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WO2009019508A1 - Calcium ion channel modulators & uses thereof - Google Patents

Calcium ion channel modulators & uses thereof Download PDF

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Publication number
WO2009019508A1
WO2009019508A1 PCT/GB2008/050652 GB2008050652W WO2009019508A1 WO 2009019508 A1 WO2009019508 A1 WO 2009019508A1 GB 2008050652 W GB2008050652 W GB 2008050652W WO 2009019508 A1 WO2009019508 A1 WO 2009019508A1
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groups
carbon atoms
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substituted
atoms
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French (fr)
Inventor
Raymond John Boffey
Svenja Burckhardt
Julie Elaine Cansfield
Nawaz Mohammed Khan
Geoff Lawton
David Tickle
Ngoc-Tri Vo
Srinivasan Kanumilli
Jonathan E. H. Buston
Andy Smith
Robert A. J. Wybrow
Roland Zbigniew Kozlowski
Dayle Spencer Hogg
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Lectus Therapeutics Ltd
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Lectus Therapeutics Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to ion channel modulators, and more particularly to compounds which inhibit the interaction between the pore-forming ( ⁇ ) subunits of Cav voltage-gated calcium channels and accessory (Cav ⁇ subunit) proteins.
  • Voltage-dependent calcium (Cav) channels conduct calcium tons across cell membranes in response to changes in the membrane voltage and thereby can regulate cellular excitability by modulating (increasing or decreasing) the electrical activity of the cell.
  • Cavlx channels are involved in both skeletal (Cav1.1) and cardiac smooth muscle contraction (Cav1.2), as well as neuroendocrine release (Cav1.3 and Cav1.4). Cav2.x channels are important in neurotransmitter release (Cav2.1 and Cav2.2) and controlling neuronal excitability (Cav2.3). Cav channels which belong to the Cavi .x and Cav2.x families are defined by their threshold for activation as high threshold and are also known as L- or N-type channels respectively. L-type Cav channels are pharmacologically defined by their sensitivity to inhibition by dihydropyridines. Cav channels which belong to the Cav3.x class (Cav3.1 , Cav3.2, Cav3.3) are activated at much lower membrane voltages and are defined as low threshold or T-type calcium channels.
  • Cav channels are composed of an ⁇ 1 subunit, which forms the pore-region of the channel through which Ca 2+ ions can flow. conserveed transmembrane and pore domains of the ⁇ 1 subunits are less than 40% identical between the related families (Cav1 ,x : Cav2.x : Cav3.x) but greater than 70% identical within a family' which leads to difficulty in identifying compounds that pharmacologically discriminate between these related Cav channel subtypes.
  • Cav channel ⁇ subunits are intracellular proteins endogenously associated with Cav channel ⁇ 1 subunits, which finely tune many of their functional and electrophysiological / kinetic properties".
  • Ten different genes encode voltage-gated Cav channel alpha 1 subunits" 1 .
  • Cav ⁇ subunits (Cav ⁇ i , Cav ⁇ 2, Cav ⁇ 3, Cav ⁇ 4) have been shown to interact and regulate the functional activity of Cav1.x, Cav2.x and Cav3.x channels l( ⁇ V " vl ' v ".
  • Cav ⁇ subunits include altering the threshold for activation and the kinetics for both activation and inactivation, as well as regulating trafficking of the Cav ⁇ i subunit to the cell membrane.
  • the predominant effect of the combined ⁇ - ⁇ interaction is dependent upon the nature of each of the two proteins such that combining one type of Cava subunit with any of the ⁇ (1-4) subunits will lead to differential effects on functional expression and kinetics of the channel.
  • the ⁇ subunit potentially adds a further source of modulation of the final Cav current.
  • Mammalian homologues of Cav channel ⁇ subunits consist of four homologous domains each with six transmembrane segments. These domains can form tetrameric protein complexes that span the plasma membrane of cells and aliow the passage of Ca 2+ ions. These tetrameric protein complexes of Cav channels constitute the ion channel pore-forming domain.
  • Cav channels consisting of a tetramer of transmembrane spanning Cav2 channel subunits may be associated with and regulated by cytosolic accessory (Cav ⁇ ) proteins that are able to modulate the function of ion channel pore-forming domains (for review, see v ⁇ ").
  • cytosolic accessory (Cav ⁇ ) proteins that are able to modulate the function of ion channel pore-forming domains (for review, see v ⁇ ").
  • Cav ⁇ subunits bind to Cav channel ⁇ 1 subunits through an ⁇ interaction domain (AID) located between domains I and Il of the pore-forming ⁇ -1 subunit. Binding of the Cav ⁇ subunit to the AID can increase the trafficking of the Cav channel to the cell membrane and modulate the kinetics of the Cav current.
  • AID ⁇ interaction domain
  • Cav2.2 calcium channels also known as N-type channels, are located at nerve terminals, dendrites and neuroendocrine cells and are involved in neurotransmitter release'. There is substantial evidence for their involvement in pain.
  • ⁇ -Conotoxin -GVlA a specific peptide blocker of Cav2.2 blocks electrically evoked responses of dorsal horn neurons and this is enhanced in nerve-injured rats'*.
  • blockade of the N-type calcium channel with ⁇ -conotoxin-GVIA also abolishes injury-induced wind-up and post-discharge phenomena. It is suggested that nerve injury results in either increased frequency of opening of the N-type calcium channel, or an increase in the population. Blockade of these channels is expected to decrease the enhanced excitatory neurotransmitter release that occurs after nerve injury, thus inhibiting the manifestations of enhanced pain x .
  • Neuronal Cav2.2 channels may bind to any Cav ⁇ subunit whereas cardiac calcium currents are of the Cav1.2 type and their activity appears to be modulated by Cav ⁇ 2 proteins * .
  • the presence of Cav2.2 with Cav ⁇ 2 produces non-inactivating currents in chromaffin cells"" whereas the association of Cav2.2 with Cav ⁇ 3 produces inactivating currents.
  • Cav2.2 would appear to be preferentially co-localised with Cav ⁇ 3 because ⁇ - conotoxin-GVIA binding sites are immunoprecipitated by an antibody to Cav ⁇ 3 in rabbit brain*"'.
  • Mice lacking the N-type Cav ⁇ 3 subunit show reduced levels of Cav2.2 channels with altered sensitivity to inflammatory pain when compared to wild-type x ⁇ v .
  • Cav ⁇ 3 subunits hyperpolarise the voltage-dependence of activation and also hyperpolarise the voltage-dependence of steady-state inactivation of Cav2.2 channels* ViXvl .
  • These channels are located at the presynaptic terminals of nociceptive neurons in dorsal horn of the spinal cord where they regulate the release of the key pro- nociceptive neurotransmitters such as glutamate and substance P.
  • selective blockers of N-type channels can be used to ameliorate chronic painTM'.
  • chronic pain is postherpetic neuralgia (PHN), traditionally defined as the persistence of pain for more than 1 month after the disappearance of the rash associated with shinglesTM".
  • Shingles is caused by the varicella-zoster virus (VZV) and can persist for years in the dorsal root ganglia of cranial or spinal nerves after resolution of the original infection.
  • VZV varicella-zoster virus
  • PRIALT the synthetic analogue of ⁇ -conotoxin-MVIfA, is effective in patients with PHN, as well as phantom-limb pain, and HIV-related neuropathic pain who are refractory to opioids'TM,
  • Pregabalin received Food and Drug Administration (FDA) approval on December 30, 2004, for the management of neuropathic pain associated with diabetic peripheral neuropathy (DPN) and PHN. Moreover, pregabalin is approved for use as adjunctive therapy for adult patients with partial onset seizuresTMTM. Pregabaiin is structurally related to gabapentin (Neurontin ® ; Pfizer), These compounds are thought to reduce trafficking of the Cav2 channel subunit by an interaction with another accessory subunit, called ⁇ 2 - ⁇ .
  • Pregabalin is six-times more potent than gabapentin in binding affinity to the ⁇ 2 - ⁇ voltage-gated caicium channel*TM.
  • the manufacturer states that 50 mg of pregabalin is approximately equal to 300 mg of gabapentin.
  • pregabalin and gabapentin alter channel function without complete blockade of the calcium channel resulting in virtually no change in systemic blood pressure or coronary blood flow changes.
  • Overactive bladder is an unmet medical need. Symptoms of overactive bladder include increased urinary frequency, urgency, nocturia (the disturbance of night-time sleep because of the need to urinate) and accidental loss of urine (urge incontinence) due to a sudden and unstoppable need to urinate. Urge incontinence is usually associated with an overactive detrusor muscle, the smooth muscle of the bladder which contracts and causes it to empty. There is no single etiology for overactive bladder. Neurogenic overactive bladder occurs as the result of neurological damage found in a variety of disorders such as stroke, Parkinson's disease, diabetes, multiple sclerosis, peripheral neuropathy, or spinal cord lesions. In these cases, the overactivity of the detrusor muscle is termed detrusor hyperreflexia.
  • Overactive bladder may result from hypersensitivity of sensory neurons of the urinary bladder, arising from inflammatory conditions, hormonal imbalances, and prostate hypertrophy. Destruction of the sensory nerve fibres, either from a crushing injury to the sacral region of the spinal cord, or from a disease that causes damage to the dorsal root fibres as they enter the spinal cord may also lead to overactive bladder. In addition, damage to the spinal cord or brain stem causing interruption of transmitted signals may lead to abnormalities in micturition. Therefore, both peripheral and central mechanisms can contribute to overactive bladder. Carbone et ai. (2003) have previously reported the effects of gabapentin on neurogenic detrusor overactivity"TM 1 . This study demonstrated a positive effect on symptoms and significant improvement in urodynamic parameters after treatment with gabapentin and suggested that the effects of the drug should be explored further in controlled studies in both neurogenic and nonneurogenic detrusor overactivity.
  • Cav2.2 may exert a central role in mediating control of reflex bladder activity by NO through suppressing the excitability and/or the release of transmitters from bladder afferent nerves.
  • novel modulators of the protein-protein interaction between Cav2.2 channels and Cav ⁇ 3 accessory proteins may offer a novel mode of reducing hyperexcitability produced by over-expression of Cav2.2.
  • Such a reduction of hyperactivity in primary afferent neurons is anticipated to lead to an alleviation of pain and of disorders of the lower urinary tract.
  • “Cavx” channels consist of at least 10 members which includes one of the following mammalian channels: Cav1.1 , Cav1.2, Cav1.3, Cav1.4, Cav2.1 , Cav2.2, Cav2.3, Cav3.1 , Cav3.2 or Cav3.3 and any mammalian or non-mammalian equivalents or variants (including splice variants) thereof.
  • “Cav ⁇ ” proteins may include one or more of the following mammalian subunits: Cav ⁇ i, Cav ⁇ 2, Cav ⁇ 3, Cav ⁇ 4 and any mammalian or non-mammalian equivalents or variants (including splice variants) thereof.
  • interactions between each combination of Cavx channel and Cav ⁇ protein may confer modulation (increasing or decreasing) of a number of features of functional Cav channels including, but not limited to (i) the transport or chaperone of Cav channels to the plasma membrane of a given cell type XXVi>MVi )on " i ' xxvl " and/or (ii) gating properties such as channel inactivationTM*.
  • Cav ⁇ subunits can also exert effects on other gating properties by mechanisms which may alter the time and voltage dependency of the open (conducting state), closed (nonconducting state) and inactivated states (non-conducting state) of Cav channels.
  • Cavx channel blockers compounds which inhibit the interaction between Cavx channels and Cav ⁇ proteins and thus reduce either the conducting state of Cavx channels (e.g. though increasing the rate of inactivation) and/ or decreasing the transport of Cavx channels to the plasma membrane.
  • Cavx channel inhibitors have potential utility in the treatment, prevention, inhibition, amelioration or alleviation of symptoms of a number of conditions or disease states including:
  • Lower urinary tract disorders is intended to encompass both painful (any lower urinary tract disorder involving sensations or symptoms that a patient subjectively describes as producing or resulting in pain) and non-painful lower urinary tract disorders (any lower urinary tract disorder involving sensations or symptoms, including mild or general discomfort, that is subjectively described as not producing or resulting in pain).
  • Lower urinary tract disorders also includes any lower urinary tract disorder characterised by overactive bladder with and/or without loss of urine, urinary frequency, urinary urgency, and nocturia.
  • lower urinary tract disorders includes overactive bladder or overactive urinary bladder (including, overactive detrusor, detrusor instability, detrusor hyperreflexia, sensory urgency and the symptoms of detrusor overactivity), urge incontinence or urinary urge incontinence, stress incontinence or urinary stress incontinence, lower urinary tract symptoms including obstructive urinary symptoms such as slow urination, dribbling at the end of urination, inability to urinate and/or the need to strain to urinate at an acceptable rate or irritate symptoms such as frequency and/or urgency.
  • overactive bladder or overactive urinary bladder including, overactive detrusor, detrusor instability, detrusor hyperreflexia, sensory urgency and the symptoms of detrusor overactivity
  • urge incontinence or urinary urge incontinence urge incontinence or urinary urge incontinence
  • stress incontinence or urinary stress incontinence lower urinary tract symptoms including obstructive urinar
  • Lower urinary tract disorders may also include neurogenic bladder that occurs as the result of neurological damage due to disorders including but not limited to stroke, Parkinson's disease, diabetes, multiple sclerosis, peripheral neuropathy, or spinal cord lesions. Lower urinary tract disorders may also include prostatitis, interstitial cystitis, benign prostatic hyperplasia, and, in spinal cord injured patients, spastic bladder.
  • Anxiety and Anxiety-Related Conditions is intended to include, but is not limited to, anxiety, generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, social phobia, performance anxiety, posttraumatic stress disorder, acute stress reaction, adjustment disorders, hypochondriacal disorders, separation anxiety disorder, agoraphobia and specific phobias.
  • Specific anxiety related phobias include, but are not limited to, fear of animals, insects, storms, driving, flying, heights or crossing bridges, closed or narrow spaces, water, blood or injury, as well as extreme fear of inoculations or other invasive medical or dental procedures.
  • Epilepsy is intended to include, but is not limited to, one or more of the following seizures: simple partial seizures, complex partial seizures, secondary generalised seizures, generalised seizures including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures and atonic seizures.
  • Pain is intended to include but is not limited to one or more on the following: acute pain such as musculoskeletal pain, post operative pain and surgical pain; chronic pain such as chronic inflammatory pain (e.g. rheumatoid arthritis and osteoarthritis), neuropathic pain (e.g.
  • Cardiovascular Diseases such as angina pectoris, hypertension and congestive heart failure.
  • Gynaecological Pain for example, dysmenorrhoea, labour pain and pain associated with endometriosis.
  • Gastrointestinal Disorders including reflux esauphagitis, functional dispepsia, motility disorders (including constipation and diarrhoea), and irritable bowel syndrome.
  • Vascular and Visceral Smooth Muscle Disorders including asthma, pulmonary hypertension, chronic obstructive pulmonary disease, adult respiratory distress syndrome, peripheral vascular disease (including intermittent claudication), venous insufficiency, impotence, cerebral and coronary spasm and Raynaud's disease.
  • Chronic gliomas including those of lower and higher malignancy.
  • Diabetes including diabetic retinopathy, diabetic nephropathy and diabetic neuropathy
  • insulin resistance/insensitivity obesity
  • “Memory Loss” including Alzheimer's disease and dementia.
  • CNS-Mediated Motor Dysfunction Disorders including Parkinson's disease and ataxia.
  • Opthalamic Disorders such as ocular hypertension.
  • Cavx channel blockers for the prophylaxis or treatment of a number of disease states including lower urinary tract disorders and pain indications.
  • assays based on the interaction between Cavx channel domains and Cav ⁇ subunits immobilised through an affinity tag we have discovered a new family of compounds which inhibit the interaction between Cavx channels and Cav ⁇ proteins.
  • R1 is a hydrogen atom, an alkyl group, a cycloalkyl group which is a single ring or a bridged ring system, an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), an aralkyl group comprising an alkyl group which is substituted with an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyi groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carb
  • R2 is a hydrogen atom, an alkyi group which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups, aryl groups (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyi groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), heteroaryl groups (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkyla
  • Y is a hydroxyl group, an alkoxyl group, a group of formula NR40R41 or an aminoacid residue
  • R3 is an alkyl group, a cycloalkyl group which is a single ring or a bridged ring system (said cycloalkyl group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, acyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, alkylsulfonyl groups and hydroxyl groups), a cycloalkenyl group which is a single ring or a bridged ring system, an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, mono
  • R4 and R40 are independently selected from hydrogen atoms, alkyl groups which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups, aryl groups ⁇ which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haioalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkyiamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), heteroaryl groups (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamin
  • R4' and R41 are independently selected from hydrogen atoms and alkyl groups; or R4 and R4' together with the nitrogen atom to which they are attached and/or R40 and R41 together with the nitrogen atom to which they are attached may form a nitrogen- containing saturated or partially unsaturated 4- to 14- membered heterocyclic group having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings, said group optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, acyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, alkylsulfonyl groups and hydroxyl groups);
  • R11 is a hydrogen atom, an alkyl group, an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), an aralkyl group which comprises an alkyl group which is substituted with an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino
  • R12 is a hydrogen atom, an alkyl group, an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups) or an aralkyl group which comprises an alkyl group which is substituted with an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamin
  • R13 is an alkyl group, an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haioalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acyiamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), an aralkyl group which comprises an alkyl group which is substituted with an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haioalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups
  • R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, alkyl groups, halogen atoms, haioalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, acyiamino groups, alkoxycarbonylamino groups, alkyisulphonyl groups, arylsulphonyl groups, alkylsulphonylamino groups, arylsulphonylamino groups, aminosulphonyl groups and cyano groups, or any two adjacent ring substituents R5, R6, R7 and R8 may together form the group -O-(CH 2 ) P -O- wherein p is an integer of from 1 to 3; and
  • X is an oxygen atom, a sulphur atom or a group of formula NR10, wherein R10 is a hydrogen atom or an alkyl group.
  • Preferred compounds of the present invention include: (2) compounds according to (1) and pharmacologically acceptable salts, isosteres and prodrugs thereof, wherein R1 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cycfoalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system, an aryl group having from 5 to 14 carbon atoms (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyi groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group
  • R1 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an aminoalkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an amino group, a heteroaryl group which is a 5- to 6- membered aromatic heterocyclic group containing 1 to 2 sulfur atoms, oxygen atoms and/or nitrogen atoms which may be unsubstituted or substituted with an alkyl group having from 1 to 4 carbon atoms, and a guanidinoalkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with a guanidino group;
  • R1 is a hydrogen atom, a methyl group, a 3-aminopropyl group, a 4-aminobutyl group, a 3-methyl-[1 ,2,4]oxadiazol-5-yl group, a 5-methyl- [1 ,3,4]oxadiazol-2-yl group, a 3-methyl-isoxazol-5-yl group, a 3-guanidinopropyl group or a tetrazol-5-yl group; (5) compounds according to any one of (1) to (4) and pharmacologically acceptable salts, isosteres and prodrugs thereof wherein R2 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, aryl groups having from 5 to
  • Y is a hydroxyl group, an alkoxyl group having from 1 to 6 carbon atoms, a group of formula NR40R41 , or an aminoacid residue, wherein R40 is selected from hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, aryl groups having from 5 to 14 carbon atoms (said aryl groups being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups,
  • R41 is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, or R40 and R41 together with the nitrogen atom to which they are attached together form a nitrogen-containing saturated or partially unsaturated 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings, said group optionally further containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haioalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by
  • R11 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyaSkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkyiamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is
  • R12 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryi group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyi groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyi group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted
  • R13 is an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkyi groups having from 1 to 6 carbon atoms, hydroxyalkyi groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom
  • R2 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 4 carbon atoms, aryl groups having from 6 to 10 carbon atoms, heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, amino groups, monoalkylamino groups wherein the alkyl substituent has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl substit ⁇ ent is the same or different and has from 1 to 4 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or
  • Y is a hydroxyl group, an alkoxyl group having from 1 to 4 carbon atoms, a group of formula NR40R41, or an aminoacid residue, wherein R40 is selected from hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 4 carbon atoms, aryl groups having from 6 to 10 carbon atoms, heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially uns
  • R41 is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, or R40 and R41 together with the nitrogen atom to which they are attached together form a nitrogen-containing saturated or partially unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings, said group optionally further containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by
  • R11 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atoms, an aralkyl group comprising an alkyi group having from 1 to 4 carbon atoms which is substituted with one or more aryl groups having from 6 to 10 carbon atoms, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms or a heteroaralkyl group which comprises an alkyl group having from 1 to 4 carbon atoms which is substituted with one or more heteroaryl groups which are 5- to 7- memberecl aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms;
  • R12 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atoms or an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with one or aryl groups having from 6 to 10 carbon atoms; and
  • R13 is an alkyl group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atoms, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with one or aryl groups having from 6 to 10 carbon atoms, an alkoxyalkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an alkoxy group having from 1 to 4 carbon atoms, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms or a heteroaralkyl group which comprises an alkyl group having from 1 to 4 carbon atoms which is substituted with one or more heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms;
  • R2 is a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 3 carbon atoms, amino groups, monoalkylamino groups wherein the alkyl substituent has from 1 to 3 carbon atoms, dialkylamino groups wherein each alkyl substituent is the same or different and has from 1 to 3 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom and groups of formula COY 1 or
  • R2 is a group of formula COY, wherein
  • Y is a hydroxyl group, an alkoxyl group having from 1 to 3 carbon atoms, a group of formula NR40R41 , or an aminoacid residue, wherein R40 is selected from hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkoxyl groups having from 1 to 3 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and carboxy groups, cycloalkyl groups having from 3 to 6 carbon atoms atoms which are single rings or bridged ring systems and saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom;
  • R41 is a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms, or
  • R40 and R41 together with the nitrogen atom to which they are attached together form a nitrogen-containing saturated or partially unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings, said group optionally further containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur;
  • R2 is a group of formula COY, wherein Y is selected from hydroxyl groups, ethoxy groups, t-butoxy groups, amino groups, methylamino groups, ethylamino groups, i-propylamino groups, dimethylamino groups, 2-(methoxysulphonyl)ethylamino groups, pyrrolidin-1-yi groups, tetrahydropyran-4- ylamino groups, cyclohexylamino groups, piperidin-1-yl groups, cyclopropylamino groups, 2-methoxyethylamino groups, morpholin-4-yl groups, 2-(pyrrolidin-1- yl)ethylamino groups, and amioacid residues selected from ornithine, lysine and glycine, or an aS
  • R3 is an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system
  • said cycloalkyl group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoal
  • R3 is a cycloalkyl group having from 4 to 10 carbon atoms which is a single ring or a bridged ring system
  • said cycloalkyl group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups comprising carbonyi groups substituted with an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted with a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1
  • R3 is a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 4-hydroxycyclohexyl group, a 4,4-dimethylcyclohexyl group, a 4,4-difluorocyclohexyl group, an adamantyl group, a norbornenyl group, a piperidinyl group, a 4-acetylpiperidinyl group or a 4-methylsulfonylpiperidinyl group;
  • R4 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, aryl groups having from 5 to 14 carbon atoms (said aryl groups may be unsubstituted or be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl
  • R11 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyi groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted
  • R12 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkyiamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyi is substitute
  • R13 is an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkyiamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyi is substituted with a hydrogen
  • R4 is an alkyl group having from 1 to 4 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkoxy groups having from 1 to 4 carbon atoms, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms and dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, a cycloalkyl group having from 3 to 8 carbon atoms which is a single ring or a bridged ring system (said cycloalkyl group being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms and acyl groups having from 1 to 4 carbon atoms), an aryl
  • R4 is a methyl group, an /-propyl group, a f-butyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 4,4-difluorocyclohexyl group, an adamantyl group, a phenyl group (which is unsubstituted or is substituted with one or more substituents selected from fluorine atoms, chlorine atoms, hydroxyl groups, methyl groups, acetylamino groups, methoxy groups and diethylamino groups), a benzyl group (which is unsubstituted or is substituted with a methoxy group or a hydroxyl group), a phenethyl group (which is un
  • R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, hydroxyalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, hydroxyl groups, haloalkoxy groups having from 1 to 4 carbon atoms, halogen atoms, cyano groups, or any two adjacent ring substituents R5, R6, R7 and R8 may together form the group -O-(CH 2 ) P -O- wherein p is an integer of from 1 to 2;
  • R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, methyl groups, methoxy groups, fluorine atoms, chlorine atoms, bromine atoms, hyroxymethyl groups, trifluoromethoxy groups, trifluoromethyl groups, i-propyl groups, ethoxy groups, hydroxyl groups, cyano groups, methylsuiphonyl groups, or to adjacent ring substituents R5, R6, R7 and R8 may together form the group -O-CH 2 -;
  • R1 is a hydrogen atom, an alkyl group, a cycSoalkyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroaralkyl group, an aminoalkyl group or a guanidinoalkyl group;
  • R2 is an alkyl group which is substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups, aryl groups, heteroaryl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitrogen-containing unsaturated or partially saturated 4- to 8- membered heterocyclic groups, said groups optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms, and groups of formula COY 1 or R2 is a group of formula COY;
  • Y is a hydroxyl group, an alkoxyl group, a group of formula NHR40 or an aminoacid residue
  • R3 is an alkyl group, a cycloalkyl group, a cycloaSkenyl group, an aryl group, a heteroaryl group, a nitrogen-containing unsaturated or partially saturated 4- to 8- membered heterocyclic group, a cycloalkylalkyl group or an aralkyl group;
  • R4 and R40 are independently selected from hydrogen atoms, alkyl groups which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups, aryl groups, heteroaryl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitrogen-containing unsaturated or partially saturated 4- to 8- membered heterocyclic groups, said groups optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms, carboxy groups, aminocarbonyi groups, monoalkylaminocarbonyl groups, dialkylaminocarbonyl groups and alkoxycarbonyigroups, aryl groups, cycloalkyl groups, cycloalkenyl groups, groups of formula COR11 , groups of formula SO 2 RH 1 groups of formula CONR11 R12, groups of formula SO 2 NRI 1R12 , groups of formula CONR12SO 2 R11 and groups of formula CO 2 RI 3 wherein R11 , R12 and R13
  • R11 is a hydrogen atom, an alkyl group, an aryl group, an aralkyl group, a heteroaryl group or a heteroaralkyl group;
  • R12 is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group
  • R13 is an alkyl group, an aryi group, an aralkyl group, an alkoxyalkyl group, a heteroaryl group or a heteroarylalkyi group;
  • R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyl groups, alkylsulphonylamino groups, arylsulphonylamino groups, aminosulphonyl groups and cyano groups; and
  • X is an oxygen atom, a sulphur atom or a group of formula NR10, wherein R10 is a hydrogen atom or an alkyl group.
  • R1 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system, an aryi group having from 5 to 14 carbon atoms (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to
  • R2 is an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, aryl groups having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkyiamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon carbon atoms
  • R3 is an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system, a cycloalkenyl group having from 4 to 14 carbon atoms which is a single ring or a bridged ring system, an aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyi groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkyiamino groups wherein the alkyl group has
  • R4 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, aryl groups having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the aSkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be
  • R11 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkyiamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonyiamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms,
  • R12 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alk
  • R13 is an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino
  • R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising a carbonyl group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to
  • R1 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an aminoalkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an amino group, a heteroaryl group which is a 5- to 6-membered aromatic heterocyclic group containing 1 to 2 sulphur atoms, oxygen atoms and/or nitrogen atoms which may be unsubstituted or substituted with an alkyl group having from 1 to 4 carbon atoms, and a guanid ⁇ noalkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with a guanidino group,
  • R2 is a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 3 carbon atoms, amino groups, monoalkylamino groups wherein the alkyl substituent has from 1 to 3 carbon atoms, dialkylamino groups wherein each alkyl substituent is the same or different and has from 1 to 3 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom and groups of formula COY, or
  • R2 is a group of formula COY, wherein
  • Y is a hydroxyl group, an alkoxyl group having from 1 to 3 carbon atoms, a group of formula NR40R41 , or an aminoacid residue, wherein
  • R40 is selected from hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkoxyl groups having from 1 to 3 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and carboxy groups, cycloalkyl groups having from 3 to 6 carbon atoms atoms which are single rings or bridged ring systems and saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom;
  • R41 is a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms, or R40 and R41 together with the nitrogen atom to which they are attached together form a nitrogen-containing saturated or partially unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings, said group optionally further containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur,
  • R3 is a cycloalkyl group having from 4 to 10 carbon atoms which is a single ring or a bridged ring system (said cycloalkyi group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups substituted with an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted with a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon
  • R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, hydroxyalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, hydroxyl groups, haloalkoxy groups having from 1 to 4 carbon atoms, halogen atoms and cyano groups, or any two adjacent ring substituents R5, R6, R7 and R8 may together form the group
  • X is an oxygen atom, a sulphur atom or a group of formula NR10, wherein R10 is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms;
  • R1 is a hydrogen atom, a methyl group, a 3-aminopropyl group, a 4-aminobutyl group, a 3-methyl-[1 ,2,4]oxadiazot-5-yl group, a 5-methyl-[1 ,3,4]oxadiazol-2-yl group, a 3-methyl- isoxazol-5-yt group or a 3-guanidinopropyl group;
  • R2 is a group of formula COY, wherein Y is selected from hydroxyl groups, ethoxy groups, t-butoxy groups, amino groups, methylamino groups, ethylamino groups, i- propylamino groups, dimethylamino groups, 2- ⁇ methoxysulphonyi)ethylamino groups, pyrrolidin-1-yl groups, tetrahydropyran-4-yla ⁇ nino groups, cyclohexylamino groups, piperidin-1-yl groups, cyclopropylamino groups, 2-methoxyethylamino groups, morpholin-4-yl groups, 2-(pyrrolidin-1-yl)ethylamino groups, and amioacid residues selected from ornithine, lysine and glycine, or an alkyl group having from 1 to 3 carbon atoms which may be unsubstituted or substituted with a substituent selected from carboxy groups,
  • R4 is a methyl group, an /-propyl group, a f-butyl group, a cyclopropyi group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 4,4-difluorocyclohexyl group, an adamantyl group, a phenyl group (which is unsubstituted or is substituted with one or more substituents selected from fluorine atoms, chlorine atoms, hydroxyl groups, methyl groups, acetylamino groups, methoxy groups and diethylamino groups), a benzyl group (which is unsubstituted or is substituted with a methoxy group or a hydroxyl group), a phenethyl group (which is unsubstituted or is substituted with a hydroxyl group), a pyridinyl group, a thiazolyl group,
  • R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, methyl groups, methoxy groups, fluorine atoms, chlorine atoms, bromine atoms, hyroxymethyl groups, trifluoromethoxy groups, trifluoromethyl groups, i-propyl groups, ethoxy groups, hydroxyl groups, cyano groups, methylsulphonyl groups, or to adjacent ring substituents R5, R6, R7 and R8 may together form the group -O-CH 2 -; and X is a sulphur atom, an amino group or a methySamino group; and
  • a pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and an active ingredient, wherein said active ingredient is a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof for use as a medicament there is provided a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof for use as a medicament.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of a disease in which Cavx channels are involved.
  • a compound according to any one of (1 ) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel opening.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel inhibition.
  • a seventh aspect of the present invention there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Lower Urinary Tract Disorders.
  • a ninth aspect of the present invention there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Epilepsy.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Pain Disorders.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Gynaecological Pain.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiac Arrhythmias.
  • a thirteenth aspect of the present invention there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Thromboembolic Events.
  • a fourteenth aspect of the present invention there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiovascular Diseases.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Disorders of the Auditory System,
  • a sixteenth aspect of the present invention there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Migraine.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Inflammatory and Immunological Diseases.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Gastrointestinal Disorders.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Vascular and Visceral Smooth Muscle Disorders.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Cell Proliferative Disorders.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Metabolic Disorders.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of CNS-Mediated Motor Dysfunction Disorders.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Opthalamic Disorders.
  • a method for the prophylaxis or treatment of a disease in which Cavx is involved comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a method for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel opening comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a method for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel inhibition comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a method for the prophylaxis or treatment of Lower Urinary Tract Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a method for the prophylaxis or treatment of Anxiety and Anxiety-Related Conditions comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a method for the prophylaxis or treatment of Epilepsy comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a method for the prophylaxis or treatment of Pain Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a method for the prophylaxis or treatment of Gynaecological Pain comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a method for the prophylaxis or treatment of Cardiac Arrhythmias comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a method for the prophylaxis or treatment of Thromboembolic Events comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof
  • a thirty-fifth aspect of the present invention there is provided a method for the prophylaxis or treatment of Cardiovascular Diseases comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a method for the prophylaxis or treatment of Disorders of the Auditory System comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof
  • a method for the prophylaxis or treatment of Migraine comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a method for the prophylaxis or treatment of Inflammatory and Immunological Diseases comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a method for the prophylaxis or treatment of Gastrointestinal Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a method for the prophylaxis or treatment of Vascular and Visceral Smooth Muscle Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a method for the prophylaxis or treatment of Ceil Proliferative Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a method for the prophylaxis or treatment of Metabolic Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a method for the prophylaxis or treatment of Memory Loss comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a method for the prophylaxis or treatment of CNS-Mediated Motor Dysfunction Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a method for the prophylaxis or treatment of Opthalamic Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and at least two active ingredients, wherein said active ingredients comprise at least one compound according to any one of (1 ) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in combination at least one compound selected from the group consisting of muscarinic receptor antagonists, ⁇ 3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel ⁇ 2 ⁇ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists, alpha-1 adrenoceptor antagonists, tricyclic antidepressants, N-methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductas
  • a pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in combination at least one compound selected from the group consisting of muscarinic receptor antagonists, ⁇ 3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel ⁇ 2 ⁇ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists and ⁇ -1 adrenoceptor antagonists; and
  • a pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in combination at least one compound selected from the group consisting of neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel ⁇ 2 ⁇ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, N-methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetyl
  • the combinations of preferred option (1) are of particular use in the prophylaxis or treatment of lower urinary tract disorders.
  • the combinations of preferred option (2) are of particular use in the prophylaxis or treatment of pain.
  • a forty-eighth aspect of the present invention there is provided use of at least one compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof and at least one compound selected from the group consisting of muscarinic receptor antagonists, ⁇ 3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, caicium channel ⁇ 2 ⁇ deita ligands, potassium channel inhibitors, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNFUs), 5-HT antagonists and ⁇ -1 adrenoceptor antagonists in the manufacture of a medicament for the prophylaxis or treatment of lower urinary tract disorders.
  • muscarinic receptor antagonists ⁇ 3 adrenergic receptor agonists
  • neurokinin K receptor antagonists neurokinin K receptor antagonists
  • vanilloid VR1 agonists caicium channel ⁇ 2
  • a forty-ninth aspect of the present invention there is provided use of at least one compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof and at least one compound selected from the group consisting of neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel ⁇ 2 ⁇ delta iigands, potassium channel inhibitors, caicium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, N-methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein
  • the alkyl groups in the definitions of R1 , R2, R3, R4, R4 J , R40, R41 , R5, R6, R7, R8, R9, R10, R11 , R12 and R13 are preferably alkyl groups having from 1 to 6 carbon atoms, more preferably alkyl groups having from 1 to 4 carbon atoms and most preferably methyl groups, ethyl groups, /-propyl groups and t- butyl groups.
  • the cycloalkyl groups in the definition of R1 , R3, R4 and R40 are preferably cycloalkyl groups having from 3 to 14 carbon atoms which may either be unsubstituted or may be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyi groups comprising carbonyl groups substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different
  • the cycloalkyl groups more preferably have from 5 to 10 carbon atoms, and are most preferably cyclopentyl, cyclohexyl, cycloheptyl and adamantyl groups which may be subsitiuted with one or more substiituents selected from fluorine atoms, hydroxyl groups and methyl groups.
