WO2010073011A2 - Compounds useful as medicaments - Google Patents

Compounds useful as medicaments Download PDF

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Publication number
WO2010073011A2
WO2010073011A2 PCT/GB2009/002945 GB2009002945W WO2010073011A2 WO 2010073011 A2 WO2010073011 A2 WO 2010073011A2 GB 2009002945 W GB2009002945 W GB 2009002945W WO 2010073011 A2 WO2010073011 A2 WO 2010073011A2
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Prior art keywords
thiadiazol
compound
formula
benzenesulfonamide
dichloro
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PCT/GB2009/002945
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French (fr)
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WO2010073011A3 (en
Inventor
Jacob Westman
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Betagenon Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to pharmaceutically-useful compounds.
  • the invention also relates to the use of such compounds in the treatment of conditions ameliorated by the activation of AMPK, such as skin diseases, lung disease, obesity, dry-type age-related macular degeneration, cardioprotection or, preferably, hyperinsulinemia, diabetes, cancer, fibrosis, neurodegenerative diseases, sexual dysfunction, heart failure, inflammation and osteoporosis.
  • AMPK AMPK
  • AMPK represents a new target for the treatment of several diseases, including metabolic syndrome.
  • Hyperinsulinemia hypersecretion of insulin
  • Metabolic syndrome has become increasingly common, and affects an estimated 47 million adults in the US alone.
  • the syndrome is characterized by a combination of metabolic risk factors such as central obesity, atherogenic dyslipidemia, hypertension, insulin resistance or glucose intolerance.
  • the syndrome is also characterised by hyperinsulinemia, a prothrombotic state in the blood, and a proinflammatory state.
  • Underlying causes of metabolic syndrome include obesity, physical inactivity and genetic factors. Sufferers are at an increased risk of coronary heart disease and other diseases related to the build up of plaques in artery walls, for example stroke, peripheral vascular disease and type 2 diabetes.
  • Type 2 diabetes is the most common metabolic disease with a high incidence in western countries, with more than 170 million people currently affected by type 2 diabetes.
  • Type 2 diabetes is a chronic, presently incurable disease and sufferers have a high risk of developing life threatening complications as the disease progresses.
  • the overall cost to society of diabetes and its complications is huge.
  • Insulin is both a potent hormone and growth factor. In addition to obesity, hyperinsulinemia is apparent in conditions such as impaired glucose tolerance, early or mild type 2 diabetes, polycystic ovary syndrome and Alzheimer's disease. Evidence is accumulating that hyperinsulinemia plays a major role in the development of these diseases.
  • a medicament that reduces insulin resistance and/or hyperinsulinemia may therefore represent an efficient therapeutic strategy to treat or prevent disorders caused by, linked to, or contributed to by insulin resistance and/or hyperinsulinemia or associated conditions.
  • insulin secretagogues such as sulphonylureas stimulate only the insulin secretion step
  • metformin mainly acts on glucose production from the liver
  • peroxisome proliferator-activated receptor- ⁇ (PPAR- ⁇ ) agonists such as the thiazolidinediones, enhance insulin action
  • exenatide needs to be administered by subcutaneous injection, has storage stability shortcomings, is reported to cause nausea and vomiting and, more recently, has been shown to be coupled to several severe cases of acute pancreatitis.
  • insulin secretagogues and insulin injections may cause hypoglycaemia and weight gain and patients may also become unresponsive to insulin secretagogues over time.
  • Metformin an indirect AMPK activator
  • ⁇ -glucosidase inhibitors often lead to gastrointestinal problems and PPAR-agonists tend to cause increased weight gain and oedema.
  • Dipeptidyl peptidase-IV (DPP-IV) inhibitors belong to a new class of oral antidiabetic agents for the treatment of patients with type 2 diabetes. Inhibition of the enzyme DPP- IV results in prolonged activity of glucagon-like peptide-1 (GLP-1) and glucose- dependent insulinotropic peptide (GIP), the incretin hormones. Sitagliptin was the first DPP-IV inhibitor to be approved by FDA for treatment of type 2 diabetes and several other DPP-IV inhibitors are in late clinical phases.
  • Several side-effects for DPP-IV inhibitors as a class may be expected, such as inflammation, allergic reactions and hypertension since many peptides, neuropeptides, and cytokines are cleaved by DPP-IV. Some of the reported side effects of certain DPP-IV inhibitors include anemia, thrombocytopenia, and splenomegaly.
  • AMP-activated protein kinase is a protein kinase enzyme that consists of three protein sub-units and is activated by hormones, cytokines, exercise, and stresses that diminish cellular energy state (e.g. glucose deprivation). Activation of AMPK increases processes that generate adenosine 5'-triphosphate (ATP) (e.g. fatty-acid oxidation) and restrains others such as fatty acid-, glycerolipid- and protein-synthesis that consume ATP, but are not acutely necessary for survival. Conversely, when cells are presented with a sustained excess of glucose, AMPK activity diminishes and fatty acid-, glycerolipid- and protein-synthesis are enhanced.
  • ATP adenosine 5'-triphosphate
  • AMPK activity diminishes and fatty acid-, glycerolipid- and protein-synthesis are enhanced.
  • AMPK thus is a protein kinase enzyme that plays an important role in cellular energy homeostasis. Therefore, the activation of AMPK is coupled to glucose lowering effects and triggers several other biological effects, including the inhibition of cholesterol synthesis, lipogenesis, triglyceride synthesis, and the reduction of hyperinsulinemia.
  • AMPK is a preferred a preferred target for the treatment of the metabolic syndrome and especially type 2 diabetes.
  • AMPK is also involved in a number of pathways that are important for many different diseases (e.g. AMPK is also involved in a number of pathways that are important in cancer, CNS disorders, fibrosis, osteoporosis, heart failure and sexual dysfunction).
  • Current anti-diabetic drugs e.g. metformin, glitazones
  • AMPK activators due to the biological effects of AMPK activation at the cell level, compounds that are AMPK activators, and preferably direct activators of AMPK 1 may find utility as anti-diabetic drugs, as well as for the treatment of many other diseases (some of which are listed below)
  • ALS amyotrophic lateral sclerosis
  • a medicament such as an AMPK activator may be effective in the treatment of neurodegenerative diseases due to stimulation of autophagy. Traumatic brain injury studies in mice using rapamycin, a known mTOR signaling inhibitor were able to show an increased the number of surviving neurons at the site of injury (Erlich et al, Neurobiol. of Disease,2007, 26(1), 86-93). Since AMPK activator inhibits mTOR signalling it may therefore be neuroprotective following traumatic brain injury. AMPK activation may have neuroprotective properties during ischemia/hypoxia (Spasi et al, The Neuroscientist, 2009,15 (4), 309-316).
  • an AMPK activator may be useful in the treatment of brain injury caused by brain ischemia and stroke.
  • AD Alzheimer's disease 1 longitudinal studies have established a strong association with hyperinsulinemia. Hyperinsulinemia is also related to a significant decline in memory-related cognitive scores, but not to decline in other cognitive domains. Thus, hyperinsulinemia is associated with a higher risk of AD and decline in memory.
  • Insulin-degrading enzyme also appears to constitute a mechanistic link between hyperinsulinemia and AD (Wei and Folstein (2006), Neurobiology of Aging, 27, 190-198). This enzyme degrades both insulin and amyloid- ⁇ (A ⁇ ) peptide, a short peptide found in excess in the AD brain. Evidence suggests that hyperinsulinemia may elevate A ⁇ through insulin's competition with the latter for insulin-degrading enzyme. Formation of neurofibrillary tangles, which contain hyperphosphorylated tau, represents a key step in the pathogenesis of neurodegenerative diseases.
  • peripherally injected insulin directly targets the brain and causes rapid cerebral insulin receptor signal transduction, revealing an additional link between hyperinsulinemia and neurodegeneration.
  • Transforming growth factor b1 present in keratinocytes, has shown to in transgenic mice expressing wild-type TGFbI in the epidermis to develope inflammatory skin lesions, with gross appearance of psoriasis like plaques, generalized scaly erythema, and Koebner's phenomenon.
  • the TGFbI wt skin exhibited multiple molecular changes that typically occur in human Th1 inflammatory skin disorders, such as psoriasis (EMBO Journal (2004) 23, 1770-1781). This observation suggests that certain pathological condition-induced TGFbI overexpression in the skin may synergize with or induce molecules required for the development of Th1 inflammatory skin disorders such as psoriasis and other skin disorders.
  • an AMPK activator able to affect TGFbI signaling may be of therapeutic value in skin disorders such as, but not limited to, psoriasis. Fibrosis
  • fibrosis is involved in many pathological states in the body (T. A. Wynn (2008) J. Pathology 214, 199-210. It has been shown that AMPK negatively regulates TGF ⁇ -stimulated myofibroblast transdifferentiation and may therefore play a role in disorders where fibrosis develops (Mishra et al (2008), J. Biol. Chem. 283, 10461- 10469).
  • the resulting reduction of collagen may be of therapeutic value in any disease state or condition where fibrosis play a role for example, but not limited to, scar healing, keloids, scleroderma, cystic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia (NSIP), respiratory bronchiolitis, interstitial lung disease (RBILD), desquamative interstitial pneumonia (DIP), acute interstitial pneumonia (AIP), cryptogenic organizing pneumonia (COP) and lymphoid interstitial pneumonia (LIP), organ transplant fibrosis, systemic sclerosis, liver cirrhosis, macular eye degeneration, retinal and vitreal retinopathy, Crohn ' s/inflammatory bowel disease, nephrogenic systemic fibrosis, ulcerative colitis post surgical scar tissue formation, radiation and chemotherapeutic-drug induced fibrosis, and cardiovascular fibrosis including endomyocardial fibrosis.
  • NIP nonspecific
  • Metformin an indirect AMPK activator, has recently been investigated on the differentiation and mineralization of osteoblastic MC3T3-E1 cells as well as intracellular signal transduction. Metformin can increase collagen-l and osteocalcin mRNA expression, stimulate alkaline phosphatase activity, and enhance cell mineralization (Kanazawa et al. Biochem. Biophys. Res. Commun. 2008, 375(3), 414-419). Metformin can also, when activating AMPK, induce endothelial nitric oxide synthase (eNOS) and bone morphogenetic protein-2 (BMP-2) expressions. Thus, it may be that an AMPK activator can induce the differentiation and mineralization of osteoblasts via activation of the AMPK signaling pathway, and that an AMPK activator may find utility in the treatment of osteoporosis by promoting bone formation.
  • eNOS endothelial nitric oxide synthase
  • BMP-2 bone morphogenetic protein-2
  • Insulin per se can promote the proliferation of mesangial cells and the production of matrix proteins, and also stimulates the expression of growth factors such as IGF-1 and TGF- ⁇ , that are involved in mitogenic and fibrotic processes in nephropathy. Insulin also interferes with the systemic RAS and specifically increases the effect of angiotensin Il on mesangial cells. Hyperinsulinemia also increases levels of endothelin-1 and is associated with increased oxidative stress, in conclusion, reduction of hyperinsulinemic levels may be of therapeutic value for patients with progressive renal disease (e.g. chronic renal failure; Sarafidis and Ruilope Am. J.
  • progressive renal disease e.g. chronic renal failure; Sarafidis and Ruilope Am. J.
  • adiponectin an adipose-derived hormone
  • AMPK adipose-derived hormone
  • Obesity is associated with resistance to the effects of leptin and leptin stimulates fatty acid oxidation via the phosphorylation and activation of AMPK and Acetyl-CoA carboxylase (ACC).
  • AMPK Acetyl-CoA carboxylase
  • Studies in obese Wistar rats have shown a lower level of AMPK activation in diet-induced obesity.
  • an AMPK activator may be of therapeutic value in obesity (Janovska A et al, MoI. Cell. Endocrinology. 2008, 284(1-2), 1-10.
  • Central obesity is a typical sign of Cushing's syndrome. In a patient study the patients exhibited a 70% lower AMPK activity in visceral adipose tissue as compared to control patients.
  • glucocorticoids inhibit AMPK activity in adipose tissue (Kola et al, J. Clin.Endocrinol. Metab. 2008, 93(12), 4969-4973). Therefore an AMPK activator may also be beneficial as a therapeutic in Cushing's syndrome.
  • AMPK activity increases during ischemia and functions to sustain ATP, cardiac function and myocardial viability.
  • the beneficial effects of AMPK activation provides the rationale for targeting AMPK in the development of new therapeutic strategies for cardiometabolic disease and cardioprotection (Wong et al, Clin. ScL, 2009, 116, 607-620).
  • Erectile dysfunction is associated with reduced penile nitric oxide synthase (NOS) expression.
  • NOS penile nitric oxide synthase
  • Studies in obese rats show that treatment with the indirect AMPK activator metformin increase nNOS and eNOS expression in penile tissue.
  • the levels of AMPK and phosphorylated AMPK were also decreased but were subsequently elevated by metformin treatment.
  • Oxidative stress causes retinal pigment epithelium (RPE) cell dysfunction and is a major risk factor leading to the development of dry-type age-related macular degeneration.
  • Sublethal oxidative stress dose-dependently inhibits RPE cell phagocytosis of photoreceptor outer segments (POS) and activates AMPK.
  • POS photoreceptor outer segments
  • Aicar a pharmacological activator of AMPK has also been shown to inhibit RPE cell phagocytosis of POS in a dose-dependent manner (Qin and De Vries, J. Biol. Chem. 2008, 283(11), 6744-6751).
  • an AMPK activator could have therapeutic potential in treating dry macular degeneration.
  • cancer cells require high rates of fatty acid and protein synthesis for their invasive growth and survival.
  • inhibition of cancer cell proliferation is possibly using AMPK activators.
  • the effects are associated with down-regulation of mTOR and eEF2.
  • AMPK activators also suppress lipid synthesis in tumour cells. It has also been shown that it is a link between AMPK and other anti-cancer targets such as LKB1 and caspase-3 activation.
  • PCOS Polycystic ovary syndrome
  • AICAR ⁇ -aminoimidazole ⁇ -carboxamide
  • AICAR ⁇ -aminoimidazole ⁇ -carboxamide
  • Metformin an indirect AMPK activator, could be shown to reduce several inflammatory parameters in animal models of multiple sclerosis and thus an AMPK activator could have a possible therapeutic value for the treatment of multiple sclerosis and other inflammatory diseases (Nath et al J. Immunology, 2009, 182, 8005-8014).
  • AMPK plays a role in modulating neutrophil function and neutrophil-dependent inflammatory events, such as acute lung injury (Zhao et al, Am. J. Physiol. Lung Cell MoI. Physiol., 2008. 295. L497-L504. This may also apply to reduction of the inflammatory response present in asthmatic patients. Studies in mice that develop lupus-like disease similar to human systemic lupus erythematosus has shown that AMPK activation inhibits a inflammatory cascade. This observation suggests that an AMPK activator may be of therapeutic value for systemic lupus erythematosus (Radjavi et al, FASEB J.2008, 22:942.12).
  • COPD chronic obstructive pulmonary disease
  • TGF- ⁇ has emerged as an important contributor to small airway disease (SAD), also called obstructive bronchiolitis.
  • SAD small airway disease
  • Several studies have reported an increased expression of TGF- ⁇ 1 in the airway epithelium of smokers. TGF- ⁇ 1 expression in epithelial cells from patients with chronic bronchitis has been correlated with basal membrane thickness and the number of peribronchiolar fibroblasts.
  • an AMPK activator that targets TGF- ⁇ signalling may represent a suitable therapeutic option in SAD.
  • WO 2005/002673 and WO 2004/004720 disclose a single thiadiazole for use in the treatment of diseases that may be ameliorated by the inhibition of raf kinase (e.g. Alzheimer's disease). There is no suggestion or disclosure of 1 ,3,4-thiadiazoles substituted in the 5-position by a substituted phenyl group attached via an alkyl linker.
  • thiadiazole compounds containing a naphthalene substituent attached via and amido linker for use in the treatment of human cytomegalovirus.
  • thiadiazoles that are substituted in the 2-position with a single-ringed heteroaromatic or, particularly, aryl group.
  • Bovet el al discloses that a thiadiazole bearing an unsubstituted benzyl substituent in the 5-position does not have hypoglycemic activity and there is no disclosure or suggestion of substituted benzyl substituents in the 5-position.
  • WO 2004/103980 discloses inter alia thiadiazoles that may be useful in the treatment of diabetes.
  • JP 03258771 discloses inter alia 1 ,2,4-oxadiazoles that may be useful as herbicides. However, there is no mention of the use of the compounds disclosed therein in the treatment of diabetes.
  • X represents -Q-[CR x R y ] n -Z- or -C(O)-;
  • T represents N 1 or more preferably S or O;
  • G represents O, or more preferably, N; provided that when T is O or S, then G is N, and provided that when T is N, then G is O; when G is N, the dotted line between the point of attachment of X to the ring and G is a double bond and the dotted line between the point of attachment of X to the ring and T is a single bond; when T is N, the dotted line between the point of attachment of X to the ring and T is a double bond and the dotted line between the point of attachment of X to the ring and G is a single bond;
  • Ai to A 5 respectively represent C(R 1 ), C(R 2 ), C(R 3 ), C(R 4 ) and C(R 5 ), or, alternatively, up to two of A 1 to A 5 may independently represent N;
  • Di to D 5 each respectively represent C(R 6a ), C(R 6b ), C(R 6c ), C(R 6d ) and C(R 6e ), or, alternatively, up to two of D 1 to D 5 may independently represent N;
  • Q and Z independently represent S(O) 2 , or more preferably, a bond, S, or O;
  • B represents S(O) 2 , or more preferably, a bond, S, or O; one of R x and R y is Cy 1 or Het 1 (which latter two groups are optionally substituted by one or more R 6f substituents) and the other is H or, more preferably, R x and R y are independently selected from H, halo, C 1-6 alkyl (optionally substituted by one or more halo atoms), or R x and R y are linked to form, along with the carbon atom to which they are attached, a non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or Ci -6 alkyl (optionally substituted by one or more halo atoms);
  • Cy 1 represents a 5- to 8-membered aromatic, fully saturated or partially unsaturated carbocyclic ring;
  • Het 1 represents a 5- to 8-membered heterocyclic group that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N;
  • R 6a to R 6e independently represents, on each occasion when used herein, H, cyano, -NO 2 , halo, -R 8 , -OR 8 , -N(R 8 )C(O)R 8 , -NR 9 R 10 , -SR 11 , -Si(R 12 J 3 , -OC(O)R 13 , -C(O)OR 13 , -C(O)R 14 , -C(O)NR 15a R 15b , -S(O) 2 NR 15c R 15d , aryl or heteroaryl (which aryl and heteroaryl groups are themselves optionally and independently substituted by one or more groups selected from halo and R 16 ), or any two R 6a to R 6e groups which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I 1 an aromatic or non-aromatic 3- to 8-membered ring, optionally
  • R 7 on each occasion when used herein, is selected from H or C r C 6 alkyl, Ci-C 6 cycloalkyl, aryl and heteroaryl (wherein the latter four groups are optionally substituted by one or more halo atoms);
  • salts that may be mentioned include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of formula I in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • Examples of pharmaceutically acceptable addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids; from organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, arylsulphonic acids; and from metals such as sodium, magnesium, or preferably, potassium and calcium.
  • mineral acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids
  • organic acids such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, arylsulphonic acids
  • metals such as sodium, magnesium, or preferably, potassium and calcium.
  • “Pharmaceutically functional derivatives” of compounds of formula I as defined herein includes ester derivatives and/or derivatives that have, or provide for, the same biological function and/or activity as any relevant compound. Thus, for the purposes of this invention, the term also includes prodrugs of compounds of formula I.
  • prodrug of a relevant compound of formula I includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)).
  • parenteral administration includes all forms of administration other than oral administration.
  • Prodrugs of compounds of formula I may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesizing the parent compound with a prodrug substituent.
  • Prodrugs include compounds of formula I wherein a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group in a compound of formula I is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.
  • prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N- Mannich bases.
  • General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs” p. I-92, Elesevier, New York-Oxford (1985).
  • Compounds of formula I may contain double bonds and may thus exist as E (entadel) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.
  • Compounds of formula I may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e.
  • a 'chiral pool' method by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by •conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.
  • alkyl refers to an unbranched or branched, cyclic, saturated or unsaturated (so forming, for example, an alkenyl or alkynyl) hydrocarbyl radical, which may be substituted or unsubstituted (with, for example, one or more halo atoms).
  • alkyl refers to an acyclic group, it is preferably C M0 alkyl and, more preferably, Ci -6 alkyl (such as ethyl, propyl, (e.g. n-propyl or isopropyl), butyl (e.g. branched or unbranched butyl), pentyl or, more preferably, methyl).
  • alkyl is a cyclic group (which may be where the group “cycloalkyl” is specified), it is preferably C 3- I 2 cycloalkyl and, more preferably, C5. 1 0 (e.g. C 5-7 ) cycloalkyl.
  • alkylene refers to d.i 0 (e.g. Ci -6 ) alkylene and, preferably Ci -3 alkylene, such as pentylene, butylene (branched or unbranched), preferably, propylene ( ⁇ -propylene or isopropylene), ethylene or, more preferably, methylene (i.e. -CH 2 -).
  • halogen when used herein, includes fluorine, chlorine, bromine and iodine.
  • aryl when used herein includes C 6-I4 (such as C 6-I3 (e.g. C 6- I 0 )) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 14 ring carbon atoms, in which at least one ring is aromatic. The point of attachment of aryl groups may be via any atom of the ring system. However, when aryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule via an aromatic ring.
  • C 6- I 4 aryl groups include phenyl, naphthyl and the like, such as 1 ,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl. Most preferred aryl groups include phenyl.
  • carbocyclic when used herein in connection with the Cy 1 group includes references to carbocyclic groups (e.g. Cs -6 carbocyclic groups) that are monocyclic and which may be may be fully saturated, partly unsaturated or wholly aromatic in character.
  • Cy 1 groups may be selected from the group comprising of cyclobutyl, cyclobutenyl, cyclopropyl, cyclopropenyl, preferably cyclopentenyl, more preferably, cyclohexenyl, yet more particularly, cyclopentyl, cyclohexyl, and phenyl.
  • the point of attachment of carbocyclic groups may be via any atom of the ring system.
  • heterocyclic when used herein in connection with the Het 1 group includes references to heterocyclic groups that are monocyclic and which may be fully saturated, partly unsaturated or wholly aromatic in character.
  • Het 1 represents a 5- to 8-membered heterocyclic group, that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N.
  • the Het 1 group may contain up to 3 heteroatom ring members selected from O, N and S.
  • the heterocyclic group may contain 1 , 2 or 3 heteratom ring members.
  • Het 1 may be selected from the group comprising of azepinyl, diazepinyl, dihydrofuranyl (e.g. 2,3-dihydrofuranyl, 2,5-dyhdrofuranyl), 4,5-dihydro-1/-/-maleimido, dioxolanyl, furanyl, furazanyl, hydantoinyl, imidazolyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, 1 ,2- or 1 ,3-oxazinanyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolinyl, pyrrolyl, sulfolanyl, a
  • Het 1 groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • a heteroatom such as a nitrogen atom
  • heteroaryl when used herein refers to an aromatic group containing one or more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, O and S (so forming, for example, a mono-, bi-, or tricyclic heteroaromatic group).
  • Heteroaryl groups include those which have between 5 and 14 (e.g. 10) members and may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic. However, when heteroaryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule via an aromatic ring.
  • Heterocyclic groups that may be mentioned include benzothiadiazolyl (including 2,1 ,3-benzothiadiazolyl), isothiochromanyl and, more preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1 ,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl, benzoxadiazolyl (including 2,1 ,3-benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro- 2H-1 ,4-benzoxazinyl), benzoxazolyl, benzomo ⁇ holinyl, benzoselenadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, fur
  • heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
  • the point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • Heteroaryl groups may also be in the N- or S- oxidised form.
  • heteroaryl groups include pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl, indazolyl, pyrimidinyl, thiophenetyl, pyranyl, carbazolyl, acridinyl, quinolinyl, benzoimidazolyl, benzthiazolyl, purinyl, cinnolinyl and pterdinyl.
  • Particularly preferred heteroaryl groups include monocylic heteroaryl groups.
  • R 16 groups may be the same or different.
  • a term such as "Ai to A 5 " this will be understood by the skilled person to mean any of (i.e. some or all, as applicable) A 1 , A 2 , A 3 , A 4 and A 5 inclusively.
