.
  • R 4 is selected from hydrogen, Ci_ 6 alkyl, C 3 _ 6 cycloalkyl, or halosubstitutedCi. 6 alkyl, COCH 3, or SO 2 Me;
  • R 5 is
  • R 6 is a substituted or unsubstituted (Ci_6)alkyl or chloro
  • R 8a is H or Ci. 6 alkyl
  • R 8b is H or Ci.ealkyl
  • R 11 is Ci_6 alkyl, halosubstitutedCi. ⁇ alkyl, Ci_6 alkoxy, hydroxy, cyano, halo, Ci.
  • Y is phenyl, optionally substituted with one, two or three substituents;
  • R 1 is selected from hydrogen, Ci -6 alkyl, C 3 . 6 cycloalkyl, or halosubstitutedCi_ 6 alkyl;
  • R 2 is (CH 2 ) m R 3 where m is O or 1 ; or R 1 and R 2 together with N to which they are attached form an optionally substituted 5- or 6- membered non-aromatic heterocyclyl ring;
  • R 3 is an optionally substituted 4- to 8- membered non-aromatic heterocyclyl group, an optionally substituted C 3 . 8 cycloalkyl group, an optionally substituted straight or branched Ci 40 alkyl or R 5 ;
  • R 4 is selected from hydrogen, Ci -6 alkyl, C 3 . 6 cycloalkyl, or halosubstitutedCi_ 6 alkyl, COCH 3, or SO 2 Me;
  • R 5 is
  • R 6 is (Ci -6 )alkyl, chloro or CHxFn wherein n is 1, 2, or 3, x is 0, 1 or 2 and n and x add up to 3 and R 10 is hydrogen or R 10 is (Ci -6 )alkyl, chloro or CHxFn wherein n is 1, 2, or 3, x is 0, 1 or 2 and n and x add up to 3 and R 6 is hydrogen;
  • R 7 is OH, Q.galkoxy, NR 8a R 8b , NHCOR 9 , NHSO 2 R 9 , SOqR 9 ;
  • R 8a is H or Ci -6 alkyl
  • R 8b is H or C 1 6 alkyl
  • R 9 is Ci_ 6 alkyl; and q is 0, 1 or 2.
  • halogen or halo' are used to represent fluorine, chlorine, bromine or iodine.
  • 'alkyl' as a group or part of a group means a straight or branched chain alkyl group or combinations thereof, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, pentyl, hexyl, 1,1-dimethylethyl, or combinations thereof.
  • 'alkoxy' as a group or as part of a group means a straight, branched or cyclic chain alkyl group having an oxygen atom attached to the chain, for example a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy group, pentoxy, hexyloxy group, cyclopentoxy or cyclohexyloxy group.
  • 'cycloalkyl' means a closed non-aromatic carbon ring, for example cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or cyclooctyl.
  • 'alkenyl' as a group or part of a group means a straight or branched chain carbon chain or combinations containing 1 or more double bonds for example an ethenyl, n-propenyl, i- propenyl, butenyl, pentenyl, hexenyl or combinations thereof.
  • 'cycloalkenyF means a closed non-aromatic carbon ring containing 1 or more double bonds, for example cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, or cyclooctenyl.
  • alkynyl' as a group or part of a group means a straight or branched chain carbon chain or combinations containing 1 or more triple carbon bonds for example a ethynyl, propynyl, butynyl, pentynyl, hexynyl or combinations thereof.
  • 'cycloalkynyF means a closed non-aromatic carbon ring containing 1 or more triple bonds, for example cyclobutynyl, cyclopentynyl, cyclohexynyl or cycloheptynyl, or cyclooctynyl.
  • the ring may optionally contain 1, 2, 3 or 4 further hetero atoms.
  • the ring may be saturated or unsaturated.
  • the further hetero atoms are selected from oxygen, nitrogen or sulphur.
  • An example of a 4- membered heterocyclyl ring is azetidinyl
  • Examples of 5- membered heterocyclyl rings include pyrrolidinyl
  • Examples of 6-membered heterocyclyl rings are morpholinyl, piperazinyl or piperidinyl.
  • An additional example is tetrahydropyridinyl.
  • Examples of a 7- membered heterocyclyl ring are azapine or oxapine.
  • Examples of 8-membered heterocyclyl rings are azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl.
  • R is an optionally substituted non-aromatic heterocyclyl group
  • the ring may contain 1, 2, 3, or 4 hetero atoms.
  • the hetero atoms are selected from oxygen, nitrogen or sulphur.
  • 4- membered groups are 2- or 3- azetidinyl, oxetanyl, thioxetanyl, thioxetanyl-s-oxide and thioxetanyl-s,s-dioxide.
  • 5- membered heterocyclyl groups in this instance include dioxalanyl, pyrrolidinyl, tetrahydrofuranyl and tetrahydrothiophenyl.
  • 6-membered heterocyclyl groups are morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiomorpholinyl and thiomorpholinyl-s,s-dioxide. Additional examples are tetrahydropyridinyl, dioxanyl, and tetrahydro-thiopyran 1,1 dioxide. Examples of a 7- membered heterocyclyl ring are azapine or oxapine.
  • 8- membered groups are azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl, oxacylcooctanyl, or thiacyclooctanyl.
  • Y is phenyl, unsubstituted or substituted with one, two or three substituents
  • R 1 is selected from hydrogen, Ci -6 alkyl, C 3 . 6 cycloalkyl, or halosubstitutedCi_ 6 alkyl;
  • R 2 is (CH 2 ) m R 3 where m is 0 or 1 ; or R 1 and R 2 together with N to which they are attached form an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl ring;
  • R 3 is an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl group, an unsubstituted or substituted C 3 . 8 cycloalkyl group, an unsubstituted or substituted straight or branched Cn 0 alkyl, an unsubstituted or substituted C 5 . 7 cycloalkenyl or R 5 ;
  • R 4 is selected from hydrogen, Ci -6 alkyl, C 3 _ 6 cycloalkyl, or halosubstitutedCi. 6 alkyl, COCH 3, or SO 2 Me;
  • p is 0, 1 or 2
  • X is CH 2 , 0, S, SO or SO 2 ;
  • R 6 is (C 3-6 )cycloalkyl, 4- to 7- membered non aromatic heterocyclic group or unsubstituted C 2 . 6 alkyl or substituted (Ci_ 6 )alkyl;
  • R 7 is OH, d.galkoxy, NR 8a R 8b , NHCOR 9 , NHSO 2 R 9 , SOqR 9 ;
  • R 8a is H or C ⁇ alkyl;
  • R 8b is H or Ci -6 alkyl
  • R 9 is C U6 alkyl; and q is O, 1 or 2, wherein R 6 is not CHxFn wherein n is 1, 2, or 3, x is 0, 1 or 2 and n and x add up to 3.
  • X is CH 2 , O or S.
  • Y is a substituted phenyl. In one embodiment Y is substituted by 1 or 2 substituents.
  • R 1 is hydrogen.
  • R 4 is C ⁇ .s alkyl or hydrogen, in a further embodiment methyl or hydrogen, even more preferably hydrogen.
  • R 6 is unsubstituted or substituted C 2 - 6 alkyl, more preferably ethyl, isopropyl or tert butyl.
  • R 7 is OH. In one embodiment X is CH 2 .
  • R is an optionally substituted Cs.scycloalkyl group or an optionally substituted 4- to 8- membered nonaromatic heterocyclyl group
  • m is 1.
  • R 2 is CH 2 R 3 .
  • R 3 is an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl group.
  • the substituent or substituents may be selected from: Ci_ 6 alkyl, halosubstitutedCi_ 6 alkyl, Ci_ 6 alkoxy, a hydroxy group, a cyano group, halo, a Ci_ 6 alkyl sulfonyl group, -CONH 2 ,-NHCOCH 3 , -COOH, halosubstituted Ci -6 alkoxy, or SO 2 NR 8a R 8b wherein R 8a and R 8b are as defined above.
  • Y is substituted by halo, cyano, methyl, trifluoromethyl, methoxy or trifluoromethoxy.
  • compounds of formula (V) are compounds of formula (Va):
  • R 3 is an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl group
  • R 6 is unsubstituted or substituted C 2 _ 6 alkyl
  • R 11 is selected from halo, cyano, methyl, trifluoromethyl, methoxy or trifluoromethoxy; and d is O, 1, 2 or 3.
  • R 3 is cyclohexyl or tetrahydropyran group.
  • R 6 is ethyl, isopropyl or tert-butyl
  • R 1 and R 2 together with N to which they are attached form a 4- to 8- membered non- aromatic heterocyclyl ring which is substituted, or when R is substituted
  • R 1 and R 2 together with N to which they are attached form a 4- to 8- membered non- aromatic heterocyclyl ring which is substituted, or when R is substituted there can be 1, 2 or 3 substituents.
  • R 6 When R 6 is substitued by 1, 2 or 3 substitutents the substituent or substituents are preferably selected from OH, halo, cyano, Q.galkoxy, NR 8a R 8b , NHCOR 9 , NHSO 2 R 9 , SOqR 9 ; wherein R 8a , R 8b , R 9 , andq are defined above.
  • halogen or halo' are used to represent fluorine, chlorine, bromine or iodine.
  • 'alkyl' as a group or part of a group means a straight or branched chain alkyl group or combinations thereof, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, pentyl, hexyl, 1,1-dimethylethyl, or combinations thereof.
  • 'alkoxy' as a group or as part of a group means a straight, branched or cyclic chain alkyl group having an oxygen atom attached to the chain, for example a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy group, pentoxy, hexyloxy group, cyclopentoxy or cyclohexyloxy group.
  • 'cycloalkyF means a closed 4- to 8- membered non-aromatic ring, for example cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or cyclooctyl.
  • the ring may optionally contain 1 , 2, 3 or 4 further hetero atoms.
  • the ring may be saturated or unsaturated.
  • the further hetero atoms are selected from oxygen, nitrogen or sulphur.
  • An example of a 4 membered heterocyclyl ring is azetidinyl
  • Examples of 5- membered heterocyclyl rings include pyrrolidinyl
  • Examples of 6- membered heterocyclyl rings are morpholinyl, piperizinyl or piperidinyl.
  • An additional example is tetrahydropyridinyl.
  • Examples of a 7- membered heterocyclyl ring are azapine or oxapine.
  • Examples of 8-membered heterocyclyl rings are azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl.
  • R 3 or R 6 is an optionally substituted non-aromatic heterocyclyl group
  • the ring may contain 1, 2, 3, or 4 hetero atoms.
  • the hetero atoms are selected from oxygen, nitrogen or sulphur.
  • 4- membered groups are 2- or 3- azetidinyl, oxetanyl, thioxetanyl, thioxetanyl-s-oxide and thioxetanyl-s,s-dioxide.
  • Examples of 5- membered heterocyclyl groups in this instance include dioxalanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl and tetrahydrothiophenyl-s,s-dioxide.
  • An additional example is tetrahydrothiophenyl-s-oxide.
  • 6-membered heterocyclyl groups are morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiomorpholinyl, thiomorpholinyl-s,s-dioxide, tetrahydropyridinyl, dioxanyl and tetrahydro-thi op yran- 1,1 -dioxide.
  • Additional examples are tetrahydrothiopyranyl-s-oxide, tetrahydrothiopyranyl-s,s-dioxide, thiomorpholinyl-s-oxide and tetrahydro-thiopyran-1 -oxide.
  • Examples of 7- membered heterocyclyl rings are azapine and oxapine.
  • Examples of 8- membered groups are azacyclooctanyl, azaoxacyclooctanyl, azathiacyclooctanyl, oxacylcooctanyl and thiacyclooctanyl. Additional examples are azathiacyclooctanyl-s-oxide, azathiacyclooctanyl-s,s- dioxide, thiacyclooctanyl-s-oxide and thiacyclooctanyl-s,s-dioxide
  • Y is phenyl, unsubstituted or substituted with one, two or three substituents
  • R 1 is selected from hydrogen, Ci_6 alkyl, C3.6 cycloalkyl, or halosubstitutedCi.6 alkyl;
  • R 2 is (CH 2 ) m R 3 where m is 0 or 1 ; or R 1 and R 2 together with N to which they are attached form an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl ring;
  • R 3 is an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl group, an unsubstituted or substituted C 3 _ 8 cycloalkyl group, an unsubstituted or substituted straight or branched Cn 0 alkyl, an unsubstituted or substituted C 5 . 7 cycloalkenyl or R 5 ;
  • R 4 is selected from hydrogen, Ci -6 alkyl, C 3 . 6 cycloalkyl, or halosubstitutedCi_ 6 alkyl, COCH 3, or SO 2 Me;
  • p is 0, 1 or 2
  • X is CH 2 , 0, S, SO or SO 2 ;
  • R 6 is C 3 _ 6 cycloalkyl or 4- to 7- membered non aromatic heterocyclic group, and R 10 is hydrogen or R 10 is C 3 . 6 cycloalkyl or 4- to 7- membered non aromatic heterocyclic group, and R 6 is hydrogen;
  • R 7 is OH, d. 6 alkoxy, NR 8a R 8b , NHCOR 9 , NHSO 2 R 9 or SOqR 9 ;
  • R 8a is H or C ⁇ aikyl;
  • R 8b is H or d.galkyl;
  • R 9 is C 1-6 alkyl; and q is 0, 1 or 2.
  • X is CH 2 , O or S.
  • Y is a substituted phenyl.
  • Y is substituted by 1 or 2 substituents.
  • R 1 is hydrogen.
  • R 4 is C i_ ⁇ alkyl or hydrogen, in an additional embodiment methyl or hydrogen.
  • R 4 is hydrogen.
  • hi one embodiment R 6 is C 3 _ 6 cycloalkyl or 4- to 7- membered non aromatic heterocyclic group and R 10 is hydrogen or R 10 is C 3 _ 6 cycloalkyl or 4- to 7- membered non aromatic heterocyclic group, and R 6 is hydrogen.
  • R 6 is Cs. ⁇ cycloalkyl hi one embodiment R 10 is hydrogen.
  • hi one embodiment R 7 is OH.
  • hi one embodiment X is CH 2 .
  • hi one embodiment m is 1.
  • R 2 is CH 2 R 3 .
  • R 3 is an unsubstituted or substituted C 3 .gcycloalkyl group or an unsubstituted or substituted 4- to 8- membered nonaromatic heterocyclyl group, in a further embodiment an unsubstituted or substituted 4- to 8- membered nonaromatic heterocyclyl groups
  • the substituent or substituents may be selected from: Ci_ 6 alkyl, halosubstitutedCi.
  • R 3 is an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl group;
  • R 6 is C 3 _ 6 cycloalkyl;
  • R 11 is selected from halo, cyano, methyl, trifluoromethyl, methoxy or trifluoromethoxy; and
  • d is O, 1, 2 or 3.
  • R 3 is tetrahydropyran group.
  • R 1 and R 2 together with N to which they are attached form a 4- to 8- membered non- aromatic heterocyclyl ring which is substituted, or when R 3 is substituted there can be 1, 2 or 3 substituents.
  • R 6 or R 10 When R 6 or R 10 is substituted by 1 , 2 or 3 substituents the substituent or substituents are preferably selected from halogen, OH, d.galkoxy, cyano, NR 8a R 8b , NHCOR 9 , NHSO 2 R 9 , SO q R 9 , C ⁇ alkyl.
  • halogen or halo' are used to represent fluorine, chlorine, bromine or iodine.
  • alkyl' as a group or part of a group means a straight or branched chain alkyl group or combinations thereof, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, pentyl, hexyl, 1,1-dimethylethyl, or combinations thereof.
  • 'alkoxy' as a group or as part of a group means a straight, branched or cyclic chain alkyl group having an oxygen atom attached to the chain, for example a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy group, pentoxy, hexyloxy group, cyclopentoxy or cyclohexyloxy group.
  • 'cycloalkyF means a closed 3- to 8- membered non-aromatic ring, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or cyclooctyl.
  • 'cycloalkenyF means a closed 3- to 8- membered non-aromatic ring containing at least one double bond, for example cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, or cyclooctenyl.
  • the ring may optionally contain 1 , 2, 3 or 4 further hetero atoms.
  • the ring may be saturated or unsaturated.
  • the further hetero atoms are selected from oxygen, nitrogen or sulphur.
  • An example of a 4 membered heterocyclyl ring is azetidinyl.
  • An example of a 5- membered heterocyclyl ring is pyrrolidinyl.
  • 6- membered heterocyclyl rings are morpholinyl, piperizinyl, piperidinyl or tetrahydropyridinyl.
  • Examples of a 7- membered heterocyclyl ring are azapine or oxapine.
  • Examples of 8-membered heterocyclyl rings are azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl.
  • the ring may contain 1, 2, 3, or 4 hetero atoms.
  • the hetero atoms are selected from oxygen, nitrogen or sulphur.
  • Examples of 4- membered groups are 2- or 3- azetidinyl, oxetanyl, thioxetanyl, thioxetanyl-s-oxide and thioxetanyl-s,s-dioxide.
  • Examples of 5- membered heterocyclyl groups in this instance include dioxalanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl and tetrahydrothiophenyl-s,s- dioxide.
  • An additional example is tetrahydrothiophenyl-s-oxide.
  • 6-membered heterocyclyl groups are morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiomorpholinyl, thiomorpholinyl-s,s-dioxide, tetrahydropyridinyl, dioxanyl and tetrahydro-thi op yran- 1,1 -dioxide.
  • Additional examples are tetrahydrothiopyranyl-s-oxide, tetrahydrothiopyranyl-s,s-dioxide, thiomorpholinyl-s-oxide and tetrahydro-thiopyran- 1 -oxide.
  • Examples of 7- membered heterocyclyl rings are azapine and oxapine.
  • Examples of 8- membered groups are azacyclooctanyl, azaoxacyclooctanyl, azathiacyclooctanyl, oxacylcooctanyl and thiacyclooctanyl. Additional examples are azathiacyclooctanyl-s-oxide, azathiacyclooctanyl-s,s- dioxide, thiacyclooctanyl-s-oxide and thiacyclooctanyl-s,s-dioxide.