  • the aryl groups in the definitions of R1 , R2, R3, R4, R40, R11 , R12 and R13 are preferably aryl groups having from 5 to 14 carbon atoms in one or more rings which may either be unsubstituted or may be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising
  • unsubstituted aryl groups include phenyl, indenyl, naphthyl, phenanthrenyl and anthracenyl groups. More preferred aryl groups include phenyl groups which may optionally substituted by 1 or 2 halogen atoms, alkoxy groups having from 1 to 4 carbon atoms, hydroxyalkyl groups having from 1 to 4 carbon atoms, acylylamtno groups having from 1 to 4 carbon atoms, hydroxyl groups and dialkylamino groups wherein each alkyl group is the same or different and has from 1 to 4 carbon atoms; and most preferred aryl groups are phenyl groups which are unsubstituted or are substituted with a fluorine atom, a hydroxyl group, a methoxy group, a hydroxymethyl group, a diethylamino group, a chlorine atom or a diethoxyamino group.
  • the aralkyl groups in the definitions of R1 , R3, R11 , R12 and R13 are preferably alkyl groups as defined above which are substituted with one or more aryi groups as defined above, and are more preferably benzyl and phenethyl groups which may be unsubstituted or substituted with at least one substituent selected from alkoxyl groups having from 1 to 4 carbon atoms and hydroxyl groups, and most preferably are benzyl and phenethyl groups which may be unsubstituted or substituted with a methoxy group or a hydroxyl group.
  • the heteroaryl groups in the definitions of R1 , R2, R3, R4, R40, R11 and R13 are preferably a heteroaryi group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyf groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups,
  • Examples include furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1 ,2,3-oxadiazolyl, triazoiyl, tetrazolyl, thiadiazolyf, pyranyf, pyridyl, pyridazinyl, pyrimidinyl, indazolyl, 1-methylindazolyl and pyrazinyl groups. Most preferred is thiazolyl, indazolyl, 1-methylindazolyl and pyridyl.
  • the heteroaralkyl groups in the definitions of R1 , R11 and R13 are preferably alkyl groups as defined above which are substituted with heteroaryl groups as defined above.
  • the aminoalkyl groups in the definition of R1 are preferably aSkyi groups as defined above which are substituted with an amino group, and most preferred are aminopropyl groups and aminobutyl groups.
  • the guanidinoalkyl groups in the definition of R1 are preferably alkyl groups as defined above which are substituted with a guanidino group, and most preferred are guanidinopropyl groups.
  • the alkoxyl groups in the definitions of R2, R3, R4, R40, R4', R41 , R5, R6, R7, R8, R9 and Y are preferably alkoxy groups having from 1 to 6 carbon atoms, more preferably alkoxy groups having from 1 to 4 carbon atoms and most preferably methoxy or ethoxy groups.
  • the monoalkylamino groups in the definitions of R2, R3, R4, R40, R4 ⁇ R41 , R5, R6, R7, R8 and R9 are preferably amino groups which are substituted with one alkyl group as defined above, and are more preferably methylamtno, ethySamino or t-butylamino groups.
  • dialkylamino groups in the definitions of R2, R3, R4, R40, R4', R41 , R5, R6, R7, R8 and R9 are preferably amino groups which are substituted with two alkyl groups as defined above which may be the same or different from each other, and are more preferably dimethylamino or diethylamino groups.
  • the saturated, partially unsaturated or unsaturated heterocyclic 4- to 14- membered heterocyclic groups having one or more rings including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atoms in the definitions of R2, R3, R4, R40, R4' and R41 are 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings which may be unsubstituted or substituted with at (east one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyi groups comprising a carbon
  • Preferred examples include morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 4-acetylpiperidinyl, 4- methylsulphonylpiperidinyl, tetrahydrofuranyl, N-methylpiperidinyl and N- methylpiperazinyl groups.
  • the nitrogen-containing saturated or partially unsaturated 4- to 14- membered heterocyclic groups having one or more rings including bridged saturated or partially unsaturated heterocyclic groups having two or more rings formed by R4 and R4' together with the nitrogen atom to which they are attached or R40 and R41 together with the nitrogen atom to which they are attached are nitrogen- containing saturated or partially unsaturated 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups and they optionally further contain one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur (said heterocyclic groups may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that
  • aminoacid residues in the definition of Y are the residual moieties obtained after reaction of an amino group with the carboxyl group of an amino acid, and are preferably ornithine, lysine or glycine residues.
  • the monoalkylaminocarbonyl groups in the definitions of R4 and R40 are preferably aminocarbonyl groups which are substituted with one alkyl group as defined above, and are more preferably methylaminocarbonyS, ethylaminocarbonyl or t-butylaminocarbonyl groups.
  • dialkylaminocarbonyl groups in the definitions of R4 and R40 are preferably aminocarbonyl groups which are substituted with two alkyl groups as defined above which may be the same or different from each other, and are more preferably dimethylaminocarbonyl or diethylaminocarbonyl groups.
  • the cycloalkenyl groups in the definition of R3, R4 and R40 are preferably cycloalkenyl groups having from 4 to 14 carbon atoms; the cycloalkyl group can be in a single ring or can be a bridged ring system.
  • the cycloalkenyi groups more preferably have from 5 to 10 carbon atoms, and are most preferably norbomenyl groups.
  • the cycloalkylalkyl groups in the definition of R3 are preferably alkyl groups as defined above which are substituted with a cycloalkyi groups as defined above.
  • the haloalkoxy groups in the definitions of R5, R6, R7, R8 and R9 are preferably alkoxyl groups as defined above which are substituted with one or more halogen atoms. More preferably, they are alkoxyl groups having from 1 to 4 carbon atoms that are substituted with at least one chlorine or fluorine atom and most preferably they are chloromethoxy group, trichloromethoxy groups, trifluoromethoxy groups and tetrafluoroethoxy groups.
  • the haioalkyl groups in the definitions of R2, R3, R4, R4 ⁇ R40, R41 , R5, R6, R7, R8 and R9 are preferably alkyl groups as defined above which are substituted with one or more halogen atoms. More preferably, they are alky] groups having from 1 to 4 carbon atoms that are substituted with at least one chlorine or fluorine atom and most preferably they are chloromethyl group, trichloromethyl groups, trifluoromethyl groups and tetrafluoroethyl groups.
  • the alkoxycarbonyl groups in the definitions of R2, R3, R4, R4 ⁇ R40, R41 , R5, R6, R7, R8 and R9 are preferably carbonyl groups substituted with alkoxy groups as defined, and are more preferably methoxycarbonyl or ethoxycarbonyl groups.
  • the acylamino groups in the definitions of R5, R6, R7, R8 and R9 are preferably carbonylamino groups in which the carbonyl is substituted with an hydrogen atom or an alkyl group having from 1 to 6 carbon atoms and are more preferably acetylamino or propanoylamino groups.
  • the hydroxyalkyl groups in the definitions of R5, R6, R7, R8, R9 are preferably hydroxyalkyl groups having from 1 to 6 carbon atoms, more preferably hydroxyalkyl groups having from 1 to 4 carbon atoms and most preferably hydroxymethyl groups, 2-hydroxyethyl groups, and 3-hydroxypropyl groups groups.
  • the acyl groups in the definitions of R2, R3, R4, R4' ; R40 and R41 are preferably a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, more preferably a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and most preferably an acetyl or propionyl group.
  • the alkoxycarbonylamino groups in the definitions of R5, R6, R7, R8 and R9 are preferably amino groups which are substituted with an alkoxycarbonyl group as defined above, and are more preferably methoxycarbonylamino or ethoxycarbonylamino groups.
  • the alkylsulphonyl groups in the definitions of R2, R3, R4, R4 ⁇ R40, R41 , R5, R6, R7, R8 and R9 are preferably sulphonyl groups which are substituted with an alkyl group as defined above and are more preferably a methylsulphonyl or ethylsuiphonyl group.
  • the arylsulphonyl groups in the definitions of R5, R6, R7, R8 and R9 are preferably sulphonyl groups which are substituted with an aryl group as defined above and are more preferably a phenylsulphonyl group which may be optionally substituted with one or two alkyl groups as defined above or a naphthylsulphonyl group.
  • the alkylsulphonylamino groups in the definitions of R5, R6, R7, R8 and R9 are preferably sulphonylamino groups which are substituted with an alkyl group as defined above and are more preferably a methylsulphonylamino or ethylsulphonylamino group.
  • the aryisuiphonylamino groups in the definitions of R5, R6, R7, R8 and R9 are preferably sulphonylamino groups which are substituted with an aryl group as defined above and are more preferably a phenylsulphonylamino group which may be optionally substituted with one or two alkyl groups as defined above or a naphthylsuiphonylamino group.
  • the alkoxyalkyl groups in the definition of R13 are preferably alkyl groups as defined above which are substituted by one or more alkoxy groups as defined above. More preferably they are alkyl groups having from 1 to 4 carbon atoms that are substituted with an alkoxy group having from 1 to 4 carbon atoms and most preferably methoxymethyl and 2-methyoxyethyl groups.
  • pharmacologically acceptable salts of the compound having the formula (1) described above are not specificaijy restricted and these salts can be selected by a person with an ordinary skill in the art.
  • such salts are, for example, basic salts such as an alkaline metal sait such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as calcium salt or magnesium salt; a metal salt such as aluminium salt, iron salt, zinc salt, copper salt, nickel salt or cobalt salt; an amine salt such as an ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N- methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine
  • the compounds of formula (1) of the present invention can be administered in the form of prodrugs.
  • Prodrugs are derivatives of the pharmacologically active compound in which one or more of the substituents on said compound are protected by a group which is then removable by a biological process (e.g. hydrolysis) in vivo after administration to the patient.
  • a biological process e.g. hydrolysis
  • Many suitable prodrugs would be well-known to the person in the art and can be found, for example, in "Greene's Protective Groups in Organic Synthesis", 4 th Edition, 2006, Wiley- VCH.
  • Suitable examples of such prodrugs include pharmacologically acceptable esters of the compound having the formula (1) wherein a carboxyl moiety of the compound having the formula (1) is esterified.
  • esters are not particularly restricted, and can be selected by a person with an ordinary skill in the art. In the case of said esters, it is preferable that such esters can be cleaved by a biological process such as hydrolysis in vivo.
  • the group constituting the said esters can be, for example, a C 1 -C 4 alkoxy C 1 -C 4 alkyl group such as methoxyethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl, 2- methoxyethyl, 2-ethoxyethyl, 1 ,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or t-butoxymethyl; a C 1 -C 4 alkoxylated C 1 -C 4 alkoxy C 1 -C 4 alkyi group such as 2-methoxyethoxymethyl; a C 6 -C 10 aryloxy C 1 -C 4 alkyl group such as phenoxymethyl; a halogenated C 1 -C 4 alkoxy C 1 -C 4 alkyl group such
  • the compounds of formula (1) or pharmacologically active prodrugs or salts thereof contain some substituents for which there exist isosteres, and compounds containing such isosteres in place of said substituents also form a part of the present invention.
  • isosteres or salts thereof contain a carboxyl group, this can be replaced with a tetrazolyl group.
  • Hydrates or solvates of the compounds of formula (1), isosteres thereof, prodrugs thereof and pharmacologically acceptable salts thereof can also be used and form a part of the invention.
  • Some compounds of formula (1) and their pharmacologically acceptable salts, isosteres or prodrugsthereof of the present invention may have one or more asymmetric carbons, and optical isomers (including diastereomers) due to the presence of asymmetric carbon atom(s) in the molecule can exist.
  • some of the compounds of formula (1) and their pharmacologically acceptable saits, isosteres or prodrugs thereof of the present invention may have one or more double bonds, and these can exist in cis and trans isomeric forms. These respective isomers are included in the present invention, both as individual isomers and mixtures thereof in all possible ratios.
  • Examples of the administration form of a compound having the general formula (1) of the present invention, or pharmacologically acceptable salt, isostere or prodrug thereof include oral administration by tablets, capsules, granules, powders or syrups, and parenteral administration by injection, patches or suppositories.
  • a compound having the general formula (1) or a pharmacologically acceptable salt, isostere or prodrug thereof of the present invention can also be administered by pulmonary administration in the form of a powder, solution or suspension. Preparations for these administrations are produced by known methods using additives such as excipients, lubricants, binders, disintegrants, stabilizers, corrigents, diluents and so forth.
  • excipients include organic excipients such as sugar derivatives, e.g. lactose, sucrose, glucose, mannitol or sorbitol, starch derivatives, e.g. corn starch, potato starch, ⁇ -starch, dextrin or carboxymethyl starch, cellulose derivatives, e.g. crystalline cellulose, low substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose or internally crosslinked sodium carboxymethyl cellulose, and gum Arabic, dextran or pullulan; and, inorganic excipients such as silicate derivatives, e.g.
  • lubricants include stearic acid and metal stearates such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as bee gum or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; sodium fatty acid salts; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acids such as silicic anhydride or silicate hydrate; and, starch derivatives.
  • stearic acid and metal stearates such as calcium stearate or magnesium stearate
  • talc colloidal silica
  • waxes such as bee gum or spermaceti
  • boric acid adipic acid
  • sulfates such as sodium sulfate
  • glycol fumaric acid
  • binders examples include polyvinylpyrrolidone, Macrogol and compounds similar to the aforementioned excipients.
  • disintegrants agents include compounds similar to the aforementioned excipients, and chemically crosslinked starches and celluloses such as cross sodium carmellose, sodium carboxymethyl starch or crosslinked polyvinylpyrrolidone.
  • stabilizers include paraoxybenzoate esters such as methyl paraben or propyl paraben; alcohols such as chlorobutanol, benzyl alcohol or phenyl ethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; and, sorbic acid.
  • paraoxybenzoate esters such as methyl paraben or propyl paraben
  • alcohols such as chlorobutanol, benzyl alcohol or phenyl ethyl alcohol
  • benzalkonium chloride phenols such as phenol or cresol
  • thimerosal thimerosal
  • dehydroacetic acid and, sorbic acid.
  • corrigents include ordinarily used sweeteners, sour flavourings and fragrances.
  • said solution or suspension can be produced by dissolving or suspending crystals of the present invention in water or in a mixture of water and an auxiliary solvent (e.g. ethanof, propylene glycol or polyethylene glycol).
  • a solution or suspension may also contain an antiseptic (e.g. benzalkonium chloride), solubilizing agent (e.g. a polysorbate such as Tween 80 or Span 80 or surface activator such as benzalkonium chloride), buffer, isotonic agent (e.g. sodium chloride), absorption promoter and/or thickener.
  • the suspension may additionally contain a suspending agent (such as microcrystalline cellulose or sodium carboxymethyl cellulose).
  • a composition for pulmonary administration produced in the manner described above is administered directly into the nasal cavity or oral cavity by a typical means in the field of inhalants (using, for example, a dropper, pipette, cannula or atomizer).
  • crystals of the present invention can be atomized as an aerosol in the form of a pressurized pack together with a suitable nebula (for example, a chlorofluorocarbon such as dichlorofluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or a gas such as carbon dioxide), or they can be administered using a nebulizer.
  • a suitable nebula for example, a chlorofluorocarbon such as dichlorofluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or a gas such as carbon dioxide
  • the amount of a compound having the general formula (1) or pharmacologically acceptable salt, isostere or prodrug thereof of the present invention used varies depending on the symptoms, age, administration method and so forth, and may be administered either in a single dose or by dividing into multiple doses according to the symptoms.
  • muscarinic receptor antagonists include esoxybutynin, oxybutynin [especially the chloride], tolterodine [especially the tartrate], solifenacin [especially the succinate], darifenacin [especially the hydrobromide], temiverine, fesoterodine, imidafenacin and trospium [especially the chloride].
  • ⁇ 3 adrenergic receptor agonists examples include YM-178 and solabegron, KUC- 7483.
  • neurokinin K receptor antagonists include cizolirtine and casopitant.
  • vanilloid VR1 agonists examples include capsaicin, resiniferatoxin and NDG-8243.
  • Examples of calcium channel ⁇ 2 ⁇ ligands include gabapentin and pregabalin.
  • potassium channel activators include KW-7158, NS-8 and retigabine,
  • Examples of calcium channel inhibitors include ziconotide and NMED-160.
  • Examples of sodium channel blockers include lidocaine, lamotrigine, VX-409, ralfinamide and carbamazepine.
  • Examples of serotonin and norepinephrine reuptake inhibitors (SNRIs) include duloxetine and venlafaxine
  • 5-HT antagonists including 5-HT1a antagonists and 5HT3 antagonists.
  • Examples of ⁇ -1 adrenoceptor antagonists include tamsulosin.
  • tricyclic antidepressants include amitriptyline, amoxapine, clomipramine, dosulepin (dothiepin), doxepin, imipramine, lofepramine, nortriptyline, and trimipramine.
  • N-methyl-D-aspartate (NMDA) receptor antagonists include ketamine, memantine, amantadine, AVP-923, NP-1 and EVT-101.
  • cannabinoid receptor agonists examples include GW-1000 (Sativex) and KDS- 2000.
  • Anti-convulsants examples include lacosamide, carbamazepine, topiramate, oxcarbazepine and levetiracetam
  • aldose reductase inhibitors include tolrestat, zopoirestat, zenarestat, epalrestat, sorbinil, AS-3201 , fidarestat, risarestat, ponalrestat and alrestatin.
  • opioids e.g. mu opioid agonists
  • opioids include fentanyl and tapentadol.
  • alpha adrenoceptor agonists include a r adrenoceptor agonists such as ethoxamine, phenylephrine, oxymetazoline, tetrahydralazine and xylometazoline and a 2 - adrenoceptor agonists such as clonidine, guanabenz, guanfacine and ⁇ -methyldopa.
  • P2X receptor antagonists including P2X2 receptor antagonists and P2X7 receptor antagonists.
  • acid-sensing ion channel modulators include amiloride.
  • NGF receptor modulators examples include trkA.
  • nicotinic acetylcholine receptor modulators inciude A-85380, tebanicline, ABT-366833, ABT-202, ABT-894, epibatidine analogs and S1B-1663.
  • synaptic vesicle protein 2A ligands examples include brivaracetam.
  • Examples of the administration form of the combination of the present invention are the same as given above for the compounds of general formula (1) and pharmacologically acceptable salts thereof.
  • the particular form can be chosen depending upon the condition to be treated and the nature of the compounds being administered in combination.
  • a combination of a compound of general formula (1) or a pharmacologically acceptable salt thereof with lidocaine could be administered transdermal ⁇ by means of a patch while a combination with ziconotide could be administered transmucosally.
  • test compounds dissolved in a suitable vehicle such as DMSO
  • a suitable vehicle such as DMSO
  • Cav2.2 ⁇ subunit AID After incubation with test compounds, 10 ⁇ l of Cav2.2 ⁇ subunit AID at 10x Kd was added to each well and incubated for 60 minutes at room temperature on a shaker. Unbound Cav2.2 ⁇ subunit AID domain was removed by washing 3 times in 300 ⁇ l of PBS-Tween. Bound Cav2.2 ⁇ subunit AID domain was estimated by using appropriately diluted mouse anti-FLAG antibody HRP conjugate using standard ELISA procedures. HRP was detected by addition of colourmetric HRP substrate 2,2'-azino-bis(3-ethylbenzthiazoline- 6-sulfonic acid) and microtitre plates were read in a Biotek Synergy HT microtitre plate reader equipped with a 405nm absorbance filter.
  • Test compounds were examined for their ability to inhibit the binding of Cav2.2 ⁇ subunit AID domain to Cav ⁇ 3 subunits to determine inhibition as a percentage of maximal binding in the absence of any test compound. Results are presented as the half maximal inhibitory concentration (IC 50 ) for inhibition of Cav2.2 ⁇ subunit AID binding to Cav ⁇ 3 subunits.
  • IC 50 half maximal inhibitory concentration
  • the tested compounds of Examples 2, 4, 6, 18, 27, 41 to 44, 48 to 51 and 53 to 55 of this invention displayed excellent ability to inhibit the binding of Cav2.2 ⁇ subunit AID domain to Cav ⁇ 3 subunits as measured by determination of the IC 50 (see Table 1).
  • the rat Cav ⁇ i , ⁇ 2, ⁇ 3 and ⁇ 4 subunits cDNA were ligated into an E.coli expression vector downstream of sequence coding for a poly Histidine-tag and the BCCP domain of the E.coli AccB gene.
  • the ligation mix was transformed into chemically competent
  • Colonies of Rosetta2 cells containing Cav subunit plasmids were inoculated in 5ml of LB medium containing ampicillin and chloramphenicol in 20m! tubes and grown overnight at 37°C in a shaking incubator. 2ml of overnight culture was used to inoculate another 200ml of LB containing ampicil ⁇ n and chloramphenicol in 500ml flasks and grown at 37°C until an OD600 of 0.7AU was reached. IPTG was then added to a final concentration of 1mM and induction continued at 30°C for 4 hours. Cells were then harvested by centrifugation, cell pellets were washed in PBS and stored in aliquots at - 80°C.
  • lysis buffer PBS containing 0.1% Tween 20, 1mg/ml lysozyme and 1 ⁇ g/ml DNAse I
  • Lysis was aided by incubation on a rockerat room temperature for 30min before cell debris was collected by centrifugation at 13000rpm for 10mins at 4°C. The cleared supernatant of soluble protein was removed and used immediately.
  • the cDNA for the alpha interacting domain (amino acids 357-399 Accession number NP_671482) was cloned downstream of sequences coding for GST-tag and a FLAG-tag in an E.coli expression vector. Plasmids were checked by sequencing for correct sequence and induction of E.coli cultures showed expression of a GST and FLAG-tagged soluble protein of the expected size.
  • binding reactions were assembled containing 10 ⁇ l Cav ⁇ subunit cleared lysated, 10 ⁇ l anti-FLAG agarose in the presence and absence of 10 ⁇ l purified AID protein in 250 ⁇ l phosphate buffered saline containing 300mM NaCI, 0.1% Tween20, 0.01% Triton 100 and 1% (w/v) bovine serum albumin. Reactions were incubated on a rocker at room temperature for 1 hour and FLAG bound complexes harvested by centrifugation at 700rpm for 10min. After extensive washing in PBS-T ween, FLAG bound complexes were denatured in SDS sample buffer and Western blotted. Presence of biotinylated Cav ⁇ subunits were detected by Streptavidin/HRP conjugate.

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Abstract

The present invention relates to ion channel modulators, and more particularly to compounds which inhibit the interaction between the pore-forming (α) subunits of Cav voltage-gated calcium channels and accessory (Cavβ subunit) proteins. Coumpounds are of use in the treatment and prevention of a number of diseases and conditions including pain and lower urinary tract disorders, and have the following Formula (I).

Description

CALCIUM ION CHANNEL MODULATORS & USES THEREOF
Field of the Invention
The present invention relates to ion channel modulators, and more particularly to compounds which inhibit the interaction between the pore-forming (α) subunits of Cav voltage-gated calcium channels and accessory (Cavβ subunit) proteins.
Background to the invention
Voltage-dependent calcium (Cav) channels conduct calcium tons across cell membranes in response to changes in the membrane voltage and thereby can regulate cellular excitability by modulating (increasing or decreasing) the electrical activity of the cell.
Cavlx channels are involved in both skeletal (Cav1.1) and cardiac smooth muscle contraction (Cav1.2), as well as neuroendocrine release (Cav1.3 and Cav1.4). Cav2.x channels are important in neurotransmitter release (Cav2.1 and Cav2.2) and controlling neuronal excitability (Cav2.3). Cav channels which belong to the Cavi .x and Cav2.x families are defined by their threshold for activation as high threshold and are also known as L- or N-type channels respectively. L-type Cav channels are pharmacologically defined by their sensitivity to inhibition by dihydropyridines. Cav channels which belong to the Cav3.x class (Cav3.1 , Cav3.2, Cav3.3) are activated at much lower membrane voltages and are defined as low threshold or T-type calcium channels.
Cav channels are composed of an α1 subunit, which forms the pore-region of the channel through which Ca2+ ions can flow. Conserved transmembrane and pore domains of the α1 subunits are less than 40% identical between the related families (Cav1 ,x : Cav2.x : Cav3.x) but greater than 70% identical within a family' which leads to difficulty in identifying compounds that pharmacologically discriminate between these related Cav channel subtypes.
Cav channel β subunits (Cavβ) are intracellular proteins endogenously associated with Cav channel α1 subunits, which finely tune many of their functional and electrophysiological / kinetic properties". Ten different genes encode voltage-gated Cav channel alpha 1 subunits"1 . To date, Cavβ subunits (Cavβi , Cavβ2, Cavβ3, Cavβ4) have been shown to interact and regulate the functional activity of Cav1.x, Cav2.x and Cav3.x channelsl(ΛV"vl'v".
The major functions of Cavβ subunits include altering the threshold for activation and the kinetics for both activation and inactivation, as well as regulating trafficking of the Cavαi subunit to the cell membrane. The predominant effect of the combined α-β interaction is dependent upon the nature of each of the two proteins such that combining one type of Cava subunit with any of the β(1-4) subunits will lead to differential effects on functional expression and kinetics of the channel. Thus the β subunit potentially adds a further source of modulation of the final Cav current.
Mammalian homologues of Cav channel α subunits (Cavi .x, Cav2.x and Cav3.x) consist of four homologous domains each with six transmembrane segments. These domains can form tetrameric protein complexes that span the plasma membrane of cells and aliow the passage of Ca2+ ions. These tetrameric protein complexes of Cav channels constitute the ion channel pore-forming domain.
Functional Cav channels consisting of a tetramer of transmembrane spanning Cav2 channel subunits may be associated with and regulated by cytosolic accessory (Cavβ) proteins that are able to modulate the function of ion channel pore-forming domains (for review, see vι").
Cavβ subunits bind to Cav channel α1 subunits through an α interaction domain (AID) located between domains I and Il of the pore-forming α-1 subunit. Binding of the Cavβ subunit to the AID can increase the trafficking of the Cav channel to the cell membrane and modulate the kinetics of the Cav current.
Cav2.2 channels and Pain
Cav2.2 calcium channels, also known as N-type channels, are located at nerve terminals, dendrites and neuroendocrine cells and are involved in neurotransmitter release'. There is substantial evidence for their involvement in pain. ω-Conotoxin -GVlA, a specific peptide blocker of Cav2.2 blocks electrically evoked responses of dorsal horn neurons and this is enhanced in nerve-injured rats'*. In addition, blockade of the N-type calcium channel with ω-conotoxin-GVIA, also abolishes injury-induced wind-up and post-discharge phenomena. It is suggested that nerve injury results in either increased frequency of opening of the N-type calcium channel, or an increase in the population. Blockade of these channels is expected to decrease the enhanced excitatory neurotransmitter release that occurs after nerve injury, thus inhibiting the manifestations of enhanced painx.
Neuronal Cav2.2 channels may bind to any Cavβ subunit whereas cardiac calcium currents are of the Cav1.2 type and their activity appears to be modulated by Cavβ2 proteins*. The presence of Cav2.2 with Cavβ2 produces non-inactivating currents in chromaffin cells"" whereas the association of Cav2.2 with Cavβ3 produces inactivating currents. Cav2.2 would appear to be preferentially co-localised with Cavβ3 because ω- conotoxin-GVIA binding sites are immunoprecipitated by an antibody to Cavβ3 in rabbit brain*"'. Mice lacking the N-type Cavβ3 subunit show reduced levels of Cav2.2 channels with altered sensitivity to inflammatory pain when compared to wild-typexιv.
Furthermore, Cavβ3 subunits hyperpolarise the voltage-dependence of activation and also hyperpolarise the voltage-dependence of steady-state inactivation of Cav2.2 channels*ViXvl. These channels are located at the presynaptic terminals of nociceptive neurons in dorsal horn of the spinal cord where they regulate the release of the key pro- nociceptive neurotransmitters such as glutamate and substance P. Consistent with this, selective blockers of N-type channels can be used to ameliorate chronic pain™'. One example of chronic pain is postherpetic neuralgia (PHN), traditionally defined as the persistence of pain for more than 1 month after the disappearance of the rash associated with shingles™". Shingles is caused by the varicella-zoster virus (VZV) and can persist for years in the dorsal root ganglia of cranial or spinal nerves after resolution of the original infection. PRIALT, the synthetic analogue of ω-conotoxin-MVIfA, is effective in patients with PHN, as well as phantom-limb pain, and HIV-related neuropathic pain who are refractory to opioids'™,
Compounds which are believed to inhibit chronic pain by acting at accessory proteins and reducing hyperexcitability of calcium currents have been described. Pregabalin received Food and Drug Administration (FDA) approval on December 30, 2004, for the management of neuropathic pain associated with diabetic peripheral neuropathy (DPN) and PHN. Moreover, pregabalin is approved for use as adjunctive therapy for adult patients with partial onset seizures™™. Pregabaiin is structurally related to gabapentin (Neurontin®; Pfizer), These compounds are thought to reduce trafficking of the Cav2 channel subunit by an interaction with another accessory subunit, called α2-δ. Pregabalin is six-times more potent than gabapentin in binding affinity to the α2-δ voltage-gated caicium channel*™. The manufacturer states that 50 mg of pregabalin is approximately equal to 300 mg of gabapentin. Unlike classical pore-forming domain blockers pregabalin and gabapentin alter channel function without complete blockade of the calcium channel resulting in virtually no change in systemic blood pressure or coronary blood flow changes.
Cav2,2 channels and Lower Urinary Tract Disorders
Overactive bladder is an unmet medical need. Symptoms of overactive bladder include increased urinary frequency, urgency, nocturia (the disturbance of night-time sleep because of the need to urinate) and accidental loss of urine (urge incontinence) due to a sudden and unstoppable need to urinate. Urge incontinence is usually associated with an overactive detrusor muscle, the smooth muscle of the bladder which contracts and causes it to empty. There is no single etiology for overactive bladder. Neurogenic overactive bladder occurs as the result of neurological damage found in a variety of disorders such as stroke, Parkinson's disease, diabetes, multiple sclerosis, peripheral neuropathy, or spinal cord lesions. In these cases, the overactivity of the detrusor muscle is termed detrusor hyperreflexia.
The physiology underlying micturition is complex and the exact mechanism causing overactive bladder is unknown. Overactive bladder may result from hypersensitivity of sensory neurons of the urinary bladder, arising from inflammatory conditions, hormonal imbalances, and prostate hypertrophy. Destruction of the sensory nerve fibres, either from a crushing injury to the sacral region of the spinal cord, or from a disease that causes damage to the dorsal root fibres as they enter the spinal cord may also lead to overactive bladder. In addition, damage to the spinal cord or brain stem causing interruption of transmitted signals may lead to abnormalities in micturition. Therefore, both peripheral and central mechanisms can contribute to overactive bladder. Carbone et ai. (2003) have previously reported the effects of gabapentin on neurogenic detrusor overactivity"™1. This study demonstrated a positive effect on symptoms and significant improvement in urodynamic parameters after treatment with gabapentin and suggested that the effects of the drug should be explored further in controlled studies in both neurogenic and nonneurogenic detrusor overactivity.
Further support for a pivotal role for Cav2.2 channels in the innervation of the urinary bladder comes from the finding that nitric oxide(NO), which is released by afferent nerves, acting via a cGMP signalling pathway can modulate N-type Ca2+ channels in DRG neurons innervating the urinary bladder™v Thus Cav2.2 may exert a central role in mediating control of reflex bladder activity by NO through suppressing the excitability and/or the release of transmitters from bladder afferent nerves.
Together, these studies indicate that modulation of N-type calcium channels offers a novel approach to reducing the hyperexcitability of bladder afferents in conditions of detrusor overactivity leading to overactive bladder and urinary incontinence.
Thus novel modulators of the protein-protein interaction between Cav2.2 channels and Cavβ3 accessory proteins may offer a novel mode of reducing hyperexcitability produced by over-expression of Cav2.2. Such a reduction of hyperactivity in primary afferent neurons is anticipated to lead to an alleviation of pain and of disorders of the lower urinary tract.
"Cavx" channels consist of at least 10 members which includes one of the following mammalian channels: Cav1.1 , Cav1.2, Cav1.3, Cav1.4, Cav2.1 , Cav2.2, Cav2.3, Cav3.1 , Cav3.2 or Cav3.3 and any mammalian or non-mammalian equivalents or variants (including splice variants) thereof.
"Cavβ" proteins may include one or more of the following mammalian subunits: Cavβi, Cavβ2, Cavβ3, Cavβ4 and any mammalian or non-mammalian equivalents or variants (including splice variants) thereof.
At a functional level, interactions between each combination of Cavx channel and Cavβ protein may confer modulation (increasing or decreasing) of a number of features of functional Cav channels including, but not limited to (i) the transport or chaperone of Cav channels to the plasma membrane of a given cell typeXXVi>MVi )on"i'xxvl" and/or (ii) gating properties such as channel inactivation™*.
Cavβ subunits can also exert effects on other gating properties by mechanisms which may alter the time and voltage dependency of the open (conducting state), closed (nonconducting state) and inactivated states (non-conducting state) of Cav channels.
Furthermore, the interaction between specific Cavβ subunits and different Cav channel compositions may confer differential modulation to Cav channel currents (e.g. Cav2 ***). This phenomenon may account for the wide diversity of Cav channels. However, exact subunit compositions of native Cav channels and the physiologic role that particular channels play are, in most cases, still unclear.
As such, compounds which inhibit the interaction between Cavx channels and Cavβ proteins and thus reduce either the conducting state of Cavx channels (e.g. though increasing the rate of inactivation) and/ or decreasing the transport of Cavx channels to the plasma membrane, are defined as "Cavx channel blockers" (Cav2 channel block).
Such Cavx channel inhibitors have potential utility in the treatment, prevention, inhibition, amelioration or alleviation of symptoms of a number of conditions or disease states including:
"Lower Urinary Tract Disorders". Lower urinary tract disorders is intended to encompass both painful (any lower urinary tract disorder involving sensations or symptoms that a patient subjectively describes as producing or resulting in pain) and non-painful lower urinary tract disorders (any lower urinary tract disorder involving sensations or symptoms, including mild or general discomfort, that is subjectively described as not producing or resulting in pain). "Lower urinary tract disorders" also includes any lower urinary tract disorder characterised by overactive bladder with and/or without loss of urine, urinary frequency, urinary urgency, and nocturia. Thus, lower urinary tract disorders includes overactive bladder or overactive urinary bladder (including, overactive detrusor, detrusor instability, detrusor hyperreflexia, sensory urgency and the symptoms of detrusor overactivity), urge incontinence or urinary urge incontinence, stress incontinence or urinary stress incontinence, lower urinary tract symptoms including obstructive urinary symptoms such as slow urination, dribbling at the end of urination, inability to urinate and/or the need to strain to urinate at an acceptable rate or irritate symptoms such as frequency and/or urgency. Lower urinary tract disorders may also include neurogenic bladder that occurs as the result of neurological damage due to disorders including but not limited to stroke, Parkinson's disease, diabetes, multiple sclerosis, peripheral neuropathy, or spinal cord lesions. Lower urinary tract disorders may also include prostatitis, interstitial cystitis, benign prostatic hyperplasia, and, in spinal cord injured patients, spastic bladder.
"Anxiety and Anxiety-Related Conditions". Anxiety and anxiety related conditions is intended to include, but is not limited to, anxiety, generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, social phobia, performance anxiety, posttraumatic stress disorder, acute stress reaction, adjustment disorders, hypochondriacal disorders, separation anxiety disorder, agoraphobia and specific phobias. Specific anxiety related phobias include, but are not limited to, fear of animals, insects, storms, driving, flying, heights or crossing bridges, closed or narrow spaces, water, blood or injury, as well as extreme fear of inoculations or other invasive medical or dental procedures.
"Epilepsy". Epilepsy is intended to include, but is not limited to, one or more of the following seizures: simple partial seizures, complex partial seizures, secondary generalised seizures, generalised seizures including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures and atonic seizures.