  • T when T represents S, X represents -Q-[CR x R y ] n -Z-, Z represents a bond, Q represents O or S, R x and R y are independently selected from H, halo or Ci -6 alkyl
  • C(R 1 ) to C(R 4 ) are all H, C(R 5 ) represents H, OCH 3 or Cl and when:
  • C(R 6a ) represents C(CH 3 ), C(R 6b ) represents C(CI) and C(R 6c ) to C(R 6e ) represent C(H);
  • C(R 1 ) to C(R 4 ) are all C(H), C(R 5 ) represents C(OCH 3 ), C(R b ) and C(R d ) represent H and C(R a ), C(R 0 ) and C(R e ) represent C(CH 3 );
  • C(R 4 ) represents C(OCH 3 ) while the other represents C(H) and C(R C ) represents C(CI) or C(OCH 3 ); or (d) one of C(R 1 ) or C(R 3 ) represents C(OCH 3 ), while the other represents
  • C(H), C(R 2 ), C(R 4 ) and C(R 5 ) represent H
  • C(R a ) to C(R d ) represent
  • T when T represents S, X represents -Q-[CR x R y ] n -Z-, Z represents a bond, Q represents a bond, R x and R y are independently selected from H, d-6 alkyl (optionally substituted by one or more halo atoms), C(R 6a ) represents C(CH 3 ), C(R 6b ) represents C(CI) and C(R 6c ) to C(R 6e ) represent C(H) or C(R 6e ) represents C(CH 3 ), C(R 6d ) represents C(CI) and C(R 6a ) to C(R 6c ) represent C(H) and when:
  • C(R 5 ) represents C(CI), C(F) or C(NO 2 ) and C(R 1 ) to C(R 4 ) are all H;
  • one of C(R 1 ) or C(R 3 ) represents C(F) or C(OCH 3 ), while the other represents C(H) and C(R 2 ), C(R 4 ) and C(R 5 ) represent C(H); or
  • T represents O
  • X represents -Q-[CR*R y ] n -Z- and R x and R y are independently selected from H, halo or Ci -6 alkyl (optionally substituted by one or more halo atoms)
  • T represents S
  • X represents -Q-[CR x R y ] n -Z-
  • Z represents S
  • Q represents a bond and R x and R y are independently selected from H 1 halo or Ci -6 alkyl (optionally substituted by one or more halo atoms), and Y represents -C(O)-,
  • T represents S
  • X represents -Q-[CR x R y ] n -Z- and R* and R y are independently selected from H, halo or Ci -6 alkyl (optionally substituted by one or more halo atoms)
  • T represents S
  • X represents -Q-[CR ⁇ n -Z-
  • Z represents a bond
  • Q represents
  • R x and R y are independently selected from H, halo or Ci -6 alkyl (optionally substituted by one or more halo atoms), C(R 1 ) to C(R 4 ) are all H, C(R 5 ) represents H,
  • C(R a ) to C(R b ) are selected from:
  • C(R 6a ) represents C(CH 3 ), C(R 6b ) represents C(CI) and C(R 6c ) to C(R 6e ) represent C(H);
  • C C(R 6e ) represents C(CH 3 )
  • C(R 6d ) represents C(CI)
  • C(R 6a ) to C(R 6c ) represent C(H)
  • T represents S 1 X represents -Q-[CR x R y ] n -Z-, Z represents a bond, Q represents a bond, R x and R y are independently selected from H, halo or C 1-6 alkyl (optionally substituted by one or more halo atoms), C(R 1 ) to C(R 5 ) and C(R a ) to C(R e ) are selected from:
  • C(R 1 ) to C(R 4 ) are all C(H), C(R 5 ) represents C(H), C(OCH 3 ) or C(CI) 1 C(R a ), C(R b ), C(R d ) and C(R e ) represent C(H) and C(R C ) represents C(H), C(CI), C(Br), C(F), C(CH 3 ), C(OCH 3 ), C(NHC(O)CH 3 ); (b) C(R 1 ) to C(R 4 ) are all C(H), C(R 5 ) represents C(OCH 3 ), C(R b ) and C(R d ) represent H and C(R a ), C(R C ) and C(R e ) represent C(CH 3 );
  • C(R 1 ) and C(R 3 ) are C(H), C(R 5 ) represents C(OCH 3 ), one of C(R 2 ) and C(R 4 ) represents C(OCH 3 ) while the other represents C(H) and C(R C ) represents C(CI) or C(OCH 3 ); or
  • one of C(R 1 ) or C(R 3 ) represents C(OCH 3 ), while the other represents C(H), C(R 2 ), C(R 4 ) and C(R 5 ) represent H, and C(R a ) to C(R d ) represent H, and
  • T represents S
  • X represents -Q-[CR x R y ] n -Z-
  • Z represents a bond
  • Q represents a bond
  • R x and R y are independently selected from H
  • C(R 6a ) represents C(CH 3 )
  • C(R 6b ) represents C(CI) and C(R 6c ) to C(R 66 ) represent C(H) or C(R 6e ) represents C(CH 3 )
  • C(R 6d ) represents C(CI) and C(R 6a ) to C(R 60 ) represent C(H) and C(R 1 ) to C(R 5 ) are selected from:
  • C(R 5 ) represents C(CI), C(F) or C(NO 2 ) and C(R 1 ) to C(R 4 ) are all H;
  • one of C(R 1 ) or C(R 3 ) represents C(F) or C(OCH 3 ), while the other represents C(H) and C(R 2 ), C(R 4 ) and C(R 5 ) represent C(H); or
  • one of A 2 or A 4 represents N, the other represents C(H) and C(R 1 ), C(R 3 ) and C(R 5 ) represent C(H), and
  • each of the preferred embodiments (i) to (vi) may be applied separately (i.e. individually) as a preferred definition of the compounds of formula I, or may be taken together in any combination thereof in defining more preferred compounds of formula I.
  • R 6c represents Cl or F
  • one of R 6b or R 6d represents Cl and the other represents H
  • R 6c represents Cl
  • X represents -CH 2 -
  • one of R 6b or R 6d represents Cl and the other represents H
  • Y represents -NHS(O) 2 -[CH 2 Jq-, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof).
  • Q represents S(O) 2 and Z represents S, O or, more preferably, a bond.
  • Q and Z represent a bond
  • n represents 1
  • one of R x and R y is is Cy 1 or Het 1 (which latter two groups are optionally substituted by one or more R 6f substituents), and the other is H; and
  • R x and R y are linked to form, along with the carbon atom to which they are attached, a non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or Ci -6 alkyl (optionally substituted by one or more halo atoms).
  • R x and R y are linked to form, along with the carbon atom to which they are attached, a cyclobutyl, cyclopentyl, cyclohexyl or, more preferably, cyclopropyl ring which ring is itself optionally substituted by one or more substituents selected from halo or Ci -6 alkyl (optionally substituted by one or more halo atoms, or more preferably unsubstituted).
  • each -[CR x R y ]- unit may be independently selected from:
  • R x and R y are independently selected from H, halo, Ci -6 alkyl (optionally substituted by one or more halo atoms);
  • each -[CR 1 ⁇ - unit may be independently selected from:
  • R x and R y are independently selected from H, halo, Ci -3 alkyl (optionally substituted by one or more halo atoms);
  • R x and R y are linked to form, along with the carbon atom to which they are attached, a non-aromatic ring selected from cyclobutyl, cyclopentyl, cyclohexyl or, more particularly, cyclopropyl, which ring is itself optionally substituted by one or more substituents selected from halo or Ci-6 alkyl (optionally substituted by one or more halo atoms); and
  • (c) a unit wherein -[CFW]- may represent -[CH(phenyl)]- or -[CH(pyridyl)]-, which groups are optionally substituted by one or more R 5 substituents), provided that no more than one unit (e.g. no units) is selected from (b) or (c)).
  • one -[CR x R y ]- unit forms a non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or Ci -6 alkyl (optionally substituted by one or more halo atoms) and, if other -[CR x R y ]- units are present, then the additional R x and R y groups are independently selected from H, halo, Ci -6 alkyl (optionally substituted by one or more halo atoms).
  • R x and R y are independently substituted by one or more R 6f substituents
  • the other is H or, more preferably,
  • R x and R y are independently selected from H, halo, C 1-6 alkyl (substituted by one or more halo atoms).
  • R x and R y are independently selected from halo, Ci -6 alkyl (substituted by one or more halo atoms).
  • Compounds of formula I that may be mentioned include those in which: at least one of R x and R y is unsubstituted Ci -6 alkyl.
  • R x and R y are independently selected from H, halo, C 1-6 alkyl (substituted by one or more halo atoms), or R x and R y are linked to form, along with the carbon atom to which they are attached, a non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or Ci -6 alkyl (optionally substituted by one or more halo atoms).
  • Het 1 represents pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidinyl or morpholinyl.
  • X represents -[CH(Ph)Ji-, -C(O)-, preferably -Q-[CR ⁇ VZ-, °r yet more preferably,
  • X represents -C(O)-, preferably -Q-[CR ⁇ n -Z-, or more preferably, -[CH 2 I n --
  • Compounds of formula I that may be mentioned include those in which:
  • Y represents -NHS(O) 2 -[CH 2 Iq-, -NHNHS(O) 2 -, -NHS(O) 2 NH-, -S(O) 2 - Or -S(O) 2 NH-.
  • Y represents -NHC(O)O- or, more preferably, -NHNHS(O) 2 -, -NHS(O) 2 NH-, -S(O) 2 - or - S(O) 2 NH-.
  • T represents N or, more preferably, O.
  • R 1 to R 5 when present, represents R 7 or, more preferably, -OR 7 , halo,
  • R 1 to R 5 which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I, an aromatic or non-aromatic 3- to 8-membered ring selected from 2,3-dihydrobenzo[1 ,4]dioxinyl or tetrahydroquinolinyl, which may optionally be substituted by one or more halo atoms.
  • R 1 to R 5 when present, represents R 7 or, more preferably, -OR 7 , halo,
  • R 1 to R 5 when present, represents R 7 (e.g. -CH 3 ), preferably -OR 7 (e.g.
  • -OCH 3 or more preferably, -OCHF 2 or -OCF 3 ), or, more preferably, halo, -CF 3 , -CN or
  • R 1 to R 4 when present, represents R 7 (e.g. -CH 3 ), preferably -OR 7 (e.g.
  • -OCH 3 or more preferably, -OCHF 2 or -OCF 3 ), or, more preferably, halo, -CF 3 , -CN or
  • R 5 when present, represents -CH 3 , preferably Cl, or, more preferably, H, Br, I, F, -CF 3 ,
  • R 5 when present, represents -CH 3 or, more preferably. H, -CF 3 , -CN, -C(O)R 7 ,
  • R 6a to R 6e independently represent -C(O)NR 15a R 15b or, more preferably, H, cyano, -NO 2 , - Br, -Cl, -F, -R 8 , -OR 8 , -NR 9 R 10 , -SR 11 , -C(O)OR 13 , -C(O)R 14 , -S(O) 2 NR 15c R 15d , aryl or heteroaryl (which aryl and heteroaryl groups are themselves optionally and independently substituted by one or more groups selected from halo and R 16 ), or any two R 6 groups which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I, quinoline, tetrahydroquinoline, isoquinoline or tetrahydroisoquinoline, wherein the additional ring system of the quinoline, tetra
  • R e a to R e e j nc j e p enc j en tiy represent -C(O)NR 15a R 15b or, more preferably, -R 8 or yet more preferably, H, cyano, -NO 2 , -Br, -Cl, -F, -OR 8 , -NR 9 R 10 , -SR 11 , -C(O)OR 13 , -C(O)R 14 ,
  • aryl or heteroaryl which aryl and heteroaryl groups are themselves optionally and independently substituted by one or more groups selected from halo and
  • R 6a to R 6e independently represents -C(O)NR 15a R 15b , -R 8 , or, more preferably, H, cyano, -
  • y represents -R 8 or, more preferably, H, cyano, -NO 2 , -Br, -Cl,
  • R ⁇ a tQ R 6 ⁇ independently represents H, -Br, -F or, most preferably -Cl.
  • R 6t independently represents H, halo, -R 7 , -CF 3 , -CN, -NO 2 , -C(O)R 7 , -C(O)OR 7 ,
  • n is 2, or more preferably, 1.
  • Compounds of formula I that may be mentioned include those in which: q is 1 , or more preferably, O.
  • Compounds of formula I that may be mentioned include those in which: B represents a bond; r represents 0 or 1.
  • R x and R y are linked to form, along with the carbon atom to which they are attached, a cyclopropyl ring which ring is itself optionally substituted by one or more substituents selected from halo or C 1 ⁇ alkyl (optionally substituted by one or more halo atoms);
  • Q represents a bond or O
  • R x and R y are linked to form, along with the carbon atom to which they are attached, a cyclopropyl ring which ring is itself optionally substituted by one or more substituents selected from halo or C 1-6 alkyl (optionally substituted by one or more halo atoms);
  • a 5 represents C(CF 3 ) or, more preferably, C(CI).
  • a 1 and A 3 independently represent C(halo), e.g. C(CI) or C(F), preferably N or, more preferably, C(H).
  • a 2 and A 4 represents C(R 2 );
  • a 1 , A 3 and A 5 independently represent C(H) or N.
  • a 2 represents C(R 2 );
  • a 1 and A 3 to A 5 independently represent C(H) or N.
  • a 1 and A 3 to A 5 independently represent C(H).
  • a 5 represents C(R 5 );
  • R 5 represents -CF 3 ;
  • Ai to A 4 independently represent C(H).
  • T S
  • G represents N
  • R x and R y are linked to form, along with the carbon atom to which they are attached, a cyclopropyl ring which ring is itself optionally substituted by one or more substituents selected from halo or C ⁇ alkyl (optionally substituted by one or more halo atoms);
  • Q represents a bond or O
  • T S
  • G represents N
  • a 5 represents N or, more preferably, C(H).
  • Y represents -NHC(O)NH-.
  • G represents N
  • a 2 and A 4 represent C(R 2 );
  • a 1 , A 3 and A 5 independently represent C(H) or N.
  • Y is -NHC(O)NH- or, more preferably, -NHS(O) 2 -[CH 2 Jq-; and/or q is 0.
  • Y is not -NHC(O)NH- or, more preferably, -NHS(O) 2 -[CH 2 ] q -; and/or q is 0.
  • X represents -[CH 2 ] n -; G represents N or O; R 1 to R 4 independently represent H, halo, -CF 3 , -CN, -NO 2 , -C(O)R 7 , -C(O)OR 7 ,
  • R 5 represents H, Br, I, F, -CF 3 , -CN, -C(O)R 7 , -C(O)OR 7 , -N(R 7 J 3 + Or -SO 3 R 7 ; provided that at least one of R 1 to R 5 is not H; and
  • R 6a to R 66 independently represent, H, cyano, -NO 2 , halo, -R 8 , -OR 8 , -NR 9 R 10 , -SR 11 ,
  • Y represents -NHS(O) 2 .
  • Q and Z independently represent a bond, S, or O;
  • R x and R y are independently selected from H, halo, C 1-6 alkyl (optionally substituted or, more preferably, substituted by one or more halo atoms), or R x and R y are linked to form, along with the carbon atom to which they are attached, an aromatic or non-aromatic 3- to
  • 8-membered ring optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or C 1-6 alkyl (optionally substituted by one or more halo atoms);
  • R 1 to R 5 are as defined above or, preferably, at least one of R 1 to R 5 represents -CF 3 or, more preferably, at least one of R 1 to R 4 represents -CF 3 and R s represents H.
  • Q and Z independently represent a bond, S, or O;
  • R x and R y are independently selected from H, halo, Ci -6 alkyl (optionally substituted by one or more halo atoms), or R x and R y are linked to form, along with the carbon atom to which they are attached, an aromatic or, more preferably, non-aromatic 3- to 8- membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or Ci -6 alkyl (optionally substituted by one or more halo atoms). More preferred compounds of formula I include those of the examples described hereinafter.
  • Preferred compounds of formula I include:
  • Preferred compounds of formula I include compounds (i), (H), (Ix) to (Ixv), (Ixix), (Ixxi), (Ixxvi), (xc) to (cxxv) and (clxx) to (clxxii) as described above.
  • Yet further preferred compounds of formula I include compounds (xv), (xxxvi) to (xl), (iii), (iv), (xi), (xii), (xiv), (xvi) to (xxii), (xxiv) to (xxxv), (xli) to (liii), (Ixxviii) and (Ixxix).
  • Yet further preferred compounds of formula I include compounds (i) to (iv), (vi) to (liv), (xcvi), (xcvii), (cxx) to (cxxiii), (cxxvi) to (cxli), (cxliii) to (cil), (cli), (cliii) to (clix) and (clxxiii).
  • Yet further preferred compounds of formula I include compounds (xv), (xxxvi) to (xl) and (Ixvi).
  • Compounds of formula I may be known and/or may be commercially available. Compounds of formula I that are not commercially available may be prepared in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter.
  • a process for the preparation of a compound of formula I which process comprises: (i) for compounds of formula I wherein Y represents -NHC(O)-[CH 2 ] r -B- or, more preferably, -NHC(O)NH-, -NHC(O)O-, -NHS(O) 2 NH- or -NHS(O) 2 -[CH 2 Jq-, reaction of a compound of formula II,
  • Y x represents -C(O)-[CH 2 JrB- or, more preferably, -C(O)NH-, -C(O)O-, -S(O) 2 NH-, or -S(O) 2 -[CH 2 ]q-
  • L 2 represents a suitable leaving group such as halo (e.g. chloro)
  • Di to D 5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable base (e.g. NaH, NaOH, triethylamine, pyridine, another suitable base, e.g. one of those mentioned at process step (xii) below or mixtures thereof) and an appropriate solvent (e.g.
  • a suitable base e.g. NaH, NaOH, triethylamine, pyridine, another suitable base, e.g. one of those mentioned at process step (xii) below or mixtures thereof
  • an appropriate solvent e.g.
  • pyridine which may serve as the base and solvent
  • DMF or dichloromethane e.g. further in the presence of water and, optionally, a phase transfer catalyst
  • room temperature e.g. as described in Hurst, D. T.; Stacey, A. D., Nethercleft, M., Rahim, A., Harnden, M. R. Aust J. Chem. 1998, 41, 1221 ;
  • Di to D 5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example, in the presence of a suitable solvent (e.g. a polar aprotic solvent such as toluene) and at elevated temperature (e.g. reflux), for example as described in the journal article mentioned in respect of process (i) above;
  • a suitable solvent e.g. a polar aprotic solvent such as toluene
  • elevated temperature e.g. reflux
  • dotted lines, Ai to A 5 , X, T, G and Di to D 5 are as hereinbefore defined or, more preferably, T is S or O and G is N, for example under standard oxidation conditions, e.g. in the presence of a suitable oxidising reagent (e.g. Dess-Martin periodinane, pyridinium chlorochromate, sodium dichromate, Jones' reagent, KMnO 4 , or Na 2 Cr 2 O 7 ) in an appropriate solvent (e.g. dichloromethane, tetrahydrofuran, aqueous sulfuric acid or aqueous acetic acid) and optionally at reduced to elevated temperature (e.g. from 0 0 C to 100 0 C), or e.g. as described in Kurkjy et al. (1952) J. Am. Chem. Soc. (74), 6260-6262;
  • a suitable oxidising reagent e.g. Dess-Martin periodinane,
  • L 3 represents a suitable leaving group such as halo (e.g. chloro, bromo and iodo) or methylsulfonyl
  • halo e.g. chloro, bromo and iodo
  • AA represents HO- or HS-
  • q and Di to D 5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable base (e.g. NaH, KH), in a suitable solvent (e.g. tetrahydrofuran) and optionally at reduced to elevated temperature (e.g. from 0 0 C to 100 0 C), or under the reaction conditions discussed in Kidwai et al. (2000), Bioorg. Med. Chem 8, 69-72 or Alemagna et a/. (1968) Tetrahedron, 24, 3209-3217 or Toyooka et ai, (1987) Chem. Pharm. Bull. 35(3), 1030-1035;
  • a suitable base e.g. NaH, KH
  • a suitable solvent e.g. tetrahydrofuran
  • L 5 represents a suitable leaving group such as halo (e.g. chloro)
  • the dotted lines, Ai to A 5 , X, T and G are as hereinbefore defined or, more preferably, T is S or O and G is N 1 with a compound of formula X,
  • D 1 to D 5 are as hereinbefore defined, for example under standard reaction conditions, e.g. such as those described in process (i) above;
  • dotted lines, Ai to As, X, T and G are as hereinbefore defined or, more preferably, T is S or O and G is N, with a compound corresponding to a compound of formula III, but wherein Y x instead represents -C(O)- or -S(O) 2 -, under reaction conditions known to those skilled in the art, for example in the presence of a suitable base (e.g. NaH, NaOH, triethylamine, pyridine, another suitable base mentioned at process step (i) above or mixtures thereof) and solvent (e.g. pyridine (which may serve as the base and solvent) DMF or dichloromethane (e.g.
  • a suitable base e.g. NaH, NaOH, triethylamine, pyridine, another suitable base mentioned at process step (i) above or mixtures thereof
  • solvent e.g. pyridine (which may serve as the base and solvent) DMF or dichloromethane (e.g.
  • Di to D 5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (e.g. toluene or xylenes), in the presence of suitable dehydration means (e.g. Dean-Stark apparatus, 3A molecular sieves, magnesium turnings), optionally in the presence of a suitable Lewis acid (e.g BF 3 OEt 2 ), and at elevated temperature (e.g. from 30 0 C to 150 0 C) using conventional or microwave heating means;
  • a suitable solvent e.g. toluene or xylenes
  • suitable dehydration means e.g. Dean-Stark apparatus, 3A molecular sieves, magnesium turnings
  • a suitable Lewis acid e.g BF 3 OEt 2
  • elevated temperature e.g. from 30 0 C to 150 0 C
  • L 5a represents a halogen atom (e.g. Br, Cl or I) and wherein the dotted lines, Di to D 5 , T 1 G and Y are as hereinbefore defined or, more preferably, T is S or O and G is N 1 with a compound of formula XIV,
  • Z a is O or S and A 1 to A 5 , Q, R x , R y and n are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable base (e.g. MeONa, EtONa, NaH), a suitable solvent (e.g. MeOH, EtOH 1 THF), and at elevated temperature (e.g. from 30 0 C to 150 0 C);
  • a suitable base e.g. MeONa, EtONa, NaH
  • a suitable solvent e.g. MeOH, EtOH 1 THF
  • T' represents S, NH or O and G, X 1 Y, A 1 to A 5 and Di to D 5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example, in an appropriate solvent (e.g. toluene, xylenes, DCM), optionally in the presence of an acid (e.g. methanesulfonic acid) and at reduced to elevated temperatures (e.g. from 0°C to 140 0 C);
  • an appropriate solvent e.g. toluene, xylenes, DCM
  • an acid e.g. methanesulfonic acid
  • elevated temperatures e.g. from 0°C to 140 0 C
  • L 6a represents a suitable leaving group (e.g. a halo, such as chloro, bromo, iodo, a sulfonate group or an acid anhydride) or OH, with a compound of formula XVII,
  • G' represents NH 2 or OH and T, Y and D 1 to D 5 are as hereinbefore defined, when L 6a represents a suitable leaving group, under reaction conditions known to those skilled in the art, for example such as those described in JP3258771 , e.g. in an appropriate solvent (e.g. toluene, xylenes, DCM, chloroform), optionally in the presence of an base (e.g. pyridine, Hunig's base, triethylamine) and at reduced to elevated temperatures (e.g. from O 0 C to 140 0 C) or when L 6a represents OH, under standard coupling reaction conditions, for example, in the presence of a suitable coupling reagent (e.g.
  • L 7a represents a halogen atom (e.g. Br, Cl or I) and the dotted lines, T, G, Y and D 1 to D 5 are as hereinbefore defined, with a compound of formula XIX,
  • L 8 represents a halogen atom (e.g. Br, Cl or I)
  • X aa is -Q-[CR x R y ] n - and A 1 to A 5 , Q, R x , R y and n are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in an appropriate solvent (e.g. THF, MTBE, DMA, NMP), with a suitable catalytic system (such as those described in J. E. Milne, S. L. Buchwald, J. Am. Chem. Soc, 2004, 126, 13028-13032, N. Hadei, E. A. B. Kantchev, C. J. O'Brien, M. G. Organ, Org.
  • an appropriate solvent e.g. THF, MTBE, DMA, NMP
  • a suitable catalytic system such as those described in J. E. Milne, S. L. Buchwald, J. Am. Chem. Soc, 2004,
  • E represents CH 2 or a bond and the dotted lines, T, G, Ai to A 5 and D-i to D 5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example with a suitable catalyst (e.g. Pd/C, Raney Nickel, RhCI(PPh 3 ) 3 , Lindlar catalyst), with a suitable source of hydrogen (e.g. hydrogen gas, hydrazine, dihydronaphthalene, dihydroanthracene, isopropanol, formic acid), optionally in an appropriate solvent (e.g. MeOH, EtOH 1 water or mixtures thereof), optionally at elevated pressures (e.g. greater than 1 atmosphere) and at reduced to elevated temperatures (e.g. from O 0 C to 140 0 C);
  • a suitable catalyst e.g. Pd/C, Raney Nickel, RhCI(PPh 3 ) 3 , Lindlar catalyst
  • a suitable source of hydrogen e.g. hydrogen gas, hydrazine, dihydr
  • a 1 to A 5 , and X are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (e.g. MeOH, EtOH, THF), and optionally at reduced to elevated temperature (e.g. from O 0 C to 100 0 C), followed by reaction of the resulting intermediate with a suitable oxidant (e.g. FeCI 3 ) in the presence of a suitable solvent (e.g. MeOH, EtOH 1 THF), and optionally at elevated temperature (e.g. from 30 0 C to 100 0 C); and
  • a suitable solvent e.g. MeOH, EtOH, THF
  • a suitable oxidant e.g. FeCI 3
  • R a represents a linear or branched C 1 to C 6 alkyl group, with a compound of formula XXV,
  • Compounds of formula Il may be prepared by: (a) for compounds of formula Il wherein Z is a bond, cyclisation of a compound of formula XXVI,
  • a 1 to A 5 , T and G are as hereinbefore defined or, more preferably, T is S or O and G is N, and X' is -Q-[CFW] n - or -C(O)-, under reaction conditions known to those skilled in the art, for example, in an appropriate solvent (e.g. toluene, xylenes or DCM), optionally in the presence of an acid (e.g. methanesulfonic acid) and at reduced to elevated temperatures (e.g. from O 0 C to 14O 0 C);
  • an appropriate solvent e.g. toluene, xylenes or DCM
  • an acid e.g. methanesulfonic acid
  • elevated temperatures e.g. from O 0 C to 14O 0 C
  • L 6 represents a suitable leaving group (e.g. a halo, such as chloro, bromo, iodo, a sulfonate group or an acid anhydride) or OH
  • X' and A 1 to A 5 are as hereinbefore defined with thiosemicarbazide, under reaction conditions known to those skilled in the art, for example, for example such as those described in JP3258771 , e.g. in an appropriate solvent (e.g. toluene, xylenes, DCM, chloroform), optionally in the presence of an base (e.g. pyridine, Hunig's base, triethylamine) and at reduced to elevated temperatures (e.g.