  • Y is phenyl, unsubstituted or substituted with one, two or three substituents;
  • R 1 is selected from hydrogen, Ci_ 6 alkyl, C 3 . 6 cycloalkyl, or halosubstitutedCi. 6 alkyl;
  • R 2 is (CH 2 ) m R 3 where m is 0 or 1 ; or R 1 and R 2 together with N to which they are attached form an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl ring;
  • R is hydrogen, an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl group, an unsubstituted or substituted C 3 _ 8 cycloalkyl group, an unsubstituted or substituted straight or branched Ci- io alkyl, an unsubstituted or substituted C 5 . 7 cycloalkenyl, R 5 ; or R 3 is an unsubstituted or substituted 5- to 6- membered aromatic heterocyclyl group, or group A:
  • R 4 is selected from hydrogen, Ci 6 alkyl, C 3 6 cycloalkyl, or halosubstitutedCi ⁇ alkyl, COCH 3 , or SO 2 Me;
  • R 5 is
  • p is 0, 1 or 2
  • X is CH 2 , 0, S, SO or SO 2 ;
  • R 6 is halo, an substituted or unsubstituted (Ci_ 6 )alkyl, (C 3 . 6 )cycloalkyl, 4- to 7- membered non aromatic heterocyclyl group;
  • R 7 is OH, d.galkoxy, NR 8a R 8b , NHCOR 9 , NHSO 2 R 9 , SOqR 9 ;
  • R 8a is H or d. 6 alkyl;
  • R 8b is H or Ci. 6 alkyl
  • R 9 is Q.salkyl
  • Ra is independently selected from hydrogen, fluoro, chloro or trifluoromethyl
  • Rb is independently selected from hydrogen, Ci_ 6 alkyl, Ci_ 6 alkoxy, haloCi_ 6 alkoxy, hydroxy, cyano, halo, sulfonyl, CONH 2 , COOH or NHCOOd. 6 alkyl;
  • R 12 is hydrogen or Ci. 6 alkyl; and q is O, 1 or 2, wherein the compound is not (5- ⁇ [bis-(2-methoxy-ethyl)-amino]-methyl ⁇ -4- trifluoromethyl-pyrimidin-2-yl)-(3-chlorophenyl)-amine or ⁇ 1 -[2-(3-chloro-phenylamino)-4- trifluoromethyl-pyrimidin-5-ylmethyl]-piperidin-4-yl ⁇ -methanol, formate.
  • Y is a substituted phenyl. In one embodiment Y is substituted by 1 or 2 substituents.
  • the substituent or substituents may be selected from: Ci_ 6 alkyl, halosubstitutedCi. 6 alkyl, Ci_ 6 alkoxy, a hydroxy group, a cyano group, halo, a Ci_ 6 alkyl sulfonyl group, -CONH 2 ,-NHCOCi -6 alkyl, -CH 2 COOH, -COOH, halosubstituted Ci -6 alkoxy, SCi_ 6 alkyl or SO 2 NR 8a R 8b wherein R 8a and R 8b are as defined above.
  • Y is substituted by halo, cyano, methyl, trifluoromethyl, methoxy or trifluoromethoxy or SCH 3 .
  • halo is chloro, fluoro, or bromo.
  • R 1 is selected from hydrogen, Ci -6 alkyl, C3.6 cycloalkyl and halosubstitutedCi.6 alkyl;
  • R 3 is hydrogen, 2- or 3- azetidinyl, oxetanyl, thioxetanyl, thioxetanyl-s-oxide, thioxetanyl- s,s-dioxide, dioxalanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl- s-oxide, tetrahydrothiophenyl-s,s-dioxide, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl-s-dioxide, tetrahydrothiopyranyl-s,s-dioxide, thiomorpholinyl, thiomorpholinyl, thiomorpholinyl-s, thiomorpholin
  • R 11 is selected from Ci_6 alkyl, halosubstitutedCi.6 alkyl, Ci_6 alkoxy, a hydroxy group, a cyano group, halo, a d_ 6 alkyl sulfonyl group, -CONH 2 , -NHCOC i -6 alkyl , -COOH, -CH 2 COOH, halosubstitutedCi. 6 alkoxy, SC ⁇ alkyl and SO 2 NR 8a R 8b ;
  • R 4 is selected from hydrogen, Ci_ 6 alkyl, C 3 _ 6 cycloalkyl, or halosubstitutedCi_ 6 alkyl, COCH 3j and SO 2 Me;
  • p is O, 1 or 2 and X is CH 2 , O, S, SO or SO 2 ;
  • R 6 is halo, a substituted or unsubstituted (Ci_ 6 )alkyl, (C 3 . 6 )cycloalkyl, 4- to 7- membered non aromatic heterocyclyl group;
  • R 7 is OH, d. 6 alkoxy, NR 8a R 8b , NHCOR 9 , NHSO 2 R 9 , SOqR 9 ;
  • R 8a is H or Ci. 6 alkyl
  • R 8b is H or d.galkyl
  • R 9 is C 1-6 alkyl
  • R 12 is hydrogen or Ci_ 6 alkyl
  • Ra is independently selected from hydrogen, fluoro, chloro or trifluoromethyl
  • Rb is independently selected from hydrogen, Ci -6 alkyl, Ci -6 alkoxy, haloCi_ 6 alkoxy, hydroxy, cyano, halo, sulfonyl, CONH 2 , COOH Or NHCOOC 1 6 alkyl; q is O, 1 or 2; and d is O, 1, 2 or 3, wherein the compound is not (5- ⁇ [bis-(2-methoxy-ethyl)-amino] -methyl ⁇ -4-trifluoromethyl-pyrimidin-2-yl)-(3 -chlorophenyl)- amine or ⁇ l-[2-(3-chloro-phenylamino)-4-trifluoromethyl-pyrimidin-5-ylmethyl]-piperidin-4-yl ⁇ - methanol, formate.
  • R 1 is hydrogen or methyl.
  • R 4 is C ⁇ .s alkyl or hydrogen, suitably methyl or hydrogen, even more suitably hydrogen.
  • hi one embodiment R 6 is Ci_ 6 alkyl, (C 3 . 6 )cycloalkyl or CF 3 .
  • hi one embodiment R 7 is OH.
  • hi one embodiment X is CH 2 .
  • R 3 is an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl group, an unsubstituted or substituted C 3 _ 8 cycloalkyl group, an unsubstituted or substituted straight or branched Ci -I0 alkyl, an unsubstituted or substituted C 5 .
  • R 3 is an optionally substituted 5- to 6- membered aromatic heterocyclyl group, or group A.
  • R 3 is an optionally substituted C 3 .
  • R 2 is CH 2 R 3 .
  • R 12 is hydrogen.
  • R 3 is an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl group or group A, pyridinyl, or pyrimidinyl, any of which can be optionally substituted.
  • R 1 and R 2 together with N to which they are attached form a 4- to 8- membered non- aromatic ring selected from azetidinyl, pyrrolidinyl, morpholinyl, piperizinyl, piperidinyl, tetrahydropyridinyl, azapine, oxapine, azacyclooctanyl, azaoxacyclooctanyl and azathiacyclooctanyl.
  • compounds of formula (VII) are compounds of formula (VIIb):
  • R 1 is hydrogen or methyl
  • R 3 is an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl group an unsubstituted or substituted C 3 . 8 cycloalkyl group, an unsubstituted or substituted straight or branched d.io alkyl;
  • R 6 is an substituted or unsubstituted (Ci_6)alkyl, (C3_6)cycloalkyl, or 4- to 7- membered non aromatic heterocyclyl group;
  • R 11 is selected from halo, cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy or SCH 3 ; and d is 0, 1, 2 or 3 wherein the compound is not
  • R 3 is cyclobutyl or cyclopropylmethyl.
  • R 6 is isopropyl, cyclopropyl, tert-butyl or trifluoromethyl.
  • hi one embodiment R 6 is isopropyl, cyclopropyl or trifluoromethyl.
  • R 1 is hydrogen.
  • R 1 and R 2 together with N to which they are attached form a
  • R 3 is nonaromatic heterocyclyl it is selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl-s-oxide, tetrahydrothiophenyl-s,s-dioxide morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiomorpholinyl, thiomorpholinyl-s, thiomorpholinyl-s,s-dioxide, tetrahydropyridinyl.
  • R 3 is Ci 6 straight or branched alkyl it can be substituted by optionally substituted phenyl, wherein the substituents can be selected from halo, hydroxy or cyano .
  • compounds of formula (VII) can be selected from compounds of formula (VIIc): wherein
  • R 1 is hydrogen or methyl.
  • R 3 is group A, pyridinyl, or pyrimidinyl, any of which can be optionally substituted;
  • Ra is independently selected from hydrogen, fluoro, chloro or trifluoromethyl
  • Rb is independently selected from hydrogen, Ci -6 alkyl, Ci -6 alkoxy, haloCi_ 6 alkoxy, hydroxy, cyano, halo, sulfonyl, CONH 2 , COOH or NHCOOQ.galkyl;
  • R 6 is an substituted or unsubstituted (Ci -6 )alkyl, (C 3 . 6 )cycloalkyl or 4- to 7- membered non aromatic heterocyclyl group;
  • R 11 is selected from halo, cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy SCH 3 ; and d is O, 1, 2 or 3.
  • R 1 is hydrogen.
  • the substituent or substituents may be selected from OH, halo, cyano, d. 6 alkoxy, NR 8a R 8b , NHCOR 9 , NHSO 2 R 9 , SOqR 9 ; wherein R 8a , R 8b , R 9 , andq are defined above.
  • the ring may optionally contain 1 , 2, 3 or 4 further hetero atoms.
  • the ring may be saturated or unsaturated.
  • the further hetero atoms are selected from oxygen, nitrogen or sulphur.
  • An example of a 4 membered heterocyclyl ring is azetidinyl
  • Examples of 5- membered heterocyclyl rings include pyrrolidinyl
  • Examples of 6-membered heterocyclyl rings are morpholinyl, piperizinyl, piperidinyl or tetrahydropyridinyl.
  • An additional example is thiomorpholinyl.
  • Examples of a 7- membered heterocyclyl ring are azapine or oxapine.
  • Examples of 8-membered heterocyclyl rings are azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl.
  • R 3 or R 6 is an optionally substituted non-aromatic heterocyclyl group, the ring may contain 1, 2, 3, or 4 hetero atoms. In one embodiment the hetero atoms are selected from oxygen, nitrogen or sulphur.
  • Examples of 4- membered groups are 2- or 3- azetidinyl, oxetanyl, thioxetanyl, thioxetanyl-s-oxide and thioxetanyl-s,s-dioxide.
  • Examples of 5- membered heterocyclyl groups in this instance include dioxalanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl-s -oxide and tetrahydrothiophenyl-s,s-dioxide.
  • 6-membered heterocyclyl groups are morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl-s-dioxide, tetrahydrothiopyranyl-s,s-dioxide, thiomorpholinyl, thiomorpholinyl-s,s-dioxide, tetrahydropyridinyl dioxanyl, and tetrahydro- thiopyran 1,1 dioxide.
  • Examples of a 7- membered heterocyclyl ring are azapine or oxapine.
  • 8- membered groups are azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl, oxacylcooctanyl, or thiacyclooctanyl.
  • the ring may contain 1, 2, 3, or 4 hetero atoms.
  • the hetero atoms are selected from oxygen, nitrogen or sulphur.
  • 5- membered heterocyclyl groups in this instance include furanyl, dioxalanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazinyl, isothiazolyl, isoxazolyl, thienyl, pyrazolyl or tetrazolyl.
  • 6-membered heterocyclyl groups are pyridinyl, pyrizinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl.
  • 'halogen or halo' are used to represent fluorine, chlorine, bromine or iodine.
  • 'alkyl' as a group or part of a group means a straight or branched chain alkyl group or combinations thereof, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t- butyl, pentyl, hexyl, 1,1-dimethylethyl, or combinations thereof.
  • 'alkoxy' as a group or as part of a group means a straight, branched or cyclic chain alkyl group having an oxygen atom attached to the chain, for example a methoxy, ethoxy, n- propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy group, pentoxy, hexyloxy group, cyclopentoxy or cyclohexyloxy group.
  • 'cycloalkyl' means a closed 4- to 8- membered non-aromatic ring, for example cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or cyclooctyl.
  • 'aryl' means a 5- or 6- membered aromatic ring, for example phenyl, or a 7- to 12- membered bicyclic ring system where at least one of the rings is aromatic, for example naphthyl.
  • Y is phenyl, unsubstituted or substituted with one, two or three substituents
  • R 1 is selected from hydrogen, Ci -6 alkyl, C 3 . 6 cycloalkyl, or halosubstitutedCi_ 6 alkyl;
  • R 2 is (CH 2 ) m R 3 where m is 0 or 1 ; or R 1 and R 2 together with N to which they are attached form an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl ring;
  • R is an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl group, an unsubstituted or substituted C3.8 cycloalkyl group, an unsubstituted or substituted straight or branched C L IO alkyl, an unsubstituted or substituted C5-7 cycloalkenyl, R 5 or R 3 is an unsubstituted or substituted 5- to 6- membered aromatic heterocyclyl group, or group A:
  • R 4 is selected from hydrogen, Ci -6 alkyl, C 3 _ 6 cycloalkyl, or halosubstitutedCi. 6 alkyl, COCH 3, or SO 2 Me;
  • R 5 is
  • p is 0, 1 or 2
  • X is CH 2 , 0, S, SO or SO 2 ;
  • R 6 is halo, an substituted or unsubstituted (Ci_ 6 )alkyl, substituted or unsubstituted (C 3 . 6 )cycloalkyl, or a 4- to 7- membered non aromatic heterocyclyl group and R 10 is hydrogen or R 10 is halo, an substituted or unsubstituted (Ci_ 6 )alkyl, substituted or unsubstituted (C 3 _ 6 )cycloalkyl, or a 4- to 7- membered non aromatic heterocyclyl group and R 6 is hydrogen: R 7 is OH, d.
  • R 8a is H or d. 6 alkyl
  • R 8b is H or Ci.ealkyl
  • R 9 is Cuealkyl
  • R 12 is hydrogen or Ci. ⁇ alkyl
  • q is O, 1 or 2;
  • Ra can be independently selected from hydrogen, fluoro, chloro or trifluoromethyl; and Rb can be independently be selected from hydrogen, Ci_ 5 alkyl, Ci_ 6 alkoxy, haloCi_ 6 alkoxy, hydroxy, cyano, halo, sulfonyl, CONH 2 , COOH or NHCOOC i_ 6 alkyl.
  • Y is a substituted phenyl. In one embodiment Y is substituted by 1 or 2 substituents.
  • R 1 is hydrogen.
  • R 4 is C i_ 6 alkyl or hydrogen, for example methyl or hydrogen, alternatively hydrogen.
  • hi one embodiment R 6 is isopropyl, cyclopropyl, trifluoromethyl, ?-butyl or cyclopentyl.
  • hi one embodiment R 6 is isopropyl, cyclopropyl, trifluoromethyl or ?-butyl.
  • hi one embodiment R 10 is hydrogen hi one embodiment R 7 is OH.
  • hi one embodiment X is CH 2 .
  • the substituent or substituents may be selected from: Ci_ 6 alkyl, halosubstitutedCi. 6 alkyl, Ci_ 6 alkoxy, a hydroxy group, a cyano group, halo, a Ci_ 6 alkyl sulfonyl group, -CONH 21 -NHCOCH 3 , -COOH, halosubstituted Ci -6 alkoxy, or SO 2 NR 8a R 8b wherein R 8a and R 8b are as defined above.
  • Y is substituted by halo, cyano, methyl, trifluoromethyl, methoxy or trifluoromethoxy.
  • R is an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl group, an unsubstituted or substituted C3.8 cycloalkyl group or a straight or branched Ci_ 6 alkyl group.
  • R 3 is an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl group, or an unsubstituted or substituted C 3 . 8 cycloalkyl group.
  • R 3 is pyridinyl, pyrimidinyl, imidazoyl, oxadiazoyl, triazolyl or pyrazinyl any of which can be unsubstituted or substituted or is group A.
  • R 3 is pyridinyl, pyrimidinyl, imidazoyl, oxadiazoyl, triazolyl or pyrazinyl any of which can be unsubstituted or substituted or is group A.
  • R 3 is group A, pyridinyl or pyrimidinyl.
  • R 3 is group A or pyridinyl.
  • R when R is an unsubstituted or substituted 4- to 8- membered non- aromatic heterocyclyl group it can be morpholinyl, tertahydropyranyl, thiomorpholine-s,s-dioxide, or tetrahydrothiopyran- 1 , 1 -dioxide.
  • Rb is selected from halo, methoxy, and cyano.
  • compounds of formula (VIII) are compounds of formula (Villa):
  • R 3 is an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl group, an unsubstituted or substituted C 3 . 8 cycloalkyl group or a straight or branched Q ⁇ alkyl group;
  • R 6 is isopropyl, cyclopropyl, trifluoromethyl, f-butyl or cyclopentyl.
  • R 11 is selected from halo, cyano, methyl, trifluoromethyl, methoxy or trifluoromethoxy;
  • R 12 is hydrogen or Ci_ 6 alkyl; d is 0, 1, 2 or 3; and m is 0 or 1.
  • R 3 is (C 3 6 )cycloalkyl for example cyclobutyl, cyclopropyl or cyclopentyl.
  • R 3 is tetroahydropyran.
  • compounds of formula (VIII) are compounds of formula (VIIIb):
  • R 3 is an optionally substituted 5- to 6- membered aromatic heterocyclyl group, or group A:
  • R 6 is isopropyl, cyclopropyl, trifluoromethyl, f-butyl or cyclopentyl;
  • R . 11 i ⁇ s selected from halo, cyano, methyl, trifluoromethyl, methoxy or trifluoromethoxy;
  • R is hydrogen or Ci_ 6 alkyl; d is 0, 1, 2 or 3; and m is 0 or 1.
  • compounds of formula (VIII) are compounds of formula (VIIIc):
  • R 1 and R 2 together with N to which they are attached form an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl ring;
  • R 6 is isopropyl, cyclopropyl, trifluoromethyl, f-butyl or cyclopentyl;
  • R 11 is selected from halo, cyano, methyl, trifluoromethyl, methoxy or trifluoromethoxy;
  • R 12 is hydrogen or C ⁇ alkyl; and d is O, 1, 2 or 3.
  • hi one embodiment R 6 is isopropyl
  • R 12 is hydrogen or methyl, suitably hydrogen.
  • hi one embodiment R 1 and R 2 together with N to which they are attached form an azetinyl, pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl ring.
  • R is an 5- to 6- membered aromatic heterocyclyl group
  • the substituents are halo, methoxy, and cyano.
  • R 1 and R 2 together with N to which they are attached form a 4- to 8- membered non- aromatic heterocyclyl ring which is substituted, or when R 3 is substituted there can be 1, 2 or 3 substituents.