"Pain Disorders". Pain is intended to include but is not limited to one or more on the following: acute pain such as musculoskeletal pain, post operative pain and surgical pain; chronic pain such as chronic inflammatory pain (e.g. rheumatoid arthritis and osteoarthritis), neuropathic pain (e.g. post herpetic neuralgia, trigeminal neuralgia and sympathetically maintained pain) and pain associated with cancer and fibromyalgia; pain associated with migraine; pain (both chronic and acute), and/or fever and/or inflammation of conditions such as rheumatic fever; symptoms associated with influenza or other viral infections, such as the common cold; lower back and neck pain; headache; toothache; sprains and strains; myositis; neuralgia; synovitis; arthritis, including rheumatoid arthritis; degenerative joint diseases, including osteoarthritis; gout and ankylosing spondylitis; tendinitis; bursitis; skin-related conditions, such as psoriasis, eczema, burns and dermatitis; injuries, such as sports injuries and those arising from surgical and dental procedures.
"Cardiovascular Diseases" such as angina pectoris, hypertension and congestive heart failure.
"Gynaecological Pain", for example, dysmenorrhoea, labour pain and pain associated with endometriosis.
"Disorders of the Auditory System" such as tinnitus.
"Migraine".
"Gastrointestinal Disorders" including reflux esauphagitis, functional dispepsia, motility disorders (including constipation and diarrhoea), and irritable bowel syndrome.
"Vascular and Visceral Smooth Muscle Disorders" including asthma, pulmonary hypertension, chronic obstructive pulmonary disease, adult respiratory distress syndrome, peripheral vascular disease (including intermittent claudication), venous insufficiency, impotence, cerebral and coronary spasm and Raynaud's disease.
"Ceil Proliferative Disorders" including restenosis and cancer (including leukemia); treating or preventing gliomas including those of lower and higher malignancy.
"Metabolic Disorders" such as diabetes (including diabetic retinopathy, diabetic nephropathy and diabetic neuropathy), insulin resistance/insensitivity and obesity.
"Memory Loss" including Alzheimer's disease and dementia.
Other "CNS-Mediated Motor Dysfunction Disorders" including Parkinson's disease and ataxia. "Opthalamic Disorders" such as ocular hypertension.
Thus, it would be desirable to identify Cavx channel blockers for the prophylaxis or treatment of a number of disease states including lower urinary tract disorders and pain indications. Using assays based on the interaction between Cavx channel domains and Cavβ subunits immobilised through an affinity tag, we have discovered a new family of compounds which inhibit the interaction between Cavx channels and Cavβ proteins.
Description of the Invention
In a first aspect of the present invention, there is provided a compound represented by the general formula (1) or a pharmacologically acceptable salt, isostere or prodrug thereof, wherein:
Figure imgf000011_0001
R1 is a hydrogen atom, an alkyl group, a cycloalkyl group which is a single ring or a bridged ring system, an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), an aralkyl group comprising an alkyl group which is substituted with an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyi groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), a heteroaryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), a heteroaralkyl group which comprises an alkyl group which is substituted with a heteroaryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), an aminoalkyl group or a guanidinoalkyl group;
R2 is a hydrogen atom, an alkyi group which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups, aryl groups (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyi groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), heteroaryl groups (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), amino groups, monoalkylamino groups, diaSkylamino groups, saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, acyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, alkylsulfonyl groups and hydroxyl groups) and groups of formula COY, or a group of formula COY;
Y is a hydroxyl group, an alkoxyl group, a group of formula NR40R41 or an aminoacid residue;
R3 is an alkyl group, a cycloalkyl group which is a single ring or a bridged ring system (said cycloalkyl group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, acyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, alkylsulfonyl groups and hydroxyl groups), a cycloalkenyl group which is a single ring or a bridged ring system, an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), a heteroaryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), a saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic group having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, acyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, alkylsulfonyl groups and hydroxyl groups), a cycloalkylalkyl group wherein the cycloalkyl moiety is a single ring or a bridged ring system or an aralkyl group comprising an alkyl group which is substituted with an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkyjsulphonyl groups and cyano groups);
R4 and R40 are independently selected from hydrogen atoms, alkyl groups which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups, aryl groups {which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haioalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkyiamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), heteroaryl groups (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), amino groups, monoalkylamino groups, dialkylamino groups, saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups, halogen atoms, haioalkyl groups, alkoxy groups, alkoxycarbonyf groups, carboxyl groups, acyi groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, alkylsulfonyl groups and hydroxyl groups), carboxy groups, aminocarbonyl groups, monoalkylaminocarbonyl groups, dialkylaminocarbonyl groups, alkoxycarbonylgroups, groups of formula COR11 , groups of formula SO2RH , groups of formula CONR1 1R12, groups of formula SO2NRI I R^1 groups of formula CONR12SO2R11 and groups of formula CO2RI 3 wherein R11 , R12 and R13 are as defined below, aryl groups (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haioalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), heteroaryl groups (which may be un substituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), cycloalkyl groups which are single rings or bridged ring systems (said cycloalkyl groups may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, acyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, alkylsulfonyl groups and hydroxyl groups), cycloalkenyl groups which are single rings or bridged ring systems and saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, acyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, alkylsulfonyl groups and hydroxyl groups);
R4' and R41 are independently selected from hydrogen atoms and alkyl groups; or R4 and R4' together with the nitrogen atom to which they are attached and/or R40 and R41 together with the nitrogen atom to which they are attached may form a nitrogen- containing saturated or partially unsaturated 4- to 14- membered heterocyclic group having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings, said group optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, acyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, alkylsulfonyl groups and hydroxyl groups);
R11 is a hydrogen atom, an alkyl group, an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), an aralkyl group which comprises an alkyl group which is substituted with an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), a heteroaryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkyiamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups) or a heteroaralkyl group which comprises an alkyl group which is substituted with a heteroaryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups);
R12 is a hydrogen atom, an alkyl group, an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups) or an aralkyl group which comprises an alkyl group which is substituted with an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonytamino groups, alkylsulphonyl groups and cyano groups); and
R13 is an alkyl group, an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haioalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acyiamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), an aralkyl group which comprises an alkyl group which is substituted with an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haioalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acyiamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), an alkoxyalkyl group, a heteroaryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haioalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acyiamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups) or a heteroaralkyl group which comprises an alkyl group which is substituted with a heteroaryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haioalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acyiamino groups, alkoxycarbonylamino groups, alkylsuiphonyl groups and cyano groups);
R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, alkyl groups, halogen atoms, haioalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, acyiamino groups, alkoxycarbonylamino groups, alkyisulphonyl groups, arylsulphonyl groups, alkylsulphonylamino groups, arylsulphonylamino groups, aminosulphonyl groups and cyano groups, or any two adjacent ring substituents R5, R6, R7 and R8 may together form the group -O-(CH2)P-O- wherein p is an integer of from 1 to 3; and
X is an oxygen atom, a sulphur atom or a group of formula NR10, wherein R10 is a hydrogen atom or an alkyl group.
Preferred compounds of the present invention include: (2) compounds according to (1) and pharmacologically acceptable salts, isosteres and prodrugs thereof, wherein R1 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cycfoalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system, an aryl group having from 5 to 14 carbon atoms (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyi groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acyiamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haioalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyi groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acyiamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyi groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), a heteroaryi group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms atoms (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkyiamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonyiamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, an aminoalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one amino group, and a guanidinoalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with a guanidino group;
(3) compounds according to (1) and pharmacologically acceptable salts, isosteres and prodrugs thereof wherein R1 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an aminoalkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an amino group, a heteroaryl group which is a 5- to 6- membered aromatic heterocyclic group containing 1 to 2 sulfur atoms, oxygen atoms and/or nitrogen atoms which may be unsubstituted or substituted with an alkyl group having from 1 to 4 carbon atoms, and a guanidinoalkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with a guanidino group;
(4) compounds according to (1) and pharmacologically acceptable salts, isosteres and prodrugs thereof wherein R1 is a hydrogen atom, a methyl group, a 3-aminopropyl group, a 4-aminobutyl group, a 3-methyl-[1 ,2,4]oxadiazol-5-yl group, a 5-methyl- [1 ,3,4]oxadiazol-2-yl group, a 3-methyl-isoxazol-5-yl group, a 3-guanidinopropyl group or a tetrazol-5-yl group; (5) compounds according to any one of (1) to (4) and pharmacologically acceptable salts, isosteres and prodrugs thereof wherein R2 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, aryl groups having from 5 to 14 carbon atoms (said aryl groups being unsubstituted or being substituted with at least one substituent selected from alkyi groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyi groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyi groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), heteroaryl groups which are 5- to 7- membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms {said heteroaryl groups being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyi groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyi groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), amino groups, monoalkylamino groups wherein the alkyl substituent has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl substituent is the same or different and has from 1 to 6 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, and hydroxyl groups), and groups of formula COY, or R2 is a group of formula COY1 wherein
Y is a hydroxyl group, an alkoxyl group having from 1 to 6 carbon atoms, a group of formula NR40R41 , or an aminoacid residue, wherein R40 is selected from hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, aryl groups having from 5 to 14 carbon atoms (said aryl groups being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), heteroaryl groups which are 5- to 7- membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms (said heteroaryl groups being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acyfamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyi groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, and hydroxyl groups), carboxy groups, aminocarbonyl groups, monoalkylaminocarbonyl groups comprising an aminocarbonyl group which is substituted by an alkyl group having from 1 to 6 carbon atoms, dialkylaminocarbonyl groups comprising an aminocarbonyl group which is substituted by two alkyl groups which may be the same or different and each has from 1 to 6 carbon atoms, alkoxycarbonylgroups wherein the alkoxy moiety has from 1 to 6 carbon atoms, groups of formula COR11 , groups of formula SO2RH, groups of formula CONR11R12, groups of formula SO2NRI 1 R12, groups of formula CONR12SO2RH and groups of formula CO2RI 3 wherein R11 , R12 and R13 are as defined below, aryl groups having from 5 to 14 carbon atoms (said aryl groups being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonyiamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonyiamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonyiamino groups having from 1 to 6 carbon atoms and cyano groups), heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms (said heteroaryl groups being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonyiamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonyiamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonyiamino groups having from 1 to 6 carbon atoms and cyano groups), cycloalkyl groups having from 3 to 14 carbon atoms which are single rings or bridged ring systems (said cycloalkyl groups may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haioalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy moiety has from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is attached to a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups having from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms and hydroxyl groups), cycloalkenyl groups having from 4 to 14 carbon atoms and saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom {said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haioalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, and hydroxyl groups);
R41 is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, or R40 and R41 together with the nitrogen atom to which they are attached together form a nitrogen-containing saturated or partially unsaturated 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings, said group optionally further containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haioalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkyiamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, and hydroxy I groups);
R11 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyaSkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkyiamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with one or more of said aryl groups, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms (said heteroaryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyi groups, hydroxyl groups, amino groups, monoalkyiamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups) or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with one or more of said heteroaryl groups;
R12 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryi group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyi groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyi group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups) or an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with one or more of said aryl groups; and
R13 is an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkyi groups having from 1 to 6 carbon atoms, hydroxyalkyi groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with one or more of said aryl groups, an alkoxyalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an alkoxy group having from 1 to 6 carbon atoms, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms (said heteroaryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyi groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups) or a heteroaralkyl group which comprises an alkyi group having from 1 to 6 carbon atoms which is substituted with one or more of said heteroaryl groups;
(6) compounds according to any one of (1) to (4) and pharmacologically acceptable salts, isosteres and prodrugs thereof wherein R2 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 4 carbon atoms, aryl groups having from 6 to 10 carbon atoms, heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, amino groups, monoalkylamino groups wherein the alkyl substituent has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl substitυent is the same or different and has from 1 to 4 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyi groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyi group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, and hydroxyl groups), and groups of formula COY, or R2 is a group of formula COY1 wherein
Y is a hydroxyl group, an alkoxyl group having from 1 to 4 carbon atoms, a group of formula NR40R41, or an aminoacid residue, wherein R40 is selected from hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 4 carbon atoms, aryl groups having from 6 to 10 carbon atoms, heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, and hydroxyl groups), carboxy groups, aminocarbonyl groups, monoalkylaminocarbonyl groups comprising an aminocarbonyl group which is substituted by an alkyl group having from 1 to 4 carbon atoms, dialkylaminocarbonyi groups comprising an aminocarbonyl group which is substituted by two alkyl groups which may be the same or different and each has from 1 to 4 carbon atoms, alkoxycarbonylgroups wherein the alkoxy moiety has from 1 to 4 carbon atoms, groups of formula COR11 , groups of formula SO2R1 1 , groups of formula CONR11 R12, groups of formula SO2NRI 1 R12 groups of formula CONR12SO2R11 and groups of formula CO2RI 3 wherein R11 , R12 and R13 are as defined below, aryl groups having from 6 to 10 carbon atoms, heteroaryl groups which are 5- to 7- membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms atoms, cycloalkyl groups having from 3 to 8 carbon atoms which are single rings or bridged ring systems (said cycloalkyl groups may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, hydroxyalkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups wherein the alkoxy moiety has from 1 to 4 carbon atoms, carboxyl groups, acyi groups comprising a carbonyl group which is attached to a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups having from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms and hydroxyl groups), cycloalkenyl groups having from 4 to 8 carbon atoms and saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, and hydroxy I groups);
R41 is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, or R40 and R41 together with the nitrogen atom to which they are attached together form a nitrogen-containing saturated or partially unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings, said group optionally further containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, and hydroxyl groups);
R11 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atoms, an aralkyl group comprising an alkyi group having from 1 to 4 carbon atoms which is substituted with one or more aryl groups having from 6 to 10 carbon atoms, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms or a heteroaralkyl group which comprises an alkyl group having from 1 to 4 carbon atoms which is substituted with one or more heteroaryl groups which are 5- to 7- memberecl aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms;
R12 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atoms or an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with one or aryl groups having from 6 to 10 carbon atoms; and
R13 is an alkyl group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atoms, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with one or aryl groups having from 6 to 10 carbon atoms, an alkoxyalkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an alkoxy group having from 1 to 4 carbon atoms, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms or a heteroaralkyl group which comprises an alkyl group having from 1 to 4 carbon atoms which is substituted with one or more heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms;
(7) compounds according to any one of (1) to (4) and pharmacologically acceptable salts, isosteres and prodrugs thereof wherein R2 is a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 3 carbon atoms, amino groups, monoalkylamino groups wherein the alkyl substituent has from 1 to 3 carbon atoms, dialkylamino groups wherein each alkyl substituent is the same or different and has from 1 to 3 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom and groups of formula COY1 or
R2 is a group of formula COY, wherein
Y is a hydroxyl group, an alkoxyl group having from 1 to 3 carbon atoms, a group of formula NR40R41 , or an aminoacid residue, wherein R40 is selected from hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkoxyl groups having from 1 to 3 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and carboxy groups, cycloalkyl groups having from 3 to 6 carbon atoms atoms which are single rings or bridged ring systems and saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom;
R41 is a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms, or
R40 and R41 together with the nitrogen atom to which they are attached together form a nitrogen-containing saturated or partially unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings, said group optionally further containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur;
(8) compounds according to any one of (1) to (4) and pharmacologically acceptable salts, isosteres and prodrugs thereof wherein R2 is a group of formula COY, wherein Y is selected from hydroxyl groups, ethoxy groups, t-butoxy groups, amino groups, methylamino groups, ethylamino groups, i-propylamino groups, dimethylamino groups, 2-(methoxysulphonyl)ethylamino groups, pyrrolidin-1-yi groups, tetrahydropyran-4- ylamino groups, cyclohexylamino groups, piperidin-1-yl groups, cyclopropylamino groups, 2-methoxyethylamino groups, morpholin-4-yl groups, 2-(pyrrolidin-1- yl)ethylamino groups, and amioacid residues selected from ornithine, lysine and glycine, or an aSkyl group having from 1 to 3 carbon atoms which may be unsubstituted or substituted with a substituent selected from carboxy groups, amino groups, dimethylamino groupus, aminocarbonyl groups, morpholinyl groups, piperazinyl groups and pyrrolidinyl groups;
(9) compounds according to any one of (1) to (8) and pharmacologically acceptable salts, isosteres and prodrugs thereof wherein R3 is an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system (said cycloalkyl group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkyiamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulfonyl groups having from 1 to 6 carbon atoms and hydroxyl groups), a cycloalkenyl group having from 4 to 14 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl groups being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkyiamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms (said heteroaryl groups being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkyiamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyi groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), a saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic group having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, and hydroxyl groups), a cycloalkyialkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one cycloalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system (said cycloalkyl group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulfonyl groups having from 1 to 6 carbon atoms and hydroxyl groups), or an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one aryi group having from 5 to 14 carbon atoms (said aryl group may be unsubstituted or be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups);
(10) compounds according to any one of (1) to (8) and pharmacologically acceptable salts, isosteres and prodrugs thereof wherein R3 is a cycloalkyl group having from 4 to 10 carbon atoms which is a single ring or a bridged ring system (said cycloalkyl group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups comprising carbonyi groups substituted with an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted with a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkySamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, alkylsulfonyl groups having from 1 to 4 carbon atoms and hydroxyl groups), a cycloalkenyl group having from 4 to 10 carbon atoms or a saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic group having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, and hydroxyl groups);
(11) compounds according to any one of (1) to (8) and pharmacologically acceptable salts, isosteres and prodrugs thereof wherein R3 is a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 4-hydroxycyclohexyl group, a 4,4-dimethylcyclohexyl group, a 4,4-difluorocyclohexyl group, an adamantyl group, a norbornenyl group, a piperidinyl group, a 4-acetylpiperidinyl group or a 4-methylsulfonylpiperidinyl group;
(12) compounds according to any one of (1) to (11) and pharmacologically acceptable salts, isosteres and prodrugs thereof wherein R4 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, aryl groups having from 5 to 14 carbon atoms (said aryl groups may be unsubstituted or be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsuiphonylamino groups having from 1 to 6 carbon atoms and cyano groups), heteroaryi groups which are 5- to 7- membered aromatic heterocyclic groups containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms (said heteroaryi groups being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkyiamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), amino groups, alkylamino groups wherein the alkyl substituent has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl substituent is the same or different and has from 1 to 6 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, and hydroxyl groups), carboxy groups, aminocarbonyl groups, monoalkylaminocarbonyl groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylaminocarbonyl groups wherein each alkyl group is the same or different and has from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, groups of formula R11 CO, groups of formula R11SO2l groups of formula R11 R12NCO, groups of formula R1 1 R12NSO2, groups of formula R11 SO2NRI 2CO and groups of formula CO2RI 3, wherein R11 , R12 and R13 are as defined below, an aryl group having from 5 to 14 carbon atoms (said aryl group may be unsubstituted or be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyi groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), a cycloalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system (said cycloalkyl group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyi groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxyi groups, acyl groups comprising a carbonyl group which is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulfonyl groups having from 1 to 6 carbon atoms and hydroxyl groups), a cycloalkenyl group having from 4 to 14 carbon atoms and a saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic group having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic group being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 6 carbon atoms, carboxyi groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, and hydroxyl groups);
R11 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyi groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with one or more of said aryl groups, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms (said heteroaryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyi groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups) or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with one or more of said heteroaryl groups;
R12 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkyiamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyi is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyi groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups) or an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with one or more of said aryl groups; and
R13 is an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkyiamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyi is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonyiamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with one or more of said aryl groups, an alkoxyalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an alkoxy group having from 1 to 6 carbon atoms, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms (said heteroaryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acytamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonyiamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups) or a heteroaralkyl group which comprises an alkyi group having from 1 to 6 carbon atoms which is substituted with one or more of said heteroaryi groups;
(13) compounds according to any one of (1 ) to (11) and pharmacologically acceptable salts, isosteres and prodrugs thereof wherein R4 is an alkyl group having from 1 to 4 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkoxy groups having from 1 to 4 carbon atoms, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms and dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, a cycloalkyl group having from 3 to 8 carbon atoms which is a single ring or a bridged ring system (said cycloalkyl group being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms and acyl groups having from 1 to 4 carbon atoms), an aryl group having from 6 to 10 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, hydroxyl groups, acylamino groups having from 1 to 4 carbon atoms, hydroxylalkyl groups having from 1 to 4 carbon atoms, alkylamino groups having from 1 to 4 carbon atoms and dialkylamino groups wherein each alkyl group is the same or different and has from 1 to 4 carbon atoms), an aralkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an aryl group having from 6 to 10 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkoxyl groups having from 1 to 4 carbon atoms and hydroxyl groups), a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms or a saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic group having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms and alkoxy groups having from 1 to 4 carbon atoms);
(14) compounds according to any one of (1 ) to (11) and pharmacologically acceptable salts, tsosteres and prodrugs thereof wherein R4 is a methyl group, an /-propyl group, a f-butyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 4,4-difluorocyclohexyl group, an adamantyl group, a phenyl group (which is unsubstituted or is substituted with one or more substituents selected from fluorine atoms, chlorine atoms, hydroxyl groups, methyl groups, acetylamino groups, methoxy groups and diethylamino groups), a benzyl group (which is unsubstituted or is substituted with a methoxy group or a hydroxyl group), a phenethyl group (which is unsubstituted or is substituted with a hydroxyl group), a pyridinyl group, a thiazolyl group, a piperidinyi group, a tetrahydrofuranyl group, an N-methyl-piperidinyl group, a morpholinyl group, a piperazinyl group, an N-methyl-piperazinyl group, a 1H-indazolyl group, a 1-methyl-1H-indazolyl group, a tetrahydropyranyl group group, a 2- methoxyethyl group, a 2-aminoethyl group or a 2-dimethylaminoethyl group; (15) compounds according to any one of (1) to (14) and pharmacologically acceptable salts, isosteres and prodrugs thereof wherein R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, haloalkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising a carbonyl group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, arylsulphonyl groups wherein the aryl moiety has from 5 to 14 carbon atoms (the aryl groups being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), alkylsulphonylamino groups having from 1 to 6 carbon atoms, arylsuiphonylamino groups wherein the aryl moiety has from 5 to 14 carbon atoms (the aryl moiety being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each aSkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), aminosuiphonyl groups and cyano groups, or any two adjacent ring substituents R5, R6, R7 and R8 may together form the group -O-(CH2)P-O- wherein p is an integer of from 1 to 3;
(16) compounds according to any one of (1) to (14) and pharmacologically acceptable salts, isosteres and prodrugs thereof wherein R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, hydroxyalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, hydroxyl groups, haloalkoxy groups having from 1 to 4 carbon atoms, halogen atoms, cyano groups, or any two adjacent ring substituents R5, R6, R7 and R8 may together form the group -O-(CH2)P-O- wherein p is an integer of from 1 to 2;
(17) compounds according to any one of (1) to (14) and pharmacologically acceptable salts, isosteres and prodrugs thereof wherein R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, methyl groups, methoxy groups, fluorine atoms, chlorine atoms, bromine atoms, hyroxymethyl groups, trifluoromethoxy groups, trifluoromethyl groups, i-propyl groups, ethoxy groups, hydroxyl groups, cyano groups, methylsuiphonyl groups, or to adjacent ring substituents R5, R6, R7 and R8 may together form the group -O-CH2-;
(18) compounds according to any one of (1) to (17) and pharmacologically acceptable salts, isosteres and prodrugs thereof wherein X is an oxygen atom, a sulphur atom or a group of formula NR10, wherein R10 is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms;
(19) compounds according to any one of (1) to (17) and pharmacologically acceptable salts, isosteres and prodrugs thereof wherein X is a sulphur atom, an amino group or a methylamino group;
(20) compound according to (1) and pharmacologically acceptable salts, isosteres and prodrug thereofs, wherein:
R1 is a hydrogen atom, an alkyl group, a cycSoalkyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroaralkyl group, an aminoalkyl group or a guanidinoalkyl group;
R2 is an alkyl group which is substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups, aryl groups, heteroaryl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitrogen-containing unsaturated or partially saturated 4- to 8- membered heterocyclic groups, said groups optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms, and groups of formula COY1 or R2 is a group of formula COY;
Y is a hydroxyl group, an alkoxyl group, a group of formula NHR40 or an aminoacid residue;
R3 is an alkyl group, a cycloalkyl group, a cycloaSkenyl group, an aryl group, a heteroaryl group, a nitrogen-containing unsaturated or partially saturated 4- to 8- membered heterocyclic group, a cycloalkylalkyl group or an aralkyl group;
R4 and R40 are independently selected from hydrogen atoms, alkyl groups which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups, aryl groups, heteroaryl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitrogen-containing unsaturated or partially saturated 4- to 8- membered heterocyclic groups, said groups optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms, carboxy groups, aminocarbonyi groups, monoalkylaminocarbonyl groups, dialkylaminocarbonyl groups and alkoxycarbonyigroups, aryl groups, cycloalkyl groups, cycloalkenyl groups, groups of formula COR11 , groups of formula SO2RH 1 groups of formula CONR11 R12, groups of formula SO2NRI 1R12, groups of formula CONR12SO2R11 and groups of formula CO2RI 3 wherein R11 , R12 and R13 are as defined below;
R11 is a hydrogen atom, an alkyl group, an aryl group, an aralkyl group, a heteroaryl group or a heteroaralkyl group;
R12 is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group; and
R13 is an alkyl group, an aryi group, an aralkyl group, an alkoxyalkyl group, a heteroaryl group or a heteroarylalkyi group;
R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyl groups, alkylsulphonylamino groups, arylsulphonylamino groups, aminosulphonyl groups and cyano groups; and
X is an oxygen atom, a sulphur atom or a group of formula NR10, wherein R10 is a hydrogen atom or an alkyl group.