  • an appropriate solvent e.g. toluene, xylenes, DCM, chloroform
  • an base e.g. pyridine, Hunig's base, triethylamine
  • elevated temperatures e.g.
  • a suitable coupling reagent e.g. 1 ,1 '-carbonyldiimidazole, ⁇ /./V-dicyclohexylcarbodiimide, 1-(3-dimethylamino- propyl)-3-ethylcarbodiimide (or hydrochloride thereof), ⁇ /./V-disuccinimidyl carbonate, benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate, 2-(1 H- benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate, benzotriazol-1 - yloxytris-pyrrolidinophosphonium hexafluorophosphate, bromo-tris- pyrrolidin
  • a suitable coupling reagent e.g. 1 ,1 '-carbonyldiimidazole,
  • L 7 represents a suitable leaving group (e.g. chloro, bromo, iodo) and the dotted lines, T and G are as hereinbefore defined or, more preferably, T is S or O and G is N, with a compound of formula XIX as hereinbefore defined, under reaction conditions known to those skilled in the art, for example those described under process (xiii) above;
  • a suitable leaving group e.g. chloro, bromo, iodo
  • Halo represents a halogen atom (e.g. iodo, bromo or chloro)
  • the dotted lines, A 1 to A 5 , X, T and G, are as hereinbefore defined, or, more preferably, T is S or O and G is N, with a compound of formula XII as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in a suitable solvent (e.g. tetrahydrofuran or diethyl ether) and subsequent reaction at reduced to elevated temperatures (e.g. from -78 0 C to 100 0 C), or e.g. as described in Kurkjy et al. (1952) J. Am. Chem. Soc. (74), 6260-6262.
  • a suitable solvent e.g. tetrahydrofuran or diethyl ether
  • Compounds of formula Vl wherein L 3 represents halo may be prepared by reaction of a compound of formula Il with NaNO 2 and a suitable halogen source (e.g. hydrochloric acid), under reaction conditions known to those skilled in the art, for example such as those described in Foroumadi et al. (1999) Arzneim. Forsch. 49, 1035- 1038 or Foroumadi et al (2005) Arch. Pharm. Chem. Life ScL , 338, 112-116, for example in the presence of a suitable metal (e.g. copper powder).
  • a suitable halogen source e.g. hydrochloric acid
  • dotted lines, Ai to A 5 , X, T and G are as hereinbefore defined, or, more preferably, T is S or O and G is N, with a suitable chlorine source (e.g. chlorine gas), under reaction conditions known to those skilled in the art, for example such as those described in Naganawa et al. (2006) Biorg. Med. Chem. 14, 6628-6639, e.g. in the presence of a suitable solvent (e.g. 33% aqueous acetic acid) and at reduced to room temperatures (e.g. from -20 0 C to 25 0 C).
  • a suitable chlorine source e.g. chlorine gas
  • Compounds of formula Xl may be prepared by reaction of a compound of formula Vl, wherein L 3 is halo (e.g. chloro), with hydrazine, under reaction conditions known to those skilled in the art, for example such as those described in Shafiee et al. (1976), J. Het. Chem. 13, 117-121 , e.g. in the presence of a suitable solvent (e.g. ethanol, methanol), optionally in the presence of a suitable base (e.g. triethylamine, Hunig's base) and at reduced to elevated temperatures (e.g. from -78°C to 110 0 C).
  • a suitable solvent e.g. ethanol, methanol
  • a suitable base e.g. triethylamine, Hunig's base
  • dotted lines, Di to Ds, X, T and G are as hereinbefore defined, or, more preferably, T is S or O and G is N, with a halogen (bromine, chlorine or iodine), under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (e.g. acetic acid) and in the presence of a suitable base (e.g. NaOAc) as described in Pippich et al. J. Heterocyclic Chemistry (1997) 34, 823-828.
  • a suitable solvent e.g. acetic acid
  • a suitable base e.g. NaOAc
  • a hydrazine hydrate under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (e.g. DMF, MeOH, EtOH, THF), and optionally at reduced to elevated temperatures (e.g. from O 0 C to 100 0 C).
  • a suitable solvent e.g. DMF, MeOH, EtOH, THF
  • elevated temperatures e.g. from O 0 C to 100 0 C.
  • a 1 to A 5 , X and R a are as hereinbefore defined, with Lawesson's reagent, under reaction conditions known to those skilled in the art, for example such as those described in Bradley et al. (2005), Liquid Crystals Today, 14, 15-18, e.g. in the presence of a suitable solvent (e.g. THF).
  • a suitable solvent e.g. THF
  • G' is OH or NH 2 and T is as hereinbefore defined or, more preferably, more preferably, T is S or O and G' is NH 2 , under reaction conditions known to those skilled in the art, for example such as those described in process step (b) above.
  • E and A 1 to A 5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example with a suitable metal catalyst (e.g. Pd(OAc) 2 , Pd(dba) 2 , PdCI 2 , Pd(PPh 3 ) 4 , Pd(OCOCF 3 ) 2 (PPh 3 ) 2 ), a suitable base (e.g. NaOAc, K 2 CO 3 , Na 2 CO 3 , K 3 PO 4 , triethylamine, Hunig's base, LiCI), optionally in the presence of a suitable ligand (e.g.
  • a suitable metal catalyst e.g. Pd(OAc) 2 , Pd(dba) 2 , PdCI 2 , Pd(PPh 3 ) 4 , Pd(OCOCF 3 ) 2 (PPh 3 ) 2
  • a suitable base e.g. NaOAc, K 2 CO 3 , Na 2 CO 3 , K 3 PO 4
  • L 9 represents a suitable leaving group (e.g. chloro, bromo or iodo) and Ai to A 5 are as defined hereinbefore, under reaction conditions known to those skilled in the art, for example those described above for the preparation of a compound of formula XXIX.
  • a suitable leaving group e.g. chloro, bromo or iodo
  • compounds of XXIX, XXX and XL may be prepared by synthetic methods analogous to those described in US 2,420,434 and US 2,511 ,371.
  • Compounds of formula XV may be prepared by reaction of a compound of formula XVII as hereinbefore defined, with a compound of formula XXVII as hereinbefore defined, under reaction conditions known to those skilled in the art, for example, in an appropriate solvent (e.g. DCM, Et 2 ⁇ or THF) and optionally in the presence of a base (e.g. Hunig's base, triethylamine, DMAP, pyridine) and at reduced to elevated temperatures (e.g. from 0 0 C to 80 0 C) and the uncyclised intermediate isolated.
  • an appropriate solvent e.g. DCM, Et 2 ⁇ or THF
  • a base e.g. Hunig's base, triethylamine, DMAP, pyridine
  • elevated temperatures e.g. from 0 0 C to 80 0 C
  • J represents Ci -4 alkyl
  • T represents NH
  • D 1 to D 5 are as defined hereinbefore, with hydroxylamine, under reaction conditions known to those skilled in the art, for example, in the presence of a suitable base (e.g. triethylamine, Hunig's base, DMAP), in a suitable solvent (e.g. diethyl ether, ethanol, methanol) and at reduced to elevated temperatures (e.g. from 0 0 C to 120 0 C).
  • a suitable base e.g. triethylamine, Hunig's base, DMAP
  • a suitable solvent e.g. diethyl ether, ethanol, methanol
  • morpholine and sulfur under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (e.g. DMF, MeOH, EtOH, THF), and optionally at reduced to elevated temperatures (e.g. from 0 0 C to 100°C).
  • a suitable solvent e.g. DMF, MeOH, EtOH, THF
  • elevated temperatures e.g. from 0 0 C to 100°C.
  • R a is as hereinbefore defined, under standard reaction conditions, e.g. such as those described in process (viii) above.
  • Substituents such as R 1 , R 2 , R 3 and R 4 in final compounds of formula I (or precursors thereto and other relevant intermediates) may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions (e.g. carbonyl bond reductions in the presence of suitable and, if necessary, chemoselective, reducing agents such as LiBH 4 or NaBH 4 ), oxidations, alkylations, acylations, hydrolyses, esterifications, and etherifications.
  • the precursor groups can be changed to a different such group, or to the groups defined in formula I 1 at any time during the reaction sequence.
  • the protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
  • Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.
  • the term "functional groups” means, in the case of unprotected functional groups, hydroxy-, thiolo-, aminofunction, carboxylic acid and, in the case of protected functional groups, lower alkoxy, N-, O-, S- acetyl, carboxylic acid ester.
  • compounds of formula I may be AMPK agonists, i.e. they may activate AMPK.
  • AMPK' we mean that the steady state level of phosphorylation of the Thr-172 moiety of the AMPK- ⁇ subunit is increased compared to the steady state level of phosphorylation in the absence of the agonist.
  • ACC acetyl-CoA carboxylase
  • disorder or condition ameliorated by the activation of AMPK will be understood by those skilled in the art to include lung disease, obesity, dry-type age- related macular degeneration, cardioprotection or, preferably, diabetes, hyperinsulinemia and associated conditions, cancer, a condition/disorder where fibrosis plays a role, sexual dysfunction, osteoporosis, inflammation, heart failure and neurodegenerative diseases.
  • Compounds of formula I may also be indicated for use in the treatment of a disorder or a condition caused by, linked to, or contributed to by, hyperinsulinemia.
  • a compound of formula I or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, for the manufacture of a medicament for the treatment of a disorder or condition ameliorated by the activation of AMPK.
  • hyperinsulinemia disorder or condition caused by, linked to, or contributed to by, hyperinsulinemia
  • hyperinsulinemia and associated conditions such as cardiovascular disease or, preferably, type 2 diabetes, glucose intolerance, insulin resistance, metabolic syndrome, dyslipidemia, hyperinsulinism in childhood, hypercholesterolemia, high blood pressure, obesity, fatty liver conditions, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, atherosclerosis, cerebrovascular conditions such as stroke, systemic lupus erythematosus, neurodegenerative diseases such as Alzheimer's disease, and polycystic ovary syndrome.
  • Other disease states include progressive renal disease such as chronic renal failure.
  • Preferred disorders include hyperinsulinemia and, particularly, type 2 diabetes.
  • Certain compounds of formula I may also have the additional advantage that they exhibit partial agonist activity and may therefore be useful in conditions, such as late type 2 diabetes, in which stimulation of the production of insulin is required.
  • agonist activity we include direct and indirect-acting agonists.
  • a method of treatment of a disorder or condition ameliorated by the activation of AMPK comprises the administration of an effective amount of a compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, to a patient in need of such treatment.
  • Compounds of formula I may also be of use in the treatment of cancer (primary and metastatic cancers).
  • cancer will be understood by those skilled in the art to include one or more diseases in the class of disorders that is characterized by uncontrolled division of cells and the ability of these cells to invade other tissues, either by direct growth into adjacent tissue through invasion, proliferation or by implantation into distant sites by metastasis.
  • Compounds of formula I may reduce the rate of cell proliferation when tested in an assay using a human breast cancer cell line (e.g. MDA-MB-231 ). The compounds may thus possess a beneficial inhibitory effect on the ability of tumors of this type, and of cancers generally, to survive. Compounds of formula I may also reduce the rate of cell proliferation when tested in other cancer cells lines such as MCF-7, PC-3, Jurkat, Skov- 3, HL60, MV4-11 , HT29, K562, MDA-MB231 , HCT116wt, HCT116P53-/-, A-549, DU- 145, LOVO, HCT-116 and PANC-1.
  • compounds of formula I are capable of inhibiting the proliferation of cancer cells.
  • proliferation we include an increase in the number and/or size of cancer cells.
  • compounds of formula I are capable of inhibiting metastasis of cancer cells.
  • metastasis we mean the movement or migration (e.g. invasiveness) of cancer cells from a primary tumor site in the body of a subject to one or more other areas within the subject's body (where the cells can then form secondary tumors).
  • the invention provides compounds and methods for inhibiting, in whole or in part, the formation of secondary tumors in a subject with cancer. It will be appreciated by skilled persons that the effect of a compound of formula I on "metastasis" is distinct from any effect such a compound may or may not have on cancer cell proliferation.
  • compounds of formula I may be capable of inhibiting the proliferation and/or metastasis of cancer cells selectively.
  • the combination product inhibits the proliferation and/or metastasis of cancer cells to a greater extent than it modulates the function (e.g. proliferation) of non-cancer cells.
  • the compound inhibits the proliferation and/or metastasis of cancer cells only.
  • cancer cells may be selected from the group consisting of cancer cells of the breast, bile duct, brain, colon, stomach, reproductive organs, thyroid, hematopoietic system, lung and airways, skin, gallbladder, liver, nasopharynx, nerve cells, kidney, prostate, lymph glands and gastrointestinal tract.
  • the cancer is selected from the group of colon cancer (including colorectal adenomas), breast cancer (e.g. postmenopausal breast cancer), endometrial cancer, cancers of the hematopoietic system (e.g.
  • the cancer is selected from the group of colon, prostate and, particularly, breast cancer.
  • the cancer is a non-solid tumor, it is preferably a hematopoietic tumor such as a leukemia (e.g. Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), Acute Lymphocytic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL).
  • AML Acute Myelogenous Leukemia
  • CML Chronic Myelogenous Leukemia
  • ALL Chronic Lymphocytic Leukemia
  • CLL Chronic Lymphocytic Leukemia
  • the cancer cells are breast cancer cells.
  • Compounds of formula I may also be of use in the treatment of a condition/disorder where fibrosis plays a role. Compounds of formula I may also be useful in the treatment of sexual dysfunction (e.g. the treatment of erectile dysfunction).
  • a condition/disorder where fibrosis plays a role includes (but is not limited to) cystic fibrosis or, preferably, scar healing, keloids, scleroderma, pulmonary fibrosis (including idiopathic pulmonary fibrosis), nephrogenic systemic fibrosis, and cardiovascular fibrosis (including endomyocardial fibrosis), systemic sclerosis, liver cirrhosis, eye macular degeneration, retinal and vitreal retinopathy, Crohn's/inflammatory bowel disease, post surgical scar tissue formation, radiation and chemotherapeutic-drug induced fibrosis, and cardiovascular fibrosis.
  • Compounds of formula I may also be of use in the treatment of osteoporosis.
  • Compounds of formula I may also be of use in the treatment of inflammation.
  • Compounds of formula I may also be of use in the treatment of sexual dysfunction.
  • Compounds of formula I may also be of use in the treatment of heart failure.
  • Compounds of formula I may also be of use in the treatment of lung disease.
  • Compounds of formula I may also be of use in the treatment of obesity.
  • Compounds of formula I may also be of use in the treatment of dry-type age-related macular degeneration.
  • Compounds of formula I may also be of use as an agent for cardioprotection.
  • Compounds of formula I may also be of use in the treatment of neurodegenerative diseases (e.g. Alzheimer ' s disease, Parkinson's disease and Huntington's disease, amyotrophic lateral sclerosis, polyglutamine disorders, such as spinal and bulbar muscular atrophy (SBMA), dentatorubral and pallidoluysian atrophy (DRPLA), and a number of spinocerebellar ataxias (SCA)).
  • neurodegenerative diseases e.g. Alzheimer ' s disease, Parkinson's disease and Huntington's disease, amyotrophic lateral sclerosis, polyglutamine disorders, such as spinal and bulbar muscular atrophy (SBMA), dentatorubral and pallidoluysian atrophy (DRPLA), and a number of spinocerebellar ataxias (SCA)).
  • neurodegenerative diseases e.g. Alzheimer ' s disease, Parkinson's disease and Huntington's disease, amyotrophic lateral sclerosis
  • compounds of formula I can be used in the treatment of diabetes, a disorder or condition where fibrosis plays a role, and hyperinsulinemia and associated conditions.
  • treatment include the therapeutic, or palliative, treatment of patients in need of, as well as the prophylactic treatment and/or diagnosis of patients which are susceptible to, the relevant disease states.
  • Patients include mammalian (including human) patients.
  • the term "effective amount” refers to an amount of a compound, which confers a therapeutic effect on the treated patient (e.g. sufficient to treat or prevent the disease).
  • the effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).
  • compounds of formula I may be administered alone, but are preferably administered orally, intravenously, intramuscularly, cutaneously, subcutaneously, transm ⁇ cosally (e.g. sublingually or buccally), rectally, transdermal ⁇ , nasally, pulmonarily (e.g. tracheally or bronchially), topically, by any other parenteral route, in the form of a pharmaceutical preparation comprising the compound in a pharmaceutically acceptable dosage form.
  • Preferred modes of delivery include oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal delivery.
  • Compounds of formula I will generally be administered as a pharmaceutical formulation in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which may be selected with due regard to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutically acceptable adjuvant diluent or carrier
  • Such pharmaceutically acceptable carriers may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use.
  • Suitable pharmaceutical formulations may be found in, for example, Remington The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995).
  • a parenterally acceptable aqueous solution may be employed, which is pyrogen free and has requisite pH, isotonicity, and stability. Suitable solutions will be well known to the skilled person, with numerous methods being described in the literature. A brief review of methods of drug delivery may also be found in e.g. Langer, Science (1990) 249, 1527.
  • Another aspect of the present invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, in combination with a pharmaceutically acceptable excipient, such as an adjuvant, diluent or carrier.
  • the amount of compound of formula I in the formulation will depend on the severity of the condition, and on the patient, to be treated, as well as the compound(s) which is/are employed, but may be determined non-inventively by the skilled person.
  • compounds of formula I may be administered at varying therapeutically effective doses to a patient in need thereof.
  • the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe.
  • the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease.
  • Administration may be continuous or intermittent (e.g. by bolus injection).
  • the dosage may also be determined by the timing and frequency of administration.
  • the dosage can vary from about 0.01 mg to about 1000 mg per day of a compound of formula I (or, if employed, a corresponding amount of a pharmaceutically acceptable salt or prodrug thereof).
  • the medical practitioner or other skilled person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient.
  • the above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the compounds of formula I may also be used or administered in combination with one or more additional drugs useful in the treatment of a disorder or condition ameliorated by the activation of AMPK, in combination therapy.
  • a combination product comprising:
  • each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • therapeutic agents useful in the treatment of a disorder or condition ameliorated by the activation of AMPK will be well known to those skilled in the art and include biguanides, glitazones (i.e. thiazolidinediones), oligomycins, AICAR (aminoimidazole carboxamide ribonucleotide), insulin, insulin secretagogues (such as sulphonylureas), peroxisome proliferator-activated receptor (PPAR) agonists (which also include thiazolidinediones), ⁇ -glucosidase inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, exenatide, inhibitors of 11- ⁇ hydroxysteroid dehydrogenase type 1 , inhibitors of stearoyl- CoA desaturase 1 (SCD-1), A-769662, D942 (5-(3-(4-(2-(4-Fluorophenyl)ethoxy)- phenyl)prop
  • the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise a biguanide.
  • the agent may be selected from the group consisting of phenformin, buformin, and, most preferably, metformin.
  • the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise glitazones.
  • the agent may be selected from the group consisting of troglitazone, pioglitazone and rosiglitazone.
  • the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise an oligomycin.
  • the agent may be selected from the group consisting of oligomycin A, oligomycin B, oligomycin C, oligomycin D (rutamycin A), oligomycin E, oligomycin F, rutamycin B, 44-homooligomycin A and 44-homooligomycin B.
  • the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise AICAR.
  • the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise GLP-1 or a biologically active fragment, variant, fusion of derivative thereof.
  • the agent may be selected from the group consisting of Exendin-4 (exenatide; Byetta), exenatide long acting release (LAR), exenatide derivatives (such as ZP10 developed by Zealand Pharmaceuticals), native GLP-1, human GLP-1 derivatives (such as BIM51077 (Ipsen and Roche)), DPP-IV resistant GLP-1 analogues (for example LY315902 and LY30761 SR (Lilly)), long acting GLP-1 derivatives (such as NN2211 (Liraglutide; Novo Nordisk)) and complex proteins (such as the GLP-1 -albumin complex CJC-1131).
  • the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise a dipeptidyl peptidase IV (DPP-IV) inhibitor.
  • DPP-IV dipeptidyl peptidase IV
  • the agent may be selected from the group consisting of Vildagliptin (LAF237), MK-0431-Sitagliptin and Saxagliptin.
  • the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise gastric inhibitory polypeptide (GIP), or a biologically active fragment, variant, fusion of derivative thereof.
  • GIP gastric inhibitory polypeptide
  • GIP also known as glucose-dependent insulinotropic polypeptide, is a 42-amino acid peptide hormone synthesised in and secreted from K cells in the intestinal epithelium.
  • An important determinant of GIP action is the N-terminal cleavage of the peptide to the inactive GIP (3-42).
  • DPP-4 which also cleaves GLP-1 and GLP-2, rapidly inactivates GIP both in vitro and in vivo. Hence, it may be desirable to administer GIP in combination with a DPP-4 inhibitor.
  • the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise a selective inhibitor of 11- ⁇ hydroxysteroid dehydrogenase type 1 (11 ⁇ -HSD1), an enzyme associated with conversion of cortisone to Cortisol in the liver and adipose tissue.
  • 11 ⁇ -HSD1 inhibitors/antagonists include AMG221 (developed by
  • the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise an inhibitor of stearoyl- CoA desaturase 1 (SCD-1).
  • SCD-1 inhibitors include those described in US 2005/0019251 (e.g. 6-[4-(2-bromo-4-methoxy-benzoyl)-piperazin-1-yl]- N-(3-phenyl-propyl)-nicotinamide), those described in WO 2006/130986 (e.g.
  • the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise a SIRT1 (also known as sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)) activator.
  • SIRT1 activators include resveratrol and SRT-1720 (N-[2-[3-(piperazin-1-ylmethyl)imidazo[2,1-b][1 ,3]thiazol-6-yl]phenyl]quinoxal- ine-2-carboxamide).
  • Combination products as described herein provide for the administration of compound of formula I in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises compound of formula I 1 and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including compound of formula I and the other therapeutic agent).
  • compositions including a compound of formula I; another therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK; and a pharmaceutically-acceptable adjuvant, diluent or carrier; and
  • kits of parts comprising components:
  • a pharmaceutical formulation including another therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
  • Components (a) and (b) of the kits of parts described herein may be administered simultaneously or sequentially.
  • a method of making a kit of parts as defined above comprises bringing component (a), as defined above, into association with a component (b), as defined above, thus rendering the two components suitable for administration in conjunction with each other.
  • components (a) and (b) of the kit of parts may be:
  • kit of parts comprising:
  • kits of parts described herein may comprise more than one formulation including an appropriate quantity/dose of compound of formula I 1 and/or more than one formulation including an appropriate quantity/dose of the other therapeutic agent, in order to provide for repeat dosing. If more than one formulation (comprising either active compound) is present, such formulations may be the same, or may be different in terms of the dose of either compound, chemical composition(s) and/or physical form(s).
  • kits of parts as described herein by “administration in conjunction with”, we include that respective formulations comprising compound of formula I and the other therapeutic agent are administered, sequentially, separately and/or simultaneously, over the course of treatment of the relevant condition.
  • the term "administration in conjunction with” includes that the two components of the combination product (compound of formula I and the other therapeutic agent) are administered (optionally repeatedly), either together, or sufficiently closely in time, to enable a beneficial effect for the patient, that is greater, over the course of the treatment of the relevant condition, than if either a formulation comprising compound of formula I, or a formulation comprising the other therapeutic agent, are administered (optionally repeatedly) alone, in the absence of the other component, over the same course of treatment. Determination of whether a combination provides a greater beneficial effect in respect of, and over the course of treatment of, a particular condition will depend upon the condition to be treated or prevented, but may be achieved routinely by the skilled person.
  • the term "in conjunction with” includes that one or other of the two formulations may be administered (optionally repeatedly) prior to, after, and/or at the same time as, administration with the other component.
  • the terms “administered simultaneously” and “administered at the same time as” include that individual doses of compound of formula I and the other therapeutic agent are administered within 48 hours (e.g. 24 hours) of each other.
  • the compounds/combinations/methods/uses described herein may have the advantage that, in the treatment of the conditions described herein, they may be more convenient for the physician and/or patient than, be more efficacious than, be less toxic than, have better selectivity, have a broader range of activity than, be more potent than, produce fewer side effects than, or may have other useful pharmacological properties over, similar compounds, combinations, methods (treatments) or uses known in the prior art for use in the treatment of those conditions or otherwise.
  • FIG. 1a which shows the effect of the compound of Example 1 on AMPK phosphorylation.
  • PC3 cells were cultured in serum-free medium overnight (16 h) and subsequently incubated with 5 ⁇ M (5) or 10 ⁇ M (10) of the compound of Example 1 or 0.1% DMSO (-) for 6 h.