  • R 6 When R 6 is substitued by 1, 2 or 3 substitutents the substituent or substituents may be selected from OH, halo, cyano, C ⁇ alkoxy, NR 8a R 8b , NHCOR 9 , NHSO 2 R 9 , SOqR 9 ; wherein R 8a , R 8b , R 9 , andq are defined above.
  • halogen or halo' are used to represent fluorine, chlorine, bromine or iodine.
  • alkyl' as a group or part of a group means a straight or branched chain alkyl group or combinations thereof, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, pentyl, hexyl, 1,1-dimethylethyl, or combinations thereof.
  • 'alkoxy' as a group or as part of a group means a straight, branched or cyclic chain alkyl group having an oxygen atom attached to the chain, for example a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy group, pentoxy, hexyloxy group, cyclopentoxy or cyclohexyloxy group.
  • 'cycloalkyl' means a closed 4- to 8- membered non-aromatic ring, for example cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or cyclooctyl.
  • 'cycloalkenyl' means a closed non-aromatic carbon ring containing 1 or more double bonds, for example cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, or cyclooctenyl.
  • alkynyl' as a group or part of a group means a straight or branched chain carbon chain or combinations containing 1 or more triple carbon bonds for example a ethynyl, propynyl, butynyl, pentynyl, hexynyl or combinations thereof.
  • 'aryl' means a 5- or 6- membered aromatic ring, for example phenyl, or a 7- to 12- membered bicyclic ring system where at least one of the rings is aromatic, for example naphthyl.
  • the ring may optionally contain 1 , 2, 3 or 4 further hetero atoms.
  • the ring may be saturated or unsaturated.
  • the further hetero atoms are selected from oxygen, nitrogen or sulphur.
  • An example of a 4 membered heterocyclyl ring is azetidinyl
  • Examples of 5- membered heterocyclyl rings include pyrrolidinyl
  • Examples of 6-membered heterocyclyl rings are morpholinyl, piperizinyl, piperidinyl, tetrahydropyridinyl.
  • An additional example is thiomorpholinyl.
  • Examples of a 7- membered heterocyclyl ring are azapine or oxapine.
  • Examples of 8-membered heterocyclyl rings are azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl.
  • R 3 or R 6 is an optionally substituted non-aromatic heterocyclyl group
  • the ring may contain 1, 2, 3, or 4 hetero atoms.
  • the hetero atoms are selected from oxygen, nitrogen or sulphur.
  • 4- membered groups are 2- or 3- azetidinyl, oxetanyl, thioxetanyl, thioxetanyl-s-oxide and thioxetanyl-s,s-dioxide.
  • Examples of 5- membered heterocyclyl groups in this instance include dioxalanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl and tetrahydrothiophenyl-s,s-dioxide.
  • 6-membered heterocyclyl groups are morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl-s,s- dioxide, thiomorpholinyl, thiomorpholinyl-s,s-dioxide, tetrahydropyridinyl dioxanyl, and tetrahydro-thiopyran 1,1 dioxide.
  • Examples of a 7- membered heterocyclyl ring are azapine or oxapine.
  • 8- membered groups are azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl, oxacylcooctanyl, or thiacyclooctanyl.
  • R is an aromatic heterocyclyl group
  • the ring may contain 1, 2, 3, or 4 hetero atoms.
  • the hetero atoms are selected from oxygen, nitrogen or sulphur.
  • 5- membered heterocyclyl groups in this instance include furanyl, dioxalanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazinyl, isothiazolyl, isoxazolyl, thienyl, pyrazolyl or tetrazolyl.
  • 6-membered heterocyclyl groups are pyridyl, pyrizinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl.
  • Y is phenyl, substituted with one, two or three substituents
  • R 1 is selected from hydrogen, Ci 6 alkyl, C 3 7 cycloalkyl, and halosubstitutedCi 6 alkyl;
  • R 2 is C(R 7 ) 2 R 3 ;
  • R 3 is an optionally substituted 5- to 6- membered aromatic heterocyclyl group, or group A:
  • R 4 is selected from hydrogen, Ci 6 alkyl, C 3 ⁇ cycloalkyl, and halosubstitutedCi 6 alkyl, COCH 3, or SO 2 Me;
  • R 6 is a substituted or unsubstituted d_io alkyl or C 3 . 7 cycloalkyl excluding unsubstituted methyl or CHxFn wherein n is 1 , 2, or 3, x is 0, 1 or 2 and n and x add up to 3;
  • Ra can be independently selected from hydrogen, fluoro, chloro or trifluoromethyl
  • Rb can be independently be selected from hydrogen, Ci_ 6 alkyl, Ci_ 6 alkoxy, haloCi_ 6 alkoxy, hydroxy, cyano, halo, sulfonyl, CONH 2 , COOH or NHCOOC i_ 6 alkyl
  • R 7 can be independently hydrogen or Ci_ 6 alkyl.
  • Y is substituted by 1 or 2 substituents.
  • Substituents for Y are selected from: Ci_6 alkyl, halosubstitutedCi.6 alkyl, Ci_ 6 alkoxy, hydroxy group, cyano group, halo, Ci_ 6 alkyl sulfonyl group, COOH, halosubstituted Ci -6 alkoxy, CONH 2 , -NHCOC i -6 alkyl, CH 2 COOH, Sd. 6 alkyl or SO 2 NR 8a R 8b wherein R 8a and R 8b are independently selected from H or d_ 6 alkyl.
  • Y is substituted by halo, cyano or methoxy.
  • R 1 is hydrogen or Ci_ 6 alkyl, for example hydrogen
  • hi one particular embodiment R 4 is Ci -6 alkyl or hydrogen, for example methyl or hydrogen.
  • R 4 may be hydrogen.
  • hi one particular embodiment R is CH 2 R .
  • hi one particular embodiment R 3 is group A, pyridinyl, or pyrimidinyl, any of which can be optionally substituted.
  • R 3 is a substituted 5- to 6- membered aromatic heterocyclyl group
  • the halo is fluoro.
  • substituents when R 3 is an 5- to 6- membered aromatic heterocyclyl group are halo, methoxy, and cyano.
  • Rb is selected from hydrogen, halo, methoxy, and cyano.
  • R 6 is a substituted Cuo alkyl or C 3 _ 7 cycloalkyl in one embodiment there may be 1, 2, or 3 substituents independently selected from hydroxy, halo, cyano, Ci -6 alkoxy, NR 8a R 8b wherein R 8a and R 8b are independently selected from H or Ci_ 6 alkyl, NHCOR 9 , and SO q R 9 wherein R 9 is Ci- ⁇ alkyl and q is O, 1 or 2.
  • R 6 is C2-10 alkyl, for example t-butyl.
  • halogen or halo' are used to represent fluorine, chlorine, bromine or iodine.
  • 'alkyl' as a group or part of a group means a straight or branched chain alkyl group or combinations thereof. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, pentyl, hexyl, 1,1-dimethylethyl, or combinations thereof.
  • 'alkoxy' as a group or as part of a group means a straight, branched or cyclic chain alkyl group having an oxygen atom attached to the chain, for example a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy group, pentoxy, hexyloxy group, cyclopentoxy or cyclohexyloxy group.
  • 'cycloalkyl' means a closed 3- to 7- membered non-aromatic ring, for example cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl
  • 'aryl' means a 5- or 6- membered aromatic ring, for example phenyl, or a 7- to 12- membered bicyclic ring system where at least one of the rings is aromatic, for example naphthyl.
  • R 3 is an optionally substituted aromatic heterocyclyl group
  • the ring may contain 1, 2, 3, or 4 hetero atoms.
  • the hetero atoms may for example be selected from oxygen, nitrogen or sulphur.
  • 5- membered heterocyclyl groups in this instance include furanyl, dioxalanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazinyl, isothiazolyl, isoxazolyl, thienyl, pyrazolyl or tetrazolyl.
  • 6-membered heterocyclyl groups are pyridinyl, pyrizinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl.
  • R 1 is selected from hydrogen, d_ 6 alkyl, C 3 . 6 cycloalkyl and halosubstitutedCi. ⁇ alkyl;
  • R 2 is hydrogen or (CH 2 ) m R 3 where m is 0 or 1 ; or R 1 and R 2 together with N to which they are attached form an optionally substituted 4- to 8- membered non-aromatic heterocyclyl ring;
  • R 3 is a 4- to 8- membered non-aromatic heterocyclyl group, a C 3 _ 8 cycloalkyl group, a straight or branched C 140 alkyl, a C 2 . 10 alkenyl, a C 3 . 8 cycloalkenyl, a C 2 . 10 alkynyl, a C 3 _ 8 cycloalkynyl or phenyl group, any of which can be unsubstituted or substituted, or R 5 ;
  • R 4 is selected from hydrogen, C 1 ⁇ alkyl, C 3 _ 6 cycloalkyl, halosubstitutedCi. ⁇ alkyl, COCH 3 and SO 2 Me;
  • R 5 is wherein p is 0, 1 or 2, and X is CH 2, O, S, or SO 2 ;
  • R 6 is unsubstituted or substituted phenyl, unsubstituted or substituted C 3 _ 6 cycloalkyl or an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl ring; or R 4 and R 6 together with N to which they are attached form an optionally substituted 4- to
  • R 7 is OH, Ci. 6 alkoxy, NR 8a R 8b , NHCOR 9 , NHSO 2 R 9 or SOqR 9 ;
  • R 8a is H or Ci. 6 alkyl
  • R 8b is H or Ci. 6 alkyl
  • R 9 is C U6 alkyl
  • R 10 is hydrogen, substituted or unsubstituted (Ci_ 6 )alkyl or chloro;
  • R 11 is hydrogen or Ci ⁇ alkyl
  • R 12 is hydrogen or Ci ⁇ alkyl
  • R 13 is hydrogen or Ci_ 6 alkyl; and q is O, 1 or 2 wherein the compound is not 3-methyl-7-morpholin-4-yl-lH-pyrrolo[2,3- c]pyridine-4-carboxylic acid (tetrahydro-pyran-4-yl)-amide or 3-methyl-7-morpholin-4-yl-lH- pyrrolo[2,3-c]pyridine-4-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide.
  • R 2 ; R 4 , R 6 R 11 , R 12 and R 13 are as defined for compounds of formula (X).
  • R 1 is hydrogen.
  • R 13 is hydrogen.
  • R is (CH ⁇ ) 1n R where m is 0 or 1.
  • R 3 or R 6 are independently selected from a non-aromatic heterocyclyl group
  • the ring may contain 1, 2, 3, or 4 hetero atoms.
  • the hetero atoms are selected from oxygen, nitrogen or sulphur.
  • 4- membered groups are 2- or 3- azetidinyl, oxetanyl, thioxetanyl, thioxetanyl-s-oxide and thioxetanyl-s,s-dioxide.
  • Examples of 5- membered heterocyclyl groups in this instance include dioxolanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl and tetrahydrothiophenyl-s,s-dioxide.
  • An additional example is tetrahydrothiophenyl-s -oxide.
  • 6-membered heterocyclyl groups are morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl-s,s- dioxide, thiomorpholinyl, thiomorpholinyl-s,s-dioxide, tetrahydropyridinyl, dioxanyl, and tetrahydrothiopyran- 1,1 -dioxide.
  • An additional example is tetrahydrothiopyran-1 -oxide.
  • Examples of a 7- membered heterocyclyl ring are azapine or oxapine.
  • Examples of 8- membered groups are azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl, oxacylcooctanyl, or thiacyclooctanyl. Additional examples of 8-membered groups are azathiacyclooctanyl-s-oxide, azathiacyclooctanyl- s,s-dioxide, thiacyclooctanyl-s,s-dioxide, and thiacyclooctanyl-s-oxide.
  • R 3 is a 4- to 8- membered non-aromatic heterocyclyl group, a C 3 .
  • R 3 is an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl group, an unsubstituted or substituted C 3 . 8 cycloalkyl group or an unsubstituted or substituted Ci_ 6 alkyl.
  • R 3 is an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl group, or an unsubstituted or substituted C 3 . 8 cycloalkyl group.
  • R 3 is an unsubstituted or substituted 4- to 8- membered non- aromatic heterocyclyl group, said group is selected from tetrahydrofuranyl, tetrahydropyranyl, piperidinyl or morpholinyl.
  • R 3 is a selected from tetrahydropyranyl, tetrahydrofuranyl, a C 3 _ 6 cycloalkyl group, a straight or branched Ci_ 6 alkyl, or phenyl group, any of which can be unsubstituted or substituted; hi one embodiment R is tetrahydrofuranyl, tetrahydropyranyl, or C 3 _ 6 cycloalkyl for example cyclobutyl or cyclopropyl. hi one embodiment R 3 is tetrahydrofuranyl, or C 3 _ 6 cycloalkyl for example cyclobutyl or cyclopropyl.
  • R 4 is C i_ 6 alkyl or hydrogen, for example methyl or hydrogen, hi one embodiment R 4 is hydrogen.
  • R 1 and R 2 taken together with the N to which they are attached form an optionally substituted non-aromatic heterocyclyl ring
  • R 4 and R 6 taken together with the N to which they are attached form an optionally substituted non-aromatic heterocyclyl ring
  • the ring may optionally contain 1, 2, 3 or 4 further hetero atoms.
  • the ring may be saturated or unsaturated.
  • the further hetero atoms are selected from oxygen, nitrogen or sulphur.
  • An example of a 4- membered heterocyclyl ring is azetidinyl.
  • Examples of a 5- membered heterocyclyl ring are pyrrolidinyl and pyrazolidinyl.
  • Examples of 6-membered heterocyclyl rings are morpholinyl, piperazinyl or piperidinyl. Additional examples are tetrahydropyridinyl, thiomorpholine-s,s-dioxide Further examples are thiomorpholinyl and thiomorpholinyl-s-oxide.
  • Examples of a 7- membered heterocyclyl ring are azapine or oxapine.
  • Examples of 8-membered heterocyclyl rings are azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl.
  • R 1 and R 2 together with the nitrogen to which they are attached form a morpholinyl, pyrrolidinyl, piperidinyl, azetidinyl, azapine, or thiomorpholinyl-s,s-dioxide ring.
  • R 1 and R 2 together with the nitrogen to which they are attached form a morpholinyl, pyrrolidinyl, piperidinyl, azetidinyl or azapine ring.
  • R 1 and R 2 together with the nitrogen to which they are attached form a morpholinyl, pyrrolidinyl or piperidinyl ring.
  • R 6 is phenyl, Cs.gcycloalkyl, tetrahydropyranyl, any of which can be unsubstituted or substituted.
  • hi one embodiment R 6 is a substituted phenyl, cyclohexyl or tetrahydropyranyl.
  • hi one embodiment R 6 is a substituted phenyl.
  • hi one embodiment when R 4 and R 6 together with the nitrogen to which they are attached form a morpholinyl, pyrrolidinyl or piperidinyl ring.
  • hi one embodiment R 7 is OH.
  • hi one embodiment R 10 is hydrogen, hi one embodiment R 11 is methyl or hydrogen, hi one embodiment R 12 is methyl or hydrogen, hi one embodiment R 13 is methyl or hydrogen.
  • hi one embodiment X is CH 2 .
  • R 6 When R 6 is substituted, it may be substituted by 1, 2 or 3 substituents, the substituent or substituents maybe selected from: Ci_ 6 alkyl, halosubstitutedCi. 6 alkyl e.g. trifluoromethyl, Ci_ 6 alkoxy, a hydroxy group, a cyano group, halo, a sulfonyl group, -CONH 2 , -NHCOCH 3 , - COOH, halosubstituted Ci -6 alkoxy e.g. trifluoromethyoxy and SO 2 NR 8a R 8b wherein R 8a and R 8b are as defined above.
  • R 6 is substituted by 1 or 2 substituents.
  • R 6 is substituted by halo, cyano, methyl, trifluoromethyl, methoxy or trifluoromethoxy.
  • R 1 and R 2 or R 4 and R 6 together with N to which they are attached form a 4- to 8- membered non-aromatic heterocyclyl ring which is substituted, or when R 3 is substituted, the substituent or substituents may be selected from: Ci_6 alkyl, Ci_6 alkoxy, a hydroxy group, halosubstituted e.g.
  • R 1 and R 2 or R 4 and R 6 together with N to which they are attached form a 4- to 8- membered non-aromatic heterocyclyl ring which is substituted, or when R 3 is substituted there can be 1, 2 or 3 substituents.
  • R 10 When R 10 is substituted, the substituents may be selected from halogen.
  • the invention is compounds of formula (Xc) or (Xd);
  • R 1 is hydrogen
  • R 2 is (CH 2 ) m R 3 where m is O or 1 ; or R 1 and R 2 together with N to which they are attached form a morpholinyl, pyrrolidinyl, piperidinyl, thiomorpholine-s,s-dioxide, azetidinyl or azapine ring any of which may be unsubstituted or substituted;
  • R 3 is a selected from tetrahydropyranyl, tetrahydrofuranyl, a C 3 _ 6 cycloalkyl group, a straight or branched Ci_ 6 alkyl and phenyl group, any of which can be unsubstituted or substituted;
  • R 4 is hydrogen or methyl,
  • R 6 is phenyl, C 3 _ 6 cycloalkyl or tetrahydropyranyl, any of which can be unsubstituted or substituted;
  • R 11 is hydrogen or methyl; and R 12 is hydrogen or methyl.
  • halogen or halo' are used to represent fluorine, chlorine, bromine or iodine.
  • 'alkyl' as a group or part of a group means a straight or branched chain alkyl group or combinations thereof, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, i- butyl, pentyl, hexyl, 1,1-dimethylethyl, heptyl, octyl, nonyl, decyl or combinations thereof.
  • 'alkoxy' as a group or as part of a group means a straight, branched or cyclic chain alkyl group having an oxygen atom attached to the chain, for example a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy group, i-butoxy, pentoxy, hexyloxy group, cyclopentoxy or cyclohexyloxy group.
  • 'cycloalkyl' means a closed saturated ring, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or cyclooctyl.
  • 'alkenyl' means as a group or part of a group means a straight or branched chain carbon chain or combinations thereof containing 1 or more double bonds, for example butenyl, pentenyl, hexenyl or heptenyl, or octenyl.
  • 'cycloalkenyF means a closed non-aromatic carbon ring containing 1 or more double bonds, for example cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, or cyclooctenyl.
  • alkynyl' as a group or part of a group means a straight or branched chain carbon chain or combinations containing 1 or more triple carbon bonds for example ethynyl, propynyl, butynyl, pentynyl, hexynyl or combinations thereof.