(21) compounds according to (20) and pharmacologically acceptable salts, isosteres and prodrugs thereof, wherein R1 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system, an aryi group having from 5 to 14 carbon atoms (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonytamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyi group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms atoms, a heteroaralkyl group which comprises an alkyi group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, an aminoalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one amino group, and a guanidinoalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with a guanidino group;
(22) compounds according to (20) or (21) and pharmacologically acceptable salts, isosteres and prodrugs thereof wherein R2 is an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, aryl groups having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkyiamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acyiamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms, amino groups, alkylamino groups wherein the alkyl substituent has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl substituent is the same or different and has from 1 to 6 carbon atoms, nitrogen-containing unsaturated or partially saturated 4- to 8- membered heterocyclic groups, said groups optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms, and groups of formula COY, or R2 is a group of formula COY, wherein Y is a hydroxyl group, an alkoxyl group having from 1 to 6 carbon atoms, a group of formula NHR40 (wherein R40 is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms), or an aminoacid residue;
(23) compounds according to any one of (20) to (22) and pharmacologically acceptable salts and prodrugs thereof wherein R3 is an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system, a cycloalkenyl group having from 4 to 14 carbon atoms which is a single ring or a bridged ring system, an aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyi groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkyiamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acyiamino groups comprising a carbonylamino group in which the carbonyi is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms, a nitrogen-containing unsaturated or partially saturated 4- to 8- membered heterocyclic group, said group optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms, a cycloalkylalkyl group comprising an aSkyl group having from 1 to 6 carbon atoms which is substituted with at least one cycloalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system, or an aralkyl group comprising an aSkyl group having from 1 to 6 carbon atoms which is substituted with at least one aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyi is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonyiamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups;
(24) compounds according to any one of (20) to (23) and pharmacologically acceptable salts and prodrugs thereof wherein R4 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, aryl groups having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the aSkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonyfamino groups having from 1 to 6 carbon atoms and cyano groups, heteroaryl groups which are 5- to 7- membered aromatic heterocyclic groups containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms, amino groups, alkylamino groups wherein the alkyl substituent has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl substituent is the same or different and has from 1 to 6 carbon atoms, nitrogen-containing unsaturated or partially saturated 4- to 8- membered heterocyclic groups, said groups optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms, carboxy groups, aminocarbonyl groups, monoalkylaminocarbonyl groups whrein the alkyl group has from 1 to 6 carbon atoms, dialkylaminocarbonyl groups wherein each alkyl group is the same or different and has from 1 to 6 carbon atoms, alkoxycarbonylgroups wherein the alkoxy group has from 1 to 6 carbon atom, groups of formula R11CO, groups of formula RHSO2, groups of formula R11 R12NCO, groups of formula R11 R12NSO2ι groups of formula R11 SO2NRI 2CO and groups of formula CO2R13, an aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyi groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, a cycloalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system, a cycloalkenyl group having from 4 to 14 carbon atoms which is a single ring or a bridged ring system;
R11 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkyiamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonyiamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonyiamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkyiamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonyiamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonyiamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaralkyl group which comprises an alkyS group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms,
R12 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, or an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms and cyano groups, and
R13 is an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyi group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyi is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyi groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, an alkoxyalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an alkoxy group having from 1 to 6 carbon atoms, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 suiphur atoms, oxygen atoms and/or nitrogen atoms;
(25) compounds according to any one of (20) to (24) and pharmacologically acceptable salts, isosteres or prodrugs thereof wherein R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising a carbonyl group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkyisulphonyl groups having from 1 to 6 carbon atoms, arylsulphonyl groups wherein the aryl moiety has from 5 to 14 carbon atoms (the aryl moiety being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyi groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkyisulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), alkylsulphonylamino groups having from 1 to 6 carbon atoms, aryisulphonyiamino groups wherein the aryl moiety has from 5 to 14 carbon atoms (the aryl moity being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haioalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyi groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyi groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsuiphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms) and cyano groups, aminosulphonyl groups and cyano groups;
(26) compounds according to any one of (20) to (25) and pharmacologically acceptable salts, isosteres or prodrugs thereof wherein X is an oxygen atom, a sulphur atom or a group of formula NR10, wherein R10 is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms;
(27) compounds according to (1) and pharmacologically acceptable salts, isosteres or prodrugs thereof wherein:
R1 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an aminoalkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an amino group, a heteroaryl group which is a 5- to 6-membered aromatic heterocyclic group containing 1 to 2 sulphur atoms, oxygen atoms and/or nitrogen atoms which may be unsubstituted or substituted with an alkyl group having from 1 to 4 carbon atoms, and a guanidϊnoalkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with a guanidino group,
R2 is a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 3 carbon atoms, amino groups, monoalkylamino groups wherein the alkyl substituent has from 1 to 3 carbon atoms, dialkylamino groups wherein each alkyl substituent is the same or different and has from 1 to 3 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom and groups of formula COY, or
R2 is a group of formula COY, wherein
Y is a hydroxyl group, an alkoxyl group having from 1 to 3 carbon atoms, a group of formula NR40R41 , or an aminoacid residue, wherein
R40 is selected from hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkoxyl groups having from 1 to 3 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and carboxy groups, cycloalkyl groups having from 3 to 6 carbon atoms atoms which are single rings or bridged ring systems and saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom;
R41 is a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms, or R40 and R41 together with the nitrogen atom to which they are attached together form a nitrogen-containing saturated or partially unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings, said group optionally further containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur,
R3 is a cycloalkyl group having from 4 to 10 carbon atoms which is a single ring or a bridged ring system (said cycloalkyi group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups substituted with an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted with a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, alkylsulfonyl groups having from 1 to 4 carbon atoms and hydroxyl groups), a cycloalkenyl group having from 4 to 10 carbon atoms or a saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic group having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, and hydroxyl groups), R4 is an alkyl group having from 1 to 4 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkoxy groups having from 1 to 4 carbon atoms, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyi group has from 1 to 4 carbon atoms and dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, a cycloalkyl group having from 3 to 8 carbon atoms which is a single ring or a bridged ring system (said cycloalkyl group being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms and acyl groups having from 1 to 4 carbon atoms), an aryl group having from 6 to 10 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, hydroxyl groups, acylamino groups having from 1 to 4 carbon atoms, hydroxylalkyl groups having from 1 to 4 carbon atoms, alkylamino groups having from 1 to 4 carbon atoms and dialkylamino groups wherein each alkyl group is the same or different and has from 1 to 4 carbon atoms), an aralkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an aryl group having from 6 to 10 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkoxyi groups having from 1 to 4 carbon atoms and hydroxyl groups), a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms or a saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic group having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms and alkoxy groups having from 1 to 4 carbon atoms),
R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, hydroxyalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, hydroxyl groups, haloalkoxy groups having from 1 to 4 carbon atoms, halogen atoms and cyano groups, or any two adjacent ring substituents R5, R6, R7 and R8 may together form the group
-O-(CH2)P-O- wherein p is an integer of from 1 to 2, and
X is an oxygen atom, a sulphur atom or a group of formula NR10, wherein R10 is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms;
(28) compounds according to (1) and pharmacologically acceptable salts, isosteres or prodrugs thereof wherein
R1 is a hydrogen atom, a methyl group, a 3-aminopropyl group, a 4-aminobutyl group, a 3-methyl-[1 ,2,4]oxadiazot-5-yl group, a 5-methyl-[1 ,3,4]oxadiazol-2-yl group, a 3-methyl- isoxazol-5-yt group or a 3-guanidinopropyl group;
R2 is a group of formula COY, wherein Y is selected from hydroxyl groups, ethoxy groups, t-butoxy groups, amino groups, methylamino groups, ethylamino groups, i- propylamino groups, dimethylamino groups, 2-{methoxysulphonyi)ethylamino groups, pyrrolidin-1-yl groups, tetrahydropyran-4-ylaιnino groups, cyclohexylamino groups, piperidin-1-yl groups, cyclopropylamino groups, 2-methoxyethylamino groups, morpholin-4-yl groups, 2-(pyrrolidin-1-yl)ethylamino groups, and amioacid residues selected from ornithine, lysine and glycine, or an alkyl group having from 1 to 3 carbon atoms which may be unsubstituted or substituted with a substituent selected from carboxy groups, amino groups, dimethylamino groupus, aminocarbonyl groups, morpholinyl groups, piperazinyl groups and pyrrolidinyl groups, or Y is a tetrazolyl group; R3 is a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 4- hydroxycyclohexyl group, a 4,4-dimethylcyclohexyl group, a 4,4-difluorocyclohexyl group, an adamantyl group, a norbornenyl group, a piperidinyl group, a 4- acetylpiperidinyl group or a 4-methylsulfonylpiperidinyl group;
R4 is a methyl group, an /-propyl group, a f-butyl group, a cyclopropyi group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 4,4-difluorocyclohexyl group, an adamantyl group, a phenyl group (which is unsubstituted or is substituted with one or more substituents selected from fluorine atoms, chlorine atoms, hydroxyl groups, methyl groups, acetylamino groups, methoxy groups and diethylamino groups), a benzyl group (which is unsubstituted or is substituted with a methoxy group or a hydroxyl group), a phenethyl group (which is unsubstituted or is substituted with a hydroxyl group), a pyridinyl group, a thiazolyl group, a piperidinyl group, a tetrahydrofuranyl group, an N-methyl-piperidinyl group, a morpholinyl group, a piperazinyl group, an N- methyl-piperazinyl group, a 1H-indazolyl group, a 1-methyl-1 H-indazolyl group, a tetrahydropyranyl group group, a 2-methoxyethyl group, a 2-aminoethyl group or a 2- dimethylaminoethyl group;
R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, methyl groups, methoxy groups, fluorine atoms, chlorine atoms, bromine atoms, hyroxymethyl groups, trifluoromethoxy groups, trifluoromethyl groups, i-propyl groups, ethoxy groups, hydroxyl groups, cyano groups, methylsulphonyl groups, or to adjacent ring substituents R5, R6, R7 and R8 may together form the group -O-CH2-; and X is a sulphur atom, an amino group or a methySamino group; and
(29) compounds according to (1) and pharmacologically acceptable salts, isosteres or prodrugs thereof, selected from;
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indol-3-yl(oxo)acetyl]glycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 HHndol-3-yl(oxo)acetyl]-b-alanine,
4-{[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl][1H-indol-3- yl(oxo)acetyl]amino}butanoic acid,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(6-fluoro-1 H-indol-3- yl)(oxo)acetyl]glycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1H-indoi-3-yl(oxo)acetyl]glycyi-L- ornithine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indol-3-yl(oxo)acetyl]glycyl-L- lysine,
N2-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N2-[1 H-indol-3-yl(oxo)acetyl]-D- ornithylglycine,
N-[1-bicyclo[2.2.1]hept-5-en-2-yl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indol-3- yl(oxo)acetyl]glycine,
N-[2-(cyclohexylamino)-1-cyclopentyl-2-oxoethyl]-N-[1 H-indol-3-yl(oxo)acetyl]glycine,
N-[1-cycloheptyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indol-3-yl(oxo)acetyl]glycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(5-fluoro-1H-indoi-3-yl)(oxo)acetyl]- b-alanine, N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(6-f[uoro-1 H-indol-3-yl)(oxo)acetyl]- b-alanine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(7-fluoro-1H-indol-3-yi){oxo)acetyl]- b-alanine,
N-[1 -cyclohexyl-2-(cyclohexylarriino)-2-oxoethyl]-N-[(1 -methyl-1 H-indol-3-yl)(oxo)acetyl]- b-alanine,
N-[1-cyclohexyi-2-(cyc[ohexylannino)-2-oxoethyl]-N-[(5-fluoro-1 H-indol-3- yl)(oxo)acetyl]glycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethy[]-N-[{7-fluoro-1H-indol-3- yi)(oxo)acetyl]g[ycine,
N-[1-cyclohexyl-2-(cyclohexylatnino)-2-oxoethyl]-N-[(2-methyl-1H-indol-3- yl)(oxo)acetyl]glycine,
N-[1-benzothien-3-yl(oxo)acetyl]-N-[1-cyclohexyI-2-(cyclohexylamino)-2-oxoethyl]glycine,
N-[1-cyclohexyl-2-(cyclohexytannino)-2-oxoethyl]-N-[(6-methyl-1 H-indoi-3- yl)(oxo)acetyl]glycine,
N-[(6-chloro-1H-indol-3-yl)(oxo)acetyl]-N-[1-cyclohexyl-2-(cyclohexylamino)-2- oxoethyl]glycine,
N-[1-cyclohexyl-2-(isopropylamino)-2-oxoethyl]-N-[1 H-indol-3-yl(oxo)acetyl]giycine,
N-[2-(benzylamino)-1-cyclohexyl-2-oxoethyl]-N-[1 H-indol-3-yl(oxo)acetyl]g[ycine,
N-[2-(adamantan-1 "ylamino)-1 -cyclohexyi-2-oxoethyl]-N-[1 H-indol-3- yl(oxo)acetyl]gtycine,
N-[1-cyclohexyl-2-(cyclopentylamino)-2-oxoethyl]-N-[1 H-indol-3-yt(oxo)acetyl]glycine,
N-{1-cyclohexyl-2-[(2-methoxyethyl)amino]-2-oxoethy[}-N-[1 H-indol-3- yl(oxo)acetyl]glycine,
N-[1-cyclohexy[-2-(methylamino)-2-oxoethyl]-N-[1 H-indo!-3-yl(oxo)acetyl]glycine,
N-(2-anilino-1 -cyclohexyl-2-oxoethyl)-N-[1 H-indol-3-yl(oxo)acetyl]glycine,
N-li-cyclohexyl-2-^-methoxyphenyl)amino^-oxoethyl}-N-II H-indol-3- yl(oxo)acetyl]giyctne,
N-(1-cyclohexyl-2-{[4-(diethylamino)phenyl]amino}-2-oxoethyl)-N-[1H-indo!-3- yl(oxo)acetyl]glycine,
N-[1-cyclohexyl-2-{cycloh8xylamino)"2-oxoethyl]-N-[1H-indol-3-yl(oxo)acetyl]-L-alanine1
N-{1-cyclohexyl-2-[(4-methoxybenzyl)amino]-2-oxoethyl}-N-[1 H-indol-3- yl(oxo)acetyl]glycine, N^I-cyclohexyl-Z-^-hydroxybenzyl)aminoj-2-oxoethyl}-N-[1 H-indol-3- yl(oxo)acetyl]glycine,
N-{1-cyc]ohexy[-2-oxo-2-[(2-phenylethyl)amino]ethyl}-N-[1 H-indol-3-yl(oxo)acetyl]glycine,
N-fi-cyclohexyW-^-fluorophenyl)amino^-oxoethylϊ-N-II H-indol-3- yl(oxo)acetyl]g[ycine,
N-ti-cyclohexyf-2-^-fΦhydroxyphenyl)ethyljamino}-2-oxoethyl)-N-[1H-indol-3- yl(oxo)acetyl]glycine,
N^I-cyclohexyl-2-tfΦhydroxyphenyl)aminoj-2-oxoethylϊ-N-[1 H-indol-3- yl(oxo)acetyl]g[ycine,
N-^-ftert-butylamino)-1-cycIohexyl-2-oxoethy^-N-fi H-indol-3-ylfoxo)acety^-b-alanine
N3-[1-cyclohexyi-2-(cyclohexylamino)-2-oxoethyl]-N3-[1 H-indol-3-y[(oxo)acetyl]-b- alaninamide
N-[1-cyclohexyl-2-(cyclohexyiamino)-2-oxoethyl]-N-(3-hydroxypropyl)-2-(1 H-indol-3-yl)-2- oxoacetamide,
N-[1-cyclohexyl-2-(cyclohexyIamino)-2-oxoethyl]-2-(1 H-indol-3-yl)-2-oxo-N-(2H-tetrazol-
5-ylmethyl)acetamide,
N-[1-cyclohexy]-2-(cyclohexylamino)-2-oxoethyl]-2-(1 H-indo!-3-yl)-N-(2-morpholin-4- ylethyl)-2-oxoacetamide,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-2-(1 H-indol-3-yl)-2-oxo-N-(2-piperazin-
1-ylethyl)acetamide,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-2-(1H-indol-3-y[)-2-oxo-N-(3-pyrrolidin-
1 -ylpropyi)acetatnide
N-(4-aminobutyl)-N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-2-(1 H-indol-3-yl)-2- oxoacetamide,
N-[1-cyc[ohexyl-2-(cyc[ohexylamino)-2-oxoethyl]-N-[1 H-indol-3" yl(oxo)acetyl]glycyjglycine,
N2-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N2-[1 H-indol-3- yl(oxo)acetyl]g]ycinamide, ethyl N-[1 -cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indol-3- yl(oxo)acetyl]glycinate,
N2-[1-cyclohexyl-2-(cyclohexytamino)-2-oxoethyl]-N2-[1 H-indol-3-yl(oxo)acetyl]-D-lysine,
N2-[1-cyclohexyl-2-(cyclohexy[amino)-2-oxoethy[]-N2-[1 H-indol-3-yl(oxo)acety[]-D- ornithine hydrochloride, N2-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N2-[1 H-indo!-3-yl(oxo)acetyl]-D- arginine,
N2-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N2-[1 H-indol-3-yl(oxo)acetyl]-L- ornithylglycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(4-fluoro-1H-indol-3- yf)(oxo)acetyl]glycine,
N-[1-adamantan-1-yl-2-{cyclohexylannino)-2-oxoethyl]-N-[1H-indol-3- yl(oxo)acetyl]glycine,
N2-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N2-[1 H-indo!-3-yl(oxo)acetyl]-L- arginylglycine,
N,2-dicyclohexyl-2-{[1H-indol-3-yl(oxo)acetyl]amino}acetamide,
N^I-cyclohexyl-2-[(3-hydroxybenzyl)amino^-oxoethyl}-N-E1H-indol-3- yl(oxo)acetyl]glycine,
N-fi-cyclohexyl-2-[(3-hydroxyphenyl)amino^-oxoethylϊ-N-[1 H-indol-3- yl (oxo) acety l]g lycine ,
N-fi-cyclohexyl-2-^-thydroxymethyl)phenyl]amino^-oxoethyl)-N-fiH-indol-3- yl(oxo)acetyl]glycine,
N^I-cyclohexyl^K^hydroxymethyl)phenyl)amino^-oxoethyl)-2-fiH-indol-3-yl)-2-oxo-
N-(3-pyrrolidin-1-y[propyl)acetamide,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1H-indol-3-yl(oxo)acetyl]-D-alanine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1H-indol-3-y[(oxo)acetyl]-D-alanine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indol-3-yl(oxo)acetyl]-D-alanine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]glycine,
N-[(6-bromo-1 H-indol-3-yl)(oxo)acetyl]-N-[1-cyclohexyl-2-(cyclohexylamino)-2- oxoethyl]g[ycine(
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-{oxo[6-(trifluoromethyl)-1 H-indo!-3- yl]acetyl}g lycine,
N-[1-cyclohexyl-2-fcyclohexylaminoi-2-oxoethylj-N-ffδ-isopropyi-1H-indol-3- yl)(oxo)acetyl]glycine,
N-[2-(cyclohexylamino)-2-oxo-1-piperidin-4-ylethyl]-N-[1 H-indol-3-yl(oxo)acetyl]g[ycine hydrochloride,
N-[1 -(1 -acetylpiperidin-4-yl)-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indol-3- yl (oxo) acety l]g lyci ne , N-{2-(cyclohexylamino)-1 -[1 -(methylsulfonyl)piperidin-4-yl3-2-oxoethyl}-N-[1 H-indol-3- yl(oxo)acetyl]glycine,
N-{1-cyclohexyl-2-[(3-hydroxyphenyl)amino]-2-oxoethyl}-N-[(6-methoxy-1 H-indol-3- y I) (oxo) acetyl] g lyci ne ,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(2E)-2-hydroxy-2-(2-oxo-1 ,2-dihydro-
3H-indol-3-ylidene)acetyl]glycine,
N-fi-cyclohexyl-2-[(3-methylphenyl)annino^-oxoethyl}-N-[1 H-indol-3- yl(oxo)acetyl]glycine,
N-li-cyclohexyl-2-[(3-methoxypheny^aminol-2-oxoethyl}-N-[1 H-indol-3- yl(oxo)acetyl]glycine,
N-{2-[(3-chlorophenyl)atnino]-1-cyclohexyl-2-oxoethyl}-N-[1 H-indol-3- yl(oxo)acetyl]glycine,
N-ii-cyclohexyl-2-ItS-fJuorophenyl)amino^-oxoethyl}-N-EI H-indol-3- y I (oxo) acety l]g lyci ne ,
N-[2-(tert-butylamino)-1-cyclohexy[-2-oxoethyl]-N-[(6-methoxy-1 H-indo[-3- yl)(oxo)acetyl]glycine,
N-(2-anilino-1-cyclohexyl-2-oxoethyl)-N-[(6-methoxy-1 H-indol-3-yl)(oxo)acetyl]glycine,
N-[1-cyclohexyl-2-Osopropyiamino)-2-oxoethyO-N-^β-methoxy-I H-indol-3- yl)(oxo)acetyl]glycine,
N-[1-cyclohexyl-2-(cyclopentylamino)-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]glycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(6-ethoxy-1 H-indol-3- yl) (oxo)acetyljg lyci ne ,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(6-hydroxy-1 H-indol-3- yl)(oxo)acetyljglycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(5,6-dimethoxy-1H-indol"3- yi)(oxo)acetyl]glycine,
N-[1-cyclohexyi-2-(cyclohexy[amino)-2-oxoethyl]-N-[5H-[1 ,3]dioxolo[4,5-f|indoi-7- yl(oxo)acetyl]glycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(5-methoxy-1 H-indol-3- y I) (oxo) acetyl] g lyci ne ,
N-[(5-bromo-1H-indo!-3-yl)(oxo)acetyl]-N-[1-cyclohexyl-2-(cyclohexylamino)-2- oxoethyl]glycine, N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-isl-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]-b-alanine,
4-{[1-cyclohexyl-2-(cyclohexy[amino)-2-oxoethyl][(6-methoxy-1H-indo]-3- yl)(oxo)acetyl]amino}butanoic acid,
N-[1-cyclohexyl-2-{cyclohexylamino)-2-oxoethyl]-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-N-(2- piperazin-1 -ylethyj)acetamide,
N-(4-aminobutyl)-N-[1-cyclohexy[-2-(cyclohexylamino)-2-oxoethyl]-2-{6-methoxy-1H- indol-3-yl)-2-oxoacetamide,
N2-[1-cyclohexyl-2-(cyclohexylamJno)-2-oxoethyl]-N2-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]glycinamide,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-2-(6-methoxy-I H-indol-3-yl)-N-methyl-
2-oxoacetamide,
N-[1-benzothien-3-yi(oxo)acetyl]-N-{1-cyclohexyl-2-[(3-hydroxyphenyl)amino]-2- oxoethyl}glycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(6-methoxy-1H-indol-3- yl)(oxo)acetyl]glycylglycine,
N-[1-cyclohexyl-2-(cyclohexy[amino)-2-oxoethyl]-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-N-(3- pyrrolidin-1-ylpropyl)acetamide,
N-{1-cyclohexyl-2-[(3-hydroxyphenyi)amino]-2-oxoethyl}-N-[1 H-indol-3-yl(oxo)acetyl]-b- alanine,
4-({i-cyclohexyl-2-[(3-hydroxyphenyl)aminol-2-oxoethyl}II H-indoI-3- yl(oxo)acetyl]amino)butanoic acid,
N^I-cyclohexyl-2-^Φφydroxymethyl)phenyi]amino^-oxoethyl)-N-KΘ-methoxy-1H- indol-3-yl)(oxo)acetyl]glycine,
N^I-cyclohexyl-2-[(3-hydroxyphenyl)amino^-oxoethyl^-fi H-indol-3-yl)-2-oxo-N^S- pyrrofidin-1-ylpropyl)acetamide,
N-ti-cyclohexyl-2-[(3-hydroxyphenyl)aminol-2-oxoethyl^-tiH-indol-3-yl)-N-methyl-2- oxoacetamide,,
N-ti-cyclohexyl-2-IfS-hydroxyphenyl)aminol-2-oxoethylϊ-N-p-methoxy-I H-indol-3- yl)(oxo)acetyl]-b-alanine,
4-({i-cyclohexyl-2-[(3-hydroxyphenyl)aminol-2-oxoethyl}[(6-methoxy-I H-indol-3- yl)(oxo)acetyl]amino)butanoic acid,
N-{1-cyclohexy[-2-[(3-hydroxyphenyl)amino]-2-oxoethyl}-2-(6-methoxy-1 H-indol-3-yl)-2- oxo-N-{3-pyrrolidin-1-ylpropyl)acetamide, N-li-cyclohexyl-2-IfΦhydroxyphenyl)amino]-2-oxoethyl}-N-^θ-nnethoxy-I H-indol-3- yl)(oxo)acetyl]glycine,
N-[(1 S)-1 -cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]glycine,
N-[{1 R)"1 -cyclohexyl-2-(cyclohexy[amino)-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]glycine,
N-[1-cyclohexyl-2-(cyclohexyiamino)-2-oxoethyl]-N-{oxo[6-(trifluoromethoxy)-1 H-indol-3- yl]acetyl}glycine,
N-{1-cyclohexyl-2-[(3-hydroxyphenyl)atnino]-2-oxoethyl}-2-(1 H-indo!-3-yl)-2-oxo-N-(2- piperazin-1 -yfethyl)acetamide,
N-(4-aminobutyl)-N-{1-cyclohexyi-2-[(3-hydroxyphenyl)amino]-2-oxoethyl}-2-(1H-indol-3- yl)-2-oxoacetamide,
N-{1-cyclohexyl-2-[(3-hydroxyphenyl)amino]-2-oxoethyl}-2-(6-methoxy-1 H-indoi-3-yl)-2- oxo-N-(2-piperazin-1-ylethyl)acetamide,
N-f4-aminobutyl)-N^I-cyclohexyl-2-[(3-hydroxyphenyl)atnino^-oxoethyl^-tδ-nπethoxy-
1 H-indol-3-yi)-2-oxoacetamide,
N-[1-cyclohexyl-2-(isopropylamino)-2-oxoethyl]-2-(6-methoxy-1 H-indo[-3-y[)-2-oxo-N-{3- pyrro[idin-1-ylpropyi)acetamide,
N^4-aminobutyl)-N-EI-cyclohexyl-2-fisopropyiamino^-oxoethyl^-fδ-methoxy-I H-indol-
3-yl)-2-oxoacetamide,
N,2-dicyclohexyl-2-{[{6-ιnethoxy-1 H-indol-3-yl)(oxo)acetyl]amino}acetamide,
N-(2-ani[ino-1-cyclohexyl-2-oxoethyl)-2-(6-methoxy-1H-indol-3-yl)-2-oxo-N-(3-pyrrolidin-
1 -ylpropyl)acetamide,
N-(2-aniiino-1-cyclohexyl-2-oxoethyl)-2-(6-ιnethoxy-1 H-indol-3-yl)-2-oxo-N-(2-piperazin-
1-ylethyl)acetamide,
N-[(6-cyano-1H-indol-3-y[){oxo)acetyl]-N-[1-cyclohexyl-2-(cyclohexylamino)-2- oxoethy[]glycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-{[6-(methylsulfonyi)-1H-indol-3- yl](oxo)acetyl}glycine,
N-(4-aminobutyl)-N-(2-anilino-1-cyclohexyl-2-oxoethyl)-2-(6-methoxy-1H-indo!-3-yl)-2- oxoacetamide,
N-li-cyclohexyl-2-ItS-methoxypropyl)amino^-oxoethyl}-N-[1H-indol-3- yl(oxo)acetyl]glycine, N-(1-cyclohexyl-2-{[3-(dimethylamino)propyl]amino}-2-oxoethyl)-N-[1 H-indo[-3- yl(oxo)acetyl]glycine,
N-{2-[(3-aminopropyl)amino]-1-cyclohexyt-2-oxoethyl}-N-[1H-indol-3- yl(oxo)acetyl]glycine,
N-ii-cyclohexyl-2-IfS-nnethoxypropyl)amino^-oxoethyl}-N-tfβ-methoxy-I H-indol-3- yl)(oxo)acetyl]glycine,
N-fi-cyclohexyl^tS^dimethylamino)propyl]amino}-2-oxoethyl)-N-^β-methoxy-I H-indol-
3-yl)(oxo)acetyl]glycine,
N^-[(3-aminopropyl)anninol-1-cyclohexyl-2-oxoethylϊ-N-^θ-methoxy-I H-indol-3- yl)(oxo)acetyl]glycine,
N-II-cyclohexyl-2-oxo-2-fpyridin-2-ylamino)ethy^-N-Kδ-methoxy-I H-indol-3- yl)(oxo)acetyl]glycine hydrochloride,
N-[(1 R)-1-cyclohexyl-2-oxo-2-(1 ,3-thiazot-2-ylamino)ethyl]-N-[(6-methoxy-1 H-indoI-3- yl)(oxo)acetyl]glycine,
N-((R)-cyclohexylphenylcarbamoylmethyl)-2-(1 H-indol-3-yl)-2-oxo-N-(2-piperazin-1-yl- ethyl)acetamide,
N-((R)-cyclohexy[isopropylcarbamoylmethyl)-2-(1 H-indol-3-yl)-2-oxo-N-(2-piperazin-1-yl- ethyl)acetamide,
2!N-dicyclohexyl-2-[[2-(6-methoxy-benzo[b]thiophen-3-yl)-2-oxo-acetyl]-(2-piperazin-1-yl- ethyl)-amino]-acetamide,
2-{(4-amino-buty[)-[2-(6-methoxy-benzo[b]thiophen-3-yl)-2-oxo-acetyl]-amino}-2,N- dicyclohexyl-acetamide,
{(cyclohexylcyclohexylcarbamoyl-methyl)[2-(6-methoxybenzo[b]thiophen-3-yi)-2-oxo- acetyl]amino}acetic acid,
[[2-(6-bromobenzo[b]thiophen-3-yi)-2-oxo-acetyl](cyc[ohexylcyclohexylcarbamoylmethyl)- amino]acetic acid,
{[cyclohexylcarbamoyi-(4,4-dimethylcyc[ohexyl)methyl][2-(6-methoxy-1 H-indol-3-yl)-2- oxoacetyf]amino}acetic acid,
N-[1-cyclohexy[-2-(isopropylamino)-2-oxoethyl]-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-N-(2- piperazin-1 -ylethyl)acetamide,
{[cyclohexylcarbamoyl-(4,4-dimethylcyclohexyl)methyl][2-(1H-indo!-3-yl)-2- oxoacetyl]amino}acetic acid,
{(cyclohexylcyclohexylcarbamoy[methyl)-[2-(6-hydroxymethyl-1 H-indo[-3-y[)-2- oxoacetyl]amino}acetic acid, N-[(1 R)- 1 -cyclohexyl-2-oxo-2-(piperidin-4-ylamino)ethyl]-N-[(6-methoxy-1 H-indol-3- yl)oxoacetyl]glycine,
N-[(1 R)-1 -cyclohexyl-2-oxo-2-{tetrahydro-2H-pyran-4-ylamino)ethyl]-N-[(6-methoxy-1 H- indol-3-yl)(oxo)acetyl]glycine,
N-{(1 R)-1 -cyc[ohexyl-2-[(1 -methylpiperidin-4-yl)amino]-2-oxoethyl}-N-[(6-methoxy-1 H- indol-3-yl){oxo)acetyl]glycine,
N-[(1R)-2-(cycloheptylamino)-1-cyclohexyl-2-oxoethyl]-N-[(6-methoxy-1H-indol-3- yl)(oxo)acetyl]glycine,
N-[(1 R)-1 -cyclohexyl-2-(cyc[opropylatnino)-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yl) (oxo) acetyljg lyci ne ,
N-[(1 R)-1 -cyclohexyl-2-(cyclopentylamino)-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]glycine,
N-[(1 R)-1 -cyclohexyl-2-(isopropylamino)-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yl) (oxo) acetyljg lyci ne,
N-[1-cyclohexyl-2-oxo-2-(pyridin-2-ylamino)ethyl]-N-(2-methoxyethyl)-2-(6-methoxy-1 H- indol-3-yl)-2-oxoacetamide,
{[(R)-cyclohexyl-(4,4-difluorocyclohexylcarbamoyl)methyl]-[2-(6-methoxy-1 H-indol-3-yl)-
2-oxo-acetyl]amino}acetic acid,
{((R)-cyc[ohexy[phenylcarbamoylmethyl)-[2-(6-fluoro-1 H-indol-3-yl)-2- oxoacetyl]amino}acetic acid,
{[(R)-cyclohexyl-(1H-indazol-6-ylcarbamoyl)-methyl]-[2-(6-methoxy-1H-indol-3-yl)-2- oxoacetyl]-amino}acetic acid,
{[(R)-cyclohexyl-(3-hydroxy-4-methylphenylcarbamoy[)methyl]-[2-(6-methoxy-1 H-indol-3- yl)-2-oxoacetyl]amino}acetic acid,
{[(R)-(3-acetylaminophenylcarbatnoyl)cyclohexylmethyl]-[2-(6-methoxy-1 H-indol-3-yl)-2- oxoacetyl]amino}acetic acid,
{[(R)-cyclohexyi-(4-methoxyphenyIcarbamoyl)methyl]-[2-(6-methoxy-1H-indol-3-yl)-2- oxoacetyl]amino}acetic acid,
{[(R)-cyclohexyl-(3-methoxyphenylcarbamoyl)methyl]-[2-(6-methoxy-1 H-indol-3-yl)-2- oxoacetyl]amino}acetic acid,
{((R)-cyclohexylisopropylcarbamoylmethyl)-[2-(6-fluoro-1 H-indol-3-yl)-2- oxoacetyl]amino}acetic acid,
{{{R)-cyclohexylcyclopropylcarbamoylmethyl)-[2-(6-fluoro-1H-indol-3-yl)-2- oxoacetyl]amino}acetic acid, {((R)-cyclohexyϋsopropylcarbamoylmethyl)-^θ-methoxy-I H-indol-3-yl)-2- oxoacetyl]amino}acetic acid tert-butyl ester,
N-ffR^cyclohexylisopropylcarbamoylmethyl)-2-fe-methoxy-1H-indol-3-yl^-oxo-N-fΣ- oxo-2-pyrro!idin-1-y[ethyl)acetamide,
{{(R)-cyclohexylcyc[ohexylcarbamoylmethyl)-[2-(5,6-difluoro-1H-indol-3-yi)-2-oxo- acety[]amino}acetic acid,
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-N-[{2- methanesulfonylethylcarbamoyl)methyl^-tβ-methoxy-I H-indol-3-yl)-2-oxoacetamide,
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-2-(5,6-difluoro-1 H-indol-3-yl)-2-oxo-N-(2- oxo-2-pyrrolidin-1-ylethyl)acetamide,
N-[cyclohexyl-((R)-tetrahydropyran-4-ylcarbamoyl)methyl]-2-(6-hydroxy-1 H-indol-3-yl)-2- oxo-N-(2-oxo-2-pyrrolidin-1-ylethyl)acetamide,
{[(R)-cyclohexyl-(tetrahydropyran-4-ylcarbamoyl)methyJ]-[2-(6-hydroxy-1H-indol-3-yl)-2- oxoacetyl]amino}acetic acid,
N-[(R)-cyclohexyl-(tetrahydropyran-4-ylcarbamoyl)methyl]-2-(6-hydroxy-1 H-indol-3-yl)-2- oxo-N-[(tetrahydropyran-4-ylcarbamoyl)methyl]acetamide,
(R)-2-{carbamoylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxoacetyl]amino}-2,N- dicyclohexyiacetamide,
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-N-(2-methoxyethyl)-2-(6-methoxy-1 H- indol-3-yl)-2-oxoacetamide,
N-cyclohexy[carbamoylmethyl-N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-2-(6- methoxy-1 H-indol-3-yl)-2-oxoacetamide
N-((R)-cyclohexylcyclohexylcarbamoyimethyl)-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-N-(2- oxo-2-piperidin-1-ylethyl)acetamide,
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-N-{isopropylcarbatnoylmethyl)-2-(6- methoxy-1 H-indoi-3-yl)-2-oxoacetamide,
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-N-cyclopropylcarbamoylmethyl-2-(6- methoxy-1 H-indol-3-yl)-2-oxoacetamide,
N-((R)-cyclohexylcyclohexylcarbamoy[methyl)-N-(2-hydroxy-ethyl)-2-(6-methoxy-1H- indol-3-yl)-2-oxoacetamide,
N-((R)"Cyclohexyl-cyclohexytcarbamoy[methyl)-N-diethylcarbamoy[methyl-2-(6-methoxy-
1 H-indol-3-yl)-2-oxoacetamide,
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-N-[(2-methoxyethylcarbamoyl)methyl]-2-
(6-methoxy-1 H-indol-3-yl)-2-oxoacetamide, N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-2-(6-methoxy-1 H-indol-3-yl)-N-(2- morpholin-4-yl-2-oxo-ethyl)-2-oxoacetamide,
N-{{R)-cyclohexylcyclohexylcarbamoy[ιnethy[)-2-(6-nnethoxy-1 H-indo[-3-yl)-2-oxo-N-[(2- pyrrolidin-1-yl-ethylcarbamoyQmethyljacetamide,
N-((R)-cyc[ohexylcyclohexylcarbamoylmethyl)-2-(6-methoxy-1H-indol-3-yl)-N- methylcarbamoylmethyl-2-oxoacetamide,
N-((R)-cyclohexy[cyclohexylcarbamoylmethyl)-N-dimethylcarbamoylmethyl-2-(6- methoxy-1H-indol-3-yl)-2-oxoacetamide,
{((R)-cyclohexylcyclohexylcarbamoylmethyl)-[2-(6-methoxy-1 H-indol-3-yl)-2-oxo- acetyl]amino}acetic acid methyl ester,
{[cyc]ohexylcarbamoyl-(4-hydroxycyclohexyl)methyl]-[2-(6-methoxy-1H-indol-3-y[)-2- oxoacetyl]amino}acetic acid,
N-((R)-cyclohexyicyclohexylcarbamoylmethyl)-N-(2-dimethylaminoethyl)-2-(6-methoxy-
1 H-indoi-3-yl)-2-oxoacetamide,
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-2-(6-methoxy-1H-indo!-3-yl)-2-oxo-N-(2- oxo-2-pyrrolidin-1-yl-ethyl)acetamide,
{[cyc]ohexylcarbamoyl-(4,4-difluorocyclohexyl)methyl]-[2-(6-methoxy-1H-indol-3-yl)-2- oxoacetyl]amino}acetic acid,
N-[(R)-cyclohexyl-(1 -methyl- 1 H-indazol-6-ylcarbamoyl)methyl]-2-(6-fluoro-1 H-indo!-3-yl)-
2-oxo-N-[(tetrahydropyran-4-ylcarbamoyl)methyl]acetamide,
{((R)-cyclohexylcyclohexylcarbamoylmethyl)-[2-{6-fluoro-1H-indol-3-yl)-2- oxoacetyl]amino}acetic acid,
N-((R)-cyclohexy[cyclohexylcarbamoylmethyl)-2-(6-methoxy-1 H-tndol-3-yl)-2-oxo-N-
[(tetrahydropyran^-ylcarbamoyljmethyljacetamide,
{((R)-cyclohexylphenylcarbamoylmethyl)-^-fS-methoxy-I H-indol-3-yl)-2- oxoacetyl]amino}acetic acid,
N-(4-aminobutyl)-N-((R)-cyclohexylcyclohexylcarbamoy[methyl)-2-(6-methoxy-1H-indol-
3-yl)-2-oxoacetamide,
{((R)-cyclohexylisopropylcarbamoylmethyl)-^-tβ-methoxy-I H-indol-3-yi)-2- oxoacetyl]amino}acetic acid,
{({R)-cyclohexylcyclopentylcarbamoylmethyl)-[2-(6-methoxy-1H-indol-3-yl)-2- oxoacetyl]amino}acetic acid,
4-{((R)-cyclohexylcyclohexylcarbamoylmethyl)-[2-(6-methoxy-1H-indol-3-yl)-2- oxoacetyl]amino}butyric acid, (2-{((R)-cyclohexylcyclohexylcarbamoylmethyl)-[2-(6-methoxy-1 H-indol-3-yl)-2-oxo- acetyl]amino}acetylamino)acetic acid,
3-{((R)-cyclohexylcyclohexy[carbamoylmethyl)-[2-(6-methoxy-1H-indol-3-yl)-2- oxoacetyl]amino}propionic acid,
{((R)-cyclohexylcyclohexylcarbamoylmethyl)-[2-(4-methoxy-1 H-indo[-3-yl)-2- oxoacetyl]amino}acetic acid,
{((R)-cycIohexylcyclohexylcarbamoylmethyl)-[2-(1H-indol-3-yi)-2-oxoacetyl]amino}acetic acid,
(R)-2,N-dicyclohexyl-2-[[2-(6-methoxy-1 H-indol-3-yl)-2-oxoacetyl]-(2H-tetrazol-5- ylmethyl)amino]-cetamide
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-2-(6-methoxy-1 H-indol-3-yl)-N-(3-methyl-
[1 ,2,4]oxadiazol-5-ylmethyl)-2-oxoacetamide,
N-((R)-cyclohexyicyclohexylcarbaιnoylmethyl)-2-(6-methoxy-1H-indo[-3-yl)-N-(5-methy[-
[1 ,3,4]oxadiazol-2-ylmethyl)-2-oxoacetamide,
N-((R)-cyc[ohexylcyclohexylcarbamoylmethyl)-2-(6-methoxy-1 H-tndol-3-yl)-N-{3- methylisoxazol-5-ylmethyl)-2-oxo-cetamide,
N-[(1 R)-1 -cyclohexyl-2-morpholin-4-yl-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyr]glycine,
N-[(1 R)-1-cyclohexyl-2-oxo-2-piperazin-1-ylethyl]-N-[(6-methoxy-1H-indol-3- yl)(oxo)acetyl]glycine, and
N-[(1 R)-1 -cyclohexyl-2-(4-methylpiperazin-1 -yl)-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]glycine.
In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and an active ingredient, wherein said active ingredient is a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
In a third aspect of the present invention, there is provided a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof for use as a medicament.
In a fourth aspect of the present invention, there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of a disease in which Cavx channels are involved.
In a fifth aspect of the present invention, there is provided use of a compound according to any one of (1 ) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel opening.
In a sixth aspect of the present invention, there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel inhibition.
In a seventh aspect of the present invention, there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Lower Urinary Tract Disorders.
In an eighth aspect of the present invention, there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Anxiety and Anxiety-Related Conditions.
In a ninth aspect of the present invention, there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Epilepsy.
In a tenth aspect of the present invention, there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Pain Disorders. In an eleventh aspect of the present invention, there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Gynaecological Pain.
In a twelfth aspect of the present invention, there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiac Arrhythmias.
!n a thirteenth aspect of the present invention, there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Thromboembolic Events.
In a fourteenth aspect of the present invention, there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiovascular Diseases.
In a fifteenth aspect of the present invention, there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Disorders of the Auditory System,
In a sixteenth aspect of the present invention, there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Migraine.
In a seventeenth aspect of the present invention, there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Inflammatory and Immunological Diseases. In an eighteenth aspect of the present invention, there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Gastrointestinal Disorders.
In a nineteenth aspect of the present invention, there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Vascular and Visceral Smooth Muscle Disorders.
In a twentieth aspect of the present invention, there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Cell Proliferative Disorders.
In a twenty-first aspect of the present invention, there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Metabolic Disorders.
In a twenty-second aspect of the present invention, there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Memory Loss.
In a twenty-third aspect of the present invention, there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of CNS-Mediated Motor Dysfunction Disorders.
In a twenty-fourth aspect of the present invention, there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Opthalamic Disorders.
In an twenty-fifth aspect of the present invention, there is provided a method for the prophylaxis or treatment of a disease in which Cavx is involved comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
In a twenty-sixth aspect of the present invention, there is provided a method for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel opening comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
In a twenty-seventh aspect of the present invention, there is provided a method for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel inhibition comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
In a twenty-eighth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Lower Urinary Tract Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
In a twenty-ninth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Anxiety and Anxiety-Related Conditions comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
In a thirtieth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Epilepsy comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
In a thirty-first aspect of the present invention, there is provided a method for the prophylaxis or treatment of Pain Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
In a thirty-second aspect of the present invention, there is provided a method for the prophylaxis or treatment of Gynaecological Pain comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
In a thirty-third aspect of the present invention, there is provided a method for the prophylaxis or treatment of Cardiac Arrhythmias comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
In a thirty-fourth aspect of the present invention, there Ss provided a method for the prophylaxis or treatment of Thromboembolic Events comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof
!n a thirty-fifth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Cardiovascular Diseases comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
In a thirty-sixth aspect of the present invention, there Ss provided a method for the prophylaxis or treatment of Disorders of the Auditory System comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof, In a thirty-seventh aspect of the present invention, there is provided a method for the prophylaxis or treatment of Migraine comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
In a thirty-eighth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Inflammatory and Immunological Diseases comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
In a thirty-ninth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Gastrointestinal Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
In a fortieth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Vascular and Visceral Smooth Muscle Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
In a forty-first aspect of the present invention, there is provided a method for the prophylaxis or treatment of Ceil Proliferative Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
In a forty-second aspect of the present invention, there is provided a method for the prophylaxis or treatment of Metabolic Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
In a forty-third aspect of the present invention, there is provided a method for the prophylaxis or treatment of Memory Loss comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
In a forty-fourth aspect of the present invention, there is provided a method for the prophylaxis or treatment of CNS-Mediated Motor Dysfunction Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
In a forty-fifth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Opthalamic Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
In a forty-sixth aspect of the present invention, there is provided a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof for use in the prophylaxis or treatment of any disease or condition recited in any of the fourth to twenty-fourth aspects of the invention recited above.