  • Equal amounts of protein from total cell lysates were separated by 4-12% Bis-Tris polyacrylamide gel and the phosphorylation of AMPK was immunoblotted with a specific anti-phospho-Thr-172 AMPK ⁇ antibody as described under "Experimental Procedures".
  • Figure 1b which shows the effect of the compound of Example 3 and compounds (j) and (k) of Example 4 on eEF2 phosphorylation.
  • 1 ⁇ M or 5 ⁇ M of the compound of Example 3 and compounds (j) and (k) of Example 4 were added and incubated for an additional 4 h.
  • the figure provides representative immunoblots of eEF2 phosphorylation (p) by the compound of Example 3 and compounds (j) and (k) of Example 4.
  • the compound of Example 3 and Compounds (j) and (k) of Example 4 stimulate AMPK and eEF2 phosphorylation in PC3 cells.
  • Figure 1 c which shows the effect of the compounds of Example 4 on AMPK and eEF2 phosphorylation.
  • 5 ⁇ M of the compounds (a) to (i) of Example 4 were added and incubated for an additional 1 h.
  • the figure provides representative immunoblots of AMPK and eEF2 phosphorylation (p) by compounds (a) to (i) of Example 4.
  • Compounds (a) to (i) of Example 4 stimulate AMPK and eEF2 phosphorylation in PC3 cells.
  • Figure 1d which shows the effect of the compounds of Example 4 on AMPK and eEF2 phosphorylation.
  • FIG 2 which shows the effect of compound of Example 1 on blood glucose levels in ob/ob mice.
  • Ob/ob mice were administered compound of Example 1 (30 mg/kg, gray bars) or vehicle (black bars) by oral gavage twice daily for 20 days. Blood sampling was made on fed mice at day 0, 16 hours post dose of day 12 and day 20 of dosing.
  • Figure 3a which shows that treatment of tumor cell lines with Example 2 generates a dose dependent reduction in proliferation in MDA-MB-231 human breast cancer cell lines as measured by BrdU incorporation.
  • Figure 3b which shows that treatment of tumour cell lines with Example 1 generates a dose dependent reduction in proliferation in PC3 human prostate cancer cell lines as measured by BrdU incorporation.
  • Figure 4 which shows that the compound of Example 1 inhibits TGF- ⁇ -induced secretion of collagen IV in human primary mesangial cells, as indicated by the measurement of absorbance using the ELISA procedure.
  • FIG. 5 which shows that the compound of Example 1 (referred to as L201 in the Figure) does not affect plasma insulin levels in C57BL/6JBomTac mice after acute administration. Blood samples were analyzed for plasma insulin prior to administration of the compound of Example 1 and 10, 30 and 60 min after drug administration.
  • L201 the compound of Example 1
  • FIG. 6a which shows the effect of TGF- ⁇ 1 or TGF- ⁇ 1 and the compound of Example 3 on EDA-fibronectin expression and ⁇ SMA expression in WI-38 lung fibroblast cells.
  • Wl- 38 cells were incubated with TGF- ⁇ 1 (1 ng/mL) or TGF- ⁇ 1 (1 ng/mL) and the compound of Example 3 at 0.125 and 0.625 ⁇ M respectively) for 24 h.
  • FIG. 6b which shows the effect of TGF- ⁇ 1 or TGF- ⁇ 1 and the compound of Example 3 on AMPK and SMAD2 phosphorylation in WI-38 lung fibroblast cells.
  • WI-38 cells were incubated with TGF- ⁇ 1 (1 ng/mL) or TGF- ⁇ 1 (1 ng/mL) and the compound of Example 3 at 0.125 and 0.625 ⁇ M respectively) for 24 h.
  • the figure shows that the compound of Example 3 increases the phopshorylation of AMPK and decreases SMAD2 phosphorylation.
  • Figure 7 which shows that the compound of Example 5 suppress PP2C mediated dephosphorylation of p-T172 of AMPK in a cell free system, as measured by the relative levels of p-T172 of AMPK.
  • Figure 8 which showns that the treatment of normal human fibroblast cell line WI-38 with the compound of Example 5 increases steady state levels of phosphorylated AMPK and ACC.
  • THF tetrahydrofuran where no preparative routes are included, the relevant intermediate is commercially available (e.g. from Chemical Diversity, San Diego, CA, USA or other available commercial sources).
  • LC-MS was performed on a Sciex API 150 LC/ES-MS equipped with an ACE 3 C8 column (30 x 3.0 mm) using a flow of 1 ml_/min. Two gradient systems of acetonitrile in water (with 0.1% TFA) are used for elution: A) 5-100% under 10 min, then 2 min 100% isocratic or B) 90-100% under 2 min, then 2 min 100% isocratic.
  • Direct inlet ES-MS was also performed on a Bruker Esquire LC/ES-MS. 1 H nuclear magnetic resonance was recorded on a Bruker Avance DRX 400 spectrometer at 400.01 MHz using residual solvent as internal standard.
  • N-Thiourea-(3-trifluoromethylphenyl)-acetamicle (4.71 g) and methanesulfonic acid (1.2 ml_, 1.1 eq.) were added to toluene (100 mL) and the resultant mixture refluxed. After 3 h the reaction was complete according to LC-MS analysis indicate and the solvent was evaporated to give the crude methanesulfonic acid salt as a white solid (>90% purity). The salt was then triturated by stirring in EtOAc (150 mL) for about 40 min and was then collected by filtration (4.71 g (100% purity) 78% yield).
  • the salt was dissolved in EtOAc (200 mL) and 2M NaOH (75 mL) and the layers separated. The organic phase was washed twice with 2M NaOH (75 mL) and the combined water phase extracted with 4x150 mL EtOAc. The combined organic phase was washed with water (150 mL) followed by brine (150 mL), dried (MgSO 4 ) and the solvent removed under reduced pressure to give the desired product as a white solid (2.8 g, 64% yield).
  • the compounds of Example 8 are formed in a one step reaction from commercially available 2-amino-1 ,3,4-thiodiazoles and commercially available sulfonylchloride derivatives using the following method : 50 mg of the 2-amino-1,3,4-thiodiazole is dissolved in 2 mL dichloromethane (DCM) and chilled to 0 0 C. 0.4 equiv dimethylaminopyridine (DMAP) and 1.2 equiv. pyridine is added and stirred for 5 min. 1.2 equiv. of the sulfonylchloride is added dropwise to the mixture. The reaction mixture is stirred for 12 h at rt.
  • DCM dichloromethane
  • DMAP dimethylaminopyridine
  • pyridine 1.2 equiv. pyridine
  • reaction mixture is then quenched with 2 mL NaHCO 3 (aq.) followed by 2 mL water and extracted twice with DCM (2 mL). The residue is dried over Na 2 SO 4 and concentrated.
  • the product was purified by column chromatography using silica and petroleum ether and EtOAc as eluting solvent
  • Example 9 The compound of Example 9 was formed in a one step reaction from commercially available 2-amino-1 ,3,4-thiodiazoles and commercially available chloroformate derivatives using the method as described for Example 1d.
  • the 5-substituted 1 ,3,4-thiadiazol-2-ylhydrazines are formed from the corresponding 2- amino- 1 ,3,4-thiadiazole via the 2-chloro-1 ,3,4-thiadiazole using methods well-known to the person skilled in the art. For example methods described in Potts et al ⁇ J. Org. Chem. 1966, 31 , 3528-3531).
  • General protocol for the formation of benzohydrazides The hydrazine derivative (45 mg) was dissolved in 2 mL DCM and 2 equiv. of 1 -ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDC), 0.05 equiv.
  • 1 ,3,4-thiadiazol-2-yl)hydrazine (formed as described in Example 10) is treated with sulfonic acid chlorides derivatives as described in Example 8 but with the use of potassium carbonate as base and acetonitrile as solvent to form the 1 ,3,4-thiadiazol-2- yl]-5- benzenesulfonohydrazide derivatives .
  • Table 1 The data presented in Table 1 below indicates the potency for a number of compounds of the examples that were tested in Tests A, I and J below.
  • the potency of the compounds to stimulate the phosphorylation of Thr-172 on the AMPK- ⁇ subunit was estimated by comparing the relative intensity of the Western blot for the compound in question to the Western blot obtained using the solvent vehicle as a control.
  • a "+” indicates a compound that is more potent than the control compound (with "+++” representing compounds that were significantly more potent).
  • cancer cell lines including source, tumor type, and morphology may be obtained from the American Type Culture Collection (ATCC) or its website (www.atcc.org).
  • ATCC American Type Culture Collection
  • www.atcc.org www.atcc.org
  • Example 1 The compounds of Examples 1 and 3 were obtained as described above and Compounds (a) to (k) and (I) to (n), (q), (x), (a1) and (b1), of Example 4 were obtained from VitasM-Laboratories or Interbioscreen. A stock solution of 10 mM was prepared by dissolving the compounds in 100% DMSO.
  • PC3 cells were purchased from LGC Promochem-ATCC (ATCC catalog no CRL- 1435). PC3 cells were maintained in Dulbecco's modified Eagle's medium (Gibco 21885) containing 5% fetal bovine serum (Gibco 10500-064), 25 ug/ml Gentamicin (Gibco 15750) and 1x non essential amino acids (Gibco 11140). The cells were incubated in a humidified atmosphere of 5% CO 2 at 37°C and passaged every 3 days by trypsinization.
  • PC3 cells were cultured in complete medium with 10% fetal bovine serum in 60-mm-diameter dishes, grown to 70-80% confluence and cultured in serum-free Dulbecco's modified Eagle's medium for 5 h. Cells were then treated for 1 h with the compounds of Examples 1 , 3 and compounds (a) to (i) of Example 4 or for 4h with compounds (j) and (k) of Example 4 that were dissolved in DMSO at the concentrations indicated in Figures 1a to 1d or above. Cells treated with compounds (I), (m), (n), (q), (x), (a1) and (b1), of Example 4 were handled in a corresponding manner to cells treated with compounds (j) and (k) of Example 4. The final concentration of DMSO did not exceed 0.1%, which did not affect AMPK or eEF2 phosphorylation. 0.1% DMSO was used as control.
  • PC3 cells were lysed in buffer (10OmM TRIS pH 6,8, 2%w/v Sodium dodecylsulfate (SDS), 1OmM NaF, 1OmM ⁇ -glycerophosphate, 1mM Na Vanadate). Cell debris is removed by centrifugation at 14,000 X g for 15 min at 4 0 C and the resulting supernatant is used for Western blotting. Protein concentrations of the lysates were measured using a BCA protein assay kit (Pierce #23225).
  • Filters were washed in 2OmM TRIS pH 7.5, 137mM NaCI, 25%v/v Tween20 for 3x5min. Filters were incubated in blocking solution with secondary antibody, peroxidase- conjugated Goat anti-rabbit IgG (Jackson immunoResearch #111-035-003) at room temperature for 1 h. Filters were washed as above for 3x10 min. Signal was developed with SuperSignal West Dura ECL kit (Pierce #1859024) and exposed to Hyperfilm ECL (Amersham #28906837).
  • the Western blot result showed that the compound of Example 3 stimulated the phosphorylation of Thr-172 of the AMPK ⁇ subunit. Moreover, AMPK activation by the compound of Example 3 in PC3 cells was further confirmed by enhanced phosphorylation of eEF2. These results indicate that the compound of Example 3 stimulated AMPK phosphorylation and downstream activity (see Figures 1b).
  • the Western blot result showed that compounds (a) to (k) of Example 4 stimulated the phosphorylation of Thr-172 of the AMPK ⁇ subunit. Moreover, AMPK activation by compounds (a) to (k) of Example 4 in PC3 cells was further confirmed by enhanced phosphorylation of eEF2. These results indicate that compounds (a) to (i) of Example 4 stimulate AMPK phosphorylation and downstream activity (see Fig 1c), as do compounds (j) and (k) of Example 4 (see Figures 1 b and 1d).
  • the potency of the compounds of Examples 1 , 3, 4(a), 4(b), 4(d), 4(e), 4(f), 4(h), 40), 4(k), 4(I), 4(m), 4(n), 4(q), 4(x), 4(a1), and 4(b1) to stimulate the phosphorylation of Thr-172 on the AMPK- ⁇ subunit was estimated by comparing the relative intensity of the Western blot obtained for the vehicle control to the Western blot obtained for the compound in question. As indicated in Table 1 of Example 13, the compounds were generally more potent than the control compound.
  • the aim of this study was to verify the efficacy of the compound of Example 1 in diabetic ob/ob mouse with regard to correction of the metabolic disorder hyperglycemia.
  • Ob/ob mice were gavaged twice daily with the compound of Example 1 and the effect of the compound on levels of blood glucose were assessed and the results were compared to a concurrent control group gavaged with vehicle.
  • mice Male B6.V-Lep ob /JBomTac (model number OB-M) mice were bred and delivered by Taconic. Animals were housed in Umea University animal facility in transparent polycarbonate cages, with wood chip bedding at a 12 h light/darkness cycle, a temperature of ⁇ 21°C, and a relative humidity of ⁇ 50% throughout the accommodation and dosing periods. Five animals were housed in each cage with free access to standard rodent chow (CRM(E)Rodent, Special Diets Services, Scanbur BK, Sweden) and tap water. All animal experiments were approved by the Local Ethics Review
  • mice Male ob/ob mice, 18 to 19 weeks of age were administered compound of Example 1 (30 mg/kg body weight) or vehicle (0.5% methylcellulose and 1% DMSO in PBS) by oral gavage twice daily (8:00-9:00 A.M. and 4:00-5:00 P.M.) for 20 days.
  • Mice were administered 5 ml/kg body weight of each emulsion using a teflon needle with silicone tip (Agnthos AB, Liding ⁇ , Sweden). Blood samples were drawn from the tail vein from fed animals 16 h post dose of day 12 and 20 of dosing for analysis of blood glucose.
  • Blood glucose levels were measured by using a Glucometer Elite (Bayer) according to the manufacturer's recommendations.
  • the compound of Example 1 was evaluated in diabetic ob/ob mice to test the effect of the compound of Example 1 on hyperglycemia. As shown in Figure 2, on day 12 of the treatment, the group treated with the compound of Example 1 showed a noticeable decrease in fed blood glucose when compared to mice treated with vehicle. At the end of the experiment (day 20), fed blood glucose levels in vehicle treated ob/ob mice were higher than those in the ob/ob mice treated with the compound of Example 1.
  • Example 2 in 0.2% DMSO in quadruplicate. After 18 h incubation, BrdU was added according to manufacturer's recommendations. After 6 h incubation in the presence of BrdU, the culture media was removed and BrdU incorporation was measured using "Cell Proliferation ELISA, BrdU colorimetric 11 Roche (11647229001) according to manufacturer's recommendations.
  • Proliferation rate of MDA-MB-231 cells are reduced by relevant concentrations of the test compounds as measured by BrdU incorporation (see Figure 3a).
  • the compound of Example 2 relative to the vehicle control (which displayed a BrdU incorporation of 1 unit) displayed the following (approximate) units of BrdU incorporations at different concentrations:
  • Proliferation rate of PC-3 cells are reduced by relevant concentrations of the test compounds as measured by BrdU incorporation (see Figure 3b).
  • the compound of Example 1 relative to the vehicle control (which displayed a BrdU incorporation of 1 unit) displayed the following (approximate) units of BrdU incorporations at different concentrations:

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Abstract

There is provided a compound of formula (I), wherein the dotted lines, X, T, G, Y, A1 to A5 and D1 to D5 have meanings given in the description, which compounds are useful in the treatment of conditions or disorders ameliorated by the activation of AMPK, for example skin diseases, lung disease, obesity, dry-type age-related macular degeneration, cardioprotection or, preferably, hyperinsulinemia, diabetes, cancer, fibrosis, neurodegenerative diseases, sexual dysfunction, heart failure, inflammation and osteoporosis.

Description

COMPOUNDS USEFUL AS MEDICAMENTS
Field of the Invention
This invention relates to pharmaceutically-useful compounds. The invention also relates to the use of such compounds in the treatment of conditions ameliorated by the activation of AMPK, such as skin diseases, lung disease, obesity, dry-type age-related macular degeneration, cardioprotection or, preferably, hyperinsulinemia, diabetes, cancer, fibrosis, neurodegenerative diseases, sexual dysfunction, heart failure, inflammation and osteoporosis.
Background
AMPK represents a new target for the treatment of several diseases, including metabolic syndrome. Hyperinsulinemia (hypersecretion of insulin) also represents a new target for the treatment of metabolic syndrome.
Metabolic syndrome has become increasingly common, and affects an estimated 47 million adults in the US alone. The syndrome is characterized by a combination of metabolic risk factors such as central obesity, atherogenic dyslipidemia, hypertension, insulin resistance or glucose intolerance. The syndrome is also characterised by hyperinsulinemia, a prothrombotic state in the blood, and a proinflammatory state.
Underlying causes of metabolic syndrome include obesity, physical inactivity and genetic factors. Sufferers are at an increased risk of coronary heart disease and other diseases related to the build up of plaques in artery walls, for example stroke, peripheral vascular disease and type 2 diabetes.
Diabetes is the most common metabolic disease with a high incidence in western countries, with more than 170 million people currently affected by type 2 diabetes. Type 2 diabetes is a chronic, presently incurable disease and sufferers have a high risk of developing life threatening complications as the disease progresses. The overall cost to society of diabetes and its complications is huge.
Thus, to a large extent, obesity, metabolic syndrome and diabetes are interrelated and there is a substantial need for better pharmacological treatment of patients with one or more of these conditions. When the above is coupled with the epidemic increase in obesity in western society, there is an urgent unmet clinical need to develop novel and innovative strategies leading to new drugs with a superior effect and/or less side effects.
Insulin is both a potent hormone and growth factor. In addition to obesity, hyperinsulinemia is apparent in conditions such as impaired glucose tolerance, early or mild type 2 diabetes, polycystic ovary syndrome and Alzheimer's disease. Evidence is accumulating that hyperinsulinemia plays a major role in the development of these diseases.
A medicament that reduces insulin resistance and/or hyperinsulinemia may therefore represent an efficient therapeutic strategy to treat or prevent disorders caused by, linked to, or contributed to by insulin resistance and/or hyperinsulinemia or associated conditions.
No existing therapies for the different forms of diabetes appear to reduce hyperinsulinemia:
(a) insulin secretagogues, such as sulphonylureas stimulate only the insulin secretion step;
(b) metformin mainly acts on glucose production from the liver;
(c) peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, such as the thiazolidinediones, enhance insulin action; and
(d) α-glucosidase inhibitors interfere with gut glucose production.
All of these therapies fail to arrest progression of the disease and, over time, also fail to normalize glucose levels and/or to stop subsequent complications.
More recent therapies for the treatment of type 2 diabetes have limitations and/or side effects. For example, exenatide needs to be administered by subcutaneous injection, has storage stability shortcomings, is reported to cause nausea and vomiting and, more recently, has been shown to be coupled to several severe cases of acute pancreatitis.
Furthermore, other existing therapies for the treatment of type 2 diabetes are known to give rise to undesirable side effects. For example, insulin secretagogues and insulin injections may cause hypoglycaemia and weight gain and patients may also become unresponsive to insulin secretagogues over time. Metformin (an indirect AMPK activator) and α-glucosidase inhibitors often lead to gastrointestinal problems and PPAR-agonists tend to cause increased weight gain and oedema.
Dipeptidyl peptidase-IV (DPP-IV) inhibitors belong to a new class of oral antidiabetic agents for the treatment of patients with type 2 diabetes. Inhibition of the enzyme DPP- IV results in prolonged activity of glucagon-like peptide-1 (GLP-1) and glucose- dependent insulinotropic peptide (GIP), the incretin hormones. Sitagliptin was the first DPP-IV inhibitor to be approved by FDA for treatment of type 2 diabetes and several other DPP-IV inhibitors are in late clinical phases. Several side-effects for DPP-IV inhibitors as a class may be expected, such as inflammation, allergic reactions and hypertension since many peptides, neuropeptides, and cytokines are cleaved by DPP-IV. Some of the reported side effects of certain DPP-IV inhibitors include anemia, thrombocytopenia, and splenomegaly.
Therefore, there is a substantial need for better pharmacological treatment of patients with type 2 diabetes. Recently, even more diseases have been found to be interrelated to common targets for type 2 diabetes, which will be discussed in more detail below.
AMP-activated protein kinase (AMPK) is a protein kinase enzyme that consists of three protein sub-units and is activated by hormones, cytokines, exercise, and stresses that diminish cellular energy state (e.g. glucose deprivation). Activation of AMPK increases processes that generate adenosine 5'-triphosphate (ATP) (e.g. fatty-acid oxidation) and restrains others such as fatty acid-, glycerolipid- and protein-synthesis that consume ATP, but are not acutely necessary for survival. Conversely, when cells are presented with a sustained excess of glucose, AMPK activity diminishes and fatty acid-, glycerolipid- and protein-synthesis are enhanced. AMPK thus is a protein kinase enzyme that plays an important role in cellular energy homeostasis. Therefore, the activation of AMPK is coupled to glucose lowering effects and triggers several other biological effects, including the inhibition of cholesterol synthesis, lipogenesis, triglyceride synthesis, and the reduction of hyperinsulinemia.
Given the above, AMPK is a preferred a preferred target for the treatment of the metabolic syndrome and especially type 2 diabetes. AMPK is also involved in a number of pathways that are important for many different diseases (e.g. AMPK is also involved in a number of pathways that are important in cancer, CNS disorders, fibrosis, osteoporosis, heart failure and sexual dysfunction). Current anti-diabetic drugs (e.g. metformin, glitazones) are known to not be significantly potent AMPK activators, but only activate AMPK indirectly and with low efficacy. However, due to the biological effects of AMPK activation at the cell level, compounds that are AMPK activators, and preferably direct activators of AMPK1 may find utility as anti-diabetic drugs, as well as for the treatment of many other diseases (some of which are listed below)
Neurological Diseases/Damage
An important component in diseases such as Alzheimer's, Parkinson's (PD) and Huntington's (HD) disease is the buildup of large insoluble aggregates of misfolded proteins in different classes of cells. In addition to Alzheimer's, Parkinson's and Huntington's disease, a number of polyglutamine disorders show the same buildup of insoluble aggregates and examples are spinal and bulbar muscular atrophy (SBMA), dentatorubral and pallidoluysian atrophy (DRPLA), and a number of spinocerebellar ataxias (SCA). In addition, amyotrophic lateral sclerosis (ALS) is another disease where misfolded proteins are present. Normally, in these cells, a system exists that removes such aggregates, autophagy proteolysis. Animals with lowered autophagy function show a high presence of insoluble aggregates and simultaneously a loss of cells and nerve function. It is possible to stimulate autophagy in a cell, for example, interruption of mTOR-dependent signalling by rapamycin is known to stimulate autophagy in mammalian cells. As activation of AMPK also inhibits mTOR-dependent signaling, one would expect stimulation of autophagy by AMPK activation and tests on AMPK in cell lines also suggest a role of AMPK in the stimulation of autophagy (Meley et al, J Biol Chem. 2006 Nov 17;281 (46):34870-34879). Therefore, a medicament such as an AMPK activator may be effective in the treatment of neurodegenerative diseases due to stimulation of autophagy. Traumatic brain injury studies in mice using rapamycin, a known mTOR signaling inhibitor were able to show an increased the number of surviving neurons at the site of injury (Erlich et al, Neurobiol. of Disease,2007, 26(1), 86-93). Since AMPK activator inhibits mTOR signalling it may therefore be neuroprotective following traumatic brain injury. AMPK activation may have neuroprotective properties during ischemia/hypoxia (Spasi et al, The Neuroscientist, 2009,15 (4), 309-316). Thus, an AMPK activator may be useful in the treatment of brain injury caused by brain ischemia and stroke. In Alzheimer's disease (AD)1 longitudinal studies have established a strong association with hyperinsulinemia. Hyperinsulinemia is also related to a significant decline in memory-related cognitive scores, but not to decline in other cognitive domains. Thus, hyperinsulinemia is associated with a higher risk of AD and decline in memory.
Insulin-degrading enzyme also appears to constitute a mechanistic link between hyperinsulinemia and AD (Wei and Folstein (2006), Neurobiology of Aging, 27, 190-198). This enzyme degrades both insulin and amyloid-β (Aβ) peptide, a short peptide found in excess in the AD brain. Evidence suggests that hyperinsulinemia may elevate Aβ through insulin's competition with the latter for insulin-degrading enzyme. Formation of neurofibrillary tangles, which contain hyperphosphorylated tau, represents a key step in the pathogenesis of neurodegenerative diseases. Promoting peripheral insulin stimulation, rapidly increased insulin receptor tyrosine phosphorylation, mitogen- activated protein kinase and phosphatidylinositol (Pl) 3-kinase pathway activation, and dose-dependent tau phosphorylation at Ser(202) in the central nervous system in an insulin receptor-dependent manner.
Thus, peripherally injected insulin directly targets the brain and causes rapid cerebral insulin receptor signal transduction, revealing an additional link between hyperinsulinemia and neurodegeneration.