  • 'cycloalkynyF means a closed non-aromatic carbon ring containing 1 or more triple carbon bonds for example cyclopropynyl, cyclobutynyl, cyclopentynyl, cyclohexynyl or combinations thereof.
  • 'aryl' means a 5- or 6- membered aromatic ring, for example phenyl, or a 7- to 12- membered bicyclic ring system where at least one of the rings is aromatic, for example naphthyl.
  • X 1 is NR 4 or O;
  • R 1 is selected from hydrogen, Ci -6 alkyl, C 3 . 6 cycloalkyl and halosubstitutedCi_ 6 alkyl;
  • R 2 is hydrogen or (CH 2 ) m R 3 where m is 0 or 1 ; or R 1 and R 2 together with N to which they are attached form an optionally substituted 4- to 8- membered non-aromatic heterocyclyl ring;
  • R 3 is a 4- to 8- membered non-aromatic heterocyclyl group, a C3.8 cycloalkyl group, a straight or branched Ci. 10 alkyl, a C 2 -ioalkenyl, a C 3 _ 8 cycloalkenyl, a C 2 -ioalkynyl, a C 3 _ 8 cycloalkynyl or phenyl group, any of which can be unsubstituted or substituted, or R 5 ;
  • R 4 is selected from hydrogen, Ci_ 6 alkyl, C 3 . 6 cycloalkyl, halosubstitutedCi_ 6 alkyl, COCH 3 and SO 2 Me;
  • p is 0, 1 or 2
  • X is CH 2, O, S, or SO 2 ;
  • R 6 is unsubstituted or substituted phenyl, unsubstituted or substituted C 3 6 cycloalkyl or an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl ring;
  • R 7 is OH, d. 6 alkoxy, NR 8a R 8b , NHCOR 9 , NHSO 2 R 9 or SOqR 9 ;
  • R 8a is H or C ⁇ alkyl;
  • R 8b is H or d.galkyl
  • R 9 is Cusalkyl
  • R 10 is hydrogen, substituted or unsubstituted (Ci_6)alkyl or chloro;
  • R 12 is hydrogen or d. ⁇ alkyl;
  • R 13 is hydrogen or d. ⁇ alkyl; and
  • q is O, 1 or 2.
  • R 1 is hydrogen, hi one embodiment R 2 is (CH 2 ) m R 3 where m is O or 1.
  • Xi is NR 4 . In one embodiment Xi is O.
  • R 3 or R 6 are independently selected from a non-aromatic heterocyclyl group
  • the ring may contain 1, 2, 3, or 4 hetero atoms.
  • the hetero atoms are selected from oxygen, nitrogen or sulphur.
  • 4- membered groups are 2- or 3- azetidinyl, oxetanyl, thioxetanyl, thioxetanyl-s-oxide and thioxetanyl-s,s-dioxide.
  • Examples of 5- membered heterocyclyl groups in this instance include dioxolanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl-s,s-dioxide and tetrahydrothiophenyl-s-oxide.
  • 6-membered heterocyclyl groups are morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl-s,s-dioxide, thiomorpholinyl, thiomorpholinyl-s,s-dioxide, tetrahydropyridinyl, dioxanyl, tetrahydrothiopyran- 1,1 -dioxide and tetrahydrothiopyran-1 -oxide.
  • Examples of a 7- membered heterocyclyl ring are azapine or oxapine.
  • Examples of 8- membered groups are azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl, oxacylcooctanyl, thiacyclooctanyl and azathiacyclooctanyl-s-oxide, azathiacyclooctanyl-s,s- dioxide, thiacyclooctanyl-s,s-dioxide, and thiacyclooctanyl-s-oxide.
  • R 3 is an unsubstituted or substituted Ci_6 alkyl group.
  • R 4 is C i_ ⁇ alkyl or hydrogen, for example methyl or hydrogen. In one embodiment R 4 is hydrogen.
  • R 1 and R 2 taken together with the N to which they are attached form an optionally substituted non-aromatic heterocyclyl ring the ring may optionally contain 1, 2, 3 or 4 further hetero atoms.
  • the ring may be saturated or unsaturated.
  • the further hetero atoms are selected from oxygen, nitrogen or sulphur.
  • An example of a 4- membered heterocyclyl ring is azetidinyl.
  • Examples of a 5- membered heterocyclyl ring are pyrrolidinyl and pyrazolidinyl.
  • 6-membered heterocyclyl rings are morpholinyl, piperazinyl, piperidinyl, tetrahydropyridinyl, thiomorpholine-s,s-dioxide, thiomorpholinyl and thiomorpholinyl-s-oxide.
  • Examples of a 7- membered heterocyclyl ring are azapine or oxapine.
  • Examples of 8-membered heterocyclyl rings are azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl.
  • R 1 and R 2 together with the nitrogen to which they are attached form a morpholinyl, pyrrolidinyl or piperidinyl ring. In another embodiment, R 1 and R 2 together with the nitrogen to which they are attached form a morpholinyl ring. In one embodiment R 6 is an unsubstituted or substituted phenyl.
  • R 7 is OH. In one embodiment R 10 is hydrogen.
  • R 12 is methyl or hydrogen. In another embodiment R 12 is methyl. In one embodiment R 13 is methyl or hydrogen. In another embodiment R 13 is hydrogen.
  • R 6 When R 6 is substituted, it may be substituted by 1, 2 or 3 substituents, the substituent or substituents may be selected from: Cu 6 alkyl, halosubstitutedCi_ 6 alkyl e.g. trifluoromethyl, Ci_ 6 alkoxy, a hydroxy group, a cyano group, halo, a Ci ⁇ alkyl sulfonyl group, -CONH 2 ,-NHCOCH 3 , - COOH, halosubstituted Ci -6 alkoxy e.g. trifluoromethyloxy and SO 2 NR 8a R 8b wherein R 8a and R 8b are as defined above. In one embodiment R 6 is substituted by 1 or 2 substituents.
  • R 6 is substituted by substitutents selected from halo, cyano, methyl, trifluoromethyl, methoxy and trifluoromethoxy.
  • R 6 is substituted by halo, for example chloro. In another embodiment R 6 is 3-chlorophenyl.
  • R 1 and R 2 together with N to which they are attached form a 4- to 8- membered non- aromatic heterocyclyl ring which is substituted, or when R 3 is substituted, the substituent or substituents may be selected from: Ci_ 6 alkyl, Ci_ 6 alkoxy, a hydroxy group, halosubstituted Ci. ⁇ alkyl e.g. trifluoromethyl, halosubstituted C ⁇ alkoxy e.g.
  • R 10 When R 10 is substituted, the substituents may be selected from halogen.
  • the compound of formula (XI) is a compound of formula (XIa);
  • X 1 is NR 4 ; R 1 is hydrogen;
  • R 2 is (CH 2 ) m R 3 where m is O or 1 ; or R 1 and R 2 together with N to which they are attached form a morpholinyl, pyrrolidinyl, or piperidinyl ring any of which may be unsubstituted or substituted;
  • R is an unsubstituted or substituted straight or branched Ci. ⁇ alkyl; R 4 is hydrogen or methyl,
  • R 6 is unsubstituted or substituted phenyl; and R 12 is hydrogen or methyl.
  • halogen or halo' are used to represent fluorine, chlorine, bromine or iodine.
  • 'alkyl' as a group or part of a group means a straight or branched chain alkyl group or combinations thereof, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, i- butyl, pentyl, hexyl, 1,1-dimethylethyl, heptyl, octyl, nonyl, decyl or combinations thereof.
  • 'alkoxy' as a group or as part of a group means a straight, branched or cyclic chain alkyl group having an oxygen atom attached to the chain, for example a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy group, i-butoxy, pentoxy, hexyloxy group, cyclopentoxy or cyclohexyloxy group.
  • 'cycloalkyl' means a closed saturated ring, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or cyclooctyl.
  • alkenyl' as a group or part of a group means a straight or branched chain carbon chain or combinations thereof containing 1 or more double bonds, for example butenyl, pentenyl, hexenyl or heptenyl, or octenyl.
  • 'cycloalkenyP means a closed non-aromatic carbon ring containing 1 or more double bonds, for example cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, or cyclooctenyl.
  • alkynyl' as a group or part of a group means a straight or branched chain carbon chain or combinations thereof containing 1 or more triple carbon bonds for example ethynyl, propynyl, butynyl, pentynyl, hexynyl or combinations thereof.
  • 'cycloalkynyl' means a closed non-aromatic carbon ring containing 1 or more triple carbon bonds for example cyclopropynyl, cyclobutynyl, cyclopentynyl, cyclohexynyl or combinations thereof.
  • 'aryl' means a 5- or 6- membered aromatic ring, for example phenyl, or a 7- to 12- membered bicyclic ring system where at least one of the rings is aromatic, for example naphthyl.
  • X 4 is O, SO 2 , S, or a bond, or X 4 is -NHCO or -NHCH 2 such that R 6 X 4 is R 6 CONH or
  • R 1 is selected from hydrogen, Ci_ 6 alkyl, C 3 . 6 cycloalkyl and halosubstitutedCi_ 6 alkyl;
  • R 2 is hydrogen or (CH 2 ) m R 3 where m is 0 or 1 ; or R 1 and R 2 together with N to which they are attached form an optionally substituted 4- to 8- membered non-aromatic heterocyclyl ring;
  • R 3 is a 4- to 8- membered non-aromatic heterocyclyl group, a C 3 .
  • cycloalkyl group a straight or branched Ci.io alkyl, a C ⁇ oalkenyl, a Cs.scycloalkenyl, a C 2 -ioalkynyl, a C 3 _ 8 cycloalkynyl or phenyl group, any of which can be unsubstituted or substituted, or R 5 ;
  • p is 0, 1 or 2
  • X is CH 2, O, S, or SO 2 ;
  • R 6 is phenyl, C 3 . 6 cycloalkyl, a straight or branched Ci_ 6 alkyl group, -CH 2 -C 3 . 6 cycloalkyl, -CH 2 -phenyl, 4- to 8- membered non-aromatic heterocyclyl group, or a bicyclic group any of which can be unsubstituted or substituted, however when X 4 is a bond R 6 is substituted phenyl; R 7 is OH, d.galkoxy, NR 8a R 8b , NHCOR 9 , NHSO 2 R 9 or SOqR 9 ;
  • R 8a is H or C ⁇ alkyl
  • R 8b is H or C 1 6 alkyl
  • R 9 is C 1 6 alkyl
  • R 10 is hydrogen, substituted or unsubstituted (C 1 . 6 )alkyl or chloro;
  • R 11 is hydrogen or Ci_ 6 alkyl;
  • R 12 is hydrogen or Ci_ 6 alkyl
  • R 13 is hydrogen or Ci_ 6 alkyl
  • q is O, 1 or 2.
  • compounds of formula (XII) are compounds of fomula (XIIa) or
  • X 4 , R 1 , R 2 ; R 6 ; R 11 , R 12 , and R 13 are as defined for compounds of formula (XII).
  • hi one embodiment R 1 is hydrogen or methyl.
  • hi one embodiment R 13 is hydrogen or methyl.
  • hi one embodiment R 2 is (CH 2 ) m R 3 where m is O or 1.
  • R 3 or R 6 are independently selected from a non-aromatic heterocyclyl group, the ring may contain 1, 2, 3, or 4 hetero atoms. In one embodiment the hetero atoms are selected from oxygen, nitrogen or sulphur.
  • Examples of 4- membered groups are 2- or 3- azetidinyl, oxetanyl, thioxetanyl, thioxetanyl-s-oxide and thioxetanyl-s,s-dioxide.
  • Examples of 5- membered heterocyclyl groups in this instance include dioxolanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl-s,s-dioxide, and tetrahydrothiophenyl-s-oxide.
  • 6-membered heterocyclyl groups are morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl-s,s-dioxide, thiomorpholinyl, thiomorpholinyl-s,s-dioxide, tetrahydropyridinyl, dioxanyl, tetrahydrothiopyran- 1,1 -dioxide, and tetrahydrothiopyran- 1 -oxide.
  • 7- membered heterocyclyl groups are azapine and oxapine.
  • 8- membered groups are azacyclooctanyl, azaoxacyclooctanyl, azathiacyclooctanyl, oxacylcooctanyl, thiacyclooctanyl, azathiacyclooctanyl-s-oxide, azathiacyclooctanyl-s,s-dioxide, thiacyclooctanyl-s,s-dioxide and thiacyclooctanyl-s-oxide.
  • R 3 is an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl group, or an unsubstituted or substituted C 3 . 8 cycloalkyl group
  • R 3 is an unsubstituted or substituted 4- to 8- membered non- aromatic heterocyclyl group, said group is tetrahydropyranyl.
  • R 3 is tetrahydropyranyl or cyclobutyl.
  • R 4 is hydrogen.
  • hi one embodiment R 1 is hydrogen.
  • R 13 is hydrogen. hi one embodiment R 12 is hydrogen or methyl.
  • the ring may optionally contain 1 , 2, 3 or 4 further hetero atoms.
  • the ring may be saturated or unsaturated.
  • the further hetero atoms are selected from oxygen, nitrogen or sulphur.
  • An example of a 4- membered heterocyclyl ring is azetidinyl.
  • Examples of a 5- membered heterocyclyl ring are pyrrolidinyl and pyrazolidinyl.
  • 6-membered heterocyclyl rings are morpholinyl, piperazinyl, piperidinyl, tetrahydropyridinyl, thiomorpholine-s,s-dioxide, thiomorpholinyl and thiomorpholinyl-s-oxide.
  • Examples of a 7- membered heterocyclyl ring are azapine or oxapine.
  • Examples of 8-membered heterocyclyl rings are azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl.
  • R 1 and R 2 together with the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl-s,s-dioxide, pyrrolidinyl or piperidinyl ring.
  • R 5 is a bicyclic group it can be selected from a 7 to 10 membered aromatic group for example napthyl, 7 to 10 membered heteroaromatic for example indolyl, isoindolyl, benzofuranyl, benzothiophenyl, quinolinyl and isoquinolinyl or a 7 to 10 membered heteroaromatic group for example dihydrobenzofuranyl, indolinyl and dihydrothiophenyl.
  • R 6 When R 6 is a bicyclic group it can be an indolyl, benzofuranyl, or napthyl group hi one embodiment R 6 is phenyl, C 3 _ 6 cycloalkyl, straight or branched Ci_ 6 alkyl or -CH 2 C 3 . ⁇ cycloalkyl, tetrahyrdofuranyl any of which can be unsubstituted or substituted.
  • R 6 is a substituted phenyl.
  • hi one embodiment when R 4 and R 6 together with the nitrogen to which they are attached form a morpholinyl, pyrrolidinyl or piperidinyl ring.
  • hi one embodiment R 7 is OH.
  • hi one embodiment R 10 is hydrogen.
  • hi one embodiment R 11 is methyl or hydrogen.
  • hi one embodiment R 13 is methyl or hydrogen.
  • hi one embodiment X is CH 2 .
  • R 6 When R 6 is substituted, it may be substituted by 1, 2 or 3 substituents, the substituent or substituents maybe selected from: Ci -6 alkyl, halosubstitutedCi_ 6 alkyl e.g. trifluoromethyl, Ci -6 alkoxy, a hydroxy group, a cyano group, halo, a Ci_ 6 alkyl sulfonyl group, -CONH 2 , -NHCOCH 3 , - COOH, halosubstituted Ci -6 alkoxy e.g. trifiuoromethyoxy, NR 8a R 8b and SO 2 NR 8a R 8b wherein R 8a and R 8b are as defined above.
  • the substituent or substituents maybe selected from: Ci -6 alkyl, halosubstitutedCi_ 6 alkyl e.g. trifluoromethyl, Ci -6 alkoxy, a hydroxy group, a cyano group,
  • R 6 is substituted by 1 or 2 substituents.
  • hi one embodiment R 6 is substituted by halo, cyano, methyl, trifluoromethyl, ethyl, propyl, isopropyl, methoxy, trifluoromethoxy or -SO 2 CH 3 .
  • the substituent or substituents may be selected from: Ci -6 alkyl, Ci -6 alkoxy, a hydroxy group, halosubstituted Ci 6 alkyl e.g. trifluoromethyl, halosubstituted Ci ⁇ alkoxy e.g.
  • R 10 When R 10 is substituted, the substituents may be selected from fluoro, chloro or bromo. hi one embodiment compounds of formula (XII) are compounds of formula (XIIc) or (XIId);
  • X 4 is O, S, SO 2 , or bond, or X 4 is -NHCO or -NHCH 2 such that R 6 X 4 is R 6 CONH or R 6 CH 2 NH;
  • R 1 is hydrogen
  • R 2 is (CH 2 ) m R 3 where m is O or 1 ; or R 1 and R 2 together with N to which they are attached form a morpholinyl, pyrrolidinyl, piperidinyl, thiomorpholine-s,s-dioxide ring any of which may be unsubstituted or substituted; R 3 is a selected from tetrahydrfuranyl, a C 3 . 6 cycloalkyl group;
  • R 6 is an phenyl, C 3 _ 6 cycloalkyl, straight or branched Ci_ 6 alkyl or -CH 2 C 3 _ 6 cycloalkyl - CH 2 phenyl any of which can be unsubstituted or substituted.
  • R 11 is hydrogen or methyl; and
  • R 12 is hydrogen or methyl.
  • R 6 is substituted phenyl. In one embodiment X 4 is O.
  • halogen or halo' are used to represent fluorine, chlorine, bromine or iodine.
  • 'alkyl' as a group or part of a group means a straight or branched chain alkyl group or combinations thereof, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, i- butyl, pentyl, hexyl, 1,1-dimethylethyl, heptyl, octyl, nonyl, decyl or combinations thereof.
  • 'alkoxy' as a group or as part of a group means a straight, branched or cyclic chain alkyl group having an oxygen atom attached to the chain, for example a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy group, i-butoxy, pentoxy, hexyloxy group, cyclopentoxy or cyclohexyloxy group.
  • 'cycloalkyl' means a closed saturated ring, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or cyclooctyl.
  • alkenyl means as a group or part of a group means a straight or branched chain carbon chain or combinations thereof containing 1 or more double bonds, for example butenyl, pentenyl, hexenyl or heptenyl, or octenyl.
  • 'cycloalkenyP means a closed non-aromatic carbon ring containing 1 or more double bonds, for example cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, or cyclooctenyl.
  • 'alkynyP as a group or part of a group means a straight or branched chain carbon chain or combinations containing 1 or more triple carbon bonds for example ethynyl, propynyl, butynyl, pentynyl, hexynyl or combinations thereof.