In a forty-seventh aspect of the present invention there is provided a pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and at least two active ingredients, wherein said active ingredients comprise at least one compound according to any one of (1 ) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in combination at least one compound selected from the group consisting of muscarinic receptor antagonists, β3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α2 δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists, alpha-1 adrenoceptor antagonists, tricyclic antidepressants, N-methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal anti-inflammatory drugs (NSAIDs). Preferred pharmaceutical combinations according to the present invention include:
(1) a pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in combination at least one compound selected from the group consisting of muscarinic receptor antagonists, β3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α2 δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists and α-1 adrenoceptor antagonists; and
(2) a pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in combination at least one compound selected from the group consisting of neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α2 δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, N-methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal anti-inflammatory drugs (NSAIDs).
The combinations of preferred option (1) are of particular use in the prophylaxis or treatment of lower urinary tract disorders. The combinations of preferred option (2) are of particular use in the prophylaxis or treatment of pain.
In a forty-eighth aspect of the present invention there is provided use of at least one compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof and at least one compound selected from the group consisting of muscarinic receptor antagonists, β3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, caicium channel α2 δ deita ligands, potassium channel inhibitors, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNFUs), 5-HT antagonists and α-1 adrenoceptor antagonists in the manufacture of a medicament for the prophylaxis or treatment of lower urinary tract disorders.
In a forty-ninth aspect of the present invention there is provided use of at least one compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof and at least one compound selected from the group consisting of neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α2 δ delta iigands, potassium channel inhibitors, caicium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, N-methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal anti-inflammatory drugs (NSAIDs) in the manufacture of a medicament for the prophylaxis or treatment of pain.
Detailed Description of the Invention
In the compounds of the present invention, the alkyl groups in the definitions of R1 , R2, R3, R4, R4J, R40, R41 , R5, R6, R7, R8, R9, R10, R11 , R12 and R13 are preferably alkyl groups having from 1 to 6 carbon atoms, more preferably alkyl groups having from 1 to 4 carbon atoms and most preferably methyl groups, ethyl groups, /-propyl groups and t- butyl groups.
In the compounds of the present invention, the cycloalkyl groups in the definition of R1 , R3, R4 and R40, are preferably cycloalkyl groups having from 3 to 14 carbon atoms which may either be unsubstituted or may be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyi groups comprising carbonyl groups substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulfonyl groups having from 1 to 6 carbon atoms and hydroxyl groups; the cycloalkyl group can be in a single ring or can be a bridged ring system. The cycloalkyl groups more preferably have from 5 to 10 carbon atoms, and are most preferably cyclopentyl, cyclohexyl, cycloheptyl and adamantyl groups which may be subsitiuted with one or more substiituents selected from fluorine atoms, hydroxyl groups and methyl groups.
In the compounds of the present invention, the aryl groups in the definitions of R1 , R2, R3, R4, R40, R11 , R12 and R13 are preferably aryl groups having from 5 to 14 carbon atoms in one or more rings which may either be unsubstituted or may be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups. Examples of the unsubstituted aryl groups include phenyl, indenyl, naphthyl, phenanthrenyl and anthracenyl groups. More preferred aryl groups include phenyl groups which may optionally substituted by 1 or 2 halogen atoms, alkoxy groups having from 1 to 4 carbon atoms, hydroxyalkyl groups having from 1 to 4 carbon atoms, acylylamtno groups having from 1 to 4 carbon atoms, hydroxyl groups and dialkylamino groups wherein each alkyl group is the same or different and has from 1 to 4 carbon atoms; and most preferred aryl groups are phenyl groups which are unsubstituted or are substituted with a fluorine atom, a hydroxyl group, a methoxy group, a hydroxymethyl group, a diethylamino group, a chlorine atom or a diethoxyamino group.
In the compounds of the present invention, the aralkyl groups in the definitions of R1 , R3, R11 , R12 and R13 are preferably alkyl groups as defined above which are substituted with one or more aryi groups as defined above, and are more preferably benzyl and phenethyl groups which may be unsubstituted or substituted with at least one substituent selected from alkoxyl groups having from 1 to 4 carbon atoms and hydroxyl groups, and most preferably are benzyl and phenethyl groups which may be unsubstituted or substituted with a methoxy group or a hydroxyl group.
in the compounds of the present invention, the heteroaryl groups in the definitions of R1 , R2, R3, R4, R40, R11 and R13 are preferably a heteroaryi group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyf groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups. Examples include furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1 ,2,3-oxadiazolyl, triazoiyl, tetrazolyl, thiadiazolyf, pyranyf, pyridyl, pyridazinyl, pyrimidinyl, indazolyl, 1-methylindazolyl and pyrazinyl groups. Most preferred is thiazolyl, indazolyl, 1-methylindazolyl and pyridyl.
In the compounds of the present invention, the heteroaralkyl groups in the definitions of R1 , R11 and R13 are preferably alkyl groups as defined above which are substituted with heteroaryl groups as defined above. In the compounds of the present invention, the aminoalkyl groups in the definition of R1 are preferably aSkyi groups as defined above which are substituted with an amino group, and most preferred are aminopropyl groups and aminobutyl groups.
In the compounds of the present invention, the guanidinoalkyl groups in the definition of R1 are preferably alkyl groups as defined above which are substituted with a guanidino group, and most preferred are guanidinopropyl groups.
in the compounds of the present invention, the alkoxyl groups in the definitions of R2, R3, R4, R40, R4', R41 , R5, R6, R7, R8, R9 and Y are preferably alkoxy groups having from 1 to 6 carbon atoms, more preferably alkoxy groups having from 1 to 4 carbon atoms and most preferably methoxy or ethoxy groups.
in the compounds of the present invention, the monoalkylamino groups in the definitions of R2, R3, R4, R40, R4\ R41 , R5, R6, R7, R8 and R9 are preferably amino groups which are substituted with one alkyl group as defined above, and are more preferably methylamtno, ethySamino or t-butylamino groups.
In the compounds of the present invention, the dialkylamino groups in the definitions of R2, R3, R4, R40, R4', R41 , R5, R6, R7, R8 and R9 are preferably amino groups which are substituted with two alkyl groups as defined above which may be the same or different from each other, and are more preferably dimethylamino or diethylamino groups.
In the compounds of the present invention, the saturated, partially unsaturated or unsaturated heterocyclic 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atoms in the definitions of R2, R3, R4, R40, R4' and R41 are 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings which may be unsubstituted or substituted with at (east one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyi groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, and hydroxyl groups. Preferred examples include morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 4-acetylpiperidinyl, 4- methylsulphonylpiperidinyl, tetrahydrofuranyl, N-methylpiperidinyl and N- methylpiperazinyl groups.
In the compounds of the present invention, the nitrogen-containing saturated or partially unsaturated 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings formed by R4 and R4' together with the nitrogen atom to which they are attached or R40 and R41 together with the nitrogen atom to which they are attached are nitrogen- containing saturated or partially unsaturated 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups and they optionally further contain one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur (said heterocyclic groups may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, and hydroxyl groups). Preferred examples include 4-acetylpiperidin-1-yl, 4-methylsulphonylpiperidin-1-yl, piperazin-1-yl and N-methyl-piperazin-1-yl groups. In the compounds of the present invention, the aminoacid residues in the definition of Y are the residual moieties obtained after reaction of an amino group with the carboxyl group of an amino acid, and are preferably ornithine, lysine or glycine residues.
In the compounds of the present invention, the monoalkylaminocarbonyl groups in the definitions of R4 and R40 are preferably aminocarbonyl groups which are substituted with one alkyl group as defined above, and are more preferably methylaminocarbonyS, ethylaminocarbonyl or t-butylaminocarbonyl groups.
In the compounds of the present invention, the dialkylaminocarbonyl groups in the definitions of R4 and R40 are preferably aminocarbonyl groups which are substituted with two alkyl groups as defined above which may be the same or different from each other, and are more preferably dimethylaminocarbonyl or diethylaminocarbonyl groups.
In the compounds of the present invention, the cycloalkenyl groups in the definition of R3, R4 and R40 are preferably cycloalkenyl groups having from 4 to 14 carbon atoms; the cycloalkyl group can be in a single ring or can be a bridged ring system. The cycloalkenyi groups more preferably have from 5 to 10 carbon atoms, and are most preferably norbomenyl groups.
In the compounds of the present invention, the cycloalkylalkyl groups in the definition of R3 are preferably alkyl groups as defined above which are substituted with a cycloalkyi groups as defined above.
In the compounds of the present invention, the haloalkoxy groups in the definitions of R5, R6, R7, R8 and R9 are preferably alkoxyl groups as defined above which are substituted with one or more halogen atoms. More preferably, they are alkoxyl groups having from 1 to 4 carbon atoms that are substituted with at least one chlorine or fluorine atom and most preferably they are chloromethoxy group, trichloromethoxy groups, trifluoromethoxy groups and tetrafluoroethoxy groups.
In the compounds of the present invention, the haioalkyl groups in the definitions of R2, R3, R4, R4\ R40, R41 , R5, R6, R7, R8 and R9 are preferably alkyl groups as defined above which are substituted with one or more halogen atoms. More preferably, they are alky] groups having from 1 to 4 carbon atoms that are substituted with at least one chlorine or fluorine atom and most preferably they are chloromethyl group, trichloromethyl groups, trifluoromethyl groups and tetrafluoroethyl groups.
in the compounds of the present invention, the alkoxycarbonyl groups in the definitions of R2, R3, R4, R4\ R40, R41 , R5, R6, R7, R8 and R9 are preferably carbonyl groups substituted with alkoxy groups as defined, and are more preferably methoxycarbonyl or ethoxycarbonyl groups.
In the compounds of the present invention, the acylamino groups in the definitions of R5, R6, R7, R8 and R9 are preferably carbonylamino groups in which the carbonyl is substituted with an hydrogen atom or an alkyl group having from 1 to 6 carbon atoms and are more preferably acetylamino or propanoylamino groups.
In the compounds of the present invention, the hydroxyalkyl groups in the definitions of R5, R6, R7, R8, R9, are preferably hydroxyalkyl groups having from 1 to 6 carbon atoms, more preferably hydroxyalkyl groups having from 1 to 4 carbon atoms and most preferably hydroxymethyl groups, 2-hydroxyethyl groups, and 3-hydroxypropyl groups groups.
In the compounds of the present invention, the acyl groups in the definitions of R2, R3, R4, R4'; R40 and R41 are preferably a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, more preferably a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and most preferably an acetyl or propionyl group.
in the compounds of the present invention, the alkoxycarbonylamino groups in the definitions of R5, R6, R7, R8 and R9 are preferably amino groups which are substituted with an alkoxycarbonyl group as defined above, and are more preferably methoxycarbonylamino or ethoxycarbonylamino groups.
In the compounds of the present invention, the alkylsulphonyl groups in the definitions of R2, R3, R4, R4\ R40, R41 , R5, R6, R7, R8 and R9 are preferably sulphonyl groups which are substituted with an alkyl group as defined above and are more preferably a methylsulphonyl or ethylsuiphonyl group.
In the compounds of the present invention, the arylsulphonyl groups in the definitions of R5, R6, R7, R8 and R9 are preferably sulphonyl groups which are substituted with an aryl group as defined above and are more preferably a phenylsulphonyl group which may be optionally substituted with one or two alkyl groups as defined above or a naphthylsulphonyl group.
In the compounds of the present invention, the alkylsulphonylamino groups in the definitions of R5, R6, R7, R8 and R9 are preferably sulphonylamino groups which are substituted with an alkyl group as defined above and are more preferably a methylsulphonylamino or ethylsulphonylamino group.
In the compounds of the present invention, the aryisuiphonylamino groups in the definitions of R5, R6, R7, R8 and R9 are preferably sulphonylamino groups which are substituted with an aryl group as defined above and are more preferably a phenylsulphonylamino group which may be optionally substituted with one or two alkyl groups as defined above or a naphthylsuiphonylamino group.
In the compounds of the present invention, the alkoxyalkyl groups in the definition of R13 are preferably alkyl groups as defined above which are substituted by one or more alkoxy groups as defined above. More preferably they are alkyl groups having from 1 to 4 carbon atoms that are substituted with an alkoxy group having from 1 to 4 carbon atoms and most preferably methoxymethyl and 2-methyoxyethyl groups.
The pharmacologically acceptable salts of the compound having the formula (1) described above are not specificaijy restricted and these salts can be selected by a person with an ordinary skill in the art. As pharmacologically acceptable salts of the compound having the formula (1) described above, such salts are, for example, basic salts such as an alkaline metal sait such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as calcium salt or magnesium salt; a metal salt such as aluminium salt, iron salt, zinc salt, copper salt, nickel salt or cobalt salt; an amine salt such as an ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N- methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylammonium salt or tris(hydroxymethyl)aminomethane salt, but not restricted to these salts (preferably alkaline metal salts can be used, and particularly preferably the sodium salt can be used); or acidic salts such as a hydrohalogenic acid salt such as a hydrofluoride, hydrochloride, hydrobromide or hydroiodide; a nitrate; a perchlorate; a sulfate; a phosphate; a C1-C4 alkanesulfonic acid salt, which may be optionally substituted with a halogen atom(s) such as a methanesulfonate, trifluoromethanesulfonate or ethanesulfonate; a C6-C10 arylsulfonic acid salt, which may be optionally substituted with a C1-C4 alkyl group(s), such as a benzenesulfonate or p- toluenesulfonate; a C1-C6 aliphatic acid salt such as an acetate, malate, fumarate, succinate, citrate, tartrate, oxalate or maleate; or an amino acid salt such as a glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt or aspartic acid salt (preferably hydrochlorides, nitrates, sulfates or phosphates can be used, and particularly preferably hydrochlorides).
The compounds of formula (1) of the present invention can be administered in the form of prodrugs. Prodrugs are derivatives of the pharmacologically active compound in which one or more of the substituents on said compound are protected by a group which is then removable by a biological process (e.g. hydrolysis) in vivo after administration to the patient. Many suitable prodrugs would be well-known to the person in the art and can be found, for example, in "Greene's Protective Groups in Organic Synthesis", 4th Edition, 2006, Wiley- VCH. Suitable examples of such prodrugs include pharmacologically acceptable esters of the compound having the formula (1) wherein a carboxyl moiety of the compound having the formula (1) is esterified. The pharmacologically acceptable esters are not particularly restricted, and can be selected by a person with an ordinary skill in the art. In the case of said esters, it is preferable that such esters can be cleaved by a biological process such as hydrolysis in vivo. The group constituting the said esters (the group shown as R when the esters thereof are expressed as -COOR) can be, for example, a C1-C4 alkoxy C1-C4 alkyl group such as methoxyethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl, 2- methoxyethyl, 2-ethoxyethyl, 1 ,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or t-butoxymethyl; a C1-C4 alkoxylated C1-C4 alkoxy C1-C4 alkyi group such as 2-methoxyethoxymethyl; a C6-C10 aryloxy C1-C4 alkyl group such as phenoxymethyl; a halogenated C1-C4 alkoxy C1-C4 alkyl group such as 2,2,2-trichloroethoxymethyl or bis(2-chloroethoxy)methyl; a C1-C4 alkoxycarbonyl C1- C4 alkyl group such as methoxycarbonylmethyl; a cyano C1-C4 alkyi group such as cyanomethyl or 2-cyanoethyl; a C1-C4 alkylthiomethyl group such as methylthiomethyl or ethylthiomethyl; a C6-C10 arylthiomethyl group such as phenylthiomethyl or naphthylthiomethyl; a C1-C4 alkylsulfonyl C1-C4 lower alkyl group, which may be optionally substituted with a halogen atom(s) such as 2-methanesulfonySethyl or 2- trifluoromethanesulfonylethyl; a C6-C10 arylsulfonyl C1-C4 alkyl group such as 2- benzenesulfonylethyl or 2-toluenesulfonylethyl; a C1-C7 aliphatic acyloxy C1-C4 alkyl group such as formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1- formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1- pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 2- formyloxyethyl, 2-acetoxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2- pivaioyloxyethyl, 2-valeryloxyethyl, 2-isovaleryloxyethyl, 2-hexanoyloxyethyl, 1- formyioxypropyl, 1-acetoxypropyl, 1 -propionyloxypropyl, 1 -butyryloxypropyl, pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaIeryloxypropyl, 1-hexanoyloxypropyl, 1- acetoxybutyl, 1-propionyioxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl or 1-pivaloyloxyhexyl; a C5- C6 cycloalkylcarbonyloxy C1-C4 alkyl group such as cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1- cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1- cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl or 1- cyclohexylcarbonyloxybutyl; a C3-C10 arylcarbonyloxy C1-C4 alkyl group such as benzoyloxymethyl; a C1-C6 alkoxycarbonyloxy C1-C4 alkyl group such as methoxycarbonySoxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-
(methoxycarbonyioxy)propyl, 1-(methoxycarbonyloxy)butyl, 1-
(methoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy)hexyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)propyl, 1-(ethoxycarbonyloxy)butyl, 1- (ethoxycarbonyloxy)pentyl, 1-(ethoxycarbonyloxy)hexyl, propoxycarbonyloxymethyl, 1- (propoxycarbonyloxy)ethyl, 1 -(propoxycarbonyloxy)propyl, 1 -(propoxycarbonyloxy)butyl, isopropoxycarbonyloxy methyl, 1-(isopropoxycarbonyloxy)ethyl, 1- (isopropoxycarbonyloxy)butyl, butoxycarbonyloxymethyl, 1-(butoxycarbonyloxy)ethyl, 1- (butoxycarbonyloxy)propyl, 1-(butoxycarbonyloxy)butyl, isobutoxycarbonyloxymethyl, 1- (isobutoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy)propyl, 1-
(isobutoxycarbonyloxy)butyl, t-butoxycarbonySoxymethyl, 1-(t-butoxycarbonyloxy)ethyl, pentyloxycarbonyloxymethyl, 1-(pentyloxycarbonyloxy)ethyl, 1-
(pentyloxycarbonyioxy)propyl, hexyloxycarbonyloxymethyl, 1 -(hexyloxycarbonyloxy)ethyl or 1-(hexyloxycarbonyloxy)propy[; a C5-C6 cycloalkyloxycarbonyloxy C1-C4 alkyl group such as cyclopentyloxycarbonyloxymethyl, 1-(cyclopentyloxycarbonyloxy)ethyl, 1- (cyclopentyloxycarbonyloxy)propyl, 1-(cyclopentyloxycarbonyloxy)butyl, cyclohexyloxycarbonyloxymethyl, 1 -{cyclohexyloxycarbonyloxy)ethyl, 1 -
(cyclohexyloxycarbonyloxy)propyl or 1-(cyclohexyloxycarbonyloxy)butyl; a [5-(C1-C4 alky[)-2-oxo-1 ,3-dioxolen-4-yl]methyl group such as (5-methyl-2-oxo-1 ,3-dioxo!en-4- yi)methyl, (5-ethyl-2-oxo-1 ,3-dioxolen-4-yl)methyl, (5-propyl-2-oxo-1 ,3-dioxolen-4- yl)methyl, (δ-isopropykϋ-oxo-I .S-dioxolen^-yl)methyl or (5-butyl-2-oxo-1 ,3-dioxolen-4- yl)methy; a [5-(phenyl, which may be optionally substituted with a C1-C4 alkyl, C1-C4 alkoxy or halogen atom(s))-2-oxo-1 ,3-dioxolen-4-yl]methyl group such as (5-phenyl-2- oxo-1 ,3-dioxolen-4-yl)methyl( [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4- methoxyphenyl)-2-oxo-1 ^-dioxolen^-yljmethyl, [5-(4-fluorophenyl)-2-oxo-1 ,3-dioxolen- 4-yl]methyl or [5-{4-chlorophenyl)-2-oxo-1 ,3-dioxolen-4-yl]methyl; or a phthalidyl group, which may be optionally substituted with a C1-C4 alkyl or C1-C4 alkoxy group(s), such as phthalidyl, dimethylphthalidyl or dimethoxyphthalidyl, and is preferably a pivaloyloxymethyl group, phthalidyl group or (5-methyl-2-oxo-1 ,3-dioxolen-4-yl)methyl group, and more preferably a (5-methyl-2-oxo-1 ,3-dioxolen-4-yl)methyl group.
The compounds of formula (1) or pharmacologically active prodrugs or salts thereof contain some substituents for which there exist isosteres, and compounds containing such isosteres in place of said substituents also form a part of the present invention. For example, where the compounds of formula (1) or pharmacologically active prodrugs, isosteres or salts thereof contain a carboxyl group, this can be replaced with a tetrazolyl group.
Hydrates or solvates of the compounds of formula (1), isosteres thereof, prodrugs thereof and pharmacologically acceptable salts thereof can also be used and form a part of the invention. Some compounds of formula (1) and their pharmacologically acceptable salts, isosteres or prodrugsthereof of the present invention may have one or more asymmetric carbons, and optical isomers (including diastereomers) due to the presence of asymmetric carbon atom(s) in the molecule can exist. Furthermore, some of the compounds of formula (1) and their pharmacologically acceptable saits, isosteres or prodrugs thereof of the present invention may have one or more double bonds, and these can exist in cis and trans isomeric forms. These respective isomers are included in the present invention, both as individual isomers and mixtures thereof in all possible ratios.
Examples of the administration form of a compound having the general formula (1) of the present invention, or pharmacologically acceptable salt, isostere or prodrug thereof, include oral administration by tablets, capsules, granules, powders or syrups, and parenteral administration by injection, patches or suppositories. Moreover, a compound having the general formula (1) or a pharmacologically acceptable salt, isostere or prodrug thereof of the present invention can also be administered by pulmonary administration in the form of a powder, solution or suspension. Preparations for these administrations are produced by known methods using additives such as excipients, lubricants, binders, disintegrants, stabilizers, corrigents, diluents and so forth.
Examples of excipients include organic excipients such as sugar derivatives, e.g. lactose, sucrose, glucose, mannitol or sorbitol, starch derivatives, e.g. corn starch, potato starch, α-starch, dextrin or carboxymethyl starch, cellulose derivatives, e.g. crystalline cellulose, low substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose or internally crosslinked sodium carboxymethyl cellulose, and gum Arabic, dextran or pullulan; and, inorganic excipients such as silicate derivatives, e.g. light anhydrous silicic acid, synthetic aluminium silicate or magnesium aluminium metasilicate, phosphates, e.g. calcium phosphate, carbonates, e.g. calcium carbonate, or sulfates, e.g. calcium sulfate.
Examples of lubricants include stearic acid and metal stearates such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as bee gum or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; sodium fatty acid salts; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acids such as silicic anhydride or silicate hydrate; and, starch derivatives.
Examples of binders include polyvinylpyrrolidone, Macrogol and compounds similar to the aforementioned excipients.
Examples of disintegrants agents include compounds similar to the aforementioned excipients, and chemically crosslinked starches and celluloses such as cross sodium carmellose, sodium carboxymethyl starch or crosslinked polyvinylpyrrolidone.
Examples of stabilizers include paraoxybenzoate esters such as methyl paraben or propyl paraben; alcohols such as chlorobutanol, benzyl alcohol or phenyl ethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; and, sorbic acid.
Examples of corrigents include ordinarily used sweeteners, sour flavourings and fragrances.
In the case of producing a solution or suspension for pulmonary administration of a compound having the general formula (1) or pharmacologically acceptable salt, isostere or prodrug thereof of the present invention, for example, said solution or suspension can be produced by dissolving or suspending crystals of the present invention in water or in a mixture of water and an auxiliary solvent (e.g. ethanof, propylene glycol or polyethylene glycol). Such a solution or suspension may also contain an antiseptic (e.g. benzalkonium chloride), solubilizing agent (e.g. a polysorbate such as Tween 80 or Span 80 or surface activator such as benzalkonium chloride), buffer, isotonic agent (e.g. sodium chloride), absorption promoter and/or thickener. In addition, the suspension may additionally contain a suspending agent (such as microcrystalline cellulose or sodium carboxymethyl cellulose).
A composition for pulmonary administration produced in the manner described above is administered directly into the nasal cavity or oral cavity by a typical means in the field of inhalants (using, for example, a dropper, pipette, cannula or atomizer). In the case of using an atomizer, crystals of the present invention can be atomized as an aerosol in the form of a pressurized pack together with a suitable nebula (for example, a chlorofluorocarbon such as dichlorofluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or a gas such as carbon dioxide), or they can be administered using a nebulizer.
The amount of a compound having the general formula (1) or pharmacologically acceptable salt, isostere or prodrug thereof of the present invention used varies depending on the symptoms, age, administration method and so forth, and may be administered either in a single dose or by dividing into multiple doses according to the symptoms.
In the combinations according to the forty-seventh aspect of the present invention, typical examples of each of the classes of compounds that can be used in combination with the compounds having the general formula (1) or a pharmacologically acceptable salt, isostere or prodrug thereof of the present invention are as follows:
1. Examples of muscarinic receptor antagonists (including but not limited to selective M3 antagonists) include esoxybutynin, oxybutynin [especially the chloride], tolterodine [especially the tartrate], solifenacin [especially the succinate], darifenacin [especially the hydrobromide], temiverine, fesoterodine, imidafenacin and trospium [especially the chloride].
2. Examples of β3 adrenergic receptor agonists include YM-178 and solabegron, KUC- 7483.
3. Examples of neurokinin K receptor antagonists (including selective NK-1 antagonists) include cizolirtine and casopitant.
4. Examples of vanilloid VR1 agonists include capsaicin, resiniferatoxin and NDG-8243.
5. Examples of calcium channel α2 δ ligands include gabapentin and pregabalin.
6. Examples of potassium channel activators (including activators of KCNQ1 BKCa channels, Kv channels and KATP channels) include KW-7158, NS-8 and retigabine,
7. Examples of calcium channel inhibitors (including Cav2.2 channel inhibitors) include ziconotide and NMED-160.
8. Examples of sodium channel blockers include lidocaine, lamotrigine, VX-409, ralfinamide and carbamazepine. 9. Examples of serotonin and norepinephrine reuptake inhibitors (SNRIs) include duloxetine and venlafaxine
10. Examples of 5-HT antagonists including 5-HT1a antagonists and 5HT3 antagonists.
11. Examples of α-1 adrenoceptor antagonists include tamsulosin.
12. Examples of tricyclic antidepressants include amitriptyline, amoxapine, clomipramine, dosulepin (dothiepin), doxepin, imipramine, lofepramine, nortriptyline, and trimipramine.
13. Examples of N-methyl-D-aspartate (NMDA) receptor antagonists include ketamine, memantine, amantadine, AVP-923, NP-1 and EVT-101.
14. Examples of cannabinoid receptor agonists include GW-1000 (Sativex) and KDS- 2000.
15. Anti-convulsants. Examples include lacosamide, carbamazepine, topiramate, oxcarbazepine and levetiracetam
16. Examples of aldose reductase inhibitors include tolrestat, zopoirestat, zenarestat, epalrestat, sorbinil, AS-3201 , fidarestat, risarestat, ponalrestat and alrestatin.
17. Examples of opioids (e.g. mu opioid agonists) include fentanyl and tapentadol.
18. Examples of alpha adrenoceptor agonists include aradrenoceptor agonists such as ethoxamine, phenylephrine, oxymetazoline, tetrahydralazine and xylometazoline and a2- adrenoceptor agonists such as clonidine, guanabenz, guanfacine and α-methyldopa.
19. Examples of P2X receptor antagonists including P2X2 receptor antagonists and P2X7 receptor antagonists.
20. Examples of acid-sensing ion channel modulators include amiloride.
21. Examples of NGF receptor modulators include trkA.
22. Examples of nicotinic acetylcholine receptor modulators inciude A-85380, tebanicline, ABT-366833, ABT-202, ABT-894, epibatidine analogs and S1B-1663.
23. Examples of synaptic vesicle protein 2A ligands include brivaracetam.
Examples of the administration form of the combination of the present invention are the same as given above for the compounds of general formula (1) and pharmacologically acceptable salts thereof. The particular form can be chosen depending upon the condition to be treated and the nature of the compounds being administered in combination. For example, a combination of a compound of general formula (1) or a pharmacologically acceptable salt thereof with lidocaine could be administered transdermal^ by means of a patch while a combination with ziconotide could be administered transmucosally.
Synthesis of the Compounds of the Invention
Reaction Scheme 1
Figure imgf000094_0001
Aldehyde (R3CHO) (1 eq) and amine (R1 (R2)CHNH2) (1 eq) were stirred in a polar solvent such as methanol, ethanol or dimethylformamide at 0 to 100 °C for 30 mins. After this time, lsocyanide (R4NC) (1 eq) and glyoxylic acid (1 eq) were added and the reaction left to stir for 24 hrs at 0 to 100 °C. The actual solvents and reaction temperature used vary depending upon the reagents used.
The solvent was removed in vacuo and the product purified by flash coiumn chromatography (10% MeOH in DCM, using NH3 or AcOH additives for amine / acid containing compounds respectively) or preparative HPLC (eluting with MeCN:H2O gradients using NH3 or HCO2H additives for amine / acid containing compounds respectively) to yield the products.
Preparative HPLC conditions:
Compounds were purified using an Xbridge C18, 19x150mm, 5μm or Xbridge C18, 30x150mm, 5μm column at a flowrate of 20ml/min or 50 ml/min respectively. Solvent gradients were made using MeCN/H2O with 0.1 % HCO2H for acid methods and MeCN/H2O with 0.1% NH3 for basic methods, detecting at 210 nm and at ambient temperature. Sample injection volume, sample run time and gradient values were all compound dependant. Retention times (RT) by LC for compounds of the present invention are given in Table 1 below. Most compounds gave two peaks by LC which are rotamers; two retention times are quoted in Table 1 below.