Skin diseases
Transforming growth factor b1 (TGFbI), present in keratinocytes, has shown to in transgenic mice expressing wild-type TGFbI in the epidermis to develope inflammatory skin lesions, with gross appearance of psoriasis like plaques, generalized scaly erythema, and Koebner's phenomenon. The TGFbI wt skin exhibited multiple molecular changes that typically occur in human Th1 inflammatory skin disorders, such as psoriasis (EMBO Journal (2004) 23, 1770-1781). This observation suggests that certain pathological condition-induced TGFbI overexpression in the skin may synergize with or induce molecules required for the development of Th1 inflammatory skin disorders such as psoriasis and other skin disorders. Thus, an AMPK activator able to affect TGFbI signaling may be of therapeutic value in skin disorders such as, but not limited to, psoriasis. Fibrosis
Studies show that fibrosis is involved in many pathological states in the body (T. A. Wynn (2008) J. Pathology 214, 199-210. It has been shown that AMPK negatively regulates TGFβ-stimulated myofibroblast transdifferentiation and may therefore play a role in disorders where fibrosis develops (Mishra et al (2008), J. Biol. Chem. 283, 10461- 10469). The resulting reduction of collagen may be of therapeutic value in any disease state or condition where fibrosis play a role for example, but not limited to, scar healing, keloids, scleroderma, cystic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia (NSIP), respiratory bronchiolitis, interstitial lung disease (RBILD), desquamative interstitial pneumonia (DIP), acute interstitial pneumonia (AIP), cryptogenic organizing pneumonia (COP) and lymphoid interstitial pneumonia (LIP), organ transplant fibrosis, systemic sclerosis, liver cirrhosis, macular eye degeneration, retinal and vitreal retinopathy, Crohn's/inflammatory bowel disease, nephrogenic systemic fibrosis, ulcerative colitis post surgical scar tissue formation, radiation and chemotherapeutic-drug induced fibrosis, and cardiovascular fibrosis including endomyocardial fibrosis.
Osteoporosis
Metformin, an indirect AMPK activator, has recently been investigated on the differentiation and mineralization of osteoblastic MC3T3-E1 cells as well as intracellular signal transduction. Metformin can increase collagen-l and osteocalcin mRNA expression, stimulate alkaline phosphatase activity, and enhance cell mineralization (Kanazawa et al. Biochem. Biophys. Res. Commun. 2008, 375(3), 414-419). Metformin can also, when activating AMPK, induce endothelial nitric oxide synthase (eNOS) and bone morphogenetic protein-2 (BMP-2) expressions. Thus, it may be that an AMPK activator can induce the differentiation and mineralization of osteoblasts via activation of the AMPK signaling pathway, and that an AMPK activator may find utility in the treatment of osteoporosis by promoting bone formation.
Renal disease
Recent studies on metabolic syndrome in patients with chronic kidney disease suggest that insulin resistance and hyperinsulinemia are independently associated with an increased prevalence of the disease. Insulin per se can promote the proliferation of mesangial cells and the production of matrix proteins, and also stimulates the expression of growth factors such as IGF-1 and TGF-β, that are involved in mitogenic and fibrotic processes in nephropathy. Insulin also interferes with the systemic RAS and specifically increases the effect of angiotensin Il on mesangial cells. Hyperinsulinemia also increases levels of endothelin-1 and is associated with increased oxidative stress, in conclusion, reduction of hyperinsulinemic levels may be of therapeutic value for patients with progressive renal disease (e.g. chronic renal failure; Sarafidis and Ruilope Am. J. Nephrol., 2006, 26, 232-244). Further on, adiponectin, an adipose-derived hormone, has been studied in the pathogenesis of albuminuria and has been shown to reduce renal abnormalities likely through activation of AMPK (Sharma et al J. Clin. Invest. 2008, 118(5) 1645-1656). Thus, an AMPK activator could have therapeutic potential in renal diseases.
Obesity
Obesity is associated with resistance to the effects of leptin and leptin stimulates fatty acid oxidation via the phosphorylation and activation of AMPK and Acetyl-CoA carboxylase (ACC). Studies in obese Wistar rats have shown a lower level of AMPK activation in diet-induced obesity. Thus, an AMPK activator may be of therapeutic value in obesity (Janovska A et al, MoI. Cell. Endocrinology. 2008, 284(1-2), 1-10. Central obesity is a typical sign of Cushing's syndrome. In a patient study the patients exhibited a 70% lower AMPK activity in visceral adipose tissue as compared to control patients. It was suggested that glucocorticoids inhibit AMPK activity in adipose tissue (Kola et al, J. Clin.Endocrinol. Metab. 2008, 93(12), 4969-4973). Therefore an AMPK activator may also be beneficial as a therapeutic in Cushing's syndrome.
Cardioprotection
In the heart, AMPK activity increases during ischemia and functions to sustain ATP, cardiac function and myocardial viability. The beneficial effects of AMPK activation provides the rationale for targeting AMPK in the development of new therapeutic strategies for cardiometabolic disease and cardioprotection (Wong et al, Clin. ScL, 2009, 116, 607-620). Sexual dysfunction
Erectile dysfunction is associated with reduced penile nitric oxide synthase (NOS) expression. Studies in obese rats show that treatment with the indirect AMPK activator metformin increase nNOS and eNOS expression in penile tissue. The levels of AMPK and phosphorylated AMPK were also decreased but were subsequently elevated by metformin treatment. These results suggest a role for AMPK activators in erectile dysfunction (Kim et al J. Andrology, 2007, 28 (4) 555-560).
Dry-type age-related macular degeneration
Oxidative stress causes retinal pigment epithelium (RPE) cell dysfunction and is a major risk factor leading to the development of dry-type age-related macular degeneration. Sublethal oxidative stress dose-dependently inhibits RPE cell phagocytosis of photoreceptor outer segments (POS) and activates AMPK. Aicar, a pharmacological activator of AMPK has also been shown to inhibit RPE cell phagocytosis of POS in a dose-dependent manner (Qin and De Vries, J. Biol. Chem. 2008, 283(11), 6744-6751). Thus, an AMPK activator could have therapeutic potential in treating dry macular degeneration.
Cancer
Investigations have demonstrated that cancer cells require high rates of fatty acid and protein synthesis for their invasive growth and survival. Studies have shown that inhibition of cancer cell proliferation is possibly using AMPK activators. The effects are associated with down-regulation of mTOR and eEF2. AMPK activators also suppress lipid synthesis in tumour cells. It has also been shown that it is a link between AMPK and other anti-cancer targets such as LKB1 and caspase-3 activation.
Polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in the human, affecting approximately 10% of women of reproductive age. The syndrome is associated with a wide range of endocrine and metabolic abnormalities, including insulin resistance (see Ehrmann et a/ (2006), J. CHn. Endocrinol. Metab., Jan 91 (1 ), 48- 53). PCOS patients are typically hyperinsulinemic and insulin resistant. Hyperinsulinemia may contribute to hyperandrogenic, anovulatory dysfunction via a multitude of ways. In vitro and in vivo studies suggest that insulin synergizes with LH to promote androgen production by thecal cells. Insulin inhibits hepatic synthesis of sex hormone binding globulin, thereby increasing the free pool of androgens (Nestler (1997), Hum. Reprod., Oct 12, Suppl 1 , 53-62).
Inflammation
It has been shown that activation of AMPK by AICAR (δ-aminoimidazole^-carboxamide) acts as a potent counter regulator of inflammation and AMPK activation may therefore play a role in disorders where inflammation occurs (Sag et al. (2008) J. Immunol. 181(12), 8633-8641), such as rheumatoid arthritis. Metformin, an indirect AMPK activator, could be shown to reduce several inflammatory parameters in animal models of multiple sclerosis and thus an AMPK activator could have a possible therapeutic value for the treatment of multiple sclerosis and other inflammatory diseases (Nath et al J. Immunology, 2009, 182, 8005-8014). AMPK plays a role in modulating neutrophil function and neutrophil-dependent inflammatory events, such as acute lung injury (Zhao et al, Am. J. Physiol. Lung Cell MoI. Physiol., 2008. 295. L497-L504. This may also apply to reduction of the inflammatory response present in asthmatic patients. Studies in mice that develop lupus-like disease similar to human systemic lupus erythematosus has shown that AMPK activation inhibits a inflammatory cascade. This observation suggests that an AMPK activator may be of therapeutic value for systemic lupus erythematosus (Radjavi et al, FASEB J.2008, 22:942.12).
Lung disease
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the developed world. Genetic studies have demonstrated an association of gene polymorphisms of the TGF-β superfamily with COPD. Increased expression of TGF-β1 in cells of COPD lungs was reported, suggesting an impact of TGF-β signalling on the development and progression of COPD. Thus, an AMPK activator that targets TGF-β signalling may represent a suitable therapeutic option in COPD (Kόnighof et al 2009, SWISS MED WKLY, 139(39-40):554-563).
In the last decade, TGF-β has emerged as an important contributor to small airway disease (SAD), also called obstructive bronchiolitis. Several studies have reported an increased expression of TGF-β1 in the airway epithelium of smokers. TGF-β1 expression in epithelial cells from patients with chronic bronchitis has been correlated with basal membrane thickness and the number of peribronchiolar fibroblasts. Also, in an in vivo model, in which mice exposed to cigarette smoke exhibited has shown enhanced pro- fibrotic TGF-β signalling in small airways. Thus, an AMPK activator that targets TGF-β signalling may represent a suitable therapeutic option in SAD.
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
Alemagna ef al. (1968) Tetrahedron, 24, 3209-3217, Zwanenburg et al. (1973) Tetrahedron Lett. 50, 5009-5012, Shafiee ef al. (1976) J. Heterocyclic Chem. 13, 117- 121 and Yarovenko et al. (2003) Russian Journal of Organic Chemistry, 39(8), 1133- 1139 disclose synthetic methods to make 1 ,3,4-thiadiazoles containing an aromatic group in the 2- or 5-position (depending upon substitution pattern). However, there is no mention or suggestion in these documents of thiadiazoles that are substituted both the 2- and 5-position with a heteroaromatic or, particularly, aryl group via a linker group.
Bokin Bobai (1982), 10(8), 341-346, Pharmazie (1979), 34(9), 537-538 and Indian J. Chem. Sect B. (2008), 476, 579, disclose 1 ,3,4-thiadiazoles containing an unsubstituted phenyl group attached via an alkyl linker in the 2- or 5- position (depending on substitution). There is no suggestion or disclosure of 1 ,3,4-thiadiazoles containing a substituted phenyl group attached via an alkyl linker.
WO 2005/002673 and WO 2004/004720 disclose a single thiadiazole for use in the treatment of diseases that may be ameliorated by the inhibition of raf kinase (e.g. Alzheimer's disease). There is no suggestion or disclosure of 1 ,3,4-thiadiazoles substituted in the 5-position by a substituted phenyl group attached via an alkyl linker.
Kramer ef al. (1994) J. Heterocyclic Chem. 31 , 1439-1443 discloses a series of 2,6-di- fe/f-butylphenols linked to 1 ,3,4-oxadiazoles and 1 ,3,4-thiadiazoles via a number of linking groups in the 5-position, which may have anti-inflammatory activity. However, there is no mention of the use of the compounds disclosed therein in the treatment of diabetes or of thiadiazoles or oxadiazoles that are also substituted in the 2-position with a heteroaromatic or, particularly, aryl group via a linker group. Toyooka et al. (1991), Chem. Pharm. Bull. 39(11), 2837-2841 discloses a series of 1 ,3,4- thiadiazolyl acetic, propionic and glutaric acids with anti-inflammatory activity. However, there is no mention of the use of the compounds disclosed therein in the treatment of diabetes or of thiadiazoles or oxadiazoles that are substituted in the 5-position with a heteroaromatic or, particularly, aryl group via an alkylene linker group and in the 2- position with a heteroaromatic or, particularly, aryl group via a linker group containing at least one heteroatom.
Boots et al. (1967), J. Heterocyclic Chem. 4, 272-283, Foroumadi et al. (2006) Arch. Pharm. Chem. Life. ScL 338, 112-116 and Kidwai et al. (2000) Bioorg. Med. Chem., 8, 69-72 disclose thiaziazole or oxadiazole compounds with various antimicrobial activities. However, there is no mention of the use of the compounds disclosed therein in the treatment of diabetes or of thiadiazoles that are substituted in the 5-position with a heteroaromatic or, particularly, aryl group via an alkylene linker group and in the 2- position with a heteroaromatic or, particularly, aryl group via a linker group containing at least one heteroatom.
International patent application WO 2007/044565 discloses thiadiazole compounds for use in the treatment of HIV by inhibition of Viron Infectivity Factor (Vif). However, there is no mention of the use of thiadiazoles in the treatment of diabetes or for other therapeutic uses.
Vaillancourt et al. (2000) Bioorg. Med. Chem. Lett. 10, 2079-2081 , discloses thiadiazole compounds containing a naphthalene substituent attached via and amido linker for use in the treatment of human cytomegalovirus. However, there is no mention of thiadiazoles that are substituted in the 2-position with a single-ringed heteroaromatic or, particularly, aryl group.
Manetti et al. (2006) J. Med. Chem., 49, 3278-3286, discloses thiadiazole compounds containing an unsubstituted benzyl group in the 5-position and a phenyl group in the 2- position attached via an amido or urea linker for use in the treatment of cancer. There is no suggestion or disclosure of 1 ,3,4-thiadiazoles substituted in the 5-position by a substituted phenyl group attached via an alkyl linker. US 4054665 discloses inter alia thiadiazoles. However, there is no mention of the use of the compounds disclosed therein in the treatment of diabetes.
US 2524729 discloses inter alia thiadiazoles. However, there is no mention of the use of the compounds disclosed therein in the treatment of diabetes.
Ladwa et al. (2002) Oriental J. Chem., 18(1) 135-138 discloses inter alia thiadiazoles. However, there is no mention of the use of the compounds disclosed therein in the treatment of diabetes.
Bovet el al (1944) Comptes Rendus des Seances de Ia Societe de Biologie et de sestiliales, 138, 764-765 discloses inter alia thiadiazoles that may be useful in the treatment of diabetes. Bovet el al discloses that a thiadiazole bearing an unsubstituted benzyl substituent in the 5-position does not have hypoglycemic activity and there is no disclosure or suggestion of substituted benzyl substituents in the 5-position.
Klosa et al. (1954) Arc. Pharm. 287,12-14 discloses inter alia thiadiazoles. However, there is no mention of the use of the compounds disclosed therein in the treatment of diabetes.
Healy et al. (1960) British Medical Journal, 913-915 discloses inter alia thiadiazoles that may be useful in the treatment of diabetes. However, there is no mention or suggestion in this document of thiadiazoles that are substituted in the 5-position with a heteroaromatic or, particularly, aryl group via an alkylene linker group.
Hokfelt et al (1962) J. Med. Pharm. Chem., 5, 247-257 discloses inter alia thiadiazoles and 1 ,3,4-oxadiazoles that may be useful in the treatment of diabetes. However, there is no mention or suggestion in this document of thiadiazoles that are substituted in the 5- position with a heteroaromatic or, particularly, aryl group via an alkylene linker group.
Avetisyan et al. (1981) Khimika-Farmasevticheskii Zhurnal, 15(6), 416-418 discloses 2- benzenesulfonamido-5-para-alkoxybenzyl-1 ,3,4-thiadiazoles that may be useful in the treatment of diabetes. However, there is no mention or suggestion in this document of thiadiazoles wherein the 5-position is substituted with anything other than a para- alkoxybenzyl group. Chubb et al (1959) Can. J. Chem. 37, 1121-1123 discloses inter alia thiadiazoles that may show hypoglycemic activity. However, there is no mention or suggestion in this document of thiadiazoles that are substituted in the 5-position with a heteroaromatic or, particularly, an aryl group via an alkylene linker group.
WO 2004/103980 discloses inter alia thiadiazoles that may be useful in the treatment of diabetes. However, there is no mention or suggestion in this document of thiadiazoles substituted in the 5-position with an aromatic substituent that is attached via an alkylene linker and which aromatic group is substituted with an electron withdrawing group selected from the group consisting of bromo, iodo, fluoro, trifluoromethyl, nitrile, carbonyl groups, carboxylate groups, quarternary ammonium groups and sulfonate groups in the para-position.
JP 03258771 discloses inter alia 1 ,2,4-oxadiazoles that may be useful as herbicides. However, there is no mention of the use of the compounds disclosed therein in the treatment of diabetes.
International patent application WO 2008/104524 discloses thiadiazole compounds containing a tetrahydroisoquinoline substituent attached via an amido linker group for use in the treatment of diseases, including those mediated by SCD enzyme (e.g. diabetes, cancer and Alzheimer's disease). There is no mention of thiadiazoles that are substituted in the 2-position with a tetrahydroisoquinoline attached via anything other than an amido linker group.
International patent applications WO 2007/010273 and WO 2007/010281 both disclose e.g. thiazolidin-4-one compounds that are able to antagonize the stimulatory effect of FFAs on cell proliferation when tested in an assay using a human breast cancer cell line (MDA-MB-231). Such compounds are thus indicated in the treatment of cancer and/or as modulators of FFAs.
Disclosure of the Invention
According to the invention, there is provided a compound of formula I,
Figure imgf000015_0001
wherein:
X represents -Q-[CRxRy]n-Z- or -C(O)-;
T represents N1 or more preferably S or O;
G represents O, or more preferably, N; provided that when T is O or S, then G is N, and provided that when T is N, then G is O; when G is N, the dotted line between the point of attachment of X to the ring and G is a double bond and the dotted line between the point of attachment of X to the ring and T is a single bond; when T is N, the dotted line between the point of attachment of X to the ring and T is a double bond and the dotted line between the point of attachment of X to the ring and G is a single bond;
Y represents -S-[CH2Iq-, preferably, -NHC(O)-[CH2IrB-, -C(O)NH-[CH2JrB- or, more preferably, -C(O)-, -NHS(O)2-[CH2Jq-, -NHN=CH-, -NHNHS(O)2-, -NHNHC(O)-,
-NHC(O)NH-, -NHC(O)O-, -NHS(O)2NH-, -0-[CH2]q-, -S(O)2-, -S(O)2NH-;
Ai to A5 respectively represent C(R1), C(R2), C(R3), C(R4) and C(R5), or, alternatively, up to two of A1 to A5 may independently represent N;
Di to D5 each respectively represent C(R6a), C(R6b), C(R6c), C(R6d) and C(R6e), or, alternatively, up to two of D1 to D5 may independently represent N;
Q and Z independently represent S(O)2, or more preferably, a bond, S, or O;
B represents S(O)2, or more preferably, a bond, S, or O; one of Rx and Ry is Cy1 or Het1 (which latter two groups are optionally substituted by one or more R6f substituents) and the other is H or, more preferably, Rx and Ry are independently selected from H, halo, C1-6 alkyl (optionally substituted by one or more halo atoms), or Rx and Ry are linked to form, along with the carbon atom to which they are attached, a non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or Ci-6 alkyl (optionally substituted by one or more halo atoms);
Cy1 represents a 5- to 8-membered aromatic, fully saturated or partially unsaturated carbocyclic ring; Het1 represents a 5- to 8-membered heterocyclic group that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N;
R1 to R5 independently represent H, halo, -R7, -CF3, -CN, -NO2, -C(O)R7, -C(O)OR7, -N(R7a)R7b, -N(RV, -SR7, -OR7, -NH(O)R7 or -SO3R7, or any two of R1 to R5 which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I, an aromatic or non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo, -R7, -OR7 and =0;
R6a to R6e independently represents, on each occasion when used herein, H, cyano, -NO2, halo, -R8, -OR8, -N(R8)C(O)R8, -NR9R10, -SR11, -Si(R12J3, -OC(O)R13, -C(O)OR13, -C(O)R14, -C(O)NR15aR15b, -S(O)2NR15cR15d, aryl or heteroaryl (which aryl and heteroaryl groups are themselves optionally and independently substituted by one or more groups selected from halo and R16), or any two R6a to R6e groups which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I1 an aromatic or non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo, -R7, -OR7 and =0; R6f independently represents H, halo, -R7, -CF3, -CN, -NO2, -C(O)R7, -C(O)OR7, -N(R7a)R7b, -N(RV, -SR7, -OR7, -NH(O)R7 or -SO3R7, or any two R6f substituents which are adjacent to each other are optionally linked to form, along with two atoms of the essential ring to which they are attached, an aromatic or non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo, -R7, -OR7 and =0;
R7, on each occasion when used herein, is selected from H or CrC6 alkyl, Ci-C6 cycloalkyl, aryl and heteroaryl (wherein the latter four groups are optionally substituted by one or more halo atoms);
R7a and R7b are independently selected from H, or C1-C6 alkyl, Ci-C6 cycloalkyl, aryl and heteroaryl, or R7a and R7b are optionally linked to form, along with the nitrogen atom to which they are attached, an aromatic or non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo, -R7, -OR7 and =0; R8, R9, R10, R11, R12, R13, R14, R15a, R15b, R15c and R15d, on each occasion where used herein, independently represent H or R16; R16 represents, on each occasion when used herein, CL6 alkyl optionally substituted by one or more halo atoms; n represents 3, or preferably, 1 or 2; q represents, on each occasion where used herein, 0, 1 or 2; r represents 0, 1 , 2 or 3; or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof for use in the treatment of a condition or disorder ameliorated by the activation of AMPK.
Pharmaceutically-acceptable salts that may be mentioned include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of formula I in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
Examples of pharmaceutically acceptable addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids; from organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, arylsulphonic acids; and from metals such as sodium, magnesium, or preferably, potassium and calcium.
"Pharmaceutically functional derivatives" of compounds of formula I as defined herein includes ester derivatives and/or derivatives that have, or provide for, the same biological function and/or activity as any relevant compound. Thus, for the purposes of this invention, the term also includes prodrugs of compounds of formula I.
The term "prodrug" of a relevant compound of formula I includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)). For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral administration. Prodrugs of compounds of formula I may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesizing the parent compound with a prodrug substituent. Prodrugs include compounds of formula I wherein a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group in a compound of formula I is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.
Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N- Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs" p. I-92, Elesevier, New York-Oxford (1985).
Compounds of formula I, as well as pharmaceutically-acceptable salts, solvates and pharmaceutically functional derivatives of such compounds are, for the sake of brevity, hereinafter referred to together as the "compounds of formula I".
Compounds of formula I may contain double bonds and may thus exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.
Compounds of formula I may exist as regioisomers and may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.
Compounds of formula I may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a 'chiral pool' method), by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by •conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.
Unless otherwise stated, the term "alkyl" refers to an unbranched or branched, cyclic, saturated or unsaturated (so forming, for example, an alkenyl or alkynyl) hydrocarbyl radical, which may be substituted or unsubstituted (with, for example, one or more halo atoms). Where the term "alkyl" refers to an acyclic group, it is preferably CM0 alkyl and, more preferably, Ci-6 alkyl (such as ethyl, propyl, (e.g. n-propyl or isopropyl), butyl (e.g. branched or unbranched butyl), pentyl or, more preferably, methyl). Where the term "alkyl" is a cyclic group (which may be where the group "cycloalkyl" is specified), it is preferably C3-I2 cycloalkyl and, more preferably, C5.10 (e.g. C5-7) cycloalkyl.
When used herein, alkylene refers to d.i0 (e.g. Ci-6) alkylene and, preferably Ci-3 alkylene, such as pentylene, butylene (branched or unbranched), preferably, propylene (π-propylene or isopropylene), ethylene or, more preferably, methylene (i.e. -CH2-).
The term "halogen", when used herein, includes fluorine, chlorine, bromine and iodine.
The term "aryl" when used herein includes C6-I4 (such as C6-I3 (e.g. C6-I0)) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 14 ring carbon atoms, in which at least one ring is aromatic. The point of attachment of aryl groups may be via any atom of the ring system. However, when aryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule via an aromatic ring. C6-I4 aryl groups include phenyl, naphthyl and the like, such as 1 ,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl. Most preferred aryl groups include phenyl.
Unless otherwise stated, the term "carbocyclic" when used herein in connection with the Cy1 group includes references to carbocyclic groups (e.g. Cs-6 carbocyclic groups) that are monocyclic and which may be may be fully saturated, partly unsaturated or wholly aromatic in character. For example, Cy1 groups may be selected from the group comprising of cyclobutyl, cyclobutenyl, cyclopropyl, cyclopropenyl, preferably cyclopentenyl, more preferably, cyclohexenyl, yet more particularly, cyclopentyl, cyclohexyl, and phenyl. The point of attachment of carbocyclic groups may be via any atom of the ring system. Unless otherwise stated herein, the term "heterocyclic", when used herein in connection with the Het1 group includes references to heterocyclic groups that are monocyclic and which may be fully saturated, partly unsaturated or wholly aromatic in character.
Thus Het1 represents a 5- to 8-membered heterocyclic group, that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N.
The Het1 group may contain up to 3 heteroatom ring members selected from O, N and S. For example, the heterocyclic group may contain 1 , 2 or 3 heteratom ring members.