  • 'cycloalkynyP means a closed non-aromatic carbon ring containing 1 or more triple carbon bonds for example cyclopropynyl, cyclobutynyl, cyclopentynyl, cyclohexynyl or combinations thereof.
  • 'aryl' means a 5- or 6- membered aromatic ring, for example phenyl, or a 7- to 12- membered bicyclic ring system where at least one of the rings is aromatic, for example naphthyl.
  • Ar represents quinolinyl, isoquinolinyl, either of which can be unsubstituted or substituted with 1, 2 or 3 substituents selected from halo, Ci_ 6 alkyl, C ⁇ alkoxy, halo substituted C ⁇ alkyl, halosubstitued Ci_ 6 alkoxy, NH 2 , -SO 2 C LS aIlCyI, -NHSO 2 Ci -6 alkyl, -C 1 _ 6 alkylNR 3 R 4 , or Ar represents phenyl substituted with 1, 2 or 3 substituents at the 2, 3, 5 or 6 positions, which substituents are selected from halo, Ci_ 6 alkyl, Ci_ 6 alkoxy, halosubstituted Ci_ 6 alkyl, halosubstitued Ci -6 alkoxy, NH 2 , -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, -C 1 . 6 alkylNR 3
  • R 1 and R 2 together with the nitrogen to which they are attached form a 5- to 8- membered heterocyclyl or a 5-membered heteroaryl ring which can be unsubstituted or substituted with 1, 2 or 3 substituents selected from halo, C 1 ⁇ alkyl, cyano, -C 1 _ 6 alkylNR 3 R 4 ; and
  • R 3 and R 4 are independently selected from hydrogen, Ci_ 6 alkyl or together with the N to which they are attached form a pyrrolidinyl, piperidinyl or morpholinyl ring.
  • R 1 and R 2 taken together with the N to which they are attached form an optionally substituted 5- to 8- membered heterocyclyl ring the ring may optionally contain 1, 2, 3 or 4 further hetero atoms.
  • the ring may be saturated or unsaturated.
  • the further hetero atoms are selected from oxygen, nitrogen or sulphur.
  • Examples of a 5-membered heterocyclyl ring are pyrrolidinyl, 2,5,dihydro-lH-pyrrolyl, pyrazolidinyl, imidazolidinyl.
  • 6-membered heterocyclyl rings are morpholinyl, piperazinyl, piperidinyl, tetrahydropyridinyl, thiomorpholine- 1,1 -dioxide, thiomorpholinyl and thiomorpholinyl-1 -oxide.
  • Examples of a 7- membered heterocyclyl ring are hexahydro-lH-azepinyl or hexahydro-l,4-oxazepinyl.
  • 8- membered heterocyclyl rings are 3-oxa-8-azabicyclo[3.2.1]octanyl, azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl.
  • R 1 and R 2 taken together with the N to which they are attached form an optionally substituted 5-membered heteroaryl ring may optionally contain 1, 2 or 3 further hetero atoms.
  • the further hetero atoms are selected from oxygen, nitrogen or sulphur.
  • Examples of a 5-membered heteroaryl ring are pyrrolyl, pyrazolyl or triazolylyl.
  • substituents for Ar are selected from halo, Ci_ 6 alkyl, Ci_ 6 alkoxy, halosubstituted Cu 6 alkyl, halosubstituted d_ 6 alkoxy, -SO 2 Ci_ 5 alkyl, -NHSO 2 Ci_ 6 alkyl and NH 2
  • substituents for Ar are selected from halo, Ci_ 6 alkyl, halosubstituted Ci. 6 alkyl and NH 2 .
  • R 1 and R 2 together with the nitrogen to which they are attached form a pyrrolidinyl, pyrrolyl, 2,5,dihydro-lH-pyrrolyl, morpholinyl, thiomorpholinyl, piperidinyl, pyrazolyl, hexahydro-lH-azepinyl, hexahydro-l,4-oxazepinyl or 3-oxa-8-azabicyclo[3.2.1]octanyl, any of which can be unsubstituted or substituted with 1, 2 or 3 substituents selected from halo, Q -6 alkyl, ethylpypyrrolidinyl, or cyano.
  • R 1 and R 2 together with the nitrogen to which they are attached form a pyrrolidinyl, pyrrolyl, 2,5,dihydro-lH-pyrrolyl, morpholinyl, piperidinyl, hexahydro-lH-azepinyl, hexahydro-l,4-oxazepinyl or 3-oxa-8- azabicyclo[3.2.1]octanyl, any of which can be unsubstituted or substituted with 1, 2 or 3 substituents selected from halo, Ci -6 alkyl, ethylpypyrrolidinyl, or cyano.
  • R 3 and R 4 are independently selected from hydrogen, methyl or together with the N to which they are attached form a pyrolidinyl, piperidinyl or morpholinyl ring, hi one embodiment R 1 and R 2 together with the nitrogen to which they are attached form a pyrrolidinyl, 2,5,dihydro-lH-pyrrolyl, pyrazolidinyl, imidazolidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyridinyl, thiomorpho line- 1,1 -dioxide, thiomorpholinyl, thiomorpholinyl- 1- oxide, hexahydro-lH-azepinyl, hexahydro-l,4-oxazepinyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, azacyclooctanyl, azaoxacyclooctanyl, azathiox
  • halogen or halo' are used to represent fluorine, chlorine, bromine or iodine.
  • 'alkyl' as a group or part of a group means a straight or branched chain alkyl group or combinations thereof, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, i- butyl, pentyl, hexyl, 1,1-dimethylethyl, heptyl, octyl, nonyl, decyl or combinations thereof.
  • 'alkoxy' as a group or as part of a group means a straight, branched or cyclic chain alkyl group having an oxygen atom attached to the chain, for example a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy group, i-butoxy, pentoxy, hexyloxy group, cyclopentoxy or cyclohexyloxy group.
  • A represents a ring selected from pyrrolyl, thienyl, furanyl, isoxazolyl, pyrazolyl and pyridinyl, which can be unsubstituted or substituted with 1 , 2 or 3 substituents selected from halo, methyl, cyano, benzyl, wherein the atom through which A is attached to the pyridazinyl ring is a carbon atom; and
  • B represents phenyl substituted with 1, 2 or 3 substituents at the 2, 3, 5 or 6 positions, which substituents are selected from halo, Ci_ 6 alkyl, Ci_ 6 alkoxy, halosubstituted Ci_ 6 alkyl, halosubstitued C U6 alkoxy, NH 2 ,
  • B has one or more halo substituents.
  • B has one or two chloro substituents.
  • A is an unsubstituted or substituted pyrrol or thienyl ring.
  • A is unsubstituted or substituted with 1, 2 or 3 methyl groups.
  • B bears two substituents.
  • the terms "halogen or halo' are used to represent fluorine, chlorine, bromine or iodine.
  • alkyl' as a group or part of a group means a straight or branched chain alkyl group, or combinations thereof, having the stated number of carbon atoms for example a methyl, ethyl, n- propyl, i-propyl, n-butyl, s-butyl, t-butyl, i-butyl, pentyl, hexyl, 1,1-dimethylethyl, heptyl, octyl, nonyl, decyl or combinations thereof.
  • 'alkoxy' as a group or as part of a group means a straight, branched or cyclic chain alkyl group having the stated number of carbon atoms and having a linking oxygen atom in the chain, for example a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy group, i-butoxy, pentoxy, hexyloxy group, cyclopentoxy or cyclohexyloxy group.
  • R 1 and R 2 independently represent H, C L6 alkyl, or R 1 and R 2 together with the nitrogen atom to which they are attached form an optionally substituted 4 to 7 membered monocyclic heterocyclyl, a
  • R 3 represents halogen, -CN, -CF 3 , -OCF 3 , -OCHF 2 , Ci -3 alkyl, Ci -3 alkoxy, -COC L3 alkyl,
  • R 4 and R 5 independently represent H, halogen, -CN, -CF 3 , -OCF 3 , -OCHF 2 , C 1-3 alkyl,
  • R 6 and R 7 independently represent H or C L3 alkyl;
  • X represents -(CH 2 ) m - or -(CR 8 R 9 )-;
  • R 8 and R 9 independently represent H or C 1-3 alkyl; m represents 2 to 4; n represents O to 3; and
  • A represents an optionally substituted 6 to 10 membered aryl, an optionally substituted 5 to 7 membered monocyclic heteroaryl containing 1 to 3 heteroatoms selected from O, N and S, or a 9 to
  • the monocyclic, bicyclic or spiro bicyclic heterocyclyl may be substituted by one or more substituents (for example 1, 2 or 3), which may be the same or different, selected from the group consisting of halogen, oxo, hydroxyl, -CN, nitro, -NR 6 R 7 , - CONR 6 R 7 , -CF 3 , trifluoroethyl, -OCF 3 , -OCHF 2 , Ci.
  • substituents for example 1, 2 or 3
  • the optional substituents of the monocyclic or bicyclic heterocyclyl are selected from the group consisting of halogen, oxygen, C 1-4 alkyl, C 1-4 alkoxy and -COC M alkyl.
  • A is an 5 to 7 membered monocyclic heteroaryl or a 9 to 10 membered fused bicyclic heteroaryl it may be substituted by one or more substituents (for example 1, 2 or 3), which may be the same or different, selected from the group consisting of halogen, hydroxyl, -CN, nitro, -NR 6 R 7 , -CONR 6 R 7 , -CF 3 , -OCF 3 , -OCHF 2 , Ci -6 alkyl, Ci -6 alkoxy, -COCi_ 6 alkyl, -COCi -6 alkoxy, - NHCOCu 6 alkyl and -COOH.
  • the optional substituents of the aryl or heteroaryl are selected from the group consisting of halogen, Ci_ 3 alkyl, C 1 ⁇ alkoxy and -NHCOC 1 .
  • R 1 and R 2 independently represent H, C 1 ⁇ alkyl, or R 1 and R 2 together with the nitrogen atom to which they are attached form an optionally substituted 4 to 7 membered monocyclic heterocyclyl selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, or form an optionally substituted l,4-dioxa-8- azaspiro[4.5]decane spiro bicyclic heterocyclyl.
  • 4 to 7 membered monocyclic heterocyclyl is fluorine and one of the carbon atoms of the monocyclic heterocyclyl is disubstituted with 2 fluorine atoms.
  • m 2 or 3.
  • X represents -CH 2 -.
  • R 3 represents halogen, -CN, or C 1 ⁇ alkyl. In one embodiment, R 3 represents Cl or methyl.
  • n O
  • R 4 and R 5 independently represent H, halogen or methyl. In one embodiment, R 4 and R 5 both represent hydrogen.
  • n O and R 4 and R 5 both represent hydrogen.
  • R 6 and R 7 independently represent hydrogen or methyl. In one embodiment, R 8 and R 9 independently represent hydrogen or methyl.
  • A represents an optionally substituted phenyl or naphthyl.
  • R 1 and R 2 independently represent H, Ci_ 6 alkyl, or R 1 and R 2 together with the nitrogen atom to which they are attached form an optionally substituted 4 to 7 membered monocyclic heterocyclyl selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, or form an optionally substituted l,4-dioxa-8-azaspiro[4.5]decane spiro bicyclic heterocyclyl, and wherein the optional substituents of the monocyclic heterocyclyl or the spiro bicyclic heterocyclyl are selected from the group consisting of fluorine, methyl, methoxy and
  • X represents -(CH 2 ) m - or -(CR 8 R 9 )-; m represents 2 or 3; R 8 and R 9 independently represent H or methyl;
  • R 3 represents halogen or Ci -3 alkyl; n represents O to 3;
  • R 4 and R 5 independently represent H, halogen or methyl
  • A represents optionally substituted phenyl or naphthyl, wherein the optional substituents are selected from the group consisting of halogen, Ci -3 alkyl, Ci -3 alkoxy and
  • R 1 represents an optionally substituted tetrahydropyranyl, morpholinyl or pyridyl
  • R 2 represents halogen, -CN, -CF 3 , -OCF 3 , -OCHF 2 , C 1-3 alkyl, C 1-3 alkoxy, -COC L3 alkyl, -NR 5 R 6 or a group -CONR 5 R 6
  • R 5 and R 6 independently represent H or Ci_ 3 alkyl
  • X represents -(CR 7 R 8 ) m -;
  • R 7 and R 8 at each occurrence independently represent H or C L3 alkyl; m represents 1 to 4; n represents 0 to 3;
  • R 3 and R 4 independently represent H, halogen, -CN, -CF 3 , -OCF 3 , -OCHF 2 , Ci -3 alkyl, Ci -3 alkoxy, -COCi_ 3 alkyl, -NR 5 R 6 or a group -CONR 5 R 6 ;
  • A represents an optionally substituted 6 to 10 membered aryl, an optionally substituted 5 to 7 membered monocyclic heteroaryl containing 1 to 3 heteroatoms selected from O, N and S, or a 9 to 10 membered fused bicyclic heteroaryl containing 1 to 3 heteroatoms selected from O, N and S.
  • R 1 represents an optionally substituted tetrahydropyranyl, morpholinyl or pyridyl
  • the tetrahydropyranyl, morpholinyl or pyridyl may be substituted by one or more (for example 1 , 2 or 3) substituents, which may be the same or different, selected from the group consisting of halogen, oxygen, hydroxyl, -CN, nitro, -NR 5 R 6 , -CONR 5 R 6 , -CF 3 , trifluoroethyl, -OCF 3 , -OCHF 2 , C M alkyl, Ci -4 alkoxy and -COC M alkyl.
  • substituents which may be the same or different, selected from the group consisting of halogen, oxygen, hydroxyl, -CN, nitro, -NR 5 R 6 , -CONR 5 R 6 , -CF 3 , trifluoroethyl, -OCF 3 ,
  • A When A is an optionally substituted 6 to 10 membered aryl, an optionally substituted 5 to 7 membered monocyclic heteroaryl, or an optionally substituted 9 to 10 membered fused bicyclic heteroaryl, it may be substituted by one or more substituents (for example 1, 2 or 3), which may be the same or different, selected from the group consisting of halogen, hydroxyl, -CN, nitro, -NR 5 R 6 ,
  • R 1 may be substituted by 1 or 2 substituents, which may be the same or different, selected from the group consisting of halogen, -CF 3 , trifluoroethyl,
  • alkyl refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms.
  • C L6 alkyl means a straight or branched hydrocarbon chain containing at least 1 and at most 6 carbon atoms.
  • alkyl include, but are not limited to; methyl (Me), ethyl (Et), n-propyl, i- propyl, n-hexyl and i-hexyl.
  • alkoxy refers to an alkyl ether radical, wherein the term “alkyl” is defined above.
  • alkoxy include, but are not limited to; methoxy, ethoxy, n-propoxy, i-propoxy, n-pentoxy and i-pentoxy.
  • 'halogen' is used herein to describe a group selected from fluorine, chlorine, bromine and iodine.
  • 'aryl' refers to a C ⁇ -io monocyclic or bicyclic hydrocarbon ring wherein at least one ring is aromatic. Examples of such groups include phenyl and naphthyl.
  • heteroaryl unless stated otherwise, is intended to mean a 5 to 7 membered monocyclic aromatic or a fused 9 to 10 membered bicyclic aromatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur.
  • monocyclic aromatic rings include thienyl, furanyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl and pyridyl.
  • fused bicyclic aromatic rings include quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and the like.
  • Heteroaryl groups, as described above, may be linked to the remainder of the molecule via a carbon atom or, when present, a suitable nitrogen atom except where indicated otherwise.
  • R 1 may be substituted by 1 or 2 substituents, which may be the same or different, selected from the group consisting of halogen, -CF 3 , trifluoroethyl, -OCF 3 , -OCHF 2 , C 1 ⁇ alkyl and C 4 . 3 alkoxy.
  • R 1 represents an unsubstituted tetrahydropyranyl, (more particularly unsubstituted tetrahydro-2/f-pyran-4-ylmethyl), an unsubstituted morpholinyl, an unsubstitued pyridyl or a methyl-substituted pyridyl.
  • X represents -CH 2 - or -C 2 H 4 -.
  • R represents halogen, -CN, or C 1 . 3 alkyl. In one embodiment, R represents Cl or methyl.
  • n 0.
  • R 3 and R 4 independently represent H, halogen or methyl. In one embodiment, R 3 and R 4 both represent hydrogen.
  • n 0 and R 3 and R 4 both represent hydrogen.
  • R 5 and R 6 independently represent hydrogen or methyl.
  • A represents phenyl optionally substituted by one or more (for example 1, 2 or 3) halogen atoms. In one embodiment, A represents unsubstituted phenyl.
  • R 1 represents an unsubstituted tetrahydropyranyl, an unsubstituted morpholinyl, an unsubstitued pyridyl or a methyl-substituted pyridyl;
  • X represents -CH 2 - or -C 2 H 4 -;
  • R 3 and R 4 independently represent H, halogen or methyl
  • A represents phenyl optionally substituted by one or more (for example 1, 2 or 3) halogen atoms.
  • X 1 is NR 4 , O, S, SO or SO 2 ;
  • R 1 is selected from hydrogen, Ci -6 alkyl, C 3 . 6 cycloalkyl and halosubstitutedCi_ 6 alkyl;
  • R 2 is hydrogen or (CH 2 ) m R 3 where m is 0 or 1 ; or R 1 and R 2 together with N to which they are attached form an optionally substituted 4- to 8- membered non-aromatic heterocyclyl ring;
  • R 3 is a 4- to 8- membered non-aromatic heterocyclyl group, a C 3 .
  • cycloalkyl group a straight or branched Ci.io alkyl, a C 2 _ioalkenyl, a Cs.scycloalkenyl, a C 2 _ioalkynyl, a C 3 _ 8 cycloalkynyl or phenyl group, any of which can be unsubstituted or substituted, or R 5 ;
  • R 4 is selected from hydrogen, Ci_6 alkyl, C3.6 cycloalkyl and halosubstitutedCi.6 alkyl; R 5 is
  • p is 0, 1 or 2
  • X is CH 2, O, S, or SO 2 ;
  • R 6 is unsubstituted or substituted phenyl, unsubstituted or substituted C 3 . 6 cycloalkyl or an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl ring; R 7 is OH;
  • R 12 is hydrogen or Ci_ 6 alkyl
  • R 13 is hydrogen or Ci ⁇ alkyl
  • R 14 is hydrogen or Ci 6 alkyl. hi one embodiment Xi is NR 4 . In another embodiment Xi is O. hi one embodiment R 1 is hydrogen.