LC conditions for this analysis are: LCMS Method A
Column: XBridge C18 2x30 mm, 5 μm
Mobile Phase: Eluent A: 10 mM Aqueous Ammonium Bicarbonate
Eluent B: Acetonitrile Gradient:
Figure imgf000095_0001
Run time: 5 min
Flow rate: 1 .0 ml/min
Injection volume: 5 μl
Column temperature: 25°C
Detection: UV (TAC 215-350 nm), MS (TIC 100-1000 mz, ESI+ or ESI-)
LCMS Method B
Column: XBridge C18 2x30 mm, 5 μm
Mobile Phase: Eluent A: 0.1% Aqueous Formic Acid
Eluent B: Acetonitrile Gradient:
Figure imgf000095_0002
Figure imgf000096_0001
Run time: 5 min
Flow rate: 1.0 ml/min
Injection volume: 5 μl
Column temperature: 25°C
Detection: UV (TAC 215-350 nm), MS (TIC 100-1000 mz, ESl+ or ESI-)
LCMS Method C
Column: XBridge C18 4.6x50 mm, 5 μm Mobile Phase: Eluent A: 0.05% Aqueous Formic Acid Eluent B: 0.05% Formic Acid in Acetonitrile
Gradient:
Figure imgf000096_0002
Run time: 15 min
Flow rate: 1.5 ml/min
Injection volume: 5 μl
Column temperature: 30°C
Detection: UV (TAC 210-400 nm), MS (TlC 100-700 mz, ESI+, ESI-, APCI+, APCI-) Reaction Scheme 2
It is also possible to synthesise optically active compounds of formula (I) utlising enantiomerically pure amino acids as starting materials, using the following general reaction scheme:
Figure imgf000097_0001
Examples
Using the general procedures described above in Reaction Schemes 1 and 2, the following compounds were prepared:
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl3-N-[1 H-indol-3-yl(oxo)acetyl]glycine
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1H-indol-3-yl(oxo)acetyl]-b-alanine
4-{[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl][1 H-indol-3- yl(oxo)acetyl]amino}butanoic acid
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(6-fluoro-1 H-indo[-3- y I) (oxo)acetyl]g lyci ne
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indol-3-yl(oxo)acetyl]glycyl-L- ornithine
N-[1-cyc[ohexyl-2-(cyclohexylamino)-2-oxoethy[]-N-[1 H-indol-3-yl(oxo)acetyl]g[ycyl-L- lysine
N2-[1-cyclohexyi-2-(cyclohexylamino)-2-oxoethyl]-N2-[1 H-indol-3-yl(oxo)acetyl]-D- ornithylgiycine
N-[1-bicyclo[2,2.1]hept-5-en-2-yl-2-(cyclohexylannino)-2-oxoethyl]-N-[1 H-indol-3- yl(oxo)acetyl]glycine
N-[2-(cyclohexylamino)-1-cyclopentyl-2-oxoethyl]-N-[1 H-indol-3-yl(oxo)acetyl]glycine
N-[1-cycloheptyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indoi-3-y[(oxo)acetyl]glycine
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(5-fluoro-1 HHndol-3-yl)(oxo)acetyl]- b-alanine
N-[1-cyclohexyl-2-(cyclohexy[amino)-2-oxoethyl]-N-[(6-fluoro-1 H-indol-3-yl)(oxo)acetyl]- b-alanine
N-[1-cyclohexyi-2-(cyclohexylamino)-2-oxoethyl]-N-[(7-fluoro-1H-indol-3-yl)(oxo)acetyl]- b-alanine
N-[ 1 -cyclohexyl-2-(cyclohexylamtno)-2-oxoethyl]-N-[(1 -methyl-1 H-indo!-3-yl)(oxo)acetyl]- b-alanine
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(5-fluoro-1 H-indol-3- yl)(oxo)acetyl]glycine
N'[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(7-fluoro-1 H-indol-3- yl)(oxo)acetyl]glycine N-[1-cyclohexyl-2-(cyclohexylamιno)-2-oxoethyl]-N-[(2-methyl-1H-ιndol-3- yl)(oxo)acetyl]glycιne
N-[1-benzothιen-3-yl(oxo)acetyl]-N-[1-cyclohexyl-2-(cyclohexylatnιno)-2-oxoethyl]g[ycιne
N-[1-cyclohexyl-2-(cyclohexylamιno)-2-oxoethyl]-N-[(6-methyl-1 H-indol-3- yl)(oxo)acetyl]glycιne
N-[(6-chloro-1 H-ιndo]-3-yl)(oxo)acetyl]-N-[1-cyclohexyl-2-(cyclohexylamιno)-2- oxoethyljglyctne
N-[1-cyc[ohexyl-2-(ιsopropylatnino)-2-oxoethyl]-N-[1H-ιndol-3-yl(oxo)acetyl]glycιne
N-[2-(benzylamino)-1-cyclohexyl-2-oxoethyl]-N-[1 H-indol-3-yl(oxo)acetyl]glycine
N-[2-(adamantan-1 -ylamιno)-1 -cyclohexyl-2-oxoethyl]-N-[1 H-ιndol-3-yl(oxo)acetyl]glycιne
N-[1-cyclohexyl-2-(cyclopentylamino)-2-oxoethyl]-N-[1 H-ιndol-3-yl(oxo)acetyl]giycιne
N-{1-cyc[ohexyl-2-[(2-methoxyethyl)amιno]-2-oxoethyl}-N-[1 H-indol-3- yl(oxo)acetyl]glycιne
N-[1-cyclohexyl-2-(methylamιno)-2-oxoethyl]-N-[1 H-indol-3-yl(oxo)acetyl]glycιne
N-(2-anιlιno-1-cyc[ohexyl-2-oxoethyl)-N-[1 H-ιndo!-3-yl(oxo)acetyl]glycιne
N^I-cyclohexyl-2-^-methoxyphenyl)amino^oxoethyl}-N-E1H-indol-3- yl(oxo)acetyl]glycιne
^(i-cyclohexyl-2-^-tdiethylamino)phenyl)amino^-oxoethyl)-N-fi H-mdol-3- yl(oxo)acetyl]glycιne
N-[1-cyclohexyl-2-(cyclohexylannιno)-2-oxoethyl]-N-[1 H-ιndo[-3-yl(oxo)acetyl]-L-alanιne
N-li-cyclohexyl-2-^-methoxybenzyl)aminol-2-oxoethyl^N-[1 H-indol-3- y [(oxo) acety l]g [yci ne
N^I-cyclohexyl-2-^Φhydroxybenzyl)amino]-2-oxoethy^-N-II H-indol-3- yi(oxo)acetyl]glycιne
N-{1-cyclohexyl-2-oxo-2-[(2-phenylethyl)amιno]ethyl}-N-[1 H-ιndoJ-3-yi(oxo)acetyl]glycιne
N-{1-cyclohexyl-2-[(4-fluorophenyl)amιno]-2-oxoethyl}-N-[1 H-ιndol-3-yl(oxo)acetyl]glycιne
N-fi-cyclohexyl-2-^-f4-hydroxyphenyl)ethyl]amino}-2-oxoethyl)-N-II H-indol-3- yl(oxo)acetyl]glycιne
N-ti-cyclohexyl^t4-hydroxyphenyl)aminol-2-oxoethyl}-N-II H-indoi-3- yl(oxo)acetyl]glycιne
N-^-ftert-butylamtno)-1-cyclohexyl-2-oxoethyO-N-[1H-indol-3-yKoxo)acetylj-b-alanine
N3-[1-cyclohexyl-2-(cyclohexylamιno)-2-oxoethyl]-N3-[1H-ιndol-3-yl(oxo)acetyl]-b- alaninamide N-[1-cyc[ohexyl-2-(cyc[ohexylamino)-2-oxoethyl]-N-(3-hydroxypropyl)-2-(1 H-indol-3-yl)-2- oxoacetamide
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-2-(1 H-indol-3-yl)-2-oxo-N-(2H-tetrazol-
5-ylmethyl)acetamide
N-[1-cyclohexyi-2-(cyclohexylamino)-2-oxoethyl]-2-(1 H-indol-3-yi)-N-(2-morpholin-4- yiethyl)-2-oxoacetamide
N-[1-cyclohexyl-2-(cycIohexy[amino)-2-oxoethyl]-2-(1H-indol-3-yl)-2-oxo-N-(2-piperazin-
1-ylethyl)acetamide
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-2-(1 H-indol-3-yl)-2-oxo-N-(3-pyrrolidin-
1 -ylpropyl)acetatnide
N-(4-aminobutyl)-N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-2-(1 H-indol-3-yJ)-2- oxoacetamide
N-[1 -cyclohexyl-2-(cyc[ohexylamino)-2-oxoethyl]-N-[1 H-indol-3- yl(oxo)acetyl]glycylglycine
N2-[1-cyclohexyf-2-(cyclohexylamino)-2-oxoethyl]-N2-[1H-indol-3- yl(oxo)acetyl]glycinamide ethyl N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indo!-3- yl{oxo)acetyl]glycinate
N2-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N2-[1 H-indol-3-yl(oxo)acetyl]-D-lysine
N2-[1-cyclohexyl-2-(cyclohexylamtno)-2-oxoethy[]-N2-[1 H-indol-3-yl(oxo)acetyl]-D- ornithine hydrochloride
N2-[1-cyclohexyl-2-(cyc[ohexylamino)-2-oxoethyl3-N2-[1 H-indo!-3-yl(oxo)acetyl]-D- arginine
N2-[1 -cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N2-[1 H-indol-3-yi(oxo)acetyl]-L- ornithylglycine
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]"N-[(4-fluoro-1 H-indo!-3- yl)(oxo)acetyl]glycine
N-[1-adamantan-1-yl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indot-3-yl(oxo)acetyl]glycine
N2-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N2-[1 H-indol-3-yl(oxo)acetyl]-L- arginylglycine
N,2-dicyclohexyl-2-{[1 H-indo[-3-yl(oxo)acetyl]amino}acetamide
N^I-cyclohexyl-2-[(3-hydroxybenzyl)aminol-2-oxoethyl}-N-[1 H-indol-3- yl(oxo)acetyl]glycine N^I-cyclohexyl-2-[(3-hydroxyphenyl)aminol-2-oxoethyl}-N-E1H-indol-3- y I (oxo) acety l]g lyci ne
N-ti-cyclohexyl-2-^-thydroxymethyl)phenyl]amino^-oxoethyl)-N-fi H-indol-3- y[(oxo)acetyl]g1ycine
N-ti-cyclohexyl^^-fhydroxymethyl)phenyOamtno^-oxoethyl)-Z^1H-indol-3-yl)-2-oxo-
N-(3-pyrro!idin-1-ylpropyl)acetamide
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indo[-3-yl(oxo)acetyl]-D-atanine
N-[1-cyclohexy[-2-(cyclohexy[amino)-2-oxoethyl]-N-[1 H-indo!-3-yl(oxo)acetyl]-D-aianine
N-[1-cycIohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indol-3-yl(oxo)acetyl3-D-alanine
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]glycine
N-[{6-bromo-1 H-indol-3-yl)(oxo)acetyl]-N-[1-cyclohexyl-2-(cyclohexylamino)-2- oxoethyl]glycine
IM-[I -cyclohexyl-2-fcyclohexylamino)-2-oxoethylj-N^oxotδ-^rifluoromethyl)-I H-indol-3- yl]acetyl}g[ycine
N-II-cyclohexyl-2-^yclohexylamino)-2-oxoethyl]-N-^δ-isopropyl-1H-indol-3- yl)(oxo)acetyl]glycine
N-[2-(cyclohexylamino)-2-oxo-1-piperidin-4-ylethyl]-N-[1 H-indol-3-y[(oxo)acetyl]glycine hydrochloride
N-[1 -(1 -acetylpiperidin-Φyl)-2-tcyclohexylamino)-2-oxoethyl]-N-[1 H-tndol-3- yl(oxo)acetyl]glycine
N-{2-(cyclohexylamino)-1 -[1 -(methylsulfonyl)piperidin-4-yl]-2-oxoethyl}-N-[1 H-indo!-3- yl(oxo)acetyl]glycine
N-li-cyclohexyl-2-IfS-hydroxyphenyl)aminol-2-oxoethyl}-N-^β-methoxy-1H-indol-3- yl)(oxo)acetyl]glycine
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(2E)-2-hydroxy-2-(2-oxo-1 ,2-dihydro-
3H-indol-3-ylidene)acetyl]glycine
N-{1-cyclohexyl-2-[(3-methylphenyl)amino]-2-oxoethyl}-N-[1H-indol-3- yl(oxo)acetyl]glycine
N-{1-cyclohexyl-2-[(3-methoxyphenyl)amino]-2-oxoethy]}-N-[1 H-indol-3- y[(oxo)acetyl]glycine
N-{2-[(3-ch]orophenyl)atnino]-1-cyclohexyl-2-oxoethyl}-N-[1H-indol-3- yl(oxo)acetyl]glycine
N-{1-cyclohexyl-2-[(3-fluorophenyl)amino]-2-oxoethy[}-N-[1 H-indol-3-yl(oxo)acetyl]glycine N-[2-(tert-butytamino)-1-cyclohexy[-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]glycine
N-(2-aniiino-1-cyclohexyl-2-oxoethyl)-N-[(6-methoxy-1 H-indol-3-yl)(oxo)acetyl]glycine
N-[1-cyclohexyl-2-(isopropylamino)-2-oxoethyl]-N-[(6-methoxy-1 HHndol-3- yl)(oxo)acetyl]glycine
N-[1-cyc[ohexyl-2-(cyclopentylamino)-2-oxoethyl]-N-[(6-methoxy-1H-indol-3- yi)(oxo)acetyl]glycine
N-[1-cyclohexyi-2-(cyclohexy[amino)-2-oxoethyl]-N-[(6-ethoxy-1H-indol-3- yl)(oxo)acetyl]glycine
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl3-N-[(6-hydroxy-1 H-indo[-3- yl)(oxo)acety[]glycine
N-[1-cyclohexyl-2-(cyclohexyiamino)-2-oxoethyl]-N-[(5,6-dimethoxy-1 H-indol-3- yl)(oxo)acetyl]glycine
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[5H-[1 ,3]dioxolo[4,5-f]indol-7- yl(oxo)acetyl]glycine
N-EI-cyclohexyl-2-^yclohexylamino)-2-oxoethylj-N-ffS-methoxy-1H-indol-3- yl)(oxo)acetyl]glycine
N-[(5-bromo-1H-indol-3-yl)(oxo)acetyl]-N-[1-cyclohexyl-2-(cyclohexylamino)-2- oxoethyl]glycine
N-[1-cyclohexyi-2-(cyclohexylamino)-2-oxoethyl]-N-[(6-nnethoxy-1 H-indol-3- yl)(oxo)acetyl]-b-alanine
4-{[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl][(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]amino}butanoic acid
N-[1-cyc[ohexyl-2-(cyclohexylamino)-2-oxoethy[]-2-(6-methoxy-1H-indol-3-yl)-2-oxo-N-(2- piperazin-1 -ylethyl)acetamide
N-f4-aminobutyl)-N-II-cyclohexyl-2-^yclohexylamino)-2-oxoethyl^-fδ-methoxy-I H- indol-3-yl)-2-oxoacetamide
N2-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N2-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]glycinamide
N-[1-cyc[ohexyl-2-(cyclohexy[amino)-2-oxoethyl]-2-(6-methoxy-1 H-indol-3-yl)-N-methyl-
2-oxoacetamide
N-[1-benzothien-3-yl(oxo)acetyl3-N-{1-cyclohexy[-2-[(3-hydroxypheny[)amino]-2- oxoethyl}glycine N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(6-methoxy-1H-indol-3- yi)(oxo)acetyl]glycylglycine
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-N-(3- pyrrolidin-1 -ylpropyi)acetamide
N-{1-cyclohexyi-2-[(3-hydroxyphenyl)amino]-2-oxoethyl}-N-[1H-indol-3-yl{oxo)acetyl]-b- alanine
4-({1-cyclohexyl-2-[(3-hydroxyphenyl)amino]-2-oxoethyl}[1H-indol-3- y[(oxo)acetyl]amino)butanoic acid
N-(1 -cyclohexyl-2-{[4-(hydroxymethyl)phenyl]amino}-2-oxoethyl)-N-[(6-methoxy-1H- indol-3-yl)(oxo)acetyl]glycine
N-{1-cyclohexyl-2-[(3-hydroxyphenyl)amino]-2-oxoethyl}-2-{1H-indol-3-yl)-2-oxo-N-(3- pyrroiidin-1 -ylpropyl)acetamide
N-{1-cyclohexyl-2-[(3-hydroxyphenyl)amino]-2-oxoethyl}-2-(1 H-indol-3-yl)-N-methyl-2- oxoacetamide
N-li-cyclohexyl-2-p-hydroxyphenyl)anπino^-oxoethyl}-N-ttθ-nnethoxy-1H-indoS-3- yl)(oxo)acetyl]-b-alanine
4-({i-cyclohexyl-2-ttS-hydroxyphenyl)amino]-2-oxoethyl}^δ-methoxy-I H-indol-3- yl)(oxo)acetyl]atnino)butanoic acid
N-{1-cyclohexyl-2-[(3-hydroxyphenyl)amino]-2-oxoethyl}-2-(6-methoxy-1 H-indol-3-yl)-2- oxo-N-(3-pyrrolidin-1-ylpropyl)acetamide
N-{1-cyc[ohexyl-2-[(4-hydroxyphenyl)amino]-2-oxoethyl}-N-[(6-methoxy-1H-indol-3- yl)(oxo)acetyl]glycine
N-[(1 S)-1 -cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]glycine
N-[(1 R)-1 -cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N"[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]glycine
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-{oxo[6-(trifluoromethoxy)-1 H-indo!-3- yl]acetyl}glycine
N-{1-cyclohexy[-2-[(3-hydroxyphenyl)amino]-2-oxoethyl}-2-(1 H-indol-3-yl)-2-oxo-N-(2- piperazin-1 -ylethyl)acetamide
N-(4-aminobutyl)-N-{1-cyclohexy]-2-[(3-hydroxyphenyl)amino]-2-oxoethyl}-2-(1H-indol-3- yl)-2-oxoacetamide
N-{1-cyclohexyl-2-[(3-hydroxyphenyl)amtno]-2-oxoethyl}-2-(6-methoxy-1 H-indol-3-yl)-2- oxo-N-(2-piperazin-1-ylethyl)acetamide N-(4-aminobutyl)-N-{1-cyclohexyl-2-[(3-hydroxyphenyi)amino3-2-oxoethyl}-2-(6"methoxy-
1 H-indol-3-yl)-2-oxoacetamide
N-[1-cyclohexyl-2-(isopropylamino)-2-oxoethyl]-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-N-(3- pyrrolidin-1 -y[propyl)acetamide
N-f4-aminobutyl)-N-[1-cyclohexyl-2-(sopropylamino)-2-oxoethyl^-fβ-methoxy-I H-indol-
3-yl)-2-oxoacetamide
N,2-dicyclohexyl-2-{[(6-methoxy-1H-indol-3-yl)(oxo)acetyl]amino}acetamide
N-(2-anilino-1-cyclohexyl"2-oxoethyl)-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-N-(3-pyrrolidin-
1 -ylpropyl)acetamide
N-(2-anilino-1-cyclohexyl-2-oxoethyl)-2-(6-methoxy-1H-indol-3-yl)"2-oxo-N-(2-piperazin-
1-ylethyl)acetamide
N-[(6-cyano-1H-indol-3-yl)(oxo)acetyl3-N-[1-cyclohexyl-2-(cyclohexylamino)-2- oxoethyl]glycine
N-[1-cyclohexyl"2-(cyclohexylamino)-2-oxoethyl]-N-{[6-(methylsulfonyi)-1H-indol-3- y I] (oxo)acetyl}g lyci ne
N^4-atninobutyl)-N^-anilino-1-cyclohexyl-2-oxoethyl)-2^δ-methoxy-I H-indol-3-yl)-2- oxoacetamide
N-{1-cyclohexy[-2-[(3-methoxypropy[)amino]-2-oxoethyl}-N-[1 H-indol-3- yl(oxo)acetyl]g[ycine
N-(1-cyclohexyl-2-{[3-(dimethylamino)propyl]amino}-2-oxoethyl)-N-[1H-indol-3- yl(oxo)acetyl]glycine
N-{2-[(3-aminopropyl)amino]-1-cyclohexyl-2-oxoethyl}-N-[1 H-indol-3-yl(oxo)acetyl]g[ycine
N^I -cyclohexyl-2-EtS-methoxypropyl)aminoj-2-oxoethyl}-N-tfe-methoxy-I H-indol-3- yl)(oxo)acetyl]glycine
N-(I-cycfohexyl-2-p-tdimethylamino)propyQamino^-oxoethyl)-N-p-methoxy-I H-indol-
3-yl) (oxo) acety l]g lyci ne
N^-tfS-aminopropyl)aminol-1-cyclohexyS-2-oxoethyl}-N-^e-methoxy-I H-indol-3- yl)(oxo)acetyl]glycine
N-[1-cyclohexyl-2-oxo-2-(pyridin-2-ylamino)ethyl]-N-[(6-nπethoxy-1H-indo!-3- yl)(oxo)acetyl]glycine hydrochloride
N-[(1 R)-1-cyclohexyl-2-oxo-2-(1 ,3-thiazol-2-ylamino)ethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]glycine
N-((R)-cyclohexylphenylcarbamoylmethyl)-2-(1H-indol-3-yl)-2-oxo-N-(2-piperazin-1-yl- ethyl)acetamide N-((R)-cyclohexytisopropylcarbamoylnnethyl)-2-(1H-indol-3-yl)-2-oxo-N-(2-piperazin-1-yl- ethyl)acetamide
2,N-dicyclohexyl-2-[[2-(6-methoxy-benzo[b]thiophen-3-yl)-2-oxo-acetyl]-(2-piperazin-1-yl- ethyl)-amino]-acetamide
2-{{4-amino-butyl)-[2-(6-methoxy-benzo[b]thiophen-3-yl)-2-oxo-acetyl]-amino}-2,N- dicyclohexyl-acetamide
{(cyclohexylcyclohexylcarbamoyl-methyl)P-(6-methoxybenzofb]thiophen-3-yl)-2-oxo- acetyl]amino}acetic acid
[[2-(6-bromobenzo[b]thiophen-3-yl)-2-oxo-acetyl](cyclohexylcyc[ohexylcarbaιnoylmethyl)- amino]acetic acid
{[cyclohexylcarbamoyl-(4,4-dimethylcyclohexyl)methyl][2-{6-methoxy-1 H-indol-3-yl)-2- oxoacety[]amino}acetic acid
N-[1-cyclohexyl-2-(isopropylamino)-2-oxoethyl]-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-N-(2- piperazin-1 -ylethyl)acetatnide
{[cyclohexy[carbamoyl-(4,4-dimethylcyclohexyl)methyl][2-(1 H-indol-3-yl)-2- oxoacetyl]amino}acetic acid
{(cyclohexylcyc[ohexylcarbamoylmethyl)-[2-(6-hydroxymethyl-1H-indol-3-yl)-2- oxoacetyl]amino}acetic acid
N-[(1 R)-1 -cyclohexyi-2-oxo-2-(piperidin-4-y[amino)ethyl]-N-[(6-methoxy-1 H-indol-3- yl)oxoacetyl]glycine
N-[(1 R)-1 -cyc[ohexyl-2-oxo-2-(tetrahydro-2H-pyran-4-y[amino)ethyl]-N-[(6-methoxy-1 H- indol-3-yl)(oxo)acetyl]giycine
N-{(1 R)-1 -cyclohexyl-2-[(1 -methylpiperidin-4-yl)amino]-2-oxoethyl}-N-[(6-methoxy-1 H- indol-3-yl)(oxo)acetyl]glycine
N-[(1 R)-2-(cyclohepty[amino)-1-cyclohexyl-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]glycine
N-[(1 R)-1 -cyclohexyl-2-(cyc[opropylamino)-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]glycine
N-[(1 R)-1 -cyclohexy[-2-(cyclopentylamino)-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yi)(oxo)acetyl]glycine
N-[(1 R)-1 -cyclohexyl-2-(isopropylamino)-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- y!)(oxo)acetyl]glycine
N-[1-cyclohexyl-2-oxo-2-(pyridin-2-ylamino)ethyl]-N-(2-methoxyethyl)-2-(6-methoxy-1H- indol-3-yl)-2-oxoacetamide {[{R)-cyclohexyl-{4,4-difluorocyclohexylcarbamoyl)methyl]-[2-(6-methoxy-1 H-indol-3-yl)-
2-oxo-acetyl]amino}acetic acid
{((R)-cyclohexylphenylcarbamoylmethyl)-^-fθ-fluoro-I H-indol-3-yl)-2- oxoacetyl]amino}acetic acid
{[(R)-cyclohexyl-(1H-indazol-6-ylcarbamoyl)-methyl]-[2-(6-methoxy-1 H-indol-3-yl)-2- oxoacetyl]-amino}acetic acid
{[(RVcyclohexyS-fS-hydroxy^-methylphenylcarbamoyl)methylH≥-tβ-methoxy-I H-indol-3- yl)-2-oxoacetyl]amino}acetic acid
{[(R)-(3-acetylaminophenylcarbamoyl)cyclohexylmethyl]-[2-(6-methoxy-1 H-indol-3-yl)-2- oxoacetyl]amino}acetic acid
{[(R)-cyclohexyl-(4-methoxypheny[carbamoyl)methyl]-[2-{6-methoxy-1 H-indo!-3-yi)-2- oxoacetyl]aminojacetic acid
{[(R)-cyclohexyl-(3-methoxyphenylcarbamoyl)methyl]-[2-(6-methoxy-1 H-indol-3-yl)-2- oxoacetyl]atnino}acetic acid
{((R)-cyclohexylisopropylcarbamoylmethyl)-^^β-fluoro-1H-indol-3-yl)-2- oxoacetyl]amino}acetic acid
{((R)-cyclohexylcyclopropylcarbamoylmethyl)-[2-(6-fluoro-1 H-indof-3-yl)-2- oxoacetyl]amino}acetic acid
{((R)-cyclohexylisopropyJcarbamoylmethyl)-[2-(6-methoxy-1 H-indol-3-yl)-2- oxoacetyl]amino}acetic acid tert-butyl ester
N-((R)-cyclohexylisopropylcarbamoylmethyl)-2-(6-methoxy-1H-indol-3-yl)-2-oxo-N-(2- oxo-2-pyrrolidin-1-ylethyl)acetamide
{((R)-cyclohexylcyclohexylcarbamoylmethylH2-(5,6-difluoro-1 H-indol-3-yl)-2-oxo- acetyl]amino}acetic acid
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-N-[(2- methanesulfonylethylcarbamoyl)methyl]-2-(6-methoxy-1 H-indol-3-yl)-2-oxoacetamide
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-2-(5,6-difluoro-1 H-indol-3-yl)-2-oxo-N-(2- oxo-2-pyrrolidin-1-ylethyl)acetamide
N-fcyclohexyl-ttRHetrahydropyran-Φylcarbamoyl)methylj-2-tδ-hydroxy-I H-indol-3-yi)-2- oxo-N-(2-oxo-2-pyrrolidin-1-ylethyl)acetamide
{[(R)-cyclohexyKtetrahydropyran^-ylcarbamoyl)nnethylHS-tδ-hydroxy-1H-indol-a-yl)-2- oxoacetyl]amino}acetic acid
N-KR)-cyclohexyl-ttetrahydropyran-4-ylcarbamoyl)methyl]-2-fδ-hydroxy-I H-indol-a-yl)-2- oxo-N-[(tetrahydropyran-4-ylcarbamoyl)methyl]acetamide (^-2-{carbamoytmethyKa-fθ-methoxy-I H-indol-3-yl^-oxoacetyOamino}-2^- dicyclohexylacetamide
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-N-{2-methoxyethyl)-2-(6-methoxy-1 H- indol-3-yl)-2-oxoacetamide
N-cyclohexylcarbamoylmethyl-N-((R)-cyclohexylcyclohexylcarbamoyimethyl)-2-(6- methoxy-1 H-indo!-3-yl)-2-oxoacetamide
N-((R)-cyclohexylcyclohexylcarbamoy[methyl)-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-N-(2- oxo-2-piperidin-1-y[ethyt)acetamide
N-((R)-cyclohexy[cyclohexylcarbamoylmethy[)-N-(isopropylcarbamoylmethyl)-2-(6- methoxy-1H-indol-3-yl)-2-oxoacetamide
N-((R)-cyclohexylcyclohexy[carbamoylmethyl)-N-cyclopropylcarbamoylmethyl-2-(6- methoxy-1 H-indol-3-yl)-2-oxoacetamide
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-N-(2-hydroxy-ethyl)-2-(6-methoxy-1H- indol-3-yl)-2-oxoacetamide
N-((R)-cyclohexyl-cyclohexylcarbamoylmethyl)-N-diethylcarbainoylmethyl-2-(6-methoxy-
1 H-indol-3-yl)-2-oxoacetamide
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-N-[(2-methoxyethylcarbamoyl)methyl]-2-
(6-methoxy-1H-indol-3-yl)-2-oxoacetamide
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-2-(6-methoxy-1H-indol-3-yl)-N-(2- morpholin-4-yl-2-oxo-ethyl)-2-oxoacetamide
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-2-(6-methoxy-1 H-indot-3-yl)-2-oxo-N-[(2- pyrrolidin-1-yl-ethylcarbamoyl)nnethyljacetamide
N-((R)-cyclohexylcyclohexy[carbamoylmethyl)-2-(6-methoxy-1 H-indol-3-yl)-N- methylcarbamoy[methyl-2-oxoacetanπide
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-N-dimethylcarbamoylmethyl-2-(6- methoxy-1 H-indol-3-yl)-2-oxoacetamide
{((R)-cyclohexylcyclohexylcarbamoy[methyl)-[2-(β-methoxy-1 H-indol-3-yl)-2-oxo- acetyl]atnino}acetic acid methyl ester
{[cyclohexylcarbamoyl-(4-hydroxycyclohexyl)methyl]-[2-(6-methoxy-1 H-indo[-3-yl)-2- oxoacetyl]atnino}acetic acid
N-{(R)-cyclohexylcyclohexylcarbamoylmethyl)-N-(2-dimethylaminoethyl)-2-(6-methoxy-
1 H-indol-3-yl)-2-oxoacetatnide
N-((R)-cyclohexylcyclohexy[carbamoylmethyl)-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-N-(2- oxo-2-pyrrolidin-1-yl-ethyl)acetamide {[cyclohexy[carbamoyl-(4,4-cfifluorocyclohexyl)methyl]-[2-(6-methoxy-1H-incloi-3-yl)-2- oxoacetyl]amino}acetic acid
N-[(R)-cyclohexyl-(1 -methyl- 1 H-indazo!-6-ylcarbamoyl)methyl]-2-(6-fluoro-1 H-indo!-3-yl)-
2-oxo-N-[(tetrahydropyran-4-ylcarbamoyl)methyl]acetamide
{((R)-cyclohexylcyclohexylcarbamoylmethyl)-[2-(6-fluoro-1H-indol-3-yl)-2- oxoacetyl]amino}acetic acid
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-2-(6-methoxy-1H-indol-3-yl)-2-oxo-N-
[(tetrahydropyran-4-ylcarbamoyl)methyl]acetamide
{((R)-cyclohexyiphenylcarbamoylmethyl)-^-tδ-methoxy-1H-indol-3-yl)-2- oxoacetyl]amino}acetic acid
N-(4-atninobutyl)-N-((R)-cyclohexyicyclohexylcarbamoylmethyl)-2-(6-methoxy-1 H-indol-
3-yl)-2-oxoacetamide
{((R)-cyclohexylisopropyl carbamoyl methyl)-[2-(6-methoxy-1 H-indot-3-yl)-2- oxoacetyl]amino}acetic acid
{((R)-cyclohexylcyclopentylcarbamoylmethyl)-[2-(6-methoxy-1 H-indo!-3-yl)-2- oxoacetyl]amino}acetic acid
4-{((R)-cyclohexyicyclohexylcarbamoylmethyl)-[2-(6-methoxy-1H-indol-3-yl)-2- oxoacetyl]amino}butyric acid
(2-{((R)-cyc[ohexylcyclohexyicarbamoytmethyl)-[2-(6-methoxy-1 H-indol-3-yl)-2-oxo- acetyl]amino}acetylamino)acetic acid
3-{((R)-cyclohexylcyclohexyicarbamoylmethyl)-[2-(6-methoxy-1 H-indol-3-yl)-2- oxoacetyl]amino}propionic acid
{((R)-cyclohexylcyclohexylcarbamoylmethy[)-[2-(4-methoxy-1 H-indol-3-yl)-2- oxoacetyl]amino}acetic acid
{((R)-cyclohexylcyc[ohexylcarbamoylmethyl)-[2-(1H-indol-3-yl)-2-oxoacetyl]amino}acetic acid
(R)-2,N-dicyclohexyl-2-[[2-(6-methoxy-1 H-indol-3-yl)-2-oxoacetyl]-(2H-tetrazol-5- ylmethyl)amino]-cetamide
N-((R)-cyc[ohexylcyclohexylcarbamoylmethyl)-2-(6-methoxy-1 H-indo!-3-yl)-N-(3-methyl-
[1 ,2,4]oxadiazo!-5-yimethyl)-2-oxoacetamide
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-2-(6-methoxy-1 H-indol-3-yl)-N-(5-nnethyl-
[1 ,3,4]oxadiazoi-2-ylmethyl)-2-oxoacetamide
N-({R)-cyclohexylcyclohexylcarbamoylmethyl)-2-(6-methoxy-1H-indol-3-yl)-N-(3- methyl isoxazoi-5-yl methyl)-2-oxo-cetam ide N-[(1 R)-1 -cyc[ohexyl-2-morpholin-4-yl-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]glycine
N-E(I R)-1 -cyclohexy[-2-oxo-2-piperazin-1 -ylethyl]-N-[(6-methoxy-1 H-indol-3- yl) (oxo) acety l]g lyci ne
N-tfi R)-1-cyclohexyl-2-f4-methylpiperazin-1-yl)-2-oxoethyO-N-^e-methoxy-I H-indol-3- yl)(oxo)acetyl]glycine
With reference to formula (1), the substituents present in each compound are set in Tables 1 and 2 below. The yields of the compounds obtained, the Retention Times (RT) by LC and the mass ion data are also given for each compound.
Test Example 1
Compounds of Examples 2, 4, 6, 18, 27, 41 to 44, 48 to 51 , 53, 57 and 63 were examined for their ability to inhibit the interaction between Cav2.2 channels and Cavβ subunits using a protein-protein interaction assay.
Cloning of rat His- and biotin- tagged Cav beta3 subunit cDNA, expression of Cav β3 subunits in E. coli and lysis of E. coli containing Cav β3 subunits were carried out as described below (Materials and Methods).
Cloning of His- and FLAG- tagged Cav2.2 α subunit AID domain cDNA, expression of Cav2,2 α subunit AID domains in E coli and lysis of E. coli containing Cav2.2 α subunit AID domains were carried out as described below (Materials and Methods).
To 96-well streptavidin coated microtitre plates, 100μl of optimized concentrations of Cav β3 subunit cleared lysates (typically 1 in 10 dilutions in PBS-Tween) were added to each well. Plates were incubated at room temperature for 1 hour prior to use. Each well was then washed 3 times with 300μl of PBS-Tween. Following the final wash, 80μl of WIiIk[I %]-PBS-Tween was added to each well.
Ten microlitres (10μl) of the test compounds (dissolved in a suitable vehicle such as DMSO) were added to the wells of a prepared 96-well microtitre plate to achieve a range of concentrations to maintain a final assay volume of 100μl. Plates were incubated for 30 minutes at room temperature.
After incubation with test compounds, 10μl of Cav2.2 α subunit AID at 10x Kd was added to each well and incubated for 60 minutes at room temperature on a shaker. Unbound Cav2.2 α subunit AID domain was removed by washing 3 times in 300μl of PBS-Tween. Bound Cav2.2 α subunit AID domain was estimated by using appropriately diluted mouse anti-FLAG antibody HRP conjugate using standard ELISA procedures. HRP was detected by addition of colourmetric HRP substrate 2,2'-azino-bis(3-ethylbenzthiazoline- 6-sulfonic acid) and microtitre plates were read in a Biotek Synergy HT microtitre plate reader equipped with a 405nm absorbance filter.
Data were analysed using standard software packages. The test compounds were examined for their ability to inhibit the binding of Cav2.2 α subunit AID domain to Cav β3 subunits to determine inhibition as a percentage of maximal binding in the absence of any test compound. Results are presented as the half maximal inhibitory concentration (IC50) for inhibition of Cav2.2 α subunit AID binding to Cav β3 subunits. The tested compounds of Examples 2, 4, 6, 18, 27, 41 to 44, 48 to 51 and 53 to 55 of this invention displayed excellent ability to inhibit the binding of Cav2.2 α subunit AID domain to Cav β3 subunits as measured by determination of the IC50 (see Table 1).
Materials and Methods
Cloning of His and Biotin-tagged Cavβ subunits
The rat Cavβi , β2, β3 and β4 subunits cDNA were ligated into an E.coli expression vector downstream of sequence coding for a poly Histidine-tag and the BCCP domain of the E.coli AccB gene. The ligation mix was transformed into chemically competent
Rosetta2 cells (Novagen) according to the manufacturer's instructions. The Cavβ subunit cDNA sequence was checked by sequencing and found to correspond to published sequence.
Expression of Cavβ subunits
Colonies of Rosetta2 cells containing Cav subunit plasmids were inoculated in 5ml of LB medium containing ampicillin and chloramphenicol in 20m! tubes and grown overnight at 37°C in a shaking incubator. 2ml of overnight culture was used to inoculate another 200ml of LB containing ampicilϋn and chloramphenicol in 500ml flasks and grown at 37°C until an OD600 of 0.7AU was reached. IPTG was then added to a final concentration of 1mM and induction continued at 30°C for 4 hours. Cells were then harvested by centrifugation, cell pellets were washed in PBS and stored in aliquots at - 80°C.
Lysis of E. CoIi containing Cavβ subunits
Cell pellets were thawed on ice and 400μl of lysis buffer (PBS containing 0.1% Tween 20, 1mg/ml lysozyme and 1μg/ml DNAse I) was added and the cells were resuspended by pipetting. Lysis was aided by incubation on a rockerat room temperature for 30min before cell debris was collected by centrifugation at 13000rpm for 10mins at 4°C. The cleared supernatant of soluble protein was removed and used immediately.
Cloning of GST and FLAG-tagged Cav alpha interacting domain The cDNA for the alpha interacting domain (AID) (amino acids 357-399 Accession number NP_671482) was cloned downstream of sequences coding for GST-tag and a FLAG-tag in an E.coli expression vector. Plasmids were checked by sequencing for correct sequence and induction of E.coli cultures showed expression of a GST and FLAG-tagged soluble protein of the expected size. To test for interaction between AID and Cavβ subunits, binding reactions were assembled containing 10μl Cavβ subunit cleared lysated, 10μl anti-FLAG agarose in the presence and absence of 10μl purified AID protein in 250μl phosphate buffered saline containing 300mM NaCI, 0.1% Tween20, 0.01% Triton 100 and 1% (w/v) bovine serum albumin. Reactions were incubated on a rocker at room temperature for 1 hour and FLAG bound complexes harvested by centrifugation at 700rpm for 10min. After extensive washing in PBS-T ween, FLAG bound complexes were denatured in SDS sample buffer and Western blotted. Presence of biotinylated Cavβ subunits were detected by Streptavidin/HRP conjugate.
Cavβ subunit microtitre plate fabrication
To 96 well streptavidin coated microtitre plates 100μl of optimized concentrations of Cavβ subunit cleared lysates (typically 1 in 10 dilutions in PBS-Tween) were added to each well. Plates were incubated at room temperature for 1 hour before washing each well three times with 300μl PBS-Tween. After which the plates were used in assays or stored at -4°C until required.
Table 1
In Table 1 , for ail compounds R4' is hydrogen. The group R3 is either a racemate or is enantiomericaily pure and this is indicated.