For example, Het1 may be selected from the group comprising of azepinyl, diazepinyl, dihydrofuranyl (e.g. 2,3-dihydrofuranyl, 2,5-dyhdrofuranyl), 4,5-dihydro-1/-/-maleimido, dioxolanyl, furanyl, furazanyl, hydantoinyl, imidazolyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, 1 ,2- or 1 ,3-oxazinanyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolinyl, pyrrolyl, sulfolanyl, 3-sulfolenyl, tetrahydrofuranyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, thiomorpholinyl, triazolyl, more preferably, dihydropyranyl (e.g. 3,4- dihydropyranyl, 3,6-dihydropyranyl), dioxanyl, hexahydropyrimidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, tetrahydropyranyl, 3,4,5,6-tetrahydropyridinyl, 1 ,2,3,4- tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl, tetrahydrothiophenyl, tetramethylenesulfoxide, thiazolidinyl, triazinanyl and the like. The point of attachment of Het1 groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
The term "heteroaryl" when used herein refers to an aromatic group containing one or more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, O and S (so forming, for example, a mono-, bi-, or tricyclic heteroaromatic group). Heteroaryl groups include those which have between 5 and 14 (e.g. 10) members and may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic. However, when heteroaryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule via an aromatic ring. Heterocyclic groups that may be mentioned include benzothiadiazolyl (including 2,1 ,3-benzothiadiazolyl), isothiochromanyl and, more preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1 ,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl, benzoxadiazolyl (including 2,1 ,3-benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro- 2H-1 ,4-benzoxazinyl), benzoxazolyl, benzomoφholinyl, benzoselenadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo[1 ,2-a]pyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isoxazolyl, naphthyridinyl (including 1 ,6-naphthyridinyl or, preferably, 1 ,5-naphthyridinyl and 1 ,8-naphthyridinyl), oxadiazolyl (including 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl and 1 ,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1 ,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1,2,3,4- tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl and 1 ,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thiophenetyl, thienyl, triazolyl (including 1 ,2,3-triazolyl, 1 ,2,4-triazolyl and 1 ,3,4-triazolyl) and the like. Substituents on heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heteroaryl groups may also be in the N- or S- oxidised form. Particularly preferred heteroaryl groups include pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl, indazolyl, pyrimidinyl, thiophenetyl, pyranyl, carbazolyl, acridinyl, quinolinyl, benzoimidazolyl, benzthiazolyl, purinyl, cinnolinyl and pterdinyl. Particularly preferred heteroaryl groups include monocylic heteroaryl groups.
For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of formula I may be the same, the actual identities of the respective substituents are not in any way interdependent. For example, given that Cy1 and Het1 may be optionally substituted by one or more R6f groups then those R6f groups may be the same or different. Similarly, in the situation in which R6 and R7 are both aryl groups substituted by one or more Ci-6 alkyl groups, the alkyl groups in question may be the same or different. Additionally, in the situation in which R8, R9, R10, R11, R12, R13, R14, R15a, R15b, R15c and R15d independently represent R16 then those R16 groups may be the same or different. For the avoidance of doubt, when a term such as "Ai to A5" is employed herein, this will be understood by the skilled person to mean any of (i.e. some or all, as applicable) A1, A2, A3, A4 and A5 inclusively.
Some compounds of formula I are novel per se. In this respect, there is further provided a compound of formula I as hereinbefore defined, provided that:
(i) when T represents O, X represents -Q-[CRxRy]n-Z- and Rx and Ry are independently selected from H, halo or C1-6 alkyl (optionally substituted by one or more halo atoms), then Y represents -NHC(O)NH- or, more preferably, -C(O)-,
-NHS(O)2-[CH2Jq-, -NHN=CH-, -NHNHS(O)2-, -NHNHC(O)-, -NHC(O)O-, -NHS(O)2NH-,
-0-ICH2Iq-, -S(O)2-, -S(O)2NH-;
(ii) when T represents S, X represents -Q-[CR^n-Z-, Z represents S, Q represents a bond and Rx and Ry are independently selected from H, halo or Ci-6 alkyl (optionally substituted by one or more halo atoms), then Y represents -C(O)-,
-NHS(O)HCH2Iq-, -NHN=CH-, -NHNHS(O)2-, -NHNHC(O)-, -NHC(O)NH-, -NHC(O)O-,
-NHS(O)2NH-, -0-[CH2Jq-, -S(O)2-, -S(O)2NH-;
(iii) when T represents S, X represents -Q-[CRxRy]n-Z- and Rx and Ry are independently selected from H, halo or Ci-6 alkyl (optionally substituted by one or more halo atoms), then Y represents -C(O)-, -NHS(O)2-[CH2]q-, -NHN=CH-, -NHNHS(O)2-,
-NHC(O)O-, -NHS(O)2NH-, -S-[CH2Jq-, -0-[CH2Jq-, -S(O)2-, -S(O)2NH-;
(iv) when T represents S, X represents -Q-[CRxRy]n-Z-, Z represents a bond, Q represents O or S, Rx and Ry are independently selected from H, halo or Ci-6 alkyl
(optionally substituted by one or more halo atoms), C(R1) to C(R4) are all H, C(R5) represents H, OCH3 or Cl and when:
(a) C(Ra), C(Rb), C(Rd) and C(Re) represent H and C(RC) represents C(H) or ' C(CI);
(b) C(R6a) represents C(CH3), C(R6b) represents C(CI) and C(R6c) to C(R6e) represent C(H); or
(C) C(R6e) represents C(CH3), C(R6d) represents C(CI) and C(R6a) to C(R6c) represent C(H), then
Y represents -C(O)-, -NHN=CH-, -NHNHS(O)2-, -NHC(O)O-, -NHS(O)2NH-, -S-[CH2Jq-, -0-[CH2Jq-, -S(O)2-, -S(O)2NH-;
(v) when T represents S, X represents -Q-[CRxRy]n-Z-, Z represents a bond, Q represents a bond, Rx and Ry are independently selected from H, halo or Ci-6 alkyl (optionally substituted by one or more halo atoms) and when: (a) C(R1) to C(R4) are all C(H), C(R5) represents C(H), C(OCH3) or C(CI), C(Ra), C(Rb), C(Rd) and C(Re) represent C(H) and C(RC) represents C(H), C(CI), C(Br), C(F)1 C(CH3), C(OCH3), C(NHC(O)CH3);
(b) C(R1) to C(R4) are all C(H), C(R5) represents C(OCH3), C(Rb) and C(Rd) represent H and C(Ra), C(R0) and C(Re) represent C(CH3);
(C) C(R1) and C(R3) are C(H), C(R5) represents C(OCH3), one of C(R2) and
C(R4) represents C(OCH3) while the other represents C(H) and C(RC) represents C(CI) or C(OCH3); or (d) one of C(R1) or C(R3) represents C(OCH3), while the other represents
C(H), C(R2), C(R4) and C(R5) represent H, and C(Ra) to C(Rd) represent
H, then
Y represents -C(O)-, -NHN=CH-, -NHNHS(O)2-, -NHC(O)O-, -NHS(O)2NH-, -S-[CH2Iq-. -0-[CH2]q-, -S(O)2-, -S(O)2NH-; and
(vi) when T represents S, X represents -Q-[CRxRy]n-Z-, Z represents a bond, Q represents a bond, Rx and Ry are independently selected from H, d-6 alkyl (optionally substituted by one or more halo atoms), C(R6a) represents C(CH3), C(R6b) represents C(CI) and C(R6c) to C(R6e) represent C(H) or C(R6e) represents C(CH3), C(R6d) represents C(CI) and C(R6a) to C(R6c) represent C(H) and when:
(a) C(R1) to C(R5) are all H;
(b) C(R5) represents C(CI), C(F) or C(NO2) and C(R1) to C(R4) are all H;
(c) one of C(R1) or C(R3) represents C(F) or C(OCH3), while the other represents C(H) and C(R2), C(R4) and C(R5) represent C(H); or
(d) one of A2 or A4 represents N, the other represents C(H) and C(R1), C(R3) and C(R5) represent C(H), then
Y represents -C(O)-, -NHN=CH-, -NHNHS(O)2-, -NHC(O)O-, -NHS(O)2NH-, -S-[CH2Jq-, -0-[CH2Iq-, -S(O)2-, -S(O)2NH-, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof.
Some compounds of formula I are novel per se. In this respect, there is further presented the following embodiments.
(i) T represents O, X represents -Q-[CR*Ry]n-Z- and Rx and Ry are independently selected from H, halo or Ci-6 alkyl (optionally substituted by one or more halo atoms), and Y represents -NHC(O)NH- or, more preferably, -C(O)-, -NHS(O)2-[CH2Jq-, -NHN=CH-, -NHNHS(O)2-, -NHNHC(O)-, -NHC(O)O-, -NHS(O)2NH-,
-0-[CH2Jq-, -S(O)2-, -S(O)2NH- or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof.
(ii) T represents S, X represents -Q-[CRxRy]n-Z-, Z represents S, Q represents a bond and Rx and Ry are independently selected from H1 halo or Ci-6 alkyl (optionally substituted by one or more halo atoms), and Y represents -C(O)-,
-NHS(O)2-[CH2Jq-, -NHN=CH-, -NHNHS(O)2-, -NHNHC(O)-, -NHC(O)NH-, -NHC(O)O-,
-NHS(O)2NH-, -0-[CH2Jq-, -S(O)2-, -S(O)2NH- or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof.
(iii) T represents S, X represents -Q-[CRxRy]n-Z- and R* and Ry are independently selected from H, halo or Ci-6 alkyl (optionally substituted by one or more halo atoms), and Y represents -C(O)-, -NHS(O)2-[CH2Jq-, -NHN=CH-, -NHNHS(O)2-,
-NHC(O)O-, -NHS(O)2NH-, -S-[CH2Jq-, -O-[CH2]q-, -S(O)2-, -S(O)2NH- or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof.
(iv) T represents S, X represents -Q-[CR^n-Z-, Z represents a bond, Q represents
O or S, Rx and Ry are independently selected from H, halo or Ci-6 alkyl (optionally substituted by one or more halo atoms), C(R1) to C(R4) are all H, C(R5) represents H,
OCH3 or Cl, C(Ra) to C(Rb) are selected from:
(a) C(Ra), C(Rb), C(Rd) and C(Re) represent H and C(RC) represents C(H) or ' C(CI);
(b) C(R6a) represents C(CH3), C(R6b) represents C(CI) and C(R6c) to C(R6e) represent C(H); or
(C) C(R6e) represents C(CH3), C(R6d) represents C(CI) and C(R6a) to C(R6c) represent C(H), and
Y represents -C(O)-, -NHN=CH-, -NHNHS(O)2-, -NHC(O)O-, -NHS(O)2NH-, -S-[CH2Jq-, -0-[CH2Jq-, -S(O)2-, -S(O)2NH- or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof.
(v) T represents S1 X represents -Q-[CRxRy]n-Z-, Z represents a bond, Q represents a bond, Rx and Ry are independently selected from H, halo or C1-6 alkyl (optionally substituted by one or more halo atoms), C(R1) to C(R5) and C(Ra) to C(Re) are selected from:
(a) C(R1) to C(R4) are all C(H), C(R5) represents C(H), C(OCH3) or C(CI)1 C(Ra), C(Rb), C(Rd) and C(Re) represent C(H) and C(RC) represents C(H), C(CI), C(Br), C(F), C(CH3), C(OCH3), C(NHC(O)CH3); (b) C(R1) to C(R4) are all C(H), C(R5) represents C(OCH3), C(Rb) and C(Rd) represent H and C(Ra), C(RC) and C(Re) represent C(CH3);
(c) C(R1) and C(R3) are C(H), C(R5) represents C(OCH3), one of C(R2) and C(R4) represents C(OCH3) while the other represents C(H) and C(RC) represents C(CI) or C(OCH3); or
(d) one of C(R1) or C(R3) represents C(OCH3), while the other represents C(H), C(R2), C(R4) and C(R5) represent H, and C(Ra) to C(Rd) represent H, and
Y represents -C(O)-, -NHN=CH-, -NHNHS(O)2-, -NHC(O)O-, -NHS(O)2NH-, -S-[CH2Jq-, -0-[CH2]q-, -S(O)2-, -S(O)2NH- or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof.
(vi) T represents S, X represents -Q-[CRxRy]n-Z-, Z represents a bond, Q represents a bond, Rx and Ry are independently selected from H, Ci-6 alkyl (optionally substituted by one or more halo atoms), C(R6a) represents C(CH3), C(R6b) represents C(CI) and C(R6c) to C(R66) represent C(H) or C(R6e) represents C(CH3), C(R6d) represents C(CI) and C(R6a) to C(R60) represent C(H) and C(R1) to C(R5) are selected from:
(a) C(R1) to C(R5) are all H;
(b) C(R5) represents C(CI), C(F) or C(NO2) and C(R1) to C(R4) are all H;
(c) one of C(R1) or C(R3) represents C(F) or C(OCH3), while the other represents C(H) and C(R2), C(R4) and C(R5) represent C(H); or
(d) one of A2 or A4 represents N, the other represents C(H) and C(R1), C(R3) and C(R5) represent C(H), and
Y represents -C(O)-, -NHN=CH-, -NHNHS(O)2-, -NHC(O)O-, -NHS(O)2NH-, -S-[CH2],,-, -0-[CH2Iq-, -S(O)2-, -S(O)2NH-, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof.
For the avoidance of doubt, each of the preferred embodiments (i) to (vi) may be applied separately (i.e. individually) as a preferred definition of the compounds of formula I, or may be taken together in any combination thereof in defining more preferred compounds of formula I.
Alternatively, there is further provided a compound of formula I as hereinbefore defined, provided that: when T represents S, G represents N1 X represents -Q-[CRxRy]n-Z- and Rx and Ry are independently selected from H, halo, C1-6 alkyl (optionally substituted by one or more halo atoms), then: a) Y represents -C(O)-, -NHS(O)2-[CH2]q-, -NHN=CH-, -NHNHS(O)2-, -NHC(O)O-, -NHS(O)2NH-, -S-[CH2Jq-, -0-[CH2Iq-, -S(O)2-, -S(O)2NH-; and b) further, when Rx and Ry are independently selected from H or Ci-6 alkyl, Y represents -NHS(O)2-[CH2]q- and Z represents a bond, then Q represents a bond, A2 represents C(R2), A4 represents C(R4), at least one of R1 to R5 is not H, at least one R6 group is not H1 and R5, when present, represents H, Br, I1 F1 -CF3, -CN1 -C(O)R7, -C(O)OR7 or -N(R7J3 +, or any two of R1 to R5 which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I1 an aromatic or non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O1 S and N1 which ring is itself optionally substituted by one or more substituents selected from halo or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof.
Alternatively, there is further provided a compound of formula I as hereinbefore defined, wherein at least two of R6a to R6e are selected from Cl, F and OCH3 with the remainder each representing H; and
Y represents -S-[CH2Iq- or, preferably, -C(O)-, -NHS(O)2-[CH2Jq-, -NHN=CH-, -NHNHS(O)2-, -NHC(O)O-, -NHS(O)2NH-, -O-[CH2]q-, -S(O)2-, -S(O)2NH- or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof.
Alternatively, there is further provided a compound of formula I as hereinbefore defined, wherein
R6c represents Cl or F; one of R6b or R6d represents Cl and the other represents H; and
Y represents -S-[CH2]q- or, preferably, -C(O)-, -NHS(O)2-[CH2]q-, -NHN=CH-, -NHNHS(O)2-, -NHC(O)O-, -NHS(O)2NH-, -O-[CH2]q-, -S(O)2-, -S(O)2NH- or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof
(e.g. R6c represents Cl; X represents -CH2-; one of R6b or R6d represents Cl and the other represents H; and
Y represents -NHS(O)2-[CH2Jq-, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof).
Alternatively, there is further provided a compound of formula I as hereinbefore defined, wherein at least one of R6ato R6e represents OCHF2, OCF3 or CF3 and
Y represents -S-[CH2Jq- or, preferably, -C(O)-, -NHS(O)2-[CH2Jq-, -NHN=CH-, -NHNHS(O)2-, -NHC(O)O-, -NHS(O)2NH-, -0-[CH2Jq-, -S(O)2-, -S(O)2NH- or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof. Alternatively, there is further provided a compound of formula I as hereinbefore defined, wherein Q represents S(O)2 and Z represents S, O or, more preferably, a bond.
Alternatively, there is further provided a compound of formula I as hereinbefore defined, wherein Z represents S and Y represents -C(O)-, -NHS(O)2-[CH2Jq-, -NHN=CH-, -NHNHS(O)2-, -NHC(O)O-, -NHS(O)2NH-, -0-[CH2Jq-, -S(O)2-, -S(O)2NH-.
Alternatively, there is further provided a compound of formula I as hereinbefore defined, wherein Y represents -C(O)-, -NHN=CH-, -NHNHS(O)2-, -NHC(O)O-, -NHS(O)2NH-, -S(O)2-, -S(O)2NH-.
Alternatively, there is further provided a compound of formula I as hereinbefore defined, wherein
Q and Z represent a bond; n represents 1 ; one of Rx and Ry is is Cy1 or Het1 (which latter two groups are optionally substituted by one or more R6f substituents), and the other is H; and
Y represents -S-[CH2Jq- or, preferably, -C(O)-, -NHS(O)2-[CH2Jq-, -NHN=CH-, -NHNHS(O)2-, -NHC(O)O-, -NHS(O)2NH-, -O-[CH2]q-, -S(O)2-, -S(O)2NH- or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof.
Alternatively, there is further provided a compound of formula I as hereinbefore defined, wherein n represents 1 ; Rx and Ry are linked to form, along with the carbon atom to which they are attached, a non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or C1-6 alkyl (optionally substituted by one or more halo atoms).
Compounds of formula I that may be mentioned include those in which: Rx and Ry are linked to form, along with the carbon atom to which they are attached, a non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or Ci-6 alkyl (optionally substituted by one or more halo atoms).
Further compounds of formula I that may be mentioned include those in which: Rx and Ry are linked to form, along with the carbon atom to which they are attached, a cyclobutyl, cyclopentyl, cyclohexyl or, more preferably, cyclopropyl ring which ring is itself optionally substituted by one or more substituents selected from halo or Ci-6 alkyl (optionally substituted by one or more halo atoms, or more preferably unsubstituted).
Compounds of formula I that may be mentioned include those in which: each -[CRxRy]- unit may be independently selected from:
(a) a unit wherein Rx and Ry are independently selected from H, halo, Ci-6 alkyl (optionally substituted by one or more halo atoms);
(b) a unit wherein Rx and Ry are linked to form, along with the carbon atom to which they are attached, a non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or Ci-6 alkyl (optionally substituted by one or more halo atoms); and
(c) a unit wherein -[CRxRy]- may represent -[CH(Cy3)]- or -[CH(Hetc)]-, which Cy3 and Hetc groups are optionally substituted by one or more R5 substituents), provided that no more than one unit is selected from (b) or (c) (e.g. each -[CR1^- unit may be independently selected from:
(a) a unit wherein Rx and Ry are independently selected from H, halo, Ci-3 alkyl (optionally substituted by one or more halo atoms);
(b) a unit wherein Rx and Ry are linked to form, along with the carbon atom to which they are attached, a non-aromatic ring selected from cyclobutyl, cyclopentyl, cyclohexyl or, more particularly, cyclopropyl, which ring is itself optionally substituted by one or more substituents selected from halo or Ci-6 alkyl (optionally substituted by one or more halo atoms); and
(c) a unit wherein -[CFW]- may represent -[CH(phenyl)]- or -[CH(pyridyl)]-, which groups are optionally substituted by one or more R5 substituents), provided that no more than one unit (e.g. no units) is selected from (b) or (c)).
Further compounds of formula I that may be mentioned include those in which: one -[CRxRy]- unit forms a non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or Ci-6 alkyl (optionally substituted by one or more halo atoms) and, if other -[CRxRy]- units are present, then the additional Rx and Ry groups are independently selected from H, halo, Ci-6 alkyl (optionally substituted by one or more halo atoms).
Further compounds of formula I that may be mentioned include those in which: one -[CR51RH- unit is linked to form a cyclobutyl, cyclopentyl, cyclohexyl or, more preferably, cyclopropyl ring which ring is itself optionally substituted by one or more substituents selected from halo or Ci-6 alkyl (optionally substituted by one or more halo atoms, or more preferably unsubstituted) and, if other -[CRxRy]- units are present, then the additional Rx and Ry groups are independently selected from H, halo, Ci-6 alkyl (optionally substituted by one or more halo atoms).
Compounds of formula I that may be mentioned include those in which: when either one of Rx and Ry is Ci-6 alkyl, then it is unsubstituted, or more preferably substituted by one or more halo atoms.
Compounds of formula I that may be mentioned include those in which: one of Rx and Ry is is Cy1 or Het1 (which latter two groups are optionally substituted by one or more R6f substituents) and the other is H or, more preferably,
Rx and Ry are independently selected from H, halo, C1-6 alkyl (substituted by one or more halo atoms).
Compounds of formula I that may be mentioned include those in which:
Rx and Ry are independently selected from halo, Ci-6 alkyl (substituted by one or more halo atoms). Compounds of formula I that may be mentioned include those in which: at least one of Rx and Ry is unsubstituted Ci-6 alkyl.
Compounds of formula I that may be mentioned include those in which: one of Rx and Ry is an optionally substituted phenyl and the other is H.
Compounds of formula I that may be mentioned include those in which: Rx and Ry are independently selected from H, halo, C1-6 alkyl (substituted by one or more halo atoms), or Rx and Ry are linked to form, along with the carbon atom to which they are attached, a non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or Ci-6 alkyl (optionally substituted by one or more halo atoms).
Compounds of formula I that may be mentioned include those in which: Cy1 represents cyclopentane, cyclohexane or, more preferably, phenyl.
Compounds of formula I that may be mentioned include those in which:
Het1 represents pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidinyl or morpholinyl.
Compounds of formula I that may be mentioned include those in which:
X represents -[CH(Ph)Ji-, -C(O)-, preferably -Q-[CR^VZ-, °r yet more preferably,
-[CH2In-.
Compounds of formula I that may be mentioned include those in which: X represents -C(O)-, preferably -Q-[CR^n-Z-, or more preferably, -[CH2In--
Compounds of formula I that may be mentioned include those in which: Q represents S(O)2, preferably O or, more preferably, a bond.
Compounds of formula I that may be mentioned include those in which: Z represents S, preferably O or, more preferably, a bond.
Compounds of formula I that may be mentioned include those in which: Y represents -C(O)-, -NHS(O)2-[CH2Iq-, -NHN=CH-, -NHNHS(O)2-, -NHNHC(O)-, -NHC(O)O-, -NHS(O)2NH-, -S-[CH2Iq-, -O-[CH2]q-, -S(O)2- or -S(O)2NH-. Compounds of formula I that may be mentioned include those in which:
Y represents -C(O)-, -NHS(O)2-[CH2]q-, -NHN=CH-, -NHNHS(O)2-, -NHNHC(O)-, -NHC(O)O-, -NHS(O)2NH-, -0-[CH2Iq-, -S(O)2- Or -S(O)2NH-.
Yet further compounds of formula I that may be mentioned include those in which:
Y represents -NHS(O)2-[CH2Iq-, -NHNHS(O)2-, -NHS(O)2NH-, -S(O)2- Or -S(O)2NH-.
Compounds of formula I that may be mentioned include those in which:
Y represents -C(O)-, -NHN=CH-, -NHNHS(O)2-, -NHNHC(O)-, -NHC(O)O-, -NHS(O)2NH, -S-[CH2Jq-, -0-[CH2Iq-, -S(O)2- or -S(O)2NH-.
Yet further compounds of formula I that may be mentioned include those in which:
Y represents -NHC(O)O- or, more preferably, -NHNHS(O)2-, -NHS(O)2NH-, -S(O)2- or - S(O)2NH-.
Yet further compounds of formula I that may be mentioned include those in which: T represents N or, more preferably, O.
Compounds of formula I that may be mentioned include those in which: T represents S.
Further compounds of formula I that may be mentioned include those in which: at least one of R1 to R5 is not H.
Further compounds of formula I that may be mentioned include those in which: at least one of R1 to R5, when present, represents halo, -R7, -CF3, -CN, -C(O)R7, -C(O)OR7, -N(RV, -SR7, -OR7 or -NH(O)R7, or any two of R1 to R5 which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I, an aromatic or non-aromatic 3- to 8- membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo, -R7, -OR7 and =O.
Further compounds of formula I that may be mentioned include those in which: at least one of R1 to R5, when present, represents R7 or, more preferably, -OR7, halo,
-CF3, -CN, -C(O)R7, -C(O)OR7, -N(R7J3 + or -NH(O)R7, or any two of R1 to R5 which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I, an aromatic or non-aromatic 3- to 8-membered ring selected from 2,3-dihydrobenzo[1 ,4]dioxinyl or tetrahydroquinolinyl, which may optionally be substituted by one or more halo atoms.
Further compounds of formula I that may be mentioned include those in which: at least one of R1 to R5, when present, represents R7 or, more preferably, -OR7, halo,
-CF3, -CN, -C(O)R7, -C(O)OR7, -N(R7J3 + Or -NH(O)R7.
Yet further compounds of formula I that may be mentioned include those in which: at least one of R1 to R5, when present, represents R7 (e.g. -CH3), preferably -OR7 (e.g.
-OCH3, or more preferably, -OCHF2 or -OCF3), or, more preferably, halo, -CF3, -CN or
Yet further compounds of formula I that may be mentioned include those in which: at least one of R1 to R4, when present, represents R7 (e.g. -CH3), preferably -OR7 (e.g.
-OCH3, or more preferably, -OCHF2 or -OCF3), or, more preferably, halo, -CF3, -CN or
-N(R7)3 +.
Yet further compounds of formula I that may be mentioned include those in which:
R5, when present, represents -CH3, preferably Cl, or, more preferably, H, Br, I, F, -CF3,
-CN -C(O)R7, -C(O)OR7 or -N(R7)3 +.