  • R is (CH 2 ) m R where m is O or 1.
  • R 1 and R 2 taken together with the N to which they are attached form an optionally substituted 4- to 8-membered non-aromatic heterocyclyl ring.
  • the ring may optionally contain 1, 2, 3 or 4 further hetero atoms.
  • the ring may be saturated or unsaturated.
  • the further hetero atoms are selected from oxygen or sulphur.
  • An example of a 4- membered heterocyclyl ring is azetidinyl.
  • Examples of a 5- membered heterocyclyl ring are pyrrolidinyl and pyrazolidinyl.
  • 6-membered heterocyclyl rings are morpholinyl, piperidinyl, tetrahydropyridinyl, thiomorpholine-s,s-dioxide, thiomorpholinyl and thiomorpholinyl-s-oxide.
  • Examples of a 7- membered heterocyclyl ring are azapine or oxapine.
  • Examples of 8-membered heterocyclyl rings are azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl.
  • R 1 and R 2 together with the nitrogen to which they are attached form a morpholinyl, pyrrolidinyl or piperidinyl ring.
  • R 3 is a 4- to 8-membered non-aromatic heterocyclyl group. In another embodiment R 3 is an unsubstituted or substituted Ci -6 alkyl group. hi one embodiment R 4 is C i-6 alkyl or hydrogen, for example methyl or hydrogen. In another embodiment R 4 is hydrogen. hi one embodiment R 6 is an unsubstituted or substituted phenyl. In another embodiment R 6 is an unsubstituted or substituted 4- to 8-membered non-aromatic heterocyclyl group. When R 3 or R 6 are independently selected from a non-aromatic heterocyclyl group, the ring may contain 1, 2, 3, or 4 hetero atoms.
  • hetero atoms are selected from oxygen, nitrogen or sulphur.
  • 4- membered groups are 2- or 3- azetidinyl, oxetanyl, thioxetanyl, thioxetanyl-s-oxide and thioxetanyl-s,s-dioxide.
  • 5- membered heterocyclyl groups in this instance include dioxolanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl-s,s-dioxide and tetrahydrothiophenyl-s-oxide.
  • 6-membered heterocyclyl groups are morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl-s,s-dioxide, thiomorpholinyl, thiomorpholinyl-s,s-dioxide, tetrahydropyridinyl, dioxanyl, tetrahydrothiopyran- 1,1 -dioxide and tetrahydrothiopyran- 1 -oxide.
  • Examples of a 7- membered heterocyclyl ring are azapine or oxapine.
  • Examples of 8- membered groups are azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl, oxacylcooctanyl, thiacyclooctanyl and azathiacyclooctanyl-s-oxide, azathiacyclooctanyl-s,s- dioxide, thiacyclooctanyl-s,s-dioxide, and thiacyclooctanyl-s-oxide.
  • hi one embodiment R 12 is methyl or ethyl.
  • hi one embodiment R 13 is methyl or hydrogen
  • hi one embodiment R 14 is methyl or hydrogen.
  • the substituent or substituents may be selected from: Ci -6 alkyl, Ci -6 alkoxy, a hydroxy group, halosubstituted Ci_ 6 alkyl e.g. trifluoromethyl, halosubstituted Ci_ 6 alkoxy e.g.
  • R 8a and R 8b are independently selected from hydrogen or Ci -6 alkyl.
  • R 6 When R 6 is substituted, it may be substituted by 1, 2 or 3 substituents, the substituent or substituents maybe selected from: Ci -6 alkyl, halosubstitutedCi. 6 alkyl e.g. trifluoromethyl, Ci -6 alkoxy, a hydroxy group, a cyano group, halo and halosubstituted Ci -6 alkoxy e.g. trifluoromethyloxy. In one embodiment R 6 is substituted by 1 or 2 substituents. In another embodiment R 6 is substituted by halo, cyano, methyl, trifluoromethyl, methoxy or trifluoromethoxy. In a further embodiment R 6 is substituted by halo.
  • R 6 When R 6 is phenyl it may be substituted by two groups which together form a fused ring.
  • the fused ring is a 5-membered non-aromatic heterocyclyl ring such as tetrahydrofuranyl.
  • the compounds of formula (XVII) are compounds of formula (XVIIa);
  • R 2 is (CH 2 ) m R 3 where m is 0 or 1 ; or R 1 and R 2 together with N to which they are attached form a morpholinyl, pyrrolidinyl, or piperidinyl ring of which may be unsubstituted or substituted;
  • R 3 is an unsubstituted or substituted straight or branched Ci_ 6 alkyl
  • R 4 is hydrogen or methyl
  • R 6 is unsubstituted or substituted phenyl; and R 12 is methyl.
  • halogen or halo' are used to represent fluorine, chlorine, bromine or iodine.
  • 'alkyl' as a group or part of a group means a straight or branched chain alkyl group or combinations thereof, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, i- butyl, pentyl, hexyl, 1,1-dimethylethyl, heptyl, octyl, nonyl, decyl or combinations thereof.
  • 'alkoxy' as a group or as part of a group means a straight, branched or cyclic chain alkyl group having an oxygen atom attached to the chain, for example a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy group, i-butoxy, pentoxy, hexyloxy group, cyclopentoxy or cyclohexyloxy group.
  • 'cycloalkyl' means a closed saturated ring, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or cyclooctyl.
  • alkenyl' means as a group or part of a group means a straight or branched chain carbon chain or combinations thereof containing 1 or more double bonds, for example butenyl, pentenyl, hexenyl or heptenyl, or octenyl.
  • 'cycloalkenyP means a closed non-aromatic carbon ring containing 1 or more double bonds, for example cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, or cyclooctenyl.
  • 'alkynyP as a group or part of a group means a straight or branched chain carbon chain or combinations containing 1 or more triple carbon bonds for example ethynyl, propynyl, butynyl, pentynyl, hexynyl or combinations thereof.
  • 'cycloalkynyP means a closed non-aromatic carbon ring containing 1 or more triple carbon bonds for example cyclopropynyl, cyclobutynyl, cyclopentynyl, cyclohexynyl or combinations thereof.
  • 'aryl' means a 5- or 6- membered aromatic ring, for example phenyl, or a 7- to 12- membered bicyclic ring system where at least one of the rings is aromatic, for example naphthyl.
  • CB2 modulators such as compounds of formula (I) - (XVII) and to paracetamol includes pharmaceutically acceptable derivatives thereof.
  • the cannabinoid 2 modulators are selective for CB2 over CBl.
  • the cannabinoid 2 modulators are 100 fold selective.
  • the cannabinoid 2 modulators have an EC50 value at the cloned human cannabinoid CB2 receptor of at least 100 times the EC50 values at the cloned humna cannabinoid CBl receptor or have less than 10% efficacy at the CB 1 receptor.
  • pharmaceutically acceptable derivative means any pharmaceutically acceptable salt, ester, salt of such ester or solvate (including solvates of salts, esters, or salts of esters) of a CB2 modulator or paracetamol (acetaminophen) or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a CB2 modulator or paracetamol (acetaminophen) as applicable or an active metabolite or residue thereof.
  • compounds described above may be modified to provide pharmaceutically acceptable derivatives thereof at any of the functional groups in the compounds, and that the compounds may be derivatised at more than one position.
  • the salts, esters, salts of such esters or solvates (including solvates of salts, esters, or salts of esters) referred to above will be physiologically acceptable salts, esters, salts of such esters or solvates (including solvates of salts, esters, or salts of esters), but other salts, esters, salts of such esters or solvates (including solvates of salts, esters, or salts of esters) may find use, for example in the preparation of compounds of formula (I) - (XVII) and the physiological acceptable salts, esters, salts of such esters or solvates (including solvates of salts, esters, or salts of esters) thereof.
  • Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse , J. Pharm. Sci., 1977, 66, 1-19.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropyl amine, tromethamine, and the like.
  • basic ion exchange resins
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Preferred examples of pharmaceutically acceptable salts include the ammonium, calcium, magnesium, potassium, and sodium salts, and those formed from maleic, fumaric, benzoic, ascorbic, pamoic, succinic, hydrochloric, sulfuric, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p- aminobenzoic, glutamic, benzenesulfonic, cyclohexylsulfamic, phosphoric and nitric acids.
  • compounds of formula (I) to (X) can be selected from the examples in WO
  • compounds of formula (XI) to (XVII) can be selected from the examples below and pharmaceutically acceptable derivatives thereof.
  • the CB2 modulator is selected from: 2-(2,4-Dichlorophenylamino)-4-trifluoromethylpyrimidine-5-carboxylic acid (tetrahydropyran-4- y lmethy 1) - amide, l-[4-(3-Chloro-phenylamino)-l -methyl-lH-pyrrolo[3,2-c]pyridin-7-yl]-l-morpholin-4-yl- methanone, and jV-(3-Chlorophenyl)-l-methyl-7-(4-morpholinylcarbonyl)-l/f-imidazo[4,5-c]pyridin-4-amine and pharmaceutically acceptable derivatives thereof.
  • LG 1 and LG 2 are leaving groups for example halo, eg chlorine, LG 3 is a leaving group for example Ci_ 6 alkyl e.g methyl or ethyl, PG is hydrogen or an alkaline metal ion eg Na + and Xi, R 1 , R 2 , R 6 , R 12 and R 13 are as defined for compounds of formula (XI).
  • R 1 , R z , R", R , 1 1 0 U , O RU u , R 12 and R 13 are as defined for compounds of formula (XII) and LG is a leaving group for example halo, e.g chloro, and PG is a protecting group for example Ci_ 6 alkyl ester e.g. methyl ester.
  • R 1 , R 2 , R 6 , R 10 , R 11 , R 13 are as defined for compounds of formula (XII), LG 1 is a leaving group for example halo, e.g chloro, LG 2 is a leaving group for example halo, e.g iodo and PG 1 is a protecting group for example COOt-butyl.
  • Compounds of formula (XII) wherein X 4 is S or SO 2 can be prepared as described in Schemes 2c and 2d.
  • R 1 , R 2 , R 6 , R 10 , R 11 , R 12 and R 13 are as defined for compounds of formula (XII) and LG is a leaving group for example halo, e.g chloro, PG is a protecting group for example Q 6 alkyl ester e.g. methyl ester or ethyl ester.
  • R 1 , R 2 , R 6 , R 10 , R u , R 13 are as defined for compounds of formula (XII) and LG 1 is a leaving group for example halo, e.g chloro, LG 2 is a leaving group for example halo e.g iodo, PG 1 is a protecting group for example CO 2 - ⁇ -butyl.
  • Compounds of formula (XII) wherein X 4 is NHCH 2 such that R 6 X 4 is R 6 CH 2 NH can be prepared as described in Scheme 2e. Scheme 2e:
  • R 1 , R 2 , R 6 , R 10 , R u , R 12 and R 13 are as defined for compounds of formula (XII) and LG is a leaving group for example halo, e.g chloro, PG is a protecting group for example Ci_ 6 alkyl ester e.g. methyl ester or ethyl ester.
  • R 1 , R 2 , R 6 , R 10 , R 11 , R 12 and R 13 are as defined for compounds of formula (XII) and LG is a leaving group for example halo, e.g chloro, PG is a protecting group for example C ⁇ alkyl ester e.g. methyl ester or ethyl ester.
  • R 1 , R 2 , R 6 , R 10 , R 11 , R 12 , R 13 are as defined for compounds of formula (XII) and LG is a leaving group for example halo, e.g chloro, PG is a protecting group for example Ci_ 6 alkyl ester e.g. methyl ester or ethyl ester.
  • Compounds of formula (XII) where X 4 is a bond can be prepared as described in Scheme
  • R 1 , R 2 , R 6 , R 10 , R u , R 13 are as defined for compounds of formula (XII) and LG 1 is a leaving group for example halo, e.g chloro, LG 2 is a leaving group for example halo, e.g. iodo, PG 1 is a protecting group for example -CCh-Autyl.
  • LG 1 and LG 2 represent leaving groups.
  • compounds of formula (XXI) either LG 1 and LG 2 both represent bromine or LG 1 represents iodine and LG 2 represents chlorine.
  • Compounds of formula (XIII) are conveniently prepared by treating a compound of formula (XIX) wherein LG 2 represents bromo or chloro with an amine of formula (XVII). This is conveniently carried out in the presence of a base, such as a tertiary amine (e.g. triethylamine) and in a solvent, such as a nitrile (e.g. methylnitrile) at elevated temperature with or without microwave irradiation. An excess of the amine may be used in place of the base. The reaction can be carried out in a sealed system.
  • a base such as a tertiary amine (e.g. triethylamine)
  • a solvent such as a nitrile (e.g. methylnitrile)
  • amine of formula (XVIII) is carried out in a solvent, such as an amine (e.g. pyridine) and at elevated temperature (e.g. reflux.)
  • Amines of formula (XVIII) are either known compounds or may be prepared by standard literature methods, such as those described in 'Comprehensive Organic Transformations: a guide to functional group preparations' by Richard Larock (VCH, 1989), incorporated herein by reference. 3-oxa-8-azabicyclo[3.2.1]octane may be prepared according to the method described by J. v. Braun and W. Leistner in Chem. Ber. 1926, 59, 2327.
  • Compounds of formula (XIX) may be available commercially or may be obtained from compounds of formula (XXI), e.g. 3,6-dibromopyridazine or 3-chloro-6-iodopyridazine, by treatment with a compound of formula (XX) wherein Ar is as defined for compounds of formula (XIII) and M is a metal for example boron, via a Suzuki coupling reaction employing a palladium source, such as palladium tetrakis(triphenylphosphine) Pd(PPh 3 ) 4 or tris(dibenzylideneacetone)dipalladium Pd 2 (dba) 3 , a ligand, such as triphenylphosphine or tri(tert- butyl)phosphine, and a base, such as sodium carbonate, potassium phosphate or potassium fluoride, in a solvent such as a water/toluene mix, a water/ 1 ,
  • Boronate esters or boronic acids of formula (XX) are either known compounds or may be prepared by standard literature methods, such as those described by T. Ishiyama, M. Murata, and N. Miyaura in J. Org. Chem. 1995, 60, 7508, or A. V. Ivachtchenko, D. V. Kravchenko, V. I. Zheludeva and D. G. Pershin in J. Heterocyclic Chem. 2004, 41, 931, or R. L. Letsinger and S, H, Dandegaonker in J. Am. Chem. Soc. 1959, 81, 498.
  • 3-Chloro-6- iodopyridazine is readily obtained from 2,6-dichloropyridazine by treatment with sodium iodide and hydriodic acid, according to the method described by AJ. Goodman, S. P. Stanforth and B. Tarbit in Tetrahedron 1999, 55, 15067.
  • Compounds of formula (XXII) may be obtained by treating a compound of formula (XIX) wherein LG 2 is bromo, with sodium iodide in the presence of a catalytic quantity of a copper (I) salt, such as copper (I) iodide and a diamine ligand, such as ?ran,y-7V r /V-dimethyl-l,2- cyclohexanediamine.
  • a copper (I) salt such as copper (I) iodide
  • a diamine ligand such as ?ran,y-7V r /V-dimethyl-l,2- cyclohexanediamine.
  • the reaction is conveniently carried out in a solvent, such as 1,4-dioxane and at elevated temperature according, for example, to the method described by A. Klapars and S. L. Buchwald in J. Am. Chem. Soc. 2002, 124, 14844.
  • X represents a leaving group selected from chloro or bromo.
  • Compounds of formula (XXIII) may be converted to compounds of formula (XIII) by treatment with a compound of formula (XX) wherein Ar is as defined for compounds of formula (XIII) and M is a metal for example boron, via a Suzuki coupling reaction employing a palladium source, such as palladium tetrakis(triphenylphosphine) Pd(PPli 3 ) 4 or tris(dibenzylideneacetone)dipalladium Pd 2 (dba) 3 , a ligand, such as triphenylphosphine or tri(tert-butyl)phosphine, and a base, such as sodium carbonate, potassium phosphate or potassium fluoride, in a solvent such as a water/toluene mix, a water/1, 2-dimethoxyethane mix or 1,4-dioxane.
  • Compounds of formula (XXIII) are conveniently prepared by treating a compound of formula (XXIV) with an amine of formula (XVIII). This is conveniently carried out in the presence of a base, such as a tertiary amine (e.g. triethylamine) and in a solvent, such as a nitrile (e.g. methylnitrile) in a sealed system at elevated temperature (e.g. from approx 5O 0 C to 16O 0 C) with microwave irradiation. An excess of the amine may be used in place of the base.
  • a base such as a tertiary amine (e.g. triethylamine)
  • a solvent such as a nitrile (e.g. methylnitrile) in a sealed system at elevated temperature (e.g. from approx 5O 0 C to 16O 0 C) with microwave irradiation.
  • elevated temperature e.g. from approx 5O 0 C to
  • Boronic acids or boronate esters of formula (II) are either known compounds or may be prepared by standard literature methods, such as those described by T. Ishiyama, M. Murata, and N. Miyaura in J. Org. Chem. 1995, 60, 7508 or A. V. Ivachtchenko, D. V. Kravchenko, V. I. Zheludeva and D. G. Pershin in J. Heterocyclic Chem. 2004, 41, 931, or R. L. Letsinger and S, H, Dandegaonker in J. Am. Chem. Soc. 1959, 81, 498.
  • Compounds of formula (XXVI) may be obtained from e.g.
  • Compounds of formula (XIV) may be interconverted by treatment of compounds of formula (XIV) with a compound of formula (XXIX) wherein R 7 is methyl and Y is a leaving group such as a halogen e.g. iodo, bromo in the presence of a base, such as sodium hydride and in a solvent, such as /V,/V-dimethylformamide and at between 0 0 C and elevated temperature.
  • a halogen e.g. iodo, bromo
  • Compounds of formula (XXVI) may be converted to compounds of formula (XXX) by treatment with a compound of formula (XXXI), wherein PG is a protecting group and M is a metal such as boron, for example using the compound (l- ⁇ [(l,l-dimethylethyl)oxy]carbonyl ⁇ -l/7-pyrrol- 2-yl)boronic acid via a Suzuki coupling reaction employing a palladium source, such as palladium tetrakis(triphenylphosphine) Pd(PPli 3 ) 4 or tris(dibenzylideneacetone)dipalladium Pd 2 (dba) 3 , a ligand, such as triphenylphosphine or tri(tert-butyl)phosphine, and a base, such as sodium carbonate, potassium phosphate or potassium fluoride, in a solvent such as a water/toluene mix, a water/1, 2-dimeth
  • Process (a) typically comprises the use of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride in a suitable solvent such as ethanol, dichloromethane or 1 ,2- dichloroethane.