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
i Catterall, W A τ Perez-Reyes, E , Snutch, T P , Striessrπg, J (2005) International Union of Pharmacology XLVIII Nomenclature and structure-function relationships of voltage-gated calcium channels Pharmacol Rev 57, 411-425
M Berrow, N S , Bnce N L , Tedder, I , Page, K Wl , Dolphin, A C (1997) Properties of cloned rat alphal A catcium channels transiently expressed in the COS-7 cell line Eur J Neurosci 9, 739-746 in Randall, A , Benham, C D (1999} Recent advances in the molecular understanding of voitage-gated Ca2+ channels MoI CeIi Neurosci 14, 255-272 iv Bimbaumer, L , Qm, N , Olcese, R , Tareilus, E , Platano, D , Costantin, J Stefani, E (1998) Structures and functions of calcium channel beta subunits J Bioenβrg Biomembr 30, 357-375 v Walker, D , De Waard, M (1998) Subunit interaction sites in voltage-dependent Ca2+ channels role in channel function Trends Neurosci 21, 148-154
Vi Dolphin, A C , Wyatt, C N , Richards J , Beattie, R E , Craig, P , Lee, J H , Cπbbs, L L , Volεen, S G , Perez-Reyes, E (1999) The effect of alpha2-delta and other accessory subunits on expression and properties of the calcium channel alphal G J Physiol 519, Pt 1 35-45
VIi Lacerda, A E , Perez-Reyes, E , Wei, X , Caεtellano A , Brown, A M (1994) T-type and N-type calcium channels of Xenopus oocytes evidence for specific interactions with beta subunits Biophys J 66, 1833-1843
ViIi Dolphin, A C (2003) Beta subunits of voltage-gated calcium channels J Bioβnβrg Biomembr 35, 59S-620 ix Matthews, E A , Dickenson, A H (2001) Effects of spinally delivered N- and P type voltage-dependent calcium channel antagonists on dorsal horn neuronal responses in a rat model of neuropathy Pain 92, 235-246 x Matthews, E A , Dickenson, A H (2001} Effects of spinally delivered N- and P-type voltage-dependent calcium channel antagonists on dorsal horn neuronal responses in a rat model of neuropathy Pain 92, 235-246 xi Dzhura, I , Neely A (2003) Differential modulation of cardiac Ca2+ channel gating by beta-subumts Biophys J 85, 274-289
Ml Cahill, A L Hurley, J H , Fox, A P (2000} Coexpression of cloned alpha(1 B), beta(2a), and alpha{2)/delta subunits produces non-inactivating calcium currents similar to those found in bovine chromaffin cells J Neurosci 20 1B85-1693
XiIi Scott, V E De Waard, M , Uu, H , Gurnett, C A , Venzke, D P Lennon, V A , Campbell, K P (1996) Beta subunit heterogeneity in N-type Ca2+ channels J Bio! Criβm 271, 3207-3212 xiv Murakami, M , Felischmann, B , De Felipe, C , Freichel, M , Trost, C , Ludwig, A , Wsssenbach, U , Schwegler, H , Hofmann, F , Hescheler, J , Flockerzi, V , Cavalie, A (2002) Pain perception in mice lacking the beta3 subunit of voltage-gated caicium channels J Biol Chem 277, 40342-40351 xv Birnbaumer, L , Qm, N , Oicese, R , Tareilus, E , Platano, D , Costantin, J Stefani, E (1998) Structures and functions of calcium channel beta subunits J Bioenerg Biomembr 30, 357-375 xvi Canti, C , Bogdanov, Y , Dolphin, A C (2000) Interaction between G proteins and accessory subunits in the regulation of 1B calcium channels in Xenopus oocytes J Physio! 527, Pt 3419-432
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XXH Data on file Pfizer Iπc . August 2005 xxiii Carbone, A , Tubaro, A , Morello, P , Parascani, R , Catalani, C , Palleschi, G (2003) The Effect Of Gabapentin On Neurogenic Detrusor Overactivity, A Pilot Study Eur Urol 2(Suppl), 141, Abstract 555 xxiv Yoshimura, N , Seki, S , de Groat, W C (2001) Nitrix oxide modulates Ca(2+} channels in dorsal root ganglion neurons innervating rat urinary bladder J Neurophysio! 86, 304-311 xxv Butcher, A J , Leroy, J , Richards, M W , Pratt, W S , Dolphin, A C (2006) The importance of occupancy rather than affinity of CaV(beta) subunits for the calcium channel l-ll linker in relation to calcium channel function J Physio! 574, 387-398 xxvi Dalton, S , Takahashi, S X Miπyala, J , Colecraft, H M (2005) A single CaVbβta can reconstitute both trafficking and macroscopic conductance of voltage-dependent calcium channels J Physiol 567, 757-769 xxvi! Ankkath, J , Campbell, K P (2003) Auxiliary subunits essential components of the voltage-gated calcium channel complex Curr Opm Nθurobiol 13, 298-307
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Claims

Claims
1. A compound represented by the general formula (1 ) or a pharmacologically acceptable salt, isostere or prodrug thereof, wherein:
Figure imgf000128_0001
R1 is a hydrogen atom, an alkyl group, a cycloalkyl group which is a single ring or a bridged ring system, an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), an aralkyl group comprising an alkyl group which is substituted with an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), a heteroaryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), a heteroaralkyl group which comprises an alkyl group which is substituted with a heteroaryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), an aminoalkyl group or a guanidinoalkyl group;
R2 is a hydrogen atom, an alkyi group which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups, aryl groups (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkyisulphonyl groups and cyano groups), heteroaryl groups (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), amino groups, monoalkylamino groups, dialkylamino groups, saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, acyl groups, nitro groups, amino groups, monoalkylamino groups, dialkyiamino groups, alkylsulfonyi groups and hydroxyl groups) and groups of formula COY1 or a group of formula COY;
Y is a hydroxyl group, an alkoxyl group, a group of formula NR40R41 or an aminoacid residue;
R3 is an alkyl group, a cycloalkyl group which is a single ring or a bridged ring system (said cycloalkyl group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, acyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, alkylsulfonyi groups and hydroxyl groups), a cycloalkenyl group which is a single ring or a bridged ring system, an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acyiamino groups, alkoxycarbonylamino groups, alkylsuSphonyl groups and cyano groups), a heteroaryi group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acyiamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), a saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic group having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyi groups, carboxyl groups, acyl groups, nitro groups, amino groups, monoalkyiamino groups, dialkylamino groups, alkylsulfonyl groups and hydroxyl groups), a cycloalkylalkyl group wherein the cycloalkyl moiety is a single ring or a bridged ring system or an aralkyl group comprising an alkyl group which is substituted with an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acyiamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups);
R4 and R40 are independently selected from hydrogen atoms, alkyl groups which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyi groups, aryl groups (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyi groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acyiamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), heteroaryi groups (which may be unsubstituted or substituted with at least one substituent selected from alkyi groups, halogen atoms, haloalkyi groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acyiamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), amino groups, monoalkylamino groups, dialkylamino groups, saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at ieast one substituent selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyi groups, acyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, alkylsulfonyl groups and hydroxyl groups), carboxy groups, aminocarbonyl groups, monoalkylaminocarbonyl groups, dialkylaminocarbonyl groups, alkoxycarbonylgroups, groups of formula COR11 , groups of formula SO2RH , groups of formula CONR11R12, groups of formula SO2NRI 1 R12, groups of formula CONR12SO2RH and groups of formula CO2RI 3 wherein R1 1 , R12 and R13 are as defined below, aryl groups (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyi groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyi groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), heteroaryl groups (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyi groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), cycloalkyl groups which are single rings or bridged ring systems (said cycloalkyl groups may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyi groups, acyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, alkylsulfonyl groups and hydroxyl groups), cycloalkenyl groups which are single rings or bridged ring systems and saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyi groups, acyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, alkylsulfonyl groups and hydroxyl groups);
R4' and R41 are independently selected from hydrogen atoms and alkyl groups; or R4 and R4' together with the nitrogen atom to which they are attached and/or R40 and R41 together with the nitrogen atom to which they are attached may form a nitrogen-containing saturated or partially unsaturated 4- to 14- membered heterocyclic group having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having one or more rings, said group optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, acyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, alkylsulfonyl groups and hydroxyl groups);
R11 is a hydrogen atom, an alkyl group, an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), an aralkyl group which comprises an alkyl group which is substituted with an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), a heteroaryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups) or a heteroaralkyl group which comprises an alkyl group which is substituted with a heteroaryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups);
R12 is a hydrogen atom, an alkyi group, an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups) or an aralkyl group which comprises an alkyl group which is substituted with an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups); and
R13 is an alkyl group, an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyi groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), an aralkyl group which comprises an alkyl group which is substituted with an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), an alkoxyalkyl group, a heteroaryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups) or a heteroaralkyl group which comprises an alkyl group which is substituted with a heteroaryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups);
R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyl groups, alkylsulphonylamino groups, aryisulphonylamino groups, aminosulphonyl groups and cyano groups, or any two adjacent ring substituents R5, R6, R7 and R8 may together form the group -O-(CH2)P-O- wherein p is an integer of from 1 to 3; and
X is an oxygen atom, a sulphur atom or a group of formula NR10, wherein R10 is a hydrogen atom or an alkyl group.
2. A compound according to claim 1 or a pharmacologically acceptable salt, isostere or prodrug thereof, wherein R1 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system, an aryl group having from 5 to 14 carbon atoms (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), a heteroaryi group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms atoms (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyi groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acyiamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryi group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, an aminoalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one amino group, and a guanidinoalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with a guanidino group.
3. A compound according to claim 1 or a pharmacologically acceptable salt, isostere or prodrug thereof wherein R1 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an aminoalkyi group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an amino group, a heteroaryi group which is a 5- to 6-membered aromatic heterocyclic group containing 1 to 2 sulfur atoms, oxygen atoms and/or nitrogen atoms which may be unsubstituted or substituted with an alkyl group having from 1 to 4 carbon atoms, and a guanidinoalkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with a guanidino group.
4. A compound according to claim 1 or a pharmacologically acceptable salt, isostere or prodrug thereof wherein R1 is a hydrogen atom, a methyl group, a 3- aminopropyl group, a 4-aminobutyl group, a 3-methyl-[1 ,2,4]oxadiazol-5-yl group, a 5-methyl-[1 ,3,4]oxadiazol-2-yl group, a 3-methyl-isoxazol-5-yl group, a 3- guanidinopropyl group or a tetrazo!-5-yl group.
5. A compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt, isostere or prodrug thereof wherein R2 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, aryl groups having from 5 to 14 carbon atoms (said aryl groups being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acyiamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms (said heteroaryl groups being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyi groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonyiamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), amino groups, monoalkylamino groups wherein the alkyl substituent has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl substituent is the same or different and has from 1 to 6 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, and hydroxyl groups), and groups of formula COY, or R2 is a group of formula COY, wherein
Y is a hydroxyl group, an alkoxyl group having from 1 to 6 carbon atoms, a group of formula NR40R41 , or an aminoacid residue, wherein R40 is selected from hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, aryl groups having from 5 to 14 carbon atoms (said aryl groups being unsubstituted or being substituted with at least one substituent selected from alkyi groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonyiamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms (said heteroaryl groups being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyi group having from 1 to 6 carbon atoms, alkoxycarbonyiamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonyiamino groups having from 1 to 6 carbon atoms and cyano groups), amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyi groups that are substituted by an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, and hydroxyl groups), carboxy groups, aminocarbonyl groups, monoalkylaminocarbonyl groups comprising an aminocarbonyl group which is substituted by an alkyl group having from 1 to 6 carbon atoms, dialkylaminocarbonyl groups comprising an aminocarbonyl group which is substituted by two alkyl groups which may be the same or different and each has from 1 to 6 carbon atoms, alkoxycarbonylgroups wherein the alkoxy moiety has from 1 to 6 carbon atoms, groups of formula COR1 1 , groups of formula SO2RH , groups of formula CONR11R12, groups of formula SO2NR11 R12r groups of formula CONR12SO2R11 and groups of formula CO2RI 3 wherein R1 1 , R12 and R13 are as defined below, aryl groups having from 5 to 14 carbon atoms (said aryi groups being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms (said heteroaryl groups being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkyiamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkyiamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyj groups having from 1 to 6 carbon atoms, alkyisulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), cycloalkyl groups having from 3 to 14 carbon atoms which are single rings or bridged ring systems (said cycloalkyl groups may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy moiety has from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is attached to a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups having from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms and hydroxyl groups), cycloalkenyl groups having from 4 to 14 carbon atoms and saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 6 carbon atoms, carboxyi groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkyiamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, and hydroxyl groups);
R41 is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, or R40 and R41 together with the nitrogen atom to which they are attached together form a nitrogen-containing saturated or partially unsaturated 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having one or more rings, said group optionally further containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, aSkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 6 carbon atoms, carboxyi groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyi group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, and hydroxyl groups);
R11 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyi groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsuiphonyl groups having from 1 to 6 carbon atoms, alkylsuiphonylamino groups having from 1 to 6 carbon atoms and cyano groups), an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with one or more of said aryl groups, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms (said heteroaryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyi groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups) or a heteroaralkyi group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with one or more of said heteroaryl groups;
R12 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups) or an aralkyi group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with one or more of said aryl groups; and
R13 is an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haioalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with one or more of said aryl groups, an alkoxyalkyf group comprising an alkyl group having from 1 to 6 carbon atoms which Is substituted with an alkoxy group having from 1 to 6 carbon atoms, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms (said heteroaryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acyiamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonyiamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups) or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with one or more of said heteroaryl groups.
6. A compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt, isostere or prodrug thereof wherein R2 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 4 carbon atoms, aryl groups having from 6 to 10 carbon atoms, heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, amino groups, monoalkyiamino groups wherein the alkyl substituent has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl substituent is the same or different and has from 1 to 4 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyi groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, and hydroxyl groups), and groups of formula COY, or R2 is a group of formula COY1 wherein
Y is a hydroxyl group, an alkoxyl group having from 1 to 4 carbon atoms, a group of formula NR40R41 , or an aminoacid residue, wherein R40 is selected from hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 4 carbon atoms, aryl groups having from 6 to 10 carbon atoms, heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyi groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, and hydroxyl groups), carboxy groups, aminocarbonyl groups, monoalkylaminocarbonyl groups comprising an aminocarbonyl group which is substituted by an alkyl group having from 1 to 4 carbon atoms, dialkylaminocarbonyl groups comprising an aminocarbonyl group which is substituted by two alkyl groups which may be the same or different and each has from 1 to 4 carbon atoms, alkoxycarbonylgroups wherein the alkoxy moiety has from 1 to 4 carbon atoms, groups of formula COR11 , groups of formula SO2RH , groups of formula CONR11 R12, groups of formula SO2NRH R12, groups of formula CONR12SO2R1 1 and groups of formula CO2RI 3 wherein R11 , R12 and R13 are as defined below, aryl groups having from 6 to 10 carbon atoms, heteroaryl groups which are 5- to 7- membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms atoms, cycloalkyl groups having from 3 to 8 carbon atoms which are single rings or bridged ring systems (said cycloalkyl groups may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, hydroxyalkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups wherein the alkoxy moiety has from 1 to 4 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is attached to a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups having from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms and hydroxyl groups), cycloalkenyl groups having from 4 to 8 carbon atoms and saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, and hydroxyl groups);
R41 is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, or R40 and R41 together with the nitrogen atom to which they are attached together form a nitrogen-containing saturated or partially unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having one or more rings, said group optionally further containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein each aSkyl group may be the same or different and has from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, and hydroxyl groups);
R11 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atoms, an aralkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with one or more aryl groups having from 6 to 10 carbon atoms, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms or a heteroaralkyl group which comprises an alkyl group having from 1 to 4 carbon atoms which is substituted with one or more heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms;
R12 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atoms or an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with one or aryl groups having from 6 to 10 carbon atoms; and
R13 is an alkyl group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atoms, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with one or aryl groups having from 6 to 10 carbon atoms, an alkoxyalkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an alkoxy group having from 1 to 4 carbon atoms, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms or a heteroaralkyl group which comprises an alkyl group having from 1 to 4 carbon atoms which is substituted with one or more heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms.
7. A compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt, isostere or prodrug thereof wherein R2 is a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 3 carbon atoms, amino groups, monoalkylamino groups wherein the alkyl substituent has from 1 to 3 carbon atoms, dialkylamino groups wherein each alkyl substituent is the same or different and has from 1 to 3 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom and groups of formula COY, or
R2 is a group of formula COY, wherein
Y is a hydroxyl group, an alkoxyi group having from 1 to 3 carbon atoms, a group of formula NR40R41 , or an aminoacid residue, wherein
R40 is selected from hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkoxyl groups having from 1 to 3 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and carboxy groups, cycloalkyl groups having from 3 to 6 carbon atoms atoms which are single rings or bridged ring systems and saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom;
R41 is a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms, or R40 and R41 together with the nitrogen atom to which they are attached together form a nitrogen-containing saturated or partially unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having one or more rings, said group optionally further containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur.
8. A compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt, isostere or prodrug thereof wherein R2 is a group of formula COY, wherein Y is selected from hydroxyl groups, ethoxy groups, t-butoxy groups, amino groups, methylamino groups, ethylamino groups, i-propylamino groups, dimethylamino groups, 2-(methoxysulphonyl)ethylamino groups, pyrrolidin-1-yl groups, tetrahydropyran-4-ylamino groups, cyclohexylamino groups, piperidin-1-yl groups, cyclopropylamino groups, 2-methoxyethylamino groups, morpholin-4-yl groups, 2-(pyrrolidin-1-yl)ethylamino groups, and amioacid residues selected from ornithine, lysine and glycine, or an alkyl group having from 1 to 3 carbon atoms which may be unsubstituted or substituted with a substituent selected from carboxy groups, amino groups, dimethylamino groupus, aminocarbonyl groups, morphoϋnyl groups, piperazinyl groups and pyrrolidinyl groups.
9. A compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt, isostere or prodrug thereof wherein R3 is an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system (said cycloalkyl group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulfonyl groups having from 1 to 6 carbon atoms and hydroxyl groups), a cycloalkenyl group having from 4 to 14 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl groups being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyi groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms (said heteroaryl groups being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the aSkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), a saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic group having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyi groups that are substituted by an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyi group which is substituted by a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, and hydroxyl groups), a cycloalkylalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one cycloalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system (said cycloalkyl group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyi groups substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyi group which is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyi group may be the same or different and has from 1 to 6 carbon atoms, alkylsulfonyl groups having from 1 to 6 carbon atoms and hydroxyl groups), or an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one aryl group having from 5 to 14 carbon atoms (said aryl group may be unsubstituted or be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyi is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsuiphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups).
10. A compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt, isostere or prodrug thereof wherein R3 is a cycloalkyl group having from 4 to 10 carbon atoms which is a single ring or a bridged ring system (said cycloalkyl group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups substituted with an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted with a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, alkylsulfonyl groups having from 1 to 4 carbon atoms and hydroxyl groups), a cycloalkenyl group having from 4 to 10 carbon atoms or a saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic group having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, and hydroxyl groups).
11. A compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt, isostere or prodrug thereof wherein R3 is a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 4-hydroxycyclohexyl group, a 4,4- dimethylcyclohexyl group, a 4,4-difluorocyclohexyl group, an adamantyl group, a norbornenyl group, a piperϊdinyl group, a 4-acetylpiperidinyl group or a 4- methylsulfonylpiperidinyl group.
12. A compound according to any one of claims 1 to 1 1 or a pharmacologically acceptable salt, isostere or prodrug thereof wherein R4 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, aryl groups having from 5 to 14 carbon atoms (said aryl groups may be unsubstituted or be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonyiamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonyiamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms (said heteroaryl groups being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonyiamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonyiamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), amino groups, alkylamino groups wherein the alkyl substituent has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl substituent is the same or different and has from 1 to 6 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic groups having one or more rings, inciuding bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkyisulphonyl groups having from 1 to 6 carbon atoms, and hydroxyl groups), carboxy groups, aminocarbonyl groups, monoalkylaminocarbonyl groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylaminocarbonyl groups wherein each alkyl group is the same or different and has from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, groups of formula R11 CO, groups of formula RH SO2, groups of formula R11 R12NCO, groups of formula R11 R12NSO2ι groups of formula R11 SO2NR12CO and groups of formula CO2RI 3, wherein R11, R12 and R13 are as defined below, an aryl group having from 5 to 14 carbon atoms (said aryl group may be unsubstituted or be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkyisulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), a cycloalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system (said cycloalkyl group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulfonyl groups having from 1 to 6 carbon atoms and hydroxyl groups), a cycloalkenyl group having from 4 to 14 carbon atoms and a saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic group having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or suiphur atom (said heterocyclic group being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, and hydroxyl groups);
R11 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with one or more of said aryl groups, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms (said heteroaryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups) or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with one or more of said heteroaryl groups;
R12 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, haiogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acyiamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups) or an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with one or more of said aryl groups; and
R13 is an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, haiogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), an aralkyi group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with one or more of said aryl groups, an alkoxyalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an alkoxy group having from 1 to 6 carbon atoms, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms (said heteroaryl group being unsubstituted or being substituted with at least one substituent selected from aSkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkyiamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups) or a heteroaralkyl group which comprises an alkyi group having from 1 to 6 carbon atoms which is substituted with one or more of said heteroaryl groups.
13. A compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt, isostere and prodrug thereof wherein R4 is an alkyl group having from 1 to 4 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkoxy groups having from 1 to 4 carbon atoms, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyt group has from 1 to 4 carbon atoms and dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, a cycloalkyl group having from 3 to 8 carbon atoms which is a single ring or a bridged ring system (said cycloalkyl group being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms and acyl groups having from 1 to 4 carbon atoms), an aryl group having from 6 to 10 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, hydroxyl groups, acylamino groups having from 1 to 4 carbon atoms, hydroxylalkyl groups having from 1 to 4 carbon atoms, alkylamino groups having from 1 to 4 carbon atoms and dialkylamino groups wherein each alkyl group is the same or different and has from 1 to 4 carbon atoms), an aralkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an aryl group having from 6 to 10 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkoxyl groups having from 1 to 4 carbon atoms and hydroxyl groups), a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms or a saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic group having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms and alkoxy groups having from 1 to 4 carbon atoms).
14. A compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt, isostere or prodrug thereof wherein R4 is a methyl group, an /-propyl group, a f-butyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 4,4-difluorocyclohexyl group, an adamantyl group, a phenyl group (which is unsubstituted or is substituted with one or more substituents selected from fluorine atoms, chlorine atoms, hydroxyl groups, methyl groups, acetylamino groups, methoxy groups and diethylamino groups), a benzyl group (which is unsubstituted or is substituted with a methoxy group or a hydroxyl group), a phenethyl group (which is unsubstituted or is substituted with a hydroxyl group), a pyridinyl group, a thiazolyl group, a pipehdinyl group, a tetrahydrofuranyl group, an N-methyl-piperidinyl group, a morpholinyi group, a piperazinyl group, an N-methyl- piperazinyl group, a 1H-indazolyl group, a 1-methyl-1H-indazolyl group, a tetrahydropyranyl group group, a 2-methoxyethyl group, a 2-aminoethyl group or a 2- dimethylaminoethyl group.
15. A compound according to any one of claims 1 to 14 or a pharmacologically acceptable salt, isostere or prodrug thereof wherein R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, haioalkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising a carbonyl group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, acyiamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, arylsulphonyl groups wherein the aryl moiety has from 5 to 14 carbon atoms (the aryl groups being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acyiamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), alkyisulphonylamino groups having from 1 to 6 carbon atoms, arylsulphonylamino groups wherein the aryl moiety has from 5 to 14 carbon atoms (the aryl moiety being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyi groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkyisulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), aminosulphonyl groups and cyano groups, or any two adjacent ring substituents R5, R6, R7 and R8 may together form the group -O-(CH2)P-O- wherein p is an integer of from 1 to 3.
16. A compound according to any one of claims 1 to 14 or a pharmacologically acceptable salt, isostere or prodrug thereof wherein R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms, haloalkyi groups having from 1 to 4 carbon atoms, hydroxyalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, hydroxyl groups, haloalkoxy groups having from 1 to 4 carbon atoms, halogen atoms, cyano groups, or any two adjacent ring substituents R5, R6, R7 and R8 may together form the group -O-(CH2)P-O- wherein p is an integer of from 1 to 2.
17. A compound according to any one of claims 1 to 14 or a pharmacologically acceptable salt, isostere or prodrug thereof wherein R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, methyl groups, methoxy groups, fluorine atoms, chlorine atoms, bromine atoms, hyroxymethyl groups, trifluoromethoxy groups, trifluoromethyl groups, i-propyl groups, ethoxy groups, hydroxyl groups, cyano groups, methylsulphonyl groups, or to adjacent ring substituents R5, R6, R7 and R8 may together form the group -O-CH2-.
18. A compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt, isostere or prodrug thereof wherein X is an oxygen atom, a sulphur atom or a group of formula NR10, wherein R10 is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms.
19. A compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt, isostere or prodrug thereof wherein X is a sulphur atom, an amino group or a methylamino group.
20. A compound according to claim 1 or a pharmacologically acceptable salt, isostere or prodrug thereof, wherein:
R1 is a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroaralkyl group, an aminoalkyl group or a guanidinoalkyl group;
R2 is an alkyl group which is substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups, aryl groups, heteroaryl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitrogen-containing unsaturated or partially saturated 4- to 8- membered heterocyclic groups, said groups optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms, and groups of formula COY, or R2 is a group of formula COY;
Y is a hydroxyl group, an alkoxyl group, a group of formula NHR40 or an aminoacid residue;
R3 is an alkyl group, a cycloalkyl group, a cycloalkenyl group, an aryl group, a heteroaryl group, a nitrogen-containing unsaturated or partially saturated 4- to 8- membered heterocyclic group, a cycloalkylalkyl group or an aralkyi group;
R4 and R40 are independently selected from hydrogen atoms, alkyl groups which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups, aryl groups, heteroaryl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitrogen-containing unsaturated or partially saturated 4- to 8- membered heterocyclic groups, said groups optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms, carboxy groups, aminocarbonyl groups, monoalkylaminocarbonyl groups, dialkylaminocarbonyl groups and alkoxycarbonyigroups, aryl groups, cycloalkyl groups, cycloalkenyl groups, groups of formula COR11 , groups of formula SO2RH , groups of formula CONR11 R12, groups of formula SO2NRI 1 R12, groups of formula CONR12SO2R11 and groups of formula CO2RI 3 wherein R11 , R12 and R13 are as defined below;
R1 1 is a hydrogen atom, an alkyl group, an aryl group, an aralkyl group, a heteroaryl group or a heteroaralkyl group;
R12 is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group; and
R13 is an alkyl group, an aryl group, an aralkyl group, an alkoxyalkyi group, a heteroaryi group or a heteroarylalkyl group;
R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyl groups, alkylsulphonylamino groups, arylsulphonyiamino groups, aminosulphonyl groups and cyano groups; and
X is an oxygen atom, a sulphur atom or a group of formula NR10, wherein R10 is a hydrogen atom or an alkyl group.
21. A compound according to claim 20 or a pharmacologically acceptable salt, isostere or prodrug thereof, wherein R1 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system, an aryl group having from 5 to 14 carbon atoms (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyt group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), an aralkyi group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acySamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkyisulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), a heteroaryl group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms atoms, a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, an aminoalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one amino group, and a guanidinoalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with a guanidino group.
22. A compounds according to claim 20 or claim 21 or a pharmacologically acceptable salt, isostere or prodrug thereof wherein R2 is an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, aryl groups having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyi groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms, amino groups, alkylamino groups wherein the alkyl substituent has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl substituent is the same or different and has from 1 to 6 carbon atoms, nitrogen-containing unsaturated or partially saturated 4- to 8- membered heterocyclic groups, said groups optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms, and groups of formula COY, or R2 is a group of formula COY, wherein Y is a hydroxyl group, an alkoxyl group having from 1 to 6 carbon atoms, a group of formula NHR40 (wherein R40 is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms), or an aminoacid residue.
23. A compound according to any one of claims 20 to 22 or a pharmacologically acceptable salt, isostere or prodrug thereof wherein R3 is an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system, a cycloalkenyl group having from 4 to 14 carbon atoms which is a single ring or a bridged ring system, an aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkyiamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, a heteroaryl group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms, a nitrogen-containing unsaturated or partially saturated 4- to 8- membered heterocyclic group, said group optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms, a cycloalkylalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one cycloalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system, or an aralkyi group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsuiphonylamino groups having from 1 to 6 carbon atoms and cyano groups.
24. A compound according to any one of claims 20 to 23 or a pharmacologically acceptable salt, isostere or prodrug thereof wherein R4 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, aryl groups having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyi groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms, amino groups, alkylamino groups wherein the alkyl substituent has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl substituent is the same or different and has from 1 to 6 carbon atoms, nitrogen-containing unsaturated or partially saturated 4- to 8- membered heterocyclic groups, said groups optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms, carboxy groups, aminocarbonyl groups, monoalkylaminocarbonyl groups whrein the alkyl group has from 1 to 6 carbon atoms, diafkylaminocarbonyl groups wherein each alkyl group is the same or different and has from 1 to 6 carbon atoms, alkoxycarbonylgroups wherein the alkoxy group has from 1 to 6 carbon atom, groups of formula R11 CO, groups of formula RH SO2, groups of formula R11 R12NCO, groups of formula R1 1 R12NSO2: groups of formula R11 SO2NR12CO and groups of formula CO2RI 3, an aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyi groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, a cycloalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system, a cycloalkenyl group having from 4 to 14 carbon atoms which is a single ring or a bridged ring system;
R11 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyi groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyi group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonyiamino groups having from 1 to 6 carbon atoms and cyano groups, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms,
R12 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkyiamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonyiamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, or an aralkyi group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkyiamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms and cyano groups, and
R13 is an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkyiamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonyiamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one aryl group having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent seiected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, an alkoxyalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an alkoxy group having from 1 to 6 carbon atoms, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms.
25. A compound according to any one of claims 20 to 24 or a pharmacologically acceptable salt, isostere or prodrug thereof wherein R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising a carbonyl group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkyisulphonyi groups having from 1 to 6 carbon atoms, aryisulphonyl groups wherein the aryl moiety has from 5 to 14 carbon atoms (the aryl moiety being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups), alkylsulphonylamino groups having from 1 to 6 carbon atoms, arylsulphonylamino groups wherein the aryl moiety has from 5 to 14 carbon atoms (the aryl moity being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyi groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms) and cyano groups, aminosulphonyi groups and cyano groups.
26. A compound according to any one of claims 20 to 25 or a pharmacologically acceptable salt, isostere or prodrug thereof wherein X is an oxygen atom, a sulphur atom or a group of formula NR10, wherein R10 is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms.
27. A compound according to claim 1 or a pharmacologically acceptable salt, isostere or prodrug thereof, wherein:
R1 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an aminoalkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an amino group, a heteroaryl group which is a 5- to 6-membered aromatic heterocyclic group containing 1 to 2 sulphur atoms, oxygen atoms and/or nitrogen atoms which may be unsubstituted or substituted with an alkyl group having from 1 to 4 carbon atoms, and a guanidinoalkyl group comprising an alkyi group having from 1 to 4 carbon atoms which is substituted with a guanidino group, R2 is a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 3 carbon atoms, amino groups, monoalkylamino groups wherein the alkyl substituent has from 1 to 3 carbon atoms, dialkyiamino groups wherein each alkyl substituent is the same or different and has from 1 to 3 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom and groups of formula COY, or R2 is a group of formula COY, wherein
Y is a hydroxyl group, an alkoxyl group having from 1 to 3 carbon atoms, a group of formula NR40R41 , or an aminoacid residue, wherein R40 is selected from hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkoxyl groups having from 1 to 3 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and carboxy groups, cycloalkyl groups having from 3 to 6 carbon atoms atoms which are single rings or bridged ring systems and saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, inciuding bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom;
R41 is a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms, or R40 and R41 together with the nitrogen atom to which they are attached together form a nitrogen-containing saturated or partially unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having one or more rings, said group optionally further containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur, R3 is a cycloalkyl group having from 4 to 10 carbon atoms which is a single ring or a bridged ring system (said cycloalkyl group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups substituted with an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyi groups comprising a carbonyi group which is substituted with a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein each afkyl group may be the same or different and has from 1 to 4 carbon atoms, alkylsulfonyl groups having from 1 to 4 carbon atoms and hydroxyl groups), a cycloalkenyl group having from 4 to 10 carbon atoms or a saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic group having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyi groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, and hydroxyl groups), R4 is an alkyl group having from 1 to 4 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkoxy groups having from 1 to 4 carbon atoms, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms and dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, a cycloalkyl group having from 3 to 8 carbon atoms which is a single ring or a bridged ring system (said cycloalkyl group being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms and acyl groups having from 1 to 4 carbon atoms), an aryl group having from 6 to 10 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, hydroxyl groups, acylamino groups having from 1 to 4 carbon atoms, hydroxylalkyl groups having from 1 to 4 carbon atoms, alkylamino groups having from 1 to 4 carbon atoms and dialkylamino groups wherein each alkyi group is the same or different and has from 1 to 4 carbon atoms), an aralkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an aryi group having from 6 to 10 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkoxyl groups having from 1 to 4 carbon atoms and hydroxyl groups), a heteroaryl group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms or a saturated, partially unsaturated or unsaturated 4- to 14- membered heterocyclic group having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom {said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms and alkoxy groups having from 1 to 4 carbon atoms),
R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, hydroxyalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkyisulphonyl groups having from 1 to 4 carbon atoms, hydroxyl groups, haloalkoxy groups having from 1 to 4 carbon atoms, halogen atoms and cyano groups, or any two adjacent ring substituents R5, R6, R7 and R8 may together form the group -O-(CH2)P-O- wherein p is an integer of from 1 to 2, and
X is an oxygen atom, a sulphur atom or a group of formula NR10, wherein R10 is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms.
28. A compound according to ciaim 1 or a pharmacologically acceptable salt, isostere or prodrug thereof, wherein:
R1 is a hydrogen atom, a methyl group, a 3-aminopropyl group, a 4-aminobutyl group, a 3-methyl-[1 ,2,4]oxadiazol-5-yl group, a 5-methyl-[1 ,3,4]oxadiazo!-2-yl group, a 3-methyl-isoxazoi-5-yl group or a 3-guanidinopropyl group;
R2 is a group of formula COY, wherein Y is selected from hydroxyl groups, ethoxy groups, t-butoxy groups, amino groups, methylamino groups, ethylamino groups, i- propylamino groups, dimethylamino groups, 2-(methoxysulphonyl)ethylamino groups, pyrrolidin-1 -yl groups, tetrahydropyran-4-ylamino groups, cyclohexylamino groups, piperidin-1-yl groups, cyclopropytamino groups, 2-methoxyethylamino groups, morpholiι>4-yl groups, 2-(pyrrolidin-1 -yl)ethylamino groups, and amioacid residues selected from ornithine, lysine and glycine, or an aSkyi group having from 1 to 3 carbon atoms which may be unsubstituted or substituted with a substituent selected from carboxy groups, amino groups, dimethylamino groupus, aminocarbonyl groups, morpholinyl groups, piperazinyl groups and pyrrolidinyl groups, or Y is a tetrazolyl group;
R3 is a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 4- hydroxycyclohexyl group, a 4,4-dimethyIcyclohexyl group, a 4,4-difluorocyclohexyl group, an adamantyl group, a norbornenyl group, a piperidinyl group, a 4- acetylpiperidinyl group or a 4-methylsulfony[piperidinyi group; R4 is a methyl group, an /-propyl group, a f-butyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 4,4-difluorocyclohexyl group, an adamantyl group, a phenyl group (which is unsubstituted or is substituted with one or more substituents selected from fluorine atoms, chlorine atoms, hydroxyl groups, methyl groups, acetylamino groups, methoxy groups and diethylamino groups), a benzyl group (which is unsubstituted or is substituted with a methoxy group or a hydroxyl group), a phenethyl group (which is unsubstituted or is substituted with a hydroxyl group), a pyridinyl group, a thiazolyl group, a piperidinyl group, a tetrahydrofuranyl group, an N-methyl-piperidinyl group, a morpholinyi group, a piperazinyl group, an N-methyl-piperazinyl group, a 1 H-indazolyl group, a 1 -methyl- 1H-indazolyl group, a tetrahydropyranyl group group, a 2-methoxyethyl group, a 2- aminoethyl group or a 2-dimethylaminoethyl group;
R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, methyl groups, methoxy groups, fluorine atoms, chlorine atoms, bromine atoms, hyroxymethyl groups, trifluoromethoxy groups, trifluoromethyl groups, i-propyl groups, ethoxy groups, hydroxyl groups, cyano groups, methylsulphonyl groups, or to adjacent ring substituents R5, R6, R7 and R8 may together form the group -O-CH2-; and X is a sulphur atom, an amino group or a methylamino group.