Further compounds of formula I that may be mentioned include those in which:
R5, when present, represents -CH3 or, more preferably. H, -CF3, -CN, -C(O)R7,
-C(O)OR7 Or -N(RV
Yet further compounds of formula I that may be mentioned include those in which: R5, when present, represents H.
Further compounds of formula I that may be mentioned include those in which: R6a to R6e independently represent -C(O)NR15aR15b or, more preferably, H, cyano, -NO2, - Br, -Cl, -F, -R8, -OR8, -NR9R10, -SR11, -C(O)OR13, -C(O)R14, -S(O)2NR15cR15d, aryl or heteroaryl (which aryl and heteroaryl groups are themselves optionally and independently substituted by one or more groups selected from halo and R16), or any two R6 groups which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I, quinoline, tetrahydroquinoline, isoquinoline or tetrahydroisoquinoline, wherein the additional ring system of the quinoline, tetrahydroquinoline, isoquinoline or tetrahydroisoquinoline moiety is itself optionally substituted by one or more substituents selected from halo, -R7, -OR7 and =0.
Further compounds of formula I that may be mentioned include those in which:
Rea to Ree jncjepencjentiy represent -C(O)NR15aR15b or, more preferably, -R8 or yet more preferably, H, cyano, -NO2, -Br, -Cl, -F, -OR8, -NR9R10, -SR11, -C(O)OR13, -C(O)R14,
-S(O)2NR15cR15d, aryl or heteroaryl (which aryl and heteroaryl groups are themselves optionally and independently substituted by one or more groups selected from halo and
R16).
Yet further compounds of formula I that may be mentioned include those in which:
R6a to R6e independently represents -C(O)NR15aR15b, -R8, or, more preferably, H, cyano, -
NO2, -Br, -Cl, -F, -OR8, -NR9R10, -SR11, -C(O)OR13 or -C(O)R14.
Yet further compounds of formula I that may be mentioned include those in which:
R 6a t0 Ree jn(jepencient|y represents -R8 or, more preferably, H, cyano, -NO2, -Br, -Cl,
-F, -OR8, -NR9R10 Or -SR11.
Yet further compounds of formula I that may be mentioned include those in which: Rβa tQ R6Θ independently represents H, -Br, -F or, most preferably -Cl.
Yet further compounds of formula I that may be mentioned include those in which: at least one R6a to R6e group is not H.
Further compounds of formula I that may be mentioned include those in which:
R6t independently represents H, halo, -R7, -CF3, -CN, -NO2, -C(O)R7, -C(O)OR7,
-N(R7a)R7b, -N(RV, -SR7, -OR7, -NH(O)R7 Or -SO3R7.
Compounds of formula I that may be mentioned include those in which: n is 2, or more preferably, 1.
Compounds of formula I that may be mentioned include those in which: q is 1 , or more preferably, O. Compounds of formula I that may be mentioned include those in which: B represents a bond; r represents 0 or 1.
Further compounds of formula I that may be mentioned include those in which:
Rx and Ry are linked to form, along with the carbon atom to which they are attached, a cyclopropyl ring which ring is itself optionally substituted by one or more substituents selected from halo or C1^ alkyl (optionally substituted by one or more halo atoms);
Q represents a bond or O;
Z represents O, or more preferably, a bond; n represents 1.
Further compounds of formula I that may be mentioned include those in which: Rx and Ry are linked to form, along with the carbon atom to which they are attached, a cyclopropyl ring which ring is itself optionally substituted by one or more substituents selected from halo or C1-6 alkyl (optionally substituted by one or more halo atoms); A5 represents C(CF3) or, more preferably, C(CI).
Further compounds of formula I that may be mentioned include those in which: A5 represents N or, more preferably, C(H).
Further compounds of formula I that may be mentioned include those in which:
A1 and A3 independently represent C(halo), e.g. C(CI) or C(F), preferably N or, more preferably, C(H).
Further compounds of formula I that may be mentioned include those in which:
A2 and A4 represents C(R2);
A1, A3 and A5 independently represent C(H) or N.
Further compounds of formula I that may be mentioned include those in which:
A2 represents C(R2);
A1 and A3 to A5 independently represent C(H) or N.
Yet further compounds of formula I that may be mentioned include those in which: A2 represents C(R2); R2 represents -CF3;
A1 and A3 to A5 independently represent C(H).
Yet further compounds of formula I that may be mentioned include those in which:
A5 represents C(R5);
R5 represents -CF3;
Ai to A4 independently represent C(H).
Yet further compounds of formula I that may be mentioned include those in which:
T represents S;
G represents N;
Rx and Ry are linked to form, along with the carbon atom to which they are attached, a cyclopropyl ring which ring is itself optionally substituted by one or more substituents selected from halo or C^ alkyl (optionally substituted by one or more halo atoms);
Q represents a bond or O;
Z represents O, or more preferably, a bond; n represents 1.
Further compounds of formula I that may be mentioned include those in which:
T represents S;
G represents N;
Q represents a bond;
A5 represents N or, more preferably, C(H).
Further compounds of formula I that may be mentioned include those in which: T represents S; G represents N;
Y represents -NHC(O)NH-.
Further compounds of formula I that may be mentioned include those in which: T represents S; G represents N;
Y represents -S-[CH2],,- or, more preferably, -C(O)-, -NHN=CH-, -NHNHS(O)2-, -NHNHC(O)-, -NHC(O)O-, -NHS(O)2NH-, -0-[CHJq-, -S(O)2- or -S(O)2NH-.
Further compounds of formula I that may be mentioned include those in which: T represents S;
G represents N;
Q represents a bond;
A2 and A4 represent C(R2);
A1, A3 and A5 independently represent C(H) or N.
Compounds of formula I that may be mentioned include those in which: Q and Z are both bonds; Rx and Ry are both H; n is 1 , 2 or 3;
Y is -NHC(O)NH- or, more preferably, -NHS(O)2-[CH2Jq-; and/or q is 0.
Compounds of formula I that may be mentioned include those in which: Q and Z are not both bonds; Rx and Ry are not both H; n is not 1 , 2 or 3;
Y is not -NHC(O)NH- or, more preferably, -NHS(O)2-[CH2]q-; and/or q is 0.
Compounds of formula I that may be mentioned include those in which: Di to D5 each independently represent C(R6).
Compounds of formula I that may be mentioned include those in which: D1 to D3 each independently represent C(H); and D4 and D5 both represent C(R6).
Compounds of formula I that may be mentioned include those in which: D1 to D3 each independently represent C(H); D4 and D5 both represent C(R6); R6 represents Cl.
Compounds of formula I that may be mentioned include those in which: X represents -[CH2]n-; G represents N or O; R1 to R4 independently represent H, halo, -CF3, -CN, -NO2, -C(O)R7, -C(O)OR7,
-N(RV, -SO3R7, -OR7 or -NHC(O)R7;
R5 represents H, Br, I, F, -CF3, -CN, -C(O)R7, -C(O)OR7, -N(R7J3 + Or -SO3R7; provided that at least one of R1 to R5 is not H; and
R6a to R66 independently represent, H, cyano, -NO2, halo, -R8, -OR8, -NR9R10, -SR11,
-Si(R12J3, -C(O)OR13, -C(O)R14, -C(O)NR15aR15b, -S(O)2NR15cR15d, aryl or heteroaryl
(which aryl and heteroaryl groups are themselves optionally and independently substituted by one or more groups selected from halo and R16); and
Y represents -NHS(O)2.
Compounds of formula I that may be mentioned include those in which: G represents N;
Y represents -C(O)-, -NHS(O)2-[CH2]q-, -NHN=CH-, -NHNHS(O)2-, -NHNHC(O)-, -NHC(O)NH-, -NHC(O)O-, -NHS(O)2NH-, -S-[CH2]q-, -O-[CH2]q-, -S(O)2-, -S(O)2NH-;
Q and Z independently represent a bond, S, or O;
Rx and Ry are independently selected from H, halo, C1-6 alkyl (optionally substituted or, more preferably, substituted by one or more halo atoms), or Rx and Ry are linked to form, along with the carbon atom to which they are attached, an aromatic or non-aromatic 3- to
8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or C1-6 alkyl (optionally substituted by one or more halo atoms); and
R1 to R5 are as defined above or, preferably, at least one of R1 to R5 represents -CF3 or, more preferably, at least one of R1 to R4 represents -CF3 and Rs represents H.
Compounds of formula I that may be mentioned include those in which:
Y represents -NHC(O)NH- or, preferably, -C(O)-, -NHS(O)2-[CH2]q-, -NHN=CH-, -NHNHS(O)2-, -NHNHC(O)-, -NHC(O)O-, -NHS(O)2NH-, -S-[CH2]q-, -O-[CH2]q-, -S(O)2-, -S(O)2NH-;
Q and Z independently represent a bond, S, or O; and
Rx and Ry are independently selected from H, halo, Ci-6 alkyl (optionally substituted by one or more halo atoms), or Rx and Ry are linked to form, along with the carbon atom to which they are attached, an aromatic or, more preferably, non-aromatic 3- to 8- membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or Ci-6 alkyl (optionally substituted by one or more halo atoms). More preferred compounds of formula I include those of the examples described hereinafter.
Preferred compounds of formula I include:
(i) 3,4-dichloro-N-[5-[[3-(trifluoromethyl)phenyl]methyl]-1 ,3,4-thiadiazol-2- yljbenzenesulfonamide;
(ii) 3,4-dichloro-N-[5-[1 -(4-chlorophenyl)cyclopropyl]-1 ,3,4-thiadiazol-2- yl]benzenesulfonamide;
(iii) 3,4-dichloro-N-[5-[[4-(trifluoromethyl)phenyl]methyl]-1 ,3,4-thiadiazol-2- yljbenzenesulfonamide;
(iv) 3,4-dichloro-N-[5-[(4-chlorophenoxy)methyl]-1,3,4-thiadiazol-2-yl]benzene sulfonamide;
(V) N-[4-[[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2- yl]sulfamoyl]phenyl]acetamide;
(vi) N-[5-[(4-chlorophenoxy)methyl]-1,3,4-thiadiazol-2-yl]benzenesulfonamide;
(vii) 1 -phenyl-N-[5-(phenylsulfanylmethyl)-1 ,3,4-thiadiazol-2-yl]methanesulfonamide;
(viii) N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-1 -phenyl-methane sulfonamide;
(ix) N-[5-[2-(4-methoxyphenyl)ethyl]-1 ,3,4-thiadiazol-2-yl]-1 -phenyl-methane sulfonamide;
(x) N-[5-(3-phenoxypropyl)-1 ,3,4-thiadiazol-2-yl]-1 -phenyl-methanesulfonamide;
(xi) 3,4-dichloro-N-[5-[2-(p-tolylsulfonyl)ethyl]-1 ,3,4-thiadiazol-2- yl]benzenesulfonamide;
(xii) 3-chloro-N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]-4-fluoro- benzenesulfonamide;
(xiii) N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-1 -(4-chlorophenyl) methanesulfonamide;
(xiv) N-[5-[1 -(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-4-(trifluoromethoxy) benzenesulfonamide;
(xv) N-(5-benzhydryl-1 ,3,4-thiadiazol-2-yl)-1 -[4-(trif luoromethyl)phenyl] methanesulfonamide;
(xvi) 3,4-dichloro-N-[5-[4-(trifluoromethyl)benzoyl]-1 ,3,4-thiadiazol-2- yl]benzenesulfonamide; (xvii) 3-chloro^-fluoro-N-[5-[2-(p-tolylsulfonyl)ethyl]-1 Λ4-thiadiazol-2- yl]benzenesulfonamide;
(xviii) 1 -(4-chlorophenyl)-N-[5-[2-(p-tolylsulfonyl)ethyl]-1 ,3,4-thiadiazol-2- yljmethanesulfonamide;
(xix) N-[5-[2-(p-tolylsulfonyl)ethyl]-1 ,3,4-thiadiazol-2-ylM- (trifluoromethoxy)benzenesulfonamide;
(XX) N-[5-[2-(p-tolylsulfonyl)ethyl]-1 ,3,4-thiadiazol-2-yl]-1 -[4-(trif luoromethyl)phenyl] methanesulfonamide;
(xxi) N-tδ-^-Cp-tolylsulfonyOethyll-I .S^-thiadiazol^-yll-β-CtrifluoromethylJpyridine-S- sulfonamide;
(xxii) 3,4-dichloro-N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2- yl]benzenesulfonamide;
(xxiii) 1-(4-chlorophenyl)-N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2- yl]methanesulfonamide;
(xxiv) N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]-4- (trifluoromethoxy)benzenesulfonamide;
(xxv) N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]-1 -[4-(trifluoromethyl)phenyl] methanesulfonamide;
(xxvi) N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]-6-(trifluoromethyl)pyridine-3- sulfonamide;
(xxvii) 3-chloro-N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-4-fluoro- benzenesulfonamide;
(xxviii) N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-4- (trifluoromethoxy)benzenesulfonamide;
(xxix) N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-1 -[4-(trifluoromethyl)phenyl] methanesulfonamide;
(xxx) N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-6-(trifluoromethyl)pyridine-3- sulfonamide;
(xxxi) 3,4-dichloro-N-[5-[1 -(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2- yl]benzenesulfonamide;
(xxxii) 3-chloro-N-[5-[1 -(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-4-fluoro- benzenesulfonamide;
(xxxiii) N-[5-[1-(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-1-(4- chlorophenyl)methanesulfonamide; (xxxiv) N-[5-[1 -(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-1 -[4-(trifluoromethyl)phenyl] methanesulfonamide;
(xxxv) N-[5-[1 -(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yI]-6-(trifluoromethyl)pyridine-3- sulfonamide;
(xxxvi) N-(5-benzhydryl-1,3,4-thiadiazol-2-yl)-3,4-dichloro-benzenesulfonamide; (xxxviiJ N-Cδ-benzhydryl-I .S^-thiadiazol^-ylJ-S-chloro^-fluoro-benzenesulfonamide;
(xxxviii) N-(5-benzhydryl-1 ,3,4-thiadiazol-2-yl)-1 -(4- chlorophenyl)methanesulfonamide;
(xxxix) N-(5-benzhydryl-1 ,3,4-thiadiazol-2-yl)-4-(trifluoromethoxy)benzenesulfonamide; (xl) N-(5-benzhydryl-1,3,4-thiadiazol-2-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide;
(xli) 3,4-dichloro-N-[5-[2-(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazoI-2- yl]benzenesulfonamide;
(xlii) 3-chloro-N-[5-[2-(4-chlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl]-4-fluoro- benzenesulfonamide;
(xliii) N-[5-[2-(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-1 -(4- chlorophenyl)methanesulfonamide;
(xliv) N-[5-[2-(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-4- (trifluoromethoxy)benzenesulfonamide;
(xlv) N-[5-[2-(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-1 -[4-(trifluoromethyl)phenyl] methanesulfonamide;
(xlvi) N-[5-[2-(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-6-(trifluoromethyl)pyridine-3- sulfonamide;
(xlvii) 3,4-dichloro-N-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2- yl]benzenesulfonamide;
(xlviii) 3-chloro-4-fluoro-N-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2- yl]benzenesulfonamide;
(xlix) 1 -(4-chlorophenyl)-N-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2-yl] methanesulfonamide;
(I) N-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2-yl]-4-(trifluoromethoxy) benzenesulfonamide;
(Ii) N-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2-yl]-1 -[4- (trifluoromethyl)phenyl] methanesulfonamide;
(lii) N-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2-yl]-6- (trifluoromethyl)pyridine-3-sulfonamide; (liii) 3,4-dichloro-N-[5-[3-(trifluoromethyl)ben2oyl]-1,3,4-thiadiazol-2- yljbenzenesulfonamide;
(liv) 4-bromo-N-[5-[(4-methoxyphenyl)methyl]-1 , 3,4-thiadiazol-2- yl]benzenesulfonamide;
(Iv) 3,4-dichloro-N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]benzamide; (Ivi) 3,4-dichloro-N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]benzamide; (Ivii) 2-(4-chlorophenyl)-N-[5-[(4-chlorophenyl)methyl]-1,3,4-thiadiazol-2-yl]acetamide;
(Iviii) N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-2-(4- chlorophenyl)acetamide;
(lix) 2-(4-chlorophenoxy)-N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2- yljacetamide;
(Ix) 1 -[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]-3-(3,4-dichlorophenyl)urea;
(Ixi) 1 -(3,4-dichlorophenyl)-3-[5-[(2-fluorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]urea;
(Ixii) 1-(3,4-dichlorophenyl)-3-[5-(1-phenylethyl)-1 ,3,4-thiadiazol-2-yl]urea;
(Ixiii) 1 -(3,4-dichlorophenyl)-3-[5-[(4-fluorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]urea;
(Ixiv) 1 -(2,4-dichlorophenyl)-3-[5-[(2,4-dichlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]urea;
(Ixv) 1 -(3,4-dichlorophenyl)-3-(5-phenethyl-1 ,3,4-thiadiazol-2-yl)urea;
(Ixvi) 1 -(5-benzhydryl-1 ,3,4-thiadiazol-2-yl)-3-(2,4-dichlorophenyl)urea;
(Ixvii) 1 -(3,4-dichlorophenyl)-3-[5-[(3,4-dimethoxyphenyl)methyl]-1 ,3,4-thiadiazol-2- yljurea;
(Ixviii) 1 -[5-[(4-chloro-2-methyl-phenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-3-(3,4- dichlorophenyl)urea;
(Ixix) 1 -(3,4-dichlorophenyl)-3-[5-(phenylsulfanylmethyl)-1 ,3,4-thiadiazol-2-yl]urea; (Ixx) 1 -(3,4-dichlorophenyl)-3-[5-[(2-fluorophenoxy)methyi]-1 ,3,4-thiadiazol-2-yl]urea;
(Ixxi) 1 -(3,4-dichlorophenyl)-3-[5-[(4-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2- yljurea;
(Ixxii) 1 -(3,4-dichlorophenyl)-3-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2- yljurea;
(Ixxiii) 1 -[5-[(4-tert-butylphenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-3-(3,4- dichlorophenyl)urea;
(Ixxiv) 1 -(3,4-dichlorophenyl)-3-[5-(1-phenoxyethyl)-1 ,3,4-thiadiazol-2-yl]urea; (Ixxv) 1 -(3,4-dichlorophenyl)-3-[5-(2-fluorophenyl)-1 ,3,4-thiadiazol-2-yl]urea; (Ixxvi) 1 -(3,4-dichlorophenyl)-3-[5-[(2,4-dichlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]urea;
(Ixxvii) I^S^-dichlorophenylJ-S-fS-f^-^rifluoromethyOphenyllmethylJ-I .S^-thiadiazol^- yljurea;
(Ixxviii) (4-chlorophenyl) N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]carbamate;
(Ixxix) 3-chloro-N'-[5-[(4-chlorophenyl)methyl]-1,3,4-thiadiazol-2-yl]-4-fluoro- benzenesulfonohydrazide;
(Ixxx) 3,4,5-triethoxy-N'-[5-[[4-(trifluoromethyl)phenyl]nnethyl]-1 ,3,4-thiadiazol-2- yl]benzohydrazide;
(Ixxxi) 5-fluoro-2-(trifluoromethyl)-N'-[5-[[4-(trifluoromethy!)phenyl]methyl]-1 ,3,4- thiadiazol-2-yl]benzohydrazide;
(Ixxxii) 2-methoxy-5-methyl-Nl-[5-[[4-(trifluoromethyl)phenyl]methyl]-1 ,3,4-thiadiazol-2- yl]benzohydrazide;
(lxxxiii) 3-methylsulfanyl-N'-[5-[[4-(trifluoromethyI)phenyl]methyl]-1 ,3,4-thiadiazol-2- yljbenzohydrazide;
(lxxxiv)2-methylamino-N'-[5-[[4-(trifluoromethyl)phenyl]methyl]-1 ,3,4-thiadiazol-2- yljbenzohydrazide;
(Ixxxv) 4τmethoxy-N'-[5-[[4-(trifluoromethyl)phenyl]methyl]-1 ,3l4-thiadiazol-2- yljbenzohydrazide;
(lxxxvi) 3-bromo-4-fluoro-N'-[5-[[4-(trifluoromethyl)phenyl]methyl]-1 ,3,4-thiadiazol-2- yljbenzohydrazide;
(Ixxxvii) 2-methoxy-N'-[5-[[4-(trifluoromethyl)phenylJmethyl]-1 ,3,4-thiadiazol-2- yljbenzohydrazide;
(Ixxxviii) N'-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-3l4,5-triethoxy- benzohydrazide;
(lxxxix) N'-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-5-fluoro-2- (trifluoromethyl)benzohydrazide;
(xc) 1 -(3,4-dichlorophenyl)-3-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-urea; (xci) 1 -(3,4-dimethoxyphenyl)-3-[5-(3-chlorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-urea;
(xcii) 1 -(4-carboxyphenyl)-3-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-urea ethyl ester;
(xciii) [5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-carbamic acid 3,4-dichloro- phenyl ester;
(xciv) [5-(2-chlorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-carbamic acid 3,5-dichlorophenyl ester; (xcv) [5-pyridin-4-ylmethyl-[1,3,4]thiadiazol-2-yI]-carbamic acid 3,4-dichlorophenyl ester;
(xcvi) 1 -(4-acetamidophenyl)-3-[5-(2,3-dihydrobenzo[1 ,4]dioxin-6-ylmethyl)- [1 ,3,4]thiadiazol-2-yl]-sulfonamide;
(xcvii) 1 -(3,4-dimethylphenyl)-3-[5-(3-moφholin-4-ylbenzylH1 ,3,4]thiadiazol-2-yl]- sulfonamide;
(xcviii) 2-(3,4-dichlorophenylsulfanyl)-5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazole;
(xcix) 2-(3,4-dichlorophenylsulfanyl)-5-(3,4-dimethylbenzyl)-[1 ,3,4]thiadiazole;
(c) 2-(phenylsulfanyl)-5-(4-carboxybenzyl)-[1 ,3,4]thiadiazole ethyl ester;
(ci) 2-(3,4-dichlorophenoxy)-5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazole;
(cii) 2-(3,5-dichlorophenoxy)-5-(3-methanthiolbenzyl)-[1 ,3,4]thiadiazole;
(ciii) 2-(3l4-dimethylphenoxy)-5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazole;
(civ) 2-(3,4-dichlorobenzenesulfonyl)-5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazole;
(cv) 2-(4-chlorobenzenesulfonyl)-5-(1 l2,3,4-tetrahydroquinolin-6-ylmethyl)- [1 ,3,4]thiadiazole;
(cvi) 2-(2,6-dichlorobenzenesulfonyl)-5-(3-difluoromethoxybenzyl)-[1 ,3,4]thiadiazole;
(cvii) (3,4-dichlorophenyl)-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- methanone;
(cviii) (2-methoxyphenyl)-[5-(3-fluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-methanone; (cix) (4-acetamidophenyl)-[5-(3,4-dimethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-methanone;
(ex) 5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazole-2-sulfonic acid (3,4-dichlorophenyl)- amide;
(cxi) 5-(4-trifluoromethylbenzyl)-[1,3,4]thiadiazole-2-sulfonic acid (3-difluoromethoxy- phenyl)-amide;
(cxii) 5-(4-fluorobenzyl)-[1,3,4]thiadiazole-2-sulfonic acid (4-difluoromethoxyphenyl)- amide;
(cxiii) N-[1-(3,4-dichlorophenyl)-meth-(E)-ylidene]-N'-[5-(3-trifluoromethylbenzyl)- [1 ,3,4]thiadiazol-2-yl]-hydrazine;
(cxiv) N-[1-(3,4-diacetophenyl)-meth-(E)-ylidene]-N'-[5-(3-trifluoromethylbenzyl)- [1 ,3,4]thiadiazol-2-yl]-hydrazine;
(cxv) 1 -[3-(5-{N'-[1 -(3,4-dichlorophenyl)-meth-(E)-ylidene]-hydrazino}-[1 ,3,4]thiadiazol- 2-ylmethyl)-phenyl]-ethanone; (cxvi) 3,4-dichlorobenzoic acid N'-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiodiazol-2-yl]- hydrazide;
(cxvii) 3,4-dichlorophenylsulfonyl N'-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiodiazol-2-yl]- hydrazide;
(cxviii) acetic acid 4-[(5-benzyl-[1,3,4]thiadiazol-2-yl)-hydrazonomethyl]-phenyl ester;
(cxix) methanesulfonic acid 4-{[5-(4-ethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-hydrazono- methyl}-phenyl ester;
(cxx) 3,4-dichloro-N-{5-[1 -(4-chlorophenyl)-ethyl]-[1 ,3,4]thiadiazol-2-yl}- benzenesulfonamide;
(cxxi) 3,4-dichloro-N-{5-[1 -methyl-1 -(3-trifluoromethylphenyl)-ethyl]-[1 ,3,4]thiadiazol-2- yl}-benzenesulfonamide;
(cxxii) 3,4-dichloro-N-[5-(3-trifluoromethylphenoxymethyl)-[1 ,3,4]thiadiazol-2- yl]benzenesulfonamide;
(cxxiii) C-(3,4-dichlorophenyl)-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- methanesulfonamide;
(cxxiv) 1-(3,4-dichlorophenyl)-3-[5-(3-trifluoromethylbenzylsulfanyl)-[1 ,3,4]thiadiazol-2-yl]- urea;
(cxxv) 1 -(S^-dichlorophenyO-S-β-CS-trifluoromethylbenzoylHI ,3,4]thiadiazol-2-yl]-urea;
(cxxvi) 4-chloro-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(cxxvii) 2,4-dichloro-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzene sulfonamide;
(cxxviii) 3,4-dichloro-N-[5-(2-methoxybenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(cxxix) 4-chloro-N-[5-(2-methoxybenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide; (cxxx) 2,4-dichloro-N-[5-(2-methoxybenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide; (cxxxi) 3,4-dichloro-N-[5-(4-fluorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide; (cxxxii)4-chloro-N-[5-(4-fluorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide;
(cxxxiii) 2,4-dichloro-N-[5-(4-fluorobenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(cxxxiv) 3,4-dichloro-N-[5-(4-dimethylaminobenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(cxxxv)4-chloro-N-[5-(4-dimethylaminobenzyI)-[1,3,4]thiadiazol-2-yl]- benzenesulfonamide; (cxxxvi) 2,4-dichloro-N-[5-(4-dimethylaminobenzyl)-[1,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(cxxxvii) 4-methoxy-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(cxxxviii) 3,4-dimethoxy-N-[5-(3-trifluoromethylbenzyl)-[1,3,4]thiadiazol-2-yl]- benzene sulfonamide;
(cxxxix) 3,4,5-trimethoxy-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzene sulfonamide;
(cxl) N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide;
(cxli) 4-cyano-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(cxlii) 4-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-ylsulfamoyl]-benzoic acid ethyl ester;
(cxliii) 3,4-dichloro-N-(5-phenethyl-[1 ,3,4]thiadiazol-2-yl)-benzenesulfonamide;
(cxliv) 3,4-dichloro-N-{5-[2-(2-methoxyphenyl)-ethyl]-[1 ,3,4]thiadiazol-2-yl}- benzenesulfonamide;
(cxlv) S^-dichloro-N^δ-^-CS-trifluoromethylphenyO-ethylJ-fi .S^lthiadiazol^-yl}- benzenesu If onamide ;
(cxlvi) 4-fluoro-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide;
(cxlvii) 2,4-difluoro-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(cxlviii) (3,4-difluoro-N-[5-(2-methoxybenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide; (cxlix) (4-cyano-N-[5-(2-methoxybenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide; (cl) 4-[5-(4-fluorobenzyl)-[1 ,3,4]thiadiazol-2-ylsulfamoyl]-benzoic acid ethyl ester;
(cli) 4-cyano-N-[5-(4-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(clii) 4-[5-(4-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-ylsulfamoyl]-benzoic acid ethyl ester;
(cliii) 3,4-dichloro-N-[5-(3-difluoromethoxybenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(cliv) 4-chloro-N-[5-(3-difluoromethoxybenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(civ) S^-dichloro-N-CS-pyridin^-ylmethyO-ti .S^Jthiadiazol^-yO-benzenesulfonamide; (clvi) 3,4-dichloro-N-[5-[(4-chlorophenyI)methylsulfanyl]-1 ,3,4-thiadiazol-2-yl3benzene- sulfonamide;
(clvii) 3,4-dichloro-N-[5-[1 -(4-chlorophenoxy)cyclopropyl]-1 ,3,4-thiadiazol-2-yl]beπzene- sulfonamide;
(clviii) 3,4-dichloro-N-[5-[1 -[3-(trifluoromethyl)phenoxy]cyclopropyl]-1 ,3,4-thiadiazol-2- yl]benzenesulfonamide;
(clix) 3,4-dichloro-N-[5-[1 -[4-fluorophenyl)cyclopropyl]-1 ,3,4-thiadiazol-2-yl]benzene- sulfonamide;
(clx) 1-(3,4-dichlorophenyl)-3-[5-[1-[4-(trifluoromethyl)phenyl]cyclopropyl]-1 ,3,4-thiadia- zol-2-y!]urea;
(clxi) 3,5-dimethoxy-4-methyl-N'-[5-[[4-(trifluoromethyl)phenyl]methyl]-1,3,4-thiadiazol- 2-yl]benzohydrazide;
(clxii) 2,5-bis(trifluoromethyl)-N'-[5-[[4-(trifluoromethyl)phenyl]methyl]-1 ,3,4-thiadiazol-2- yl]benzohydrazide;
(clxiii) 2-methylsulfanyl-N'-[5-[[4-(trifluoromethyl)phenyl]methyi]-1 ,3)4-thiadiazol-2- yljbenzohydrazide;
(clxiv) N'-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-2-methoxy-5-methyl- benzohydrazide;
(clxv) N'-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-3-methylsulfanyl- benzohydrazide;
(clxvi) N'-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-2-methylamino- benzohydrazide;
(clxvii) 4-chloro-N'-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-3-fluoro- benzenesulfonohydrazide;
(clxviii) 3-chloro-N'-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-4-fluoro- benzenesulfonohydrazide;
(clxix) N'-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-4- (trifluoromethoxy)benzenesulfonohydrazide;
(clxx) 3,4-dichlorobenzoic acid N'-[5-(2,3-dihydrobenzo[1 ,4]dioxin-6-ylmethyl)- [1 ,3,4]thiadiazol-2-yl]-hydrazide;
(clxxi) 4-acetylbenzoic acid N'-[5-(3-methoxybenzyl)-[1 ,3,4]thiadiazol-2-yl]-hydrazide; (clxxii) 1 -(3,4-dimethoxyphenyl)-3-[5-(1 -phenylethyl)-[1 ,3,4]thiadiazol-2-yl]-urea; and
(clxxiiO S^-dichloro-N-tS-CS-trifluoromethylbenzylHi ^^loxadiazol-S-yl]- benzenesulfonamide. Preferred compounds of formula I include compounds (i), (H), (Ix) to (Ixv), (Ixix), (Ixxi), (Ixxvi), (xc) to (cxxv) and (clxx) to (clxxii) as described above.