  • a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride
  • a suitable solvent such as ethanol, dichloromethane or 1 ,2- dichloroethane.
  • Process (b) is typically carried out in the presence of a base such as triethylamine or an excess of tthhee ccoommppoouunndd ooff ffoorrmmuullaa HHNNRR 11 RR 22 iinn aa ssuuiittaabbllee ssoollvveenntt ssuucchh aass aa Ci_ ⁇ alcohol (e.g. isopropanol), optionally at elevated temperature (e.g. under reflux conditions).
  • a base such as triethylamine or an excess of tthhee ccoommppoouunndd ooff ffoorrmmuullaa HHNNRR 11 RR 22 iinn aa ssuuiittaabbllee ssoollvveenntt ssuucchh aass aa Ci_ ⁇ alcohol (e.g. isoprop
  • Suitable amine protecting groups include sulphonyl (e.g. tosyl), acyl (e.g. acetyl, 2',2',2'- trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g. using an acid such as hydrochloric acid) or reductively (e.g.
  • Suitable amine protecting groups include trifluoroacetyl (-COCF 3 ) which may be removed by base catalysed hydrolysis or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker), which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid.
  • a further amine protecting group includes methyl which may be removed using standard methods for N-dealkylation (e.g. 1 -chloroethyl chloro formate under basic conditions followed by treatment with methanol).
  • Process (d) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, reductive alkylation, alkylation, nucleophilic or electrophilic aromatic substitution, ester hydrolysis or amide bond formation.
  • interconversion procedures such as epimerisation, oxidation, reduction, reductive alkylation, alkylation, nucleophilic or electrophilic aromatic substitution, ester hydrolysis or amide bond formation.
  • ,/V-dealkylation of a compound of formula (XV) wherein R 1 or R 2 represents an alkyl group to give a compound of formula (XV) wherein R 1 or R 2 represents hydrogen.
  • interconversion may be interconversion of protected derivatives of formula (XV) which may subsequently be deprotected following interconversion.
  • process (d) may also comprise, for example, reacting a compound of formula (XV), wherein R 1 or R 2 represents hydrogen, with an aldehyde or ketone in the presence of a reducing agent in order to generate a compound of formula (XV) where R 1 or R 2 represents Ci-salkyl.
  • a hydride donor agent such as sodium cyanoborohydride, sodium triacetoxyborohydride or a resin bound form of cyanoborohydride in an alcoholic solvent such as ethanol and in the presence of an acid such as acetic acid, or under conditions of catalytic hydrogenation.
  • such a transformation may be carried out by reacting a compound of formula (XV), wherein R 1 or R 2 represents hydrogen, with a compound of formula R la -L or R 2a -L, wherein R la and R 2a represent and L represents a leaving group such as a halogen atom (e.g. bromine or iodine) or methylsulfonyloxy group, optionally in the presence of a suitable base such as potassium carbonate or triethylamine using an appropriate solvent such as N, N- dimethylformamide or a Ci_ 4 alkanol.
  • a suitable base such as potassium carbonate or triethylamine
  • an appropriate solvent such as N, N- dimethylformamide or a Ci_ 4 alkanol.
  • R 3 , R 4 , R 5 , n and A are as defined for formula (XV) and p represents 0 to 3.
  • a process may be effected using ozone in a suitable solvent such as dichloromethane in the presence of a Ci_ 4 alkanol (e.g. methanol), followed by reductive work-up, for example using thiourea or dimethyl sulfide, then hydrolysis of the intermediate acetal or ketal under acid conditions, for example using a dilute aqueous mineral acid such as hydrochloric or sulfuric acid, or an organic acid such as trifluoroacetic acid in a suitable solvent such as dichloromethane.
  • a suitable solvent such as dichloromethane
  • a Ci_ 4 alkanol e.g. methanol
  • Compounds of formula (XXXIV) may be prepared according to the following process: wherein R 3 , R 4 , R 5 , n and A are as defined for formula (XV) and p represents O to 3, L 2 represents a leaving group such as a bromine or iodine atom or a trifluoromethylsulfonyloxy group and M is a metal residue such as trialkylstannyl, e.g. tributylstannyl.
  • Step (i) typically comprises the use of palladium such as palladium (II) acetate and a ligand such as fr ⁇ -(2-furyl)phosphine using an appropriate solvent such as 1,4-dioxane.
  • palladium such as palladium (II) acetate
  • a ligand such as fr ⁇ -(2-furyl)phosphine
  • an appropriate solvent such as 1,4-dioxane
  • XXXVII in the presence of a palladium catalyst such as palladium (II) acetate, a base such as sodium hydrogen carbonate and an additive such as tetrabutylammonium chloride in a suitable solvent such as 7V,7V-dimethylformamide.
  • a palladium catalyst such as palladium (II) acetate
  • a base such as sodium hydrogen carbonate
  • an additive such as tetrabutylammonium chloride in a suitable solvent such as 7V,7V-dimethylformamide.
  • Compounds of formula (XXXIII) may be prepared by reduction of compounds of formula (XXXII) as defined above using a suitable reducing agent such as sodium borohydride, then conversion of the resulting alcohol to leaving group L using standard methodology, for example using methylsulfonyl chloride in the presence of a suitable base such as pyridine in an appropriate solvent.
  • a suitable reducing agent such as sodium borohydride
  • Step (i) typically comprises the coupling of a compound of formula (XXXV) wherein R 3 , R 4 , R 5 , n and A are as defined for formula (XV) and L 2 represents a leaving group such as a bromine or iodine atom or a trifluoromethylsulfonyloxy group, with a metallovmyl compound of formula (XXXVIII) where q represents 0 to 2 and M is a metal residue such as trialkylstannyl, e.g tributylstannyl using a palladium catalyst such as dichloro Zr ⁇ (triphenylphosphine) palladium (II) in an appropriate solvent such as toluene
  • Step (ii) is the hydrolysis of the first formed vinyl ether using, for example, an aqueous mineral acid such as hydrochloride acid or an aqueous organic acid such as trifluoroacetic acid or formic acid
  • an aqueous mineral acid such as hydrochloride acid
  • an aqueous organic acid such as trifluoroacetic acid or formic acid
  • Step (iii) comprises the reductive animation of compound (XXXIX) with an amine of formula R 1 R 2 NH wherein R 1 and R 2 are as defined above
  • a hydride donor agent such as sodium cyanoborohydride, sodium triacetoxyborohydride or a resin bound form of cyanoborohydride in suitable solvent such as dichloromethane, 1,2-dichloroethane or ethanol and in the presence of an acid such as hydrochloric acid or acetic acid, or under conditions of catalytic hydrogenation.
  • a dehydrating agent such as molecular sieves
  • a cerium salt such as cerium chloride
  • R 1 , R 2 , R 3 , R 4 , R 5 , n and A are as defined for formula (XV).
  • Step (i) comprises dissolving a compound of formula (XLI) and a compound of formula HNR 1 R 2 in an appropriate solvent, for example dichloromethane, adding sodiumtriacetoxyborohydride and acetic acid, and then leaving the reaction to progress under an inert atmosphere, for example argon.
  • an appropriate solvent for example dichloromethane
  • Step (ii) comprises reacting a compound of formula (XLII) with a compound of formula A-SO 2 -H or a suitable salt thereof in the presence of a base, for example potassium carbonate, a metal catalyst, for example copper (I) iodide, and a diamine ligand, for example NN- dimethylethylenediamine , using an appropriate solvent such as dimethylsulfoxide.
  • a base for example potassium carbonate
  • a metal catalyst for example copper (I) iodide
  • a diamine ligand for example NN- dimethylethylenediamine
  • R 1 , R 2 , R 3 , R 4 , n, X and A are as defined for formula (XVI) and L 1 represents a suitable leaving group, such as a halogen atom (e.g. a fluorine, bromine or iodine atom) or a trifluoromethylsulfonyloxy group.
  • a halogen atom e.g. a fluorine, bromine or iodine atom
  • a trifluoromethylsulfonyloxy group such as a halogen atom (e.g. a fluorine, bromine or iodine atom) or a trifluoromethylsulfonyloxy group.
  • process (a) when L 1 represents a fluorine atom, the process is typically carried out in the presence of a base such as potassium carbonate, and an appropriate solvent such as dimethylsulphoxide.
  • a base such as potassium carbonate
  • an appropriate solvent such as dimethylsulphoxide
  • Process (a) may be performed in the presence of a palladium, nickel or copper catalyst, for example a mixture of a palladium source such as Pd 2 (dba) 3 and a suitable ligand such as (R)-, (S)- or (+)- 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl (BINAP) or (2-dicyclohexylphosphanylphenyl)- dimethylamine or 1 , 1 '-bis-diphenylphosphino ferrocene, together with a suitable base such as sodium ?-butoxide, in an inert solvent such as 1,4-dioxane.
  • a palladium source such as Pd 2 (dba) 3
  • a suitable ligand such as (R)-, (S)- or (+)- 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl (BINA
  • a compound of formula A-SO2-M wherein R 2 , R 3 , R 4 , n and A are as defined for formula (XVI) and M is a metal residue such as sodium or potassium, in the presence of a copper (I) salt, e.g. copper (I) iodide, in a suitable solvent such as dimethylsulfoxide, optionally including a ligand such as N,N'-dimethyl -ethylene- 1,2-diamine.
  • R , R , R and n are as defined for formula (XVI), with an iodinating agent, which can act as a source of electrophilic iodine, e.g. N-iodosuccinimide, in the presence of a solvent, e.g. acetic acid.
  • an iodinating agent which can act as a source of electrophilic iodine, e.g. N-iodosuccinimide, in the presence of a solvent, e.g. acetic acid.
  • Compounds of formula (XLVI) may be obtained from Orgasynth (www.orgasynth.com) or can be prepared by analogous methods.
  • R 1 , R 2 , R 6 , R 12 , R 13 and R 14 are as defined for compounds of formula (XVII) above or are groups convertible thereto and LG is a suitable leaving group, such as a halogen atom (e.g. fluorine, chlorine, bromine or iodine) or triflate group.
  • This process typically comprises the use of a suitable acid such as methanesulfonic acid, in a suitable solvent such as 1,4-dioxane at elevated temperature such as 180 0 C and under microwave conditions.
  • the group of formula (XLVIII) is an amine group i.e.
  • R 6 is a unsubstituted or substituted C 3 _ 6 cycloalkyl or an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl ring, the use of an acid and a separate solvent is optional.
  • XLVII wherein R , R , R , R , R and R are as defined for compounds of formula (XVII) above or are groups convertible thereto and LG is a suitable leaving group, such as a halogen atom (e.g. fluorine, chlorine, bromine or iodine) or triflate group.
  • a halogen atom e.g. fluorine, chlorine, bromine or iodine
  • XLIX is first deprotonated by a strong base such as sodium hydride. This process typically comprises the use of a suitable solvent such as N,N-dimethylformamide and is carried out at elevated temperature such as 18O 0 C under microwave conditions.
  • R 1 , R 2 , R 6 , R 12 , R 13 and R 14 are as defined for compounds of formula (XVII) above or are groups convertible thereto and LG is a suitable leaving group, such as a halogen atom (e.g. fluorine, chlorine, bromine or iodine) or triflate group.
  • a halogen atom e.g. fluorine, chlorine, bromine or iodine
  • the group of formula (L) is first deprotonated by a strong base such as sodium hydride. This process typically comprises the use of a suitable solvent such as N,N-dimethylformamide and is carried out at elevated temperature such as 180 0 C under microwave conditions.
  • Suitable oxidising agents for use when X 1 is SO or SO 2 include 3-chloroperoxybenzoic acid and a suitable solvent for use in the oxidation step is dichloromethane.
  • LG is a suitable leaving group, such as a halogen atom (e.g. fluorine, chlorine, bromine or iodine) or triflate group.
  • a suitable tertiary base e.g. N-ethyl diisopropylamine or N-ethylmorpholine and a coupling agent e.g.
  • a suitable solvent for carrying out this coupling reaction is N,N-dimethylformamide.
  • LG is a suitable leaving group, such as a halogen atom (e.g. fluorine, chlorine, bromine or iodine) or triflate group
  • PG is a is a protecting group such as Ci- 6 alkyl for example methyl or ethyl.
  • Step A react (LX) and (LIX) (e.g. ethylbromo acetate) in the presence of a base e.g. sodium hydride to give (LVIII).
  • a base e.g. sodium hydride
  • Step B react (LVIII) and e.g. ethylformate in the presence of a strong base to give (LVII)
  • Step C react (LVII) and (LVI) e.g. ammonium acetate under reflux to give (LV).
  • Step D ring formation in the presence of a strong base e.g. sodium tert-butoxide at elevated temperature (e.g. 160 c C) under microwave to give (LIV).
  • Step E add leaving group e.g. by reaction of (LIV) with phenyldichlorophosphate at elevated tempterature (e.g. 170 0 C).
  • Step F deprotect e.g. using 2N sodium hydroxide.
  • references herein to compounds of formula (I) to (XVII) encompass all isomers, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). Where additional chiral centres are present in the compounds, all possible diastereoisomers, including mixtures thereof are included.
  • the different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
  • the compounds of formula (I) - (XVII) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be solvated.
  • References to solvates herein include hydrates. This invention includes within its scope the use of stoichiometric solvates (including hydrates) as well as compounds containing variable amounts of water and/or solvent.
  • the combinations of the present invention may be useful in the treatment of the disorders that follow.
  • the combinations of the invention may be useful as analgesics.
  • they may be useful in the treatment of chronic inflammatory pain (e.g. pain associated with rheumatoid arthritis, osteo-arthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis) including the property of disease modification and joint structure preservation; musculoskeletal pain; lower back and neck pain; sprains and strains; neuropathic pain; sympathetically maintained pain; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; post operative pain; headache; toothache; and dysmenorrhea.
  • the combinations of the invention may also be useful disease modification or joint structure preservation in multiple sclerosis, rheumatoid arthritis, osteo-arthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis.
  • the combinations of the invention may be particularly useful in the treatment of neuropathic pain.
  • Neuropathic pain syndromes can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain. Neuropathic pain syndromes are traditionally classified according to the disease or event that precipitated them.
  • Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HlV-related neuropathy; post-herpetic neuralgia; trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions. These conditions are difficult to treat and although several drugs are known to have limited efficacy, complete pain control is rarely achieved. The symptoms of neuropathic pain are incredibly heterogeneous and are often described as spontaneous shooting and lancinating pain, or ongoing, burning pain.
  • the combinations of the invention may also be useful in the treatment of fever.
  • the combinations of the invention may also be useful in the treatment of inflammation, for example in the treatment of skin conditions (e.g. sunburn, burns, eczema, dermatitis, psoriasis); ophthalmic diseases such as glaucoma, retinitis, retinopathies, uveitis and of acute injury to the eye tissue (e.g. conjunctivitis); lung disorders (e.g. asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease, (COPD); gastrointestinal tract disorders (e.g.
  • skin conditions e.g. sunburn, burns, eczema, dermatitis, psoriasis
  • ophthalmic diseases such as glaucoma, retinitis, retinopathies, uveitis and of acute injury to the eye tissue (e.
  • an inflammatory component such as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anaemia
  • the combinations of the invention may also be useful in the treatment of bladder hyperrelexia following bladder inflammation.
  • the combinations of the invention may also be useful in the treatment of immunological diseases such as autoimmune diseases, immunological deficiency diseases or organ transplantation.
  • immunological diseases such as autoimmune diseases, immunological deficiency diseases or organ transplantation.
  • the combinations of the invention are also effective in increasing the latency of HIV infection.
  • the combinations of the invention may also be useful in the treatment of diseases of abnormal platelet function (e.g. occlusive vascular diseases).
  • the combinations of the invention may also be useful in the treatment of neuritis, heart burn, dysphagia, pelvic hypersensitivity, urinary incontinence, cystitis or pruritis.
  • the combinations of the invention may also have diuretic action.
  • the combinations of the invention may also be useful in the treatment of impotence or erectile dysfunction.
  • the combinations of the invention may also be useful for attenuating the hemodynamic side effects of non-steroidal anti-inflammatory drugs (NSAID's) and cyclooxygenase-2 (COX-2) inhibitors.
  • NSAID's non-steroidal anti-inflammatory drugs
  • COX-2 cyclooxygenase-2
  • the combinations of the invention may also be useful in the treatment of neurodegenerative diseases and neurodegeneration such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); dementia in Parkinson's disease; metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment.
  • the compounds may also be useful for the treatment of amyotrophic lateral sclerosis (ALS) and neuroinflamation.
  • ALS amyotrophic lateral sclerosis
  • the combinations of the invention may also be useful in neuroprotection and in the treatment of neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.
  • the combinations of the invention may also be useful in the treatment of tinnitus.
  • the combinations of the invention may also be useful in the treatment of psychiatric disease for example schizophrenia, depression (which term is used herein to include bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder, dysthymic disorders with early or late onset and with or without atypical features, neurotic depression and social phobia, depression accompanying dementia for example of the Alzheimer's type, schizoaffective disorder or the depressed type, and depressive disorders resulting from general medical conditions including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion, etc), anxiety disorders (including generalised anxiety disorder and social anxiety disorder), panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder, memory disorders, including dementia, amnesic disorders and age-associated memory
  • the combinations of the invention may also be useful in preventing or reducing dependence on, or preventing or reducing tolerance or reverse tolerance to, a dependence - inducing agent.
  • dependence inducing agents include opioids (e.g. morphine), CNS depressants (e.g. ethanol), psychostimulants (e.g. cocaine) and nicotine.
  • kidney dysfunction nephritis, particularly mesangial proliferative glomerulonephritis, nephritic syndrome
  • liver dysfunction hepatitis, cirrhosis
  • gastrointestinal dysfunction diarrhoea
  • colon cancer a further aspect of the invention
  • a method of treating a human or animal subject suffering from an immune disorder, an inflammatory disorder, pain, rheumatoid arthritis, multiple sclerosis, osteoarthritis, or osteoporosis which method comprises administering to said subject an effective combination of one or more CB2 modulators and paracetamol (acetaminophen) .
  • a combination of one ore more CB2 modulators a pharmaceutically acceptable derivate thereof and paracetamol (acetaminophen) or a pharmaceutically acceptable derivate thereof for the manufacture of a therapeutic agent for the treatment or prevention of a condition such as an immune disorder, an inflammatory disorder, pain, rheumatoid arthritis, multiple sclerosis, osteoarthritis, or osteoporosis.