29. A compounds according to claim 1 or a pharmacologically acceptable salt, isostere or prodrug thereof, selected from:
N-[1 -cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indol-3-yl(oxo)acetyl]glycine, N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indol-3-yl(oxo)acetyl]-b- alanine, 4-{[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl][1H-indol-3- yl(oxo)acetyl]amino}butanoϊc acid,
N-[1 -cyclohexyl-2-(cyclohexylamino)-2-oxoethy[]-N-[(6-fluoro-1 H-indol-3- yl)(oxo)acetyl]glycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indol-3-yi(oxo)acetyl]glycyl-L- ornithine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indol-3-yl(oxo)acetyl]glycyl-L-
[ysine,
N2-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N2-[1 H-indol-3-y[(oxo)acetyl]-D- ornithylgiycine,
N-[1 -bicyclo[2.2.1 ]hept-5-en-2-y[-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indol-3- yl(oxo)acetyl]glycine,
N-[2-(cyclohexylamino)-1-cyclopentyl-2-oxoethyl]-N-[1 H-indol-3-yl(oxo)acetyl]glycine,
N-[1-cycloheptyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indol-3-yl(oxo)acetyl]glycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(5-fluoro-1 H-indol-3- yl)(oxo)acetyl]-b-alanine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-E(6-fluoro-1 H-indol-3- yi)(oxo)acetyf3-b-alanine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(7-fluoro-1 H-indol-3- y[)(oxo)acetyl]-b-alanine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(1 -methyl- 1H-indol-3- yl)(oxo)acetyl]-b-alanine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(5-fluoro-1 H-indol-3- yl)(oxo)acetyl]glycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(7-fluoro-1 H-indol-3- yl){oxo)acetyl]glycine,
N-[1-cyclohexy[-2-(cyclohexylamino)-2-oxoethyl]-N-[(2-methyl-1H-indol-3- yl)(oxo)acetyl]glycine,
N-[1-benzothien-3-yl(oxo)acetyl]-N-[1-cyclohexy[-2-(cyc[ohexylamino)-2- oxoethyl]g[ycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(6-methyl-1H-indol-3- yl)(oxo)acetyl]g[ycine,
N-[(6-chloro-1 HHndol-3-yi)(oxo)acetyl]-N-[1»cyclohexyl-2-(cyclohexylamino)-2- oxoethyl]glycine,
N-[1-cyc[ohexyl-2-(isopropylamino)-2-oxoethyl]-N-[1 H-indol-3-yl(oxo)acetyl]glycine,
N-[2-(benzylamino)-1-cyclohexyl-2-oxoethyl]-N-[1H-indol-3-yl(oxo)acetyl]g]ycine: N-[2-(adamantan-1 -ylamino)-1 -cyclohexyl-2-oxoethyl]-N-[1 H-indol-3- yl(oxo)acetyl]glycine,
N-[1-cyclohexy[-2-(cyc[openty[amino)-2-oxoethyl]-N-[1H-indol-3-yl(oxo)acetyl]glycine,
N-{1-cyclohexyl-2-E(2-methoxyethyl)amino]-2-oxoethyl}-N-[1 H-indol-3- y[(oxo)acetyl]glycine,
N-[1-cyclohexyl-2-(methylamino)-2-oxoethyl]-N-E1 H-indol-3-yl(oxo)acetyl]glycine,
N-(2-anilino-1-cyclohexyl-2-oxoethyl)-N-t1 H-indol-3-yl(oxo)acetyl]glycine,
N-{1 -cyclohexy[-2-[(4-methoxypheny[)amino]-2-oxoethyl}-N-[1 H-indol-3- yl(oxo)acetyl]glycine,
N-ti-cyclohexyl-2-^-fdiethylamino)phenyl]amino^-oxoethyl)-N-[1 H-indol-3- yl(oxo)acetyl]glycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indol-3-yl(oxo)acetyl]-L- alanine,
N-fi-cyclohexyl-2-^-methoxybenzyl)aminoj-2-oxoethyl}-N-EI H-indol-3- yi(oxo)acety[]g[ycine,
N-{1-cyclohexyl-2-[(4-hydroxybenzyl)amino]-2-oxoethyl}-N-[1 H-indol-3- yl(oxo)acetyl]glycine,
N-{1-cyclohexyI-2-oxo-2-[(2-phenylethyl)amino]ethy]}-N-E1 H-indol-3- yl(oxo)acetyl]glycine,
N-li-cyclohexyl-2-Ef4-fluorophenyl)amino^-oxoethyl}-N-EI H-indol-3- yl(oxo)acetyl]glycine,
N-(1-cyclohexyl-2-{[2-(4-hydroxyphenyl)ethyl]amino}-2-oxoethyl)-N-[1 H-indol-3- yl(oxo)acetyl]glycine,
N-li -cyclohexyl-2-^-hydroxyphenyl)aπnino^-oxoethylϊ-N-EI H-indol-3- yl(oxo)acetyl]glycine,
N-^^tert-butytamino)-1-cyclohexyl-2-oxoethylj-N-fi H-indol-3-yKoxo)acety^-b-alanine
N3-[1-cyclohexyl-2-(cyclohexy[amino)-2-oxoethyt]-N3-[1 H-indol-3-yl(oxo)acety[]-b- alaninamide
N-[1 -cyclohexy[-2-(cyclohexylamino)-2-oxoethyl]-N-(3-hydroxypropyl)-2-(1H-tndol-3- yl)-2-oxoacetamide,
N-[1-cyclohexyi-2-(cyclohexylamino)-2-oxoethyl]-2-(1 H-indol-3-yl)-2-oxo-N-(2H- tetrazol-5-y[methyl)acetamide,
N-[1-cycJohexyl-2-(cyclohexylamino)-2-oxoethyl]-2-(1H-indol-3-yl)-N-(2-morpholin-4- ylethyl)-2-oxoacetamide,
N-[1-cyclohexyl-2-(cyclohexy[amino)-2-oxoethyl]-2-(1 H-indol-3-yl)-2-oxo-N-{2- piperazin-1 -ylethyl)acetamide, N-[1 -cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-2-(1 H-indol-3-yi)-2-oxo-N-(3- pyrrolidin-1 -ylpropyl)acetamide
N-(4-aminobutyl)-N-[1-cyc[ohexyl-2-(cyclohexy[amino)-2-oxoethyl]-2-(1 H-indo!-3-yl)-
2-oxoacetamide,
N-[1 -cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indol-3- yl(oxo)acetyl]glycylgiycine,
N2-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N2-[1 H-indol-3- yl(oxo)acetyl]glycinamide, ethyl N-[1 -cyclohexyl-2-{cyclohexylamino)-2-oxoethyl]-N-[1 H-indol-3- yl(oxo)acetyl]glycinate,
N2-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N2-[1 H-indol-3-yl(oxo)acetyl]-D- iysine,
N2-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N2-[1 H-indol-3-yl(oxo)acetyl]-D- ornithine hydrochloride,
N2-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N2-[1 H-indoi-3-yl(oxo)acetyl]-D- arginine,
N2-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N2-[1 H-indoi-3-yl(oxo)acetyl]-L- ornithylglycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(4-fluoro-1 H-indo[-3- yl)(oxo)acetyl]glycine,
N-[1-adamantan-1-yl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indol"3- yl(oxo)acetyl]glycine,
N2-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl3-N2-[1 H-indol-3-yl(oxo)acetyl]-L- arginyiglycine,
N,2-dicyclohexyl-2-{[1H-indol-3-yl(oxo)acetyl]amino}acetamide,
N-li-cyclohexyl-Z-ItS-hydroxybenzyl)amino^-oxoethyl}-N-II H-indol-3- yl(oxo)acetyl]giycine,
N-{1-cyclohexyl-2-[(3-hydroxypheny[)amino]-2-oxoethyl}-N-[1 H-indo[-3- yl(oxo)acetyl]glycine,
N-(1-cyclohexyl-2-{[4-{hydroxymethyl)phenyl]amino}-2-oxoethyl)-N-[1H-indo!-3- yl(oxo)acetyl]glycine,
N-(1-cyclohexyl-2-{[4-(hydroxymethyl)phenyl]amino}-2-oxoethyl)-2-(1 H-indol-3-yl)-2- oxo-N-(3-pyrrolidin-1-ylpropyl)acetamide,
N-[1-cyc[ohexyl-2-(cyclohexylamino)-2-oxoethy[]-N-[1 H-indol-3-yl(oxo)acetyl]-D- alanine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indol-3-yl(oxo)acetyl]-D- alanine, N-[1-cyclohexy[-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indol-3-yl(oxo)acetyl]-D- alanine,
N-[1-cyclohexy[-2-(cyclohexylamino)-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]glycine,
N-[(6-bromo-1 H-indol-3-yl)(oxo)acetyl]-N-[1-cyclohexyl-2-(cyclohexylamino)-2- oxoethyl]glycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-{oxo[6-(trifluoronnethyl)-1H-indol-
3-yl]acetyl}giycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(6-isopropyl-1 H-indol-3- yl)(oxo)acetyl]glycine,
N-[2-{cyclohexylamino)-2-oxo-1-piperidin-4-ylethyl]-N-[1 H-indo!-3- yl(oxo)acetyl]glycine hydrochloride,
N-[1 -{1 -acetylpiperidin-4-yl)-2-(cyclohexylamino)-2-oxoethyl]-N-[1 H-indol-3- ylfoxojacetyljglycine,
N-{2-(cyclohexylamino)-1 -[1 -(methy[su!fony[)piperidin-4-yl]-2-oxoethyl}-N-[1 H-indol-3- yl(oxo)acetyl]glycine,
N-li-cyclohexyl-2-IfS-hydroxypheny^aminol-2-oxoethyl}-N-^θ-methoxy-I H-indol-3- yl)(oxo)acetyl]giycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(2E)-2-hydroxy-2-(2-oxo-1 ,2- dihydro-3H-indol-3-ylidene)acetyl]glycine,
N-{1-cyc]ohexyl-2-[(3-methy[phenyl)amino]-2-oxoethyl}-N-[1 H-indol-3- yl(oxo)acetyl]glycine,
N-{1-cyclohexyi-2-[(3-methoxyphenyl)amino]-2-oxoethyl}-N-[1 H-indol-3- yl(oxo)acetyl]glycine,
[^.^-[(S-chlorophenyl)aminol-1-cyclohexyl-2-oxoethyl}-N-fi H-indol-3- yl(oxo)acetyl]glycine,
N^I-cyclohexyi^tS-fluorophenyl)amino^-oxoethyl}-N-JI H-indol-3- yl(oxo)acetyl]glycine,
N-^-ttert-butylamino)-1-cyclohexyl-2-oxoethyl]-N-^δ-methoxy-I H-indol-3- yi)(oxo)acetyl]glycine,
N-(2-anilino-1-cyc[ohexyl-2-oxoethyl)-N-[(6-methoxy-1 H-indol-3- yi)(oxo)acetyl]glycine,
N-[1-cyclohexyl-2-fisopropylamino)-2-oxoethyl]-N-ttδ-methoxy-I H-indol-3- yl)(oxo)acetyl]glycine,
N-[1-cyclohexyl-2-(cyclopentylamino)-2-oxoethyl]-N-[(6-methoxy-1H-indol-3- y^oxojacetyljglycine, N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(6-ethoxy-1 H"indo!-3- yl)(oxo)acetyl]glycine,
N-[1-cyclohexyI-2-(cyclohexylamino)-2-oxoethyl]-N-[(6-hydroxy-1 H-indo!-3- yl)(oxo)acetyl]glycine,
N-[I-cyclohexyl-2-fcyclohexylamino)-2-oxoethyl]-N-ftS^-dimethoxy-1H-indol-3- yl)(oxo)acetyl]glycine,
N-II-cyclohexyl-2-^yclohexylamino)-2-oxoethyl]-N-tδH-[1.Sldioxoto^^-ηindol-?- yl(oxo)acety[]g]ycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(5-methoxy-1H-indol-3- yl)(oxo)acetyl]glycine,
N-[(5-bromo-1 H-indol-3-yl)(oxo)acetyI]-N-[1-cyclohexyi-2-(cyclohexylamino)-2- oxoethyl]glycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]-b-alanine,
4-{[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl][(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]amino}butanoic acid,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-
N-(2-piperazin-1-yiethyl)acetamide,
N-t4-aminobutyl)-N-[1-cyclohexyl-2-^yclohexylamino)-2-oxoethyl]-2-fδ-methoxy-I H- indol-3-yl)-2-oxoacetamide,
N2-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N2-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]glycinamide,
N-[1-cyclohexyl-2-(cyclohexylannino)-2-oxoethyl]-2-(6-methoxy-1 H-indoi-3-yl)-N- methyl-2-oxoacetamide,
N-[1-benzothien-3-yl(oxo)acetyl]-N-{1 -cyclohexyl-2-[(3-hydroxyphenyl)amino]-2- oxoethyl}glycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]glycylglycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-
N-(3-pyrrolidin-1-ylpropyl)acetamide,
N-{1-cyclohexyl-2-[(3-hydroxyphenyl)amino]-2-oxoethyl}-N-[1 H-indol-3-yi(oxo)acetyl]- b-alanine,
4-({i-cyclohexyl-2-EtS-hydroxyphenyl)anninol-2-oxoethylϊII H-indol-3- yl(oxo)acetyl]amino)butanoic acid,
N-ti-cyclohexyi^^-(hydroxymethyl)phenyl]aminoϊ-2-oxoethyl)-N-[(6-methoxy-I H- indol-3-yt)(oxo)acetyl]g[ycine, N-li-cyclohexyl-2-ffS-hydroxyphenyl)aminol-2-oxoethyl}-2-(I H-indol-3-yl)-2-oxo-N-ta- pyrrolidin-1 -y[propyl)acetamide,
N^I-cyclohexyl^fS-hydroxyphenyl)aminol-2-oxoethyl}-2-fi H-indol-3-yl)-N-methyl-
2-oxoacetamide,,
N-{1-cyclohexy[-2-[(3-hydroxyphenyl)amino]-2-oxoethyl}-N-[(6-methoxy-1 H-indol-3- yi)(oxo)acetyl]-b-alanine,
4-({i-cyclohexyi-2-ttS-hydroxyphenyl)amino^-oxoethylKfθ-methoxy-I H-indol-3- y[)(oxo)acetyl]amino)butanoic acid,
N-{1-cyclohexyl-2-[(3-hydroxyphenyl)amino]-2-oxoethyl}-2-(6-methoxy-1 H-indo[-3-yl)-
2-oxo-N-(3-pyrrolidin-1-ylpropyl)acetamide,
N-{1-cyclohexyl-2-[(4-hydroxyphenyl)amino]-2-oxoethyl}-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyj]glycine,
N-[(1 S)-1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-[(6-nnethoxy-1 H-tndol-3- yl)(oxo)acetyl]glycine,
N-[(1 R)-1-cyclohexyl-2-(cyc[ohexy[amino)-2-oxoethyl]-N-[(6-methoxy-1H-indol-3- yl)(oxo)acetyl]glycine,
N-[1-cyclohexyl-2-(cyclohexylamino)-2-oxoethyl]-N-{oxo[6-(trifluoromethoxy)-1 H- indo!-3-yl]acetyl}glycine,
N-{1 -cyclohexyl-2-[(3-hydroxyphenyl)amino]-2-oxoethyl}-2-(1 H-indol-3-yl)-2-oxo-N-(2- piperazin-1 -y[ethyl)acetamide,
N-(4-aminobutyl)-N-{1-cyclohexy[-2-[(3-hydroxyphenyi)amino]-2-oxoethyl}-2-(1 H- indof-3-yl)-2-oxoacetamide,
N-{1 -cyclohexyl-2-[(3-hydroxyphenyl)amino]-2-oxoethyl}-2-(6-methoxy-1H-indol-3-yl)-
2-oxo-N-(2-piperazin-1-ylethy[)acetamide:
N-(4-aminobutyl)-N-{1-cyclohexy]-2-[(3-hydroxyphenyl)amino]-2-oxoethy[}-2-(6- methoxy-1H-indol-3-yS)-2-oxoacetamide,
N-[1 -cyclohexyl-2-(isopropylamino)-2-oxoethyl]-2-(6-methoxy-1 H-indo[-3-yl)-2-oxo-N-
(3-pyrrolidin-1 -ylpropyl)acetamide,
N-(4-aminobutyl)-N-[1-cyclohexyl-2-(isopropylamino)-2-oxoethyl]-2-(6-methoxy-1 H- indol-3-yl)-2-oxoacetam ide,
N,2-dicyclohexyl-2-{[(6-methoxy-1 H-indol-3-yl)(oxo)acetyl]amino}acetamide,
N-(2-ani[ino-1-cyclohexyl-2-oxoethyl)-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-N-{3- pyrrolidin-1-ylpropyl)acetamide,
N-(2-anilino-1 -cyclohexyl-2-oxoethyl)-2-(6-methoxy-1 H-indo!-3-yl)-2-oxo-N-(2- piperazin-1 -ylethyl)acetamide,
N-[(6-cyano-1 H-indol-3-yl)(oxo)acetyl]-N-[1 -cyclohexyl-2-(cyc[ohexylamino)-2- oxoethyl]glycine, N-[1-cyclohexyl-2-(cyc[ohexy[amino)-2-oxoethyl]-N-{[6-{methylsulfonyl)-1 H-indol-3- yl](oxo)acetyl}glycine,
N-(4-aminobutyl)-N-(2-anilino-1-cyclohexyl-2-oxoethyt)-2-(6-methoxy-1H-inclol-3-yl)-
2-oxoacetamide,
N-ti-cyclohexyl-2-EfS-methoxypropyl)aminol-2-oxoethyl}-N-EI H-indol-3- y[(oxo)acety[]giycine,
N-fi-cyclohexyl-2-IIS-fdimethylamino)propyOamino^-oxoethyl)-N-II H-indol-3- yi(oxo)acetyl]glycine,
N-{2-[(3-aminopropyl)amino]-1-cyclohexy[-2-oxoethyl}-N-[1 H-indol-3- yl^xojacetyljglycine,
N-fi-cyclohexyl-2-ItS-methoxypropyl)aminol-2-oxoethylϊ-N-tfβ-methoxy-I H-indoI-3- y^oxojacetyljglycine,
N-(1-cyclohexyl-2-{[3-(dimethylamino)propyl]amino}-2-oxoethyl)-N-[(6-methoxy-1 H- indol-3-yl)(oxo)acetyl]glycine,
N^-tfS-aminopropyl)aminol-1-cyclohexyl-2-oxoethyl}-N-Efθ-methoxy-I H-indol-3- yl)(oxo)acetyl]glycine,
N^I-cyclohexyl-2-oxo-2-fpyridin-2-ylamino)ethy^-N-[tθ-methoxy-I H-indol-3- yl)(oxo)acetyl]glycine hydrochloride,
N-[(1 R)-1-cyclohexy[-2-oxo-2-(1 ,3-thiazol-2-ylamino)ethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]glycine,
N-((R)-cyclohexy[phenylcarbamoylmethyl)-2-(1 H-indol-3-yl)-2-oxo-N-(2-piperazin-1- yl-ethyl)acetamide,
N-((R)-cyclohexylisopropyicarbamoylmethyl)-2-(1 H-indoi-3-yl)-2-oxo-N-(2-piperazin-
1 -yl-ethyl)acetamide,
2,N-dicyclohexyi-2-[[2-(6-rrιethoxy-benzo[b]thiophen-3-yl)-2-oxo-acetyl3-(2-piperazin-
1-yl-ethyl)-amino]-acetamide,
2-{(4-amino-butyl)-[2-(6-methoxy-benzo[b]thiophen-3-yl)-2-oxo-acetyl]-amino}-2,N- dicyclohexyl-acetamide,
{(cyclohexylcyclohexylcarbamoyl-methyl)β-fθ-methoxybenzotblthiophen-3-yl)-2-oxo- acetyl]amino}acetic acid,
[[2-(6-brotnobenzo[b]thiophen-3-yl)-2-oxo- acetyl]{cyclohexylcyclohexylcarbamoyimethyl)-amino]acetic acid,
{[cyclohexylcarbamoyl-(4!4-dimethylcyclohexyl)methyl][2-(6-methoxy-1H-indol-3-yl)-
2-oxoacetyl]amino}acetic acid,
N-[1 -cyclohexyl-2-(isopropyJamino)-2-oxoethyl3-2-(6-methoxy-1 H-indoJ-3-yl)-2-oxo-N-
(2-piperazirv1-ylethyl)acetamide, {Ecyclohexy[carbamoyl-(4,4-dimethylcyclohexyl)methyl][2"(1H-indol-3-yi)-2- oxoacetyl]amino}acetic acid,
{(cyclohexylcyclohexylcarbamoylmethyl)-[2-(6-hydroxymethyl-1 H-indol-3-yl)-2- oxoacetyl]amino}acetic acid,
N-[(1R)-1-cyc[ohexyl-2-oxo-2-(piperidin-4-y[amino)ethyl]-N-[(6-methoxy-1H-indo[-3- yl)oxoacetyl]glycine,
N-[(1 R)-1-cyc[ohexyl-2-oxo-2-(tetrahydro-2H-pyran-4-ylamino)ethyl]-N-[(6-methoxy-
1 H-indol-3-yl)(oxo)acetyl]glycine,
N-{(1 R)-1 -cyclohexyl-2-[(1 -methylpiperidin-4-yl)amino]-2-oxoethyl}-N-[(6-methoxy-
1 H-indol-3-yl)(oxo)acetyl]glycine,
N-[(1 R)-2-(cycloheptylamino)-1 -cyc(ohexyl-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yi)(oxo)acetyl]glycine,
N-[(1R)-1-cyclohexyl-2-(cyclopropylamino)-2-oxoethyl]-N-[(6-methoxy-1 H-indo!-3- yi)(oxo)acetyl]g[ycine,
N-[(1 R)-1 -cyclohexyl-2-(cyclopentylamino)-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]g[ycine,
N-[(1 R)-1 -cyclohexyl-2-(isopropylamino)-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]g[ycine,
N-[1 -cyclohexyl-2-oxo-2-(pyridin-2-y[amino)ethyl]-N-(2-methoxyethyl)-2-(6-methoxy-
1 H-indoi-3-yl)-2-oxoacetamide,
{[(R)-cyclohexyi-(4,4-difluorocyclohexy[carbamoy[)methyl]-[2-(6-methoxy-1 H-indol-3- yl)-2-oxo-acetyl]amino}acetic acid,
{((R)-cyclohexylphenylcarbamoylmethyl)-[2-(6-fluoro-1 H-indol-3-yl)-2- oxoacetyl]amino}acetic acid,
{[(R)-cyclohexyl-fiH-indazol-e-ylcarbamoyi)-methyl]-P-(6-methoxy-I H-indol-3-yl)-2- oxoacetyl]-amino}acetic acid,
{[(R)-cyclohexyl-fS-hydroxy^-methylphenylcarbamoyl)methyl]-^-fθ-methoxy-I H- indol-3-yl)-2-oxoacetyl]amino}acetic acid,
{[(R)-(3-acetylaminophenylcarbamoyl)cyclohexylmethyl]-[2-(6-methoxy-1 H-indol-3- yl)-2-oxoacetyl]amino}acetic acid,
{[(R)-cyclohexyl-(4-methoxypheny[carbaιnoyl)methy]]-[2-(6-methoxy-1 H-indol-3-yi)-2- oxoacetyl]amino}acetic acid,
{[(R)-cyclohexyl-(3-methoxypheny[carbamoyl)ιnethyl]-[2-{6-methoxy-1 H-indol-3-yi)-2- oxoacetyl]amino}acetic acid,
{((R)-cyclohexylisopropylcarbamoy[methyl)-[2-(6-fluoro-1H-indol-3-yl)-2- oxoacetyl]amino}acetic acid, {((R)-cyclohexylcyclopropylcarbamoylmethyl)-[2-(6-fluoro-1 H-indol-3-yl)-2- oxoacetyl]amino}acetic acid,
{((^-cyclohexylisopropylcarbamoylmethylV^-fθ-methoxy-I H-indol-3-yl)-2- oxoacetyl]amino}acetic acid tert-butyl ester,
N-((R)-cyclohexylisopropy[carbamoylnnethyl)-2-(6-methoxy-1 HHndol-3-yl)-2-oxo-N-(2- oxo-2-pyrrolidin-1-ylethyl)acetamide,
{((R)"Cyclohexylcyclohexylcarbamoylmethyl)-[2-(5,6-difluoro-1 H-indol-3-yl)-2-oxo- acetyl]amino}acetic acid,
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-N-[(2- methanesulfonylethylcarbamoyl)methyl]-2-(6-methoxy-1 H-indol-3-yl)-2- oxoacetamide,
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-2-(5,6-difluoro-1 H-indol-3-yl)-2-oxo-N-
(2-oxo-2-pyrrolidin-1 -ylethyl)acetamide,
N-[cyclohexyl-((R)-tetrahydropyran-4-ylcarbamoyl)methyl]-2-(6-hydroxy-1 H-indol-3- yl)-2-oxo-N-(2-oxo-2-pyrro]idin-1-ylethyl)acetamide,
{[(R)-cyclohexyl-ftetrahydropyran-Φylcarbamoyl)methyl]-^-fδ-hydroxy-I H-indol-3-yl)-
2-oxoacetyl]amino}acetic acid,
N-[(R)-cyclohexyl-(tetrahydropyran-4-y[carbamoyi)nπethyl]-2-(6-hydroxy-1 H-indol-3- yl)-2-oxo-N-[(tetrahydropyran-4-ylcarbamoyl)methyl]acetamide,
(R)-2-{carbamoylnnethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxoacetyl]amino}-2,N- dicyclohexylacetamide,
N-((R)-cyclohexylcyclohexylcarbamoylrriethyl)-N-{2-methoxyethyl)-2-(6-methoxy-1 H- indol-3-yl)-2-oxoacetamide,
N-cyclohexylcarbamoylmethyl-N-((R)-cyc[ohexylcyclohexylcarbamoylmethyl)-2-(6- methoxy-1 H-indol-3-yl)-2-oxoacetamide
N-((R)-cyclohexyicyclohexylcarbamoylmethyl)-2-(6-methoxy-1H-indol-3-yl)-2-oxo-N-
(2-oxo-2-piperidin-1-ylethyl)acetamide,
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-N-(isopropylcarbaιnoylmethyl)-2-(6- methoxy-1 H-indol-3-yl)-2-oxoacetamide,
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-N-cyclopropylcarbamoylmethyl-2-(6- methoxy-1H-indol-3-yl)-2-oxoacetamide,
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-N-(2-hydroxy-ethy[)-2-{6-methoxy-1 H- indol-3-yl)-2-oxoacetamide,
N-((R)-cyclohexyl-cyclohexyicarbatnoylmethyl)-N-diethylcarbamoylmethyl-2-(6- methoxy-1 H-indol-3-yl)-2-oxoacetamide,
N-((R)-cyc[ohexylcyc[ohexylcarbannoylnπethyl)-N-[(2-methoxyethylcarbamoyl)methy[]-
2-(6-methoxy-1 H-indol-3-yl)-2-oxoacetamide, N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-2-(6-methoxy-1 H-indol-3-yl)-N-(2- morpholin-4-yl-2-oxo-ethyl)-2-oxoacetamide,
N-((R)-cyclohexylcyc[ohexy[carbamoyimethyl)-2-(6-πnethoxy-1 H-indol-3-yl)-2-oxo-N-
[(2-pyrrolidin-1 -yl-ethylcarbamoyl)methy[]acetamicle,
N-((R)-cyclohexy[cyclohexy[carbamoylmethyl)-2-(6-methoxy-1H-indol-3-yl)-N- methylcarbamoylmethyl-2-oxoacetamide:
N-{(R)-cyclohexylcyclohexylcarbamoylmethyl)-N-dimethylcarbamoylmethyl-2-(6- methoxy-1 H-indol-3-y[)-2-oxoacetamide,
{({R)-cyclohexylcyc[ohexylcarbamoylmethyl)-[2-(6-methoxy-1 H-indol-3-yl)-2-oxo- acetyl]amino}acetic acid methyl ester,
{[cyclohexylcarbamoyl-(4-hydroxycyclohexyl)methyl]-[2-(6-methoxy-1H-indol-3-yl)-2- oxoacetyljaminojacetic acid,
N-((R)-cyc[ohexylcyclohexylcarbamoylmethyl)-N-(2-dimethy[aminoethyl)-2-(6- methoxy-1 H-indol-3-yl)-2-oxoacetannide!
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-2-(6-ιnethoxy-1 H-indol-3-yl)-2-oxo-N-
(2-oxo-2-pyrro[idin-1-y[-ethyl)acetamide,
{[cyclohexylcarbamoyl-(4,4-difluorocyc[ohexyi)methylH2-(6-methoxy-1 H-indol-3-yi)-2- oxoacetyl]amino}acetic acid,
N-[(R)-cyclohexyl-(1 -methyl-1 H-indazol-6-ylcarbamoyl)methyl]-2-(6-f luoro-1 H-indo!-3- yl)-2-oxo-N-[ttetrahydropyran^-ylcarbamoyl)methyl]acetamtde,
{((R)-cyclohexylcyclohexylcarbatnoylmethyl)-[2-(6-fluoro-1 H-indol-3-yl)-2- oxoacetyl]amino}acetic acid,
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-N-
[(tetrahydropyran-4-y[carbamoyl)methyl]acetamide,
{((R)-cyclohexylphenylcarbamoylmethyl)-[2-(6-methoxy-1 H-indol-3-yl)-2- oxoacetytjaminojacetic acid,
N-(4-aminobutyl)-N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-2-(6-methoxy-1 H- indol-3-yl)-2-oxoacetamide,
{((R)-cyclohexylisopropylcarbamoylmethyl)-[2-(6-methoxy-1 H-indol-3-yl)-2- oxoacetyl]amino}acetic acid,
{((R)-cyclohexylcyclopentylcarbamoylmethyl)-[2-(6-methoxy-1 H-indol-3-yl)-2- oxoacetyl]atnino}acetic acid,
4-{((R)-cyclohexyicyclohexylcarbamoylmethyl)-[2-(6-methoxy-1 H-indol-3-yl)-2- oxoacetyl]aιmino}butyric acid,
(2-{((R)-cyclohexylcyclohexylcarbamoylmethyl)-[2-(6-methoxy-1 H-indol-3-yl)-2-oxo- acetyl]amino}acetylamino)acetic acid, 3-{((R)-cyclohexylcyclohexylcarbamoylmethyl)-[2-(6-methoxy-1 H-indo!-3-yl)-2- oxoacetyl]amino}propionic acid,
{((R)-cyclohexylcyclohexylcarbamoylmethyl)-[2-(4-methoxy-1H-indol-3-yl)-2- oxoacetyl]amino}acetic acid,
{((R)-cyclohexylcyclohexylcarbamoylmethyl)-[2-(1 H-indol-3-yl)-2- oxoacetyl]amino}acetic acid,
(R)-2,N-dicyclohexyl-2-[[2-(6-methoxy-1H-indo[-3-yl)-2-oxoacetyl]-(2H-tetrazoi-5- ylmethyl)amino]-cetamide
N-((R)-cyclohexylcyclohexylcarbamoylmethy[)-2-(6-methoxy-1 H-indol-3-yl)-N-(3- methyKi^^oxadiazol-5-yimethyl)-2-oxoacetamide,
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-2-(6-methoxy-1H-indol-3-yl)-N-(5- methyl-[1,3,4]oxadiazol-2-ylmethyl)-2-oxoacetamide,
N-((R)-cyclohexylcyclohexylcarbamoylmethyl)-2-(6-methoxy-1H-indol-3-yl)-N-(3- methylisoxazol-5-ylmethyl)-2-oxo-cetamide,
N-[(1 R)-1 -cyclohexyl-2-morpholin-4-yl-2-oxoethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]g[ycine,
N-[(1 R)-1 -cyclohexyl-2-oxo-2-piperazin-i -ylethyl]-N-[(6-methoxy-1 H-indol-3- yl)(oxo)acetyl]glycine, and
N-Ifi R)-1-cyclohexyl-2^-nnethylpiperazin-1-yl)-2-oxoethylj-N-Ife-methoxy-I H-indol-
3-yl)(oxo)acetyl]glycine.
30. A pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and an active ingredient, wherein said active ingredient is a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof.
31. A compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof for use as a medicament.
32. Use of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of a disease in which Cavx channels are involved.
33. Use of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel opening.
34. Use of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel inhibition.
35. Use of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Lower Urinary Tract Disorders.
36. Use of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Anxiety and Anxiety-Related Conditions.
37. Use of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Epilepsy.
38. Use of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Pain Disorders.
39. Use of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Gynaecological Pain.
40. Use of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiac Arrhythmias,
41. Use of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Thromboembolic Events.
42. Use of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiovascular Diseases.
43. Use of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Disorders of the Auditory System.
44. Use of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Migraine.
45. Use of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Inflammatory and Immunological Diseases.
46. Use of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Gastrointestinal Disorders.
47. Use of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Vascular and Visceral Smooth Muscle Disorders.
48. Use of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Cell Proliferative Disorders.
49. Use of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Metabolic Disorders.
50. Use of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Memory Loss.
51. Use of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of CNS-Mediated Motor Dysfunction Disorders.
52. Use of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of OpthaJamic Disorders.
53. A method for the prophylaxis or treatment of a disease in which Cavx is involved comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof.
54. A method for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel opening comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof.
55. A method for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel inhibition comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof.
56. A method for the prophylaxis or treatment of Lower Urinary Tract Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof.
57. A method for the prophylaxis or treatment of Anxiety and Anxiety-Related Conditions comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof.
58. A method for the prophylaxis or treatment of Epilepsy comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, iεostere or prodrug thereof.
59. A method for the prophylaxis or treatment of Pain Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof.
60. A method for the prophylaxis or treatment of Gynaecological Pain comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof.
61. A method for the prophylaxis or treatment of Cardiac Arrhythmias comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof.
62. A method for the prophylaxis or treatment of Thromboembolic Events comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof.
63. A method for the prophylaxis or treatment of Cardiovascular Diseases comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof.
64. A method for the prophylaxis or treatment of Disorders of the Auditory System comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof.
65. A method for the prophylaxis or treatment of Migraine comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof.
66. A method for the prophylaxis or treatment of Inflammatory and Immunological Diseases comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof.
67. A method for the prophylaxis or treatment of Gastrointestinal Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof.
68. A method for the prophylaxis or treatment of Vascular and Visceral Smooth Muscle Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof.
69. A method for the prophylaxis or treatment of Cell Proliferative Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof.
70. A method for the prophylaxis or treatment of Metabolic Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof.
71. A method for the prophylaxis or treatment of Memory Loss comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof.
72. A method for the prophylaxis or treatment of CNS-Mediated Motor Dysfunction Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof.
73. A method for the prophylaxis or treatment of Opthalamic Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof.
74. A compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof for use in the prophylaxis or treatment of any disease or condition recited in any of claimsa 32 to 52.
75. A pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and at least two active ingredients, wherein said active ingredients comprise at least one compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in combination at least one compound selected from the group consisting of muscarinic receptor antagonists, β3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α2 δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists, alpha-1 adrenoceptor antagonists, tricyclic antidepressants, N-methyl-D-aspartate (NWlDA) receptor antagonists, cannabinoid receptor agonists, anticonvulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal anti-inflammatory drugs (NSAiDs).
76. A pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in combination at least one compound selected from the group consisting of muscarinic receptor antagonists, β3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α2 δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists and α-1 adrenoceptor antagonists.
77. A pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof in combination at least one compound selected from the group consisting of neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α2 δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, N-methyl- D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anticonvulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal anti-inflammatory drugs (NSAIDs).
78. Use of at least one compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof and at least one compound selected from the group consisting of muscarinic receptor antagonists, β3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α2 δ delta ligands, potassium channel inhibitors, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs)1 5-HT antagonists and α-1 adrenoceptor antagonists in the manufacture of a medicament for the prophylaxis or treatment of lower urinary tract disorders.
79. Use of at least one compound according to any one of claims 1 to 29 or a pharmacologically acceptable salt, isostere or prodrug thereof and at least one compound selected from the group consisting of neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α2 δ delta ligands, potassium channel inhibitors, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, N-methyl-D- aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anticonvulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal anti-inflammatory drugs (NSAiDs) in the manufacture of a medicament for the prophylaxis or treatment of pain.
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