  • a condition such as an immune disorder, an inflammatory disorder, pain, rheumatoid arthritis, multiple sclerosis, osteoarthritis, or osteoporosis.
  • the pain is selected from inflammatory pain, viseral pain, cancer pain, neuropathic pain, lower back pain, musculoskeletal pain, post operative pain, acute pain and migraine. More preferably the inflammatory pain is pain associated with rheumatoid arthritis or osteoarthritis.
  • a combination of the invention for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect of the invention is provided a pharmaceutical composition comprising one or more CB2 modulators and paracetamol (acetaminophen) adapted for use in human or veterinary medicine.
  • modulator means both antagonist, full or partial agonist and inverse agonist.
  • modulators are agonists.
  • treatment or “treating” as used herein includes the treatment of established disorders and also includes the prophylaxis thereof.
  • prophylaxis is used herein to mean preventing symptoms in an already afflicted subject or preventing recurrance of symptoms in an afflicted subject and is not limited to complete prevention of an afflication.
  • Combinations of the invention may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parentarally, sub-lingually, dermally, intranasally, transdermally, rectally, via inhalation or via buccal administration.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavouring or colouring agent.
  • a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavouring or colouring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • composition is in the form of a soft gelatin shell capsule
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of a compound or derivative in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • a parenterally acceptable oil for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
  • a typical suppository formulation comprises a combination of the invention which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs.
  • Typical dermal and transdermal formulations comprise a conventional aqueous or nonaqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.
  • dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • each dosage unit for oral administration contains suitably from 0.001 mg to 500 mg, for example 0.01 mg to 500 mg such as from 0.01 mg to 100 mg, and each dosage unit for parenteral administration contains suitably from 0.001 mg to 100 mg, of a compound of formula (I) - (XVII) or a pharmaceutically acceptable derivative thereof calculated as the free acid (underivatised compound).
  • Each dosage unit for suppository administration contains suitably from 0.001 mg to 500 mg, for example 0.01 mg to 500 mg such as from 0.01 mg to 100 mg.
  • Each dosage unit for intranasal administration contains suitably 1-400 mg and suitably 10 to 200 mg per person.
  • a topical formulation contains suitably 0.01 to 5.0% of a compound of formula (I) - (XVII).
  • the daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 1000 mg/Kg, of a compound of formula(I) or a pharmaceutically acceptable derivative thereof calculated as the free acid (underivatised compound).
  • the daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 200 mg/Kg, of a compound of formula (I) - (XVII) or a pharmaceutically acceptable derivative thereof calculated as the free acid (underivatised compound).
  • the daily dosage regimen for suppository administration is suitably about 0.01 mg/Kg to 1000 mg/Kg, of a compound of formula(I) - (XVII) or a pharmaceutically acceptable derivative thereof calculated as the free acid (underivatised compound).
  • the daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to about 500 mg/person.
  • the active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity.
  • a suitable daily dosage of paracetamol is up to 4000mg per day.
  • Suitable unit doses include 200, 400, 500 and lOOOmg, one, two, three or four times per day.
  • the pharmaceutical composition as hereinbefore defined further comprises
  • HPMC present in less than 15% w/w, preferably in the range 0.1 to 10% w/w.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • a further aspect of the invention is a patient pack comprsing an effective combination of one or more CB2 modulators and paracetamol (acetaminophen).
  • Yeast (Saccharomyces cerevisiae) cells expressing the human cannabinoid CBl receptor were generated by integration of an expression cassette into the ura3 chromosomal locus of yeast strain MMY23.
  • This cassette consisted of DNA sequence encoding the human CBl receptor flanked by the yeast GPD promoter to the 5' end of CBl and a yeast transcriptional terminator sequence to the 3' end of CBl.
  • MMY23 expresses a yeast/mammalian chimeric G-protein alpha subunit in which the C-terminal 5 amino acids of Gpal are replaced with the C-terminal 5 amino acids of human G ⁇ il/2 (as described in Brown et al. (2000), Yeast 16: 11-22).
  • Cells were suspended at a density of 0.2 OD 6 oo/ml in SC media lacking histidine, uracil, tryptophan, adenine and leucine and supplemented with 1OmM 3-aminotriazole, 0.1M sodium phosphate pH 7.0, and lO ⁇ M fluorescein di- ⁇ -D- glucopyranoside (FDGIu). This mixture (50ul per well) was added to agonist in the assay plates (Multidrop 384, Labsystems).
  • fluorescence resulting from degradation of FDGIu to fluorescein due to exoglucanase, an endogenous yeast enzyme produced during agonist-stimulated cell growth was determined using a fluorescence microtitre plate reader (Tecan Spectrofluor or LJL analyst excitation wavelength: 485nm; emission wavelength: 535nm). Fluorescence was plotted against compound concentration and iteratively curve fitted using a four parameter fit to generate a concentration effect value.
  • E max Max [ ⁇ mp ound x] - Min [com p OU nd x] / MaX[HU2io] - Mhipimo] x 100% where Max[ compoun d xj and Min[ compO und x] are the fitted maximum and minimum respectively from the concentration effect curve for compound X, and MaX[HU2io] and Min[HU2io] are the fitted maximum and minimum respectively from the concentration effect curve for (6aR,10aR)-3-(l,l'- Dimethylheptyl)-6a,7, 10,1 Oa-tetrahydro-1 -hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9- methanol (HU210; available from Tocris). Equieffective molar ratio (EMR) values were calculated from the equation
  • EC 50 [compound x] is the EC 50 of compound X and EC 50 [HmIO] is the EC 50 of HU210.
  • Examples 93 to 156 tested according to this method had pEC 50 values of less than or equal to 5 and/or efficacy of ⁇ 30% at the cloned human cannabinoid CBl receptor, with the exception of Examples 94, 95 and 110 which had pEC 50 values of between 5 and 5.6.
  • Yeast (Saccharomyces cerevisiae) cells expressing the human cannabinoid CB2 receptor were generated by integration of an expression cassette into the ura3 chromosomal locus of yeast strain MMY23.
  • This cassette consisted of DNA sequence encoding the human CB2 receptor flanked by the yeast GPD promoter to the 5' end of CB2 and a yeast transcriptional terminator sequence to the 3' end of CB2.
  • MMY23 expresses a yeast/mammalian chimeric G-protein alpha subunit in which the C-terminal 5 amino acids of Gpal are replaced with the C-terminal 5 amino acids of human G ⁇ il/2 (as described in Brown et al. (2000), Yeast 16: 11-22).
  • Agonists were prepared as 10 mM solutions in DMSO. EC 50 values (the concentration required to produce 50% maximal response) were estimated using 4 fold dilutions (BiomekFX, Beckman) into DMSO. Agonist solutions in DMSO (1% final assay volume) were transferred into black microtitre plates from Greiner (384-well). Cells were suspended at a density of 0.2 OD 6 oo/ml in SC media lacking histidine, uracil, tryptophan, adenine and leucine and supplemented with 1OmM 3-aminotriazole, 0.1M sodium phosphate pH 7.0, and lO ⁇ M fluorescein di- ⁇ -D- glucopyranoside (FDGIu).
  • FDGIu lO ⁇ M fluorescein di- ⁇ -D- glucopyranoside
  • E max Max [ ⁇ mpound x] - Min [compound x] / MaX [H u 2I0] - Minpujio ] x 100%
  • MaX [compound x] and Min [ ⁇ mpound x] are the fitted maximum and minimum respectively from the concentration effect curve for compound X
  • MaX [ HU2io ] and Min [ HU2io ] are the fitted maximum and minimum respectively from the concentration effect curve for (6aR,10aR)-3-(l,l'- Dimethylheptyl)-6a,7, 10,1 Oa-tetrahydro-1 -hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9- methanol (HU210; available from Tocris).
  • Equieffective molar ratio (EMR) values were calculated from the equation
  • EC50 [compound x] is the EC50 of compound X and EC5O [HU2io] is the EC 5 o ⁇ f HU210.
  • the compounds of Examples 1 to 22, 23, 56, 59, 60, 62, 64-79 and 82-84 were tested according to this method and had EC 50 values of ⁇ 300nM and efficacy value of >50% at the cloned human cannabinoid CB2 receptor.
  • Example 57, 63 and 80 tested according to this method had an EC50 values between 30OnM and 100OnM and efficacy value of >50% at the cloned human cannabinoid CB2 receptor.
  • the compounds of Examples 61, 81 and 85 to 92 tested according to this method had an EC 50 values >1000nM and/or efficacy value ⁇ 50% at the cloned human cannabinoid CB2 receptor.
  • Example 58 The compound of Example 58 was not tested.
  • the compounds of Examples 93 to 119 and 144 to 148 as tested according to this method had PEC 50 values of greater than 6.5 units and efficacy of >50% at the cloned human cannabinoid CB2 receptor.
  • the compounds of Examples 120 to 129, 149 and 150 had pEC 5 o values of 6 to 6.5 units and the compounds of Examples 130 to 140, and 151 to 156 had pEC 50 values of up to 6 units at the cloned human cannabinoid CB2 receptor.
  • the compounds of Examples 157-165, 176 and 179-209 were tested for cannabinoid CB2 receptor agonist activity.
  • the compounds of Examples 158, 160, 161, 176, 181, 183, 184, 186, 188- 197, 199-203 and 205-209 had pEC50 values > 6 at the CB2 receptor.
  • the compounds of Examples 157, 162-165, 179-180, 182, 185, 187, 198 and 204 had pEC50 values > 5 at the CB2 receptor.
  • the compound of Example 159 had a pEC50 value ⁇ 4.5 at the CB2 receptor.
  • the compounds of Examples 166-175 and 177-178 were not tested for cannabinoid CB2 receptor agonist activity.
  • the compounds of Examples 1 to 22 tested according to the above methods had an EMR of greater than 100 in the CBl yeast receptor assay and an EMR of less than 100 in the CB2 yeast receptor assay.
  • Compounds of Examples 1-5, and 7-22 had at least a tenfold lower EMR for CB2 over CBl .
  • the compounds of Examples 210-243 tested according to the above methods had an EMR of between 1 and 3000 in the CBl yeast receptor assay and an EMR of between 0.1 and 100 in the CB2 yeast receptor assay.
  • Compounds of Examples 211-224, 228-234, 236, 237, and 239-243 had at least a tenfold lower EMR for CB2 over CB 1.
  • CB2 agonist effects were determined using a reporter gene assay. These studies were performed using a CHO-Kl cell line expressing human recombinant CB2 receptors (CHO-Kl CB2 CRE-LUC cells). These cells additionally express a "CRE-LUC" reporter gene construct comprising the gene for luciferase under the control of multiple cAMP response element binding protein promoters. In these cells, increases in intracellular cAMP levels leads to transcription of the luciferase gene and the subsequent production of luciferase. The expression of luciferase is measured by addition to the cells of a proprietary mixture containing luciferin, the substrate for luciferase (Luclite, Perkin Elmer, Cat No 6016919).
  • CHO-Kl CB2 CRE-LUC cells were grown in DMEM/F12 plus glutamax I medium (Gibco Cat. No. 31331-028), supplemented with 9% FBS (Gibco, Cat. No. 16000-040) and 0.5mg.ml 4 G418 (Gibco, Cat. No. 10131-027) and 0.5mg.ml 4 Hygromycin (Invitrogen, Cat. No. 10687-010).
  • Cells were grown as a monolayer culture in 162cm 2 vented Nunclon flasks (NUNC, Cat. No. 178883) in 27.5ml of media in a humidified 95% air and 5% CO 2 atmosphere at 37°C.
  • the growth media was replaced with DMEM/F 12 medium (Gibco, Cat. No. 31331-028) containing 10OnM of the CB2 inverse agonist, SR144528, and the cells were incubated at 37°C for 30-60mins. Flasks were rinsed twice with 25ml Dulbecco's phosphate buffered saline (PBS, Gibco Cat. No. 14190-094) and then harvested by incubation for lOmins in 10ml of Versene (Gibco, Cat. No.
  • Test agonists were prepared as 1OmM solutions in DMSO and diluted into phenol-red free DMEM/F12 assay buffer containing 2 ⁇ M forskolin to produce a 20 ⁇ M solution of test agonist. Subsequent serial dilutions of test agonist were prepared in the assay buffer containing forskolin and each test agonist was routinely examined over a final assay concentration range of 1 O ⁇ M to 1OnM (or lower if required).
  • the plates were mixed on a plate shaker for 5mins (800-1000 rpm) and then centrifuged briefly (5-1Os) at 250xg, placed in a Bioplate without their lids, and incubated for 4-5hr in a humidified 95% air and 5% CO 2 atmosphere at 37 0 C.
  • the 96 well plates were removed from the incubator and placed at RT for 10-15mins before addition of 25 ⁇ l of Luclite solution, prepared according to the manufacturer's instructions.
  • the plates were sealed with Topseal A (Perkin Elmer, Cat. No. 6005185), mixed on a plate shaker for 5mins (800-1000 rpm) and then centrifuged briefly (5-1Os) at 250xg. Finally, luminescence was measured using a Packard TopCount scintillation counter.
  • Vehicle 1% methylcellulose
  • Vehicle 1% methylcellulose
  • Statistica 6 and put into the macro. The fixed dose ratio is specified and the macro then calculates whether the combination was statistically synergistic. It compares the combination data to the theoretical addition of the individual compounds.
  • Figure 1 illustrates the effect of combining 2-(2,4-Dichlorophenylamino)-4- trifluoromethylpyrimidine-5-carboxylic acid (tetrahydropyran-4-ylmethyl) -amide (0.01 mg/kg) and paracetamol (30 mg/kg) alone and in combination on FCA-induced hypersensitivity.
  • Figure 2a illustrates the effects of combining 2-(2,4-Dichlorophenylamino)-4- trifluoromethylpyrimidine-5-carboxylic acid (tetrahydropyran-4-ylmethyl) -amide + paracetamol in a dose response at a fixed dose ratio of 1 :3000 in combination on FCA-induced hypersensitivity.
  • Figure 2b illustrates a theoretical additive dose response curve vs. actual observed dose response curve for an 2-(2,4-Dichlorophenylamino)-4-trifluoromethylpyrimidine-5-carboxylic acid
  • Figure 3 illustrates the effect of combining JV-(3-chlorophenyl)-l-methyl-7-(4- morpholinylcarbonyl)-l/ ⁇ -pyrrolo[3,2-c]pyridin-4-amine (0.01 mg/kg) and paracetamol (30 mg/kg) alone and in combination on FCA-induced hypersensitivity.
  • Figure 4b illustrates a theoretical additive dose response curve vs.
  • Figure 5 illustrates the effect of combining JV-(3-chlorophenyl)-l-methyl-7-(4- morpholinylcarbonyl)-l/ ⁇ -imidazo[4,5-c]pyridin-4-amine (0.25 mg/kg) and paracetamol (30 mg/kg) alone and in combination on FCA-induced hypersensitivity.
  • Figure 6a illustrates the effects of combining JV-(3-chlorophenyl)-l-methyl-7-(4- moipholinylcarbonyl)-l/f-imidazo[4,5-c]pyridin-4-amine + paracetamol in a dose response at a fixed dose ratio of 1 : 120 in combination on FCA-induced hypersensitivity.
  • Figure 6b illustrates a theoretical additive dose response curve vs. actual observed dose response curve for an jV-(3-chlorophenyl)-l-methyl-7-(4-morpholinylcarbonyl)-li7-imidazo[4,5-c]pyridin-4- amine + paracetamol combination in combination on FCA-induced hypersensitivity.
  • MDAP represents mass-directed auto-purification
  • THF represents tetrahydrofuran
  • DCM dichloromethane
  • DMSO dimethyl sulfoxide
  • TFA represents trifluoroacetic acid.
  • DDQ 2,3,-dichloro-5,6-dicyano-l,4-benzoquinone
  • PTFE polytetrafluoroethylene
  • HPLC high performance liquid chromatography
  • the column used is typically a Supelco ABZ+ column whose dimensions are 10mm internal diameter by 100mm in length.
  • the stationary phase particle size is 5 ⁇ m.
  • Needle rinse solvent MeOH: Water: DMSO 80: 10: 10
  • Methods Five methods are used depending on the analytical retention time of the compound of interest.
  • the column used is a Supelcosil ABZ+PLUS, the dimensions of which are 4.6mm x 33mm.
  • the stationary phase particle size is 3m.
  • Aqueous solvent 1 OmMoI Ammonium Acetate + 0.1% Formic Acid
  • the generic method used has 5.5 minute runtime, which comprises of a 4.7-minute gradient (0- 100% B) followed by a 0.6 minute column flush and 0.2 minute re-equilibration step.
  • the above method has a flow rate of 3ml/mins
  • the DCM layers were combined and extracted with water (2x 250ml). The water layer was re-extracted with DCM (200ml). The DCM layers were combined, dried using MgSO 4 . The MgSO 4 was filtered off and the DCM layer was evaporated to give a reddish-brown oil. This solidifies on standing. The solid was taken up into ethanol (150ml) and heated until the solid had gone into solution. The mixture was allowed to cool overnight, the crystals formed were filtered off, washed with cold ethanol (100ml). The crystals were dried in air under vacuum to give ethyl 6- chloro-4-(methylamino)-5-nitro-3-pyridinecarboxylate (52.1g, 69%)
  • Preparation b To ethyl 5-amino-6-chloro-4-(methylamino)-3-pyridinecarboxylate (49.7g, 0.21moles) was added triethylorthoformate (216ml, 1.26moles) and the mixture was heated to reflux for 1 hour. The mixture was allowed to cool and evaporated on a buchi under vacuum to give a thick semi solid. Diethyl ether (500ml) was added to the semi solid and the mixture was stirred at room temperature for 10 minutes.

Abstract

L'invention concerne la combinaison d'au moins un modulateur de CB2 et de paracétamol, utile dans le traitement d'affections induites par l'activité des récepteurs CB2, telles qu'un trouble immunitaire, un trouble inflammatoire, la douleur, la polyarthrite rhumatoïde, la sclérose en plaques, l'arthrose et l'ostéoporose.
PCT/EP2008/053354 2007-03-26 2008-03-20 Combinaison de ligand de cb2 et de paracetamol WO2008116816A1 (fr)

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WO2009124553A3 (fr) * 2008-04-09 2009-12-03 Neurokey A/S Utilisation de médicaments induisant une hypothermie
WO2009124553A2 (fr) * 2008-04-09 2009-10-15 Neurokey A/S Utilisation de médicaments induisant une hypothermie
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