Further preferred compounds of formula I include compounds (i), (ii), (xc) to (cxxv), (clxx) and (clxxi) as described above.
Yet further preferred compounds of formula I include compounds (xv), (xxxvi) to (xl), (iii), (iv), (xi), (xii), (xiv), (xvi) to (xxii), (xxiv) to (xxxv), (xli) to (liii), (Ixxviii) and (Ixxix).
Yet further preferred compounds of formula I include:
(a) 3,4-dichloro-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide;
(b) 4-chloro-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide;
(c) 3,4-dichloro-N-{5-[1 -(4-chlorophenyl)-cyclopropyl]-[1 ,3,4]thiadiazol-2-yl}-benzenesulf- onamide;
(d) 3,4-dichloro-N-[5-[1 -(4-chlorophenoxy)cyclopropyl]-1 ,3,4-thiadiazol-2-yl]benzene- sulfonamide; and
(e) 3,4-dichloro-N-[5-[1 -[3-(trifluoromethyl)phenoxy]cyclopropyl]-1 ,3,4-thiadiazol-2-yl]ben- zenesulfonamide.
Yet further preferred compounds of formula I include:
(1 ) 3,4-dichloro-N-[5-[[4-(trifluoromethyl)phenyl]methyl]-1 ,3,4-thiadiazol-2-yl]benzene- sulfonamide;
(2) S^-dichloro-N-tδ-^-^rifluoromethyObenzoyll-I .SΛ-thiadiazol^-yllbenzenesulfon- amide;
(3) 1-(3,4-dichlorophenyl)-3-[5-[[4-(trifluoromethyl)phenyl]methyl]-1 ,3,4-thiadiazol-2-yl]- urea
(4) 3,4-dichloro-N-[5-[2-(p-tolylsulfonyl)ethyl]-1 ,3,4-thiadiazol-2-yl]benzenesulfonamide;
(5) 3-chloro-N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]-4-fluorobenzenesulfon- amide;
(6) N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-1 -(4-chlorophenyl)methane- sulfonamide;
(7) N-[5-[1 -(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-4-(trifluoromethoxy)benzene- sulfonamide; (8) 3,4-dichloro-N-[5-[(4-chlorophenyl)methyl]-1,3,4-thiadiazol-2-yl]benzenesulfonamide; (9) S^-dichloro-N-tδ-K^chlorophenoxyJmethylJ-I .S^-thiadiazol^-ylJbenzenesulfon- amide;
(10) 3,4-dichloro-N-[5-[2-(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]benzenesulfon- amide;
(11 ) 3,4-dichloro-N-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazoi-2-yl]benzene- sulfonamide;
(12) 3,4-dichloro-N-[5-[1 -K-trifluoromethylphenyOcyclopropylJ-i ,3,4-thiadiazol-2- yl]benzene-sulfonamide; and
(13) I^S^-dichlorophenyO-S-IS-ti-K-CtrifluoromethyOphenyllcyclopropyll-I.S^-thiadia- zol-2-yl]urea.
Yet further preferred compounds of formula I include compounds (i) to (iv), (vi) to (liv), (xcvi), (xcvii), (cxx) to (cxxiii), (cxxvi) to (cxli), (cxliii) to (cil), (cli), (cliii) to (clix) and (clxxiii).
Yet further preferred compounds of formula I include compounds (xv), (xxxvi) to (xl) and (Ixvi).
Compounds of formula I may be known and/or may be commercially available. Compounds of formula I that are not commercially available may be prepared in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter.
According to a further aspect of the invention there is provided a process for the preparation of a compound of formula I, which process comprises: (i) for compounds of formula I wherein Y represents -NHC(O)-[CH2]r-B- or, more preferably, -NHC(O)NH-, -NHC(O)O-, -NHS(O)2NH- or -NHS(O)2-[CH2Jq-, reaction of a compound of formula II,
Figure imgf000048_0001
wherein the dotted lines, Ai to A5, X, T and G are as hereinbefore defined or, more preferably, T is S or O and G is N, with a compound of formula III,
Figure imgf000049_0001
wherein Yx represents -C(O)-[CH2JrB- or, more preferably, -C(O)NH-, -C(O)O-, -S(O)2NH-, or -S(O)2-[CH2]q-, L2 represents a suitable leaving group such as halo (e.g. chloro), and Di to D5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable base (e.g. NaH, NaOH, triethylamine, pyridine, another suitable base, e.g. one of those mentioned at process step (xii) below or mixtures thereof) and an appropriate solvent (e.g. pyridine (which may serve as the base and solvent) DMF or dichloromethane (e.g. further in the presence of water and, optionally, a phase transfer catalyst)), for example at room temperature e.g. as described in Hurst, D. T.; Stacey, A. D., Nethercleft, M., Rahim, A., Harnden, M. R. Aust J. Chem. 1998, 41, 1221 ;
(ii) for compounds of formula I wherein Y represents -NHC(O)NH-, reaction of a compound of formula Il with a compound of formula IV,
Figure imgf000049_0002
wherein Di to D5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example, in the presence of a suitable solvent (e.g. a polar aprotic solvent such as toluene) and at elevated temperature (e.g. reflux), for example as described in the journal article mentioned in respect of process (i) above;
(iii) for compounds of formula I wherein Y represents -C(O)-, oxidation of a compound of formula V,
Figure imgf000050_0001
wherein the dotted lines, Ai to A5, X, T, G and Di to D5 are as hereinbefore defined or, more preferably, T is S or O and G is N, for example under standard oxidation conditions, e.g. in the presence of a suitable oxidising reagent (e.g. Dess-Martin periodinane, pyridinium chlorochromate, sodium dichromate, Jones' reagent, KMnO4, or Na2Cr2O7) in an appropriate solvent (e.g. dichloromethane, tetrahydrofuran, aqueous sulfuric acid or aqueous acetic acid) and optionally at reduced to elevated temperature (e.g. from 00C to 1000C), or e.g. as described in Kurkjy et al. (1952) J. Am. Chem. Soc. (74), 6260-6262;
(iv) for compounds of formula I wherein Y represents -C(O)-, reaction of a compound of formula Vl,
Figure imgf000050_0002
wherein L3 represents a suitable leaving group such as halo (e.g. chloro, bromo and iodo) or methylsulfonyl, and the dotted lines, Ai to A5, X, T and G are as hereinbefore defined or, more preferably, T is S or O and G is N, with a compound of formula VII,
Figure imgf000050_0003
wherein Di to D5 are as hereinbefore defined, for example under the reaction conditions discussed in Maerten et al. (2007) Tetrahedron, 63(3), 682-689; (v) for compounds of formula I where Y represents -S-[CH2]q- or -O-[CH2]q-, reaction of a compound of formula Vl as hereinbefore defined, with a compound of formula VIII,
Figure imgf000051_0001
wherein AA represents HO- or HS-, q and Di to D5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable base (e.g. NaH, KH), in a suitable solvent (e.g. tetrahydrofuran) and optionally at reduced to elevated temperature (e.g. from 00C to 1000C), or under the reaction conditions discussed in Kidwai et al. (2000), Bioorg. Med. Chem 8, 69-72 or Alemagna et a/. (1968) Tetrahedron, 24, 3209-3217 or Toyooka et ai, (1987) Chem. Pharm. Bull. 35(3), 1030-1035;
(vi) for compounds of formula I wherein Y represents -S(O)2-, oxidation of a compound of formula I wherein Y represents -S-, for example under standard oxidation conditions, e.g. such as those described in process (iii) above;
(vii) for compounds of formula I wherein Y represents -S(O)2NH-, reaction of a compound of formula IX,
Figure imgf000051_0002
wherein L5 represents a suitable leaving group such as halo (e.g. chloro), the dotted lines, Ai to A5, X, T and G are as hereinbefore defined or, more preferably, T is S or O and G is N1 with a compound of formula X,
Figure imgf000051_0003
wherein D1 to D5 are as hereinbefore defined, for example under standard reaction conditions, e.g. such as those described in process (i) above;
(viii) for compounds of formula I wherein Y represents -NHNHC(O)- or -NHNHS(O)2-, reaction of a compound of formula Xl,
Figure imgf000052_0001
wherein the dotted lines, Ai to As, X, T and G are as hereinbefore defined or, more preferably, T is S or O and G is N, with a compound corresponding to a compound of formula III, but wherein Yx instead represents -C(O)- or -S(O)2-, under reaction conditions known to those skilled in the art, for example in the presence of a suitable base (e.g. NaH, NaOH, triethylamine, pyridine, another suitable base mentioned at process step (i) above or mixtures thereof) and solvent (e.g. pyridine (which may serve as the base and solvent) DMF or dichloromethane (e.g. further in the presence of water and, optionally, a phase transfer catalyst)) for example at room temperature e.g. as described in Hurst, D. T. and Stacey, A. D., Nethercleft, M., Rahim, A., Harnden, M. R. Aust. J. Chem. 1998, 41, 1221;
(ix) for compounds of formula I wherein Y represents -NHN=CH-, reaction of a compound of formula Xl as hereinbefore defined, with a compound of formula XII,
Figure imgf000052_0002
wherein Di to D5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (e.g. toluene or xylenes), in the presence of suitable dehydration means (e.g. Dean-Stark apparatus, 3A molecular sieves, magnesium turnings), optionally in the presence of a suitable Lewis acid (e.g BF3OEt2), and at elevated temperature (e.g. from 300C to 1500C) using conventional or microwave heating means;
(x) for compounds of formula I wherein Z is O or S, reaction of a compound of formula XIII,
Figure imgf000053_0001
wherein L5a represents a halogen atom (e.g. Br, Cl or I) and wherein the dotted lines, Di to D5, T1 G and Y are as hereinbefore defined or, more preferably, T is S or O and G is N1 with a compound of formula XIV,
Figure imgf000053_0002
wherein, Za is O or S and A1 to A5, Q, Rx, Ry and n are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable base (e.g. MeONa, EtONa, NaH), a suitable solvent (e.g. MeOH, EtOH1 THF), and at elevated temperature (e.g. from 300C to 1500C);
(xi) cyclisation of a compound of formula XV,
Figure imgf000053_0003
wherein T' represents S, NH or O and G, X1 Y, A1 to A5 and Di to D5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example, in an appropriate solvent (e.g. toluene, xylenes, DCM), optionally in the presence of an acid (e.g. methanesulfonic acid) and at reduced to elevated temperatures (e.g. from 0°C to 1400C);
(xii) reaction of a compound of formula XVI,
Figure imgf000054_0001
wherein X and A1 to A5 are as hereinbefore defined and L6a represents a suitable leaving group (e.g. a halo, such as chloro, bromo, iodo, a sulfonate group or an acid anhydride) or OH, with a compound of formula XVII,
Figure imgf000054_0002
wherein G' represents NH2 or OH and T, Y and D1 to D5 are as hereinbefore defined, when L6a represents a suitable leaving group, under reaction conditions known to those skilled in the art, for example such as those described in JP3258771 , e.g. in an appropriate solvent (e.g. toluene, xylenes, DCM, chloroform), optionally in the presence of an base (e.g. pyridine, Hunig's base, triethylamine) and at reduced to elevated temperatures (e.g. from O0C to 1400C) or when L6a represents OH, under standard coupling reaction conditions, for example, in the presence of a suitable coupling reagent (e.g. 1 ,1 '-carbonyldiimidazole, Λ/.W-dicyclohexylcarbodiimide, 1-(3-dimethylamino- propyl)-3-ethylcarbodiimide (or hydrochloride thereof), /V,/V-disuccinimidyl carbonate, benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate, 2-(1 H- benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate, benzotriazol-1 - yloxytris-pyrrolidinophosphonium hexafluorophosphate, bromo-tris- pyrrolidinophosponium hexafluoro-phosphate, 2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3- tetramethyluronium tetra-fluorocarbonate) or i-cyclohexylcarbodiimide-3- propyloxymethyl polystyrene, optionally in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, Λ/-ethyldiisopropylamine, N-
(methylpolystyrene)-4-(methylamino)pyridine, potassium bis(trimethylsilyl)-amide, sodium bis(trimethylsilyl)amide, potassium terf-butoxide, lithium diisopropylamide, lithium 2,2,6,6- tetramethylpiperidine or mixtures thereof) and an appropriate solvent (e.g. tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile or dimethylformamide) and at reduced to elevated temperatures (e.g. from 00C to 14O0C);
(xiii) for compounds of formula I wherein Z is a bond, reaction of a compound of formula XVIII,
Figure imgf000055_0001
XVIII
wherein L7a represents a halogen atom (e.g. Br, Cl or I) and the dotted lines, T, G, Y and D1 to D5 are as hereinbefore defined, with a compound of formula XIX,
Figure imgf000055_0002
wherein L8 represents a halogen atom (e.g. Br, Cl or I), Xaa is -Q-[CRxRy]n- and A1 to A5, Q, Rx, Ry and n are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in an appropriate solvent (e.g. THF, MTBE, DMA, NMP), with a suitable catalytic system (such as those described in J. E. Milne, S. L. Buchwald, J. Am. Chem. Soc, 2004, 126, 13028-13032, N. Hadei, E. A. B. Kantchev, C. J. O'Brien, M. G. Organ, Org. Lett., 2005, 7, 3805-3807, S. Huo, Org. Left., 2003, 5, 423-425, J. Zhou, G. C. Fu, J. Am. Chem. Soc, 2003, 125, 12527-12530, F. O. Arp, G. C. Fu, J. Am. Chem. Soc, 2005, 127, 10482-10483, A. A. JaIiI, N. Kurono, M. Tokuda, Synthesis, 2002, 2681-2686 and U. Kiehne, J. Bunzen, H. Staats, A. Lϋtzen, Synthesis, 2007, 1061- 1069), and at reduced to elevated temperatures (e.g. from 00C to 1400C);
(xiv) for compounds of formula I1 wherein X is -[CH2]2- or -[CH2]3-, Q and Z both represent bonds and Y is -NHS(O)2-, hydrogenation of a compound of formula XX or XXI,
Figure imgf000056_0001
wherein E represents CH2 or a bond and the dotted lines, T, G, Ai to A5 and D-i to D5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example with a suitable catalyst (e.g. Pd/C, Raney Nickel, RhCI(PPh3)3, Lindlar catalyst), with a suitable source of hydrogen (e.g. hydrogen gas, hydrazine, dihydronaphthalene, dihydroanthracene, isopropanol, formic acid), optionally in an appropriate solvent (e.g. MeOH, EtOH1 water or mixtures thereof), optionally at elevated pressures (e.g. greater than 1 atmosphere) and at reduced to elevated temperatures (e.g. from O0C to 1400C);
(xv) for compounds of formula I in which X represents -C(O)-, oxidation of a corresponding compound of formula I in which X represent -CH2-, in the presence of a suitable oxidising agent, such as potassium permanganate under conditions that will be well known to those skilled in the art;
(xvi) for compounds of formula I in which Y represents -C(O)NH-[CH2]r-B-, reaction of a compound of formula XXII,
Figure imgf000056_0002
wherein r, B and D1 to D5 are as hereinbefore defined, with a compound of formula XVI as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (e.g. DMF, MeOH, EtOH, THF), and optionally at reduced to elevated temperature (e.g. from 00C to 1000C); (xvii) for compounds of formula I in which Y represents -C(O)NH-[CH2JrB-, reaction of a compound of formula XXII, as hereinbefore defined, with a compound of formula XXIII,
XXIII
Figure imgf000057_0001
wherein A1 to A5, and X are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (e.g. MeOH, EtOH, THF), and optionally at reduced to elevated temperature (e.g. from O0C to 1000C), followed by reaction of the resulting intermediate with a suitable oxidant (e.g. FeCI3) in the presence of a suitable solvent (e.g. MeOH, EtOH1 THF), and optionally at elevated temperature (e.g. from 300C to 1000C); and
(xviii) for compounds of formula I in which Y represents -C(O)NH-[CH2]r-B-, reaction of a compound of formula XXIV,
Figure imgf000057_0002
wherein Ai to A5, X, T and G are as hereinbefore defined, Ra represents a linear or branched C1 to C6 alkyl group, with a compound of formula XXV,
Figure imgf000057_0003
wherein r, B and D1 to D5 are as hereinbefore defined, under standard reaction conditions, e.g. such as those described in process (xii) above.
Compounds of formula Il may be prepared by: (a) for compounds of formula Il wherein Z is a bond, cyclisation of a compound of formula XXVI,
Figure imgf000058_0001
wherein A1 to A5, T and G are as hereinbefore defined or, more preferably, T is S or O and G is N, and X' is -Q-[CFW]n- or -C(O)-, under reaction conditions known to those skilled in the art, for example, in an appropriate solvent (e.g. toluene, xylenes or DCM), optionally in the presence of an acid (e.g. methanesulfonic acid) and at reduced to elevated temperatures (e.g. from O0C to 14O0C);
(b) for compounds of formula II, wherein T is S, G is N and Z is a bond, reaction of a compound of formula XXVII,
Figure imgf000058_0002
wherein L6 represents a suitable leaving group (e.g. a halo, such as chloro, bromo, iodo, a sulfonate group or an acid anhydride) or OH, and X' and A1 to A5 are as hereinbefore defined with thiosemicarbazide, under reaction conditions known to those skilled in the art, for example, for example such as those described in JP3258771 , e.g. in an appropriate solvent (e.g. toluene, xylenes, DCM, chloroform), optionally in the presence of an base (e.g. pyridine, Hunig's base, triethylamine) and at reduced to elevated temperatures (e.g. from O0C to 1400C) or when L6 represents OH, under standard coupling reaction conditions, for example, in the presence of a suitable coupling reagent (e.g. 1 ,1 '-carbonyldiimidazole, Λ/./V-dicyclohexylcarbodiimide, 1-(3-dimethylamino- propyl)-3-ethylcarbodiimide (or hydrochloride thereof), Λ/./V-disuccinimidyl carbonate, benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate, 2-(1 H- benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate, benzotriazol-1 - yloxytris-pyrrolidinophosphonium hexafluorophosphate, bromo-tris- pyrrolidinophosponium hexafluoro-phosphate, 2-(1 /-/-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium tetra-fluorocarbonate) or i-cyclohexylcarbodiimide-3- propyloxymethyl polystyrene, optionally in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, Λ/-ethyldiisopropylamine, N- (methylpolystyrene)-4-(methylamino)pyridine, potassium bis(trimethylsilyl)-amide, sodium bis(trimethylsilyl)amide, potassium terf-butoxide, lithium diisopropylamide, lithium 2,2,6,6- tetramethylpiperidine or mixtures thereof) and an appropriate solvent (e.g. tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile or dimethylformamide) and at reduced to elevated temperatures (e.g. from O0C to 1400C);
(c) for compounds of formula II, wherein T is O, G is N and Z is a bond, reaction of a compound of formula XXVII as hereinbefore defined with semicarbazide, under reaction conditions known to those skilled in the art, for example such as those described in process (b) above;
(d) for compounds of formula II, wherein X is -Q-[CF^R1V, reaction of a compound of formulaXXVIII,
Figure imgf000059_0001
wherein L7 represents a suitable leaving group (e.g. chloro, bromo, iodo) and the dotted lines, T and G are as hereinbefore defined or, more preferably, T is S or O and G is N, with a compound of formula XIX as hereinbefore defined, under reaction conditions known to those skilled in the art, for example those described under process (xiii) above;
(e) for compounds of formula II, wherein X is -[CH2J2- or -[CH2]3- and Q and Z both represent bonds, hydrogenation of a compound of formula XXIX or XXX,
XXIX
Figure imgf000059_0002
Figure imgf000060_0001
wherein the dotted lines, E, A1 to A5, T and G, are as hereinbefore defined, or, more preferably, T is S or O and G is N, under reaction conditions known to those skilled in the art, for example as described in process (xiv) above;
(T) for compounds of formula Il wherein Z is O or S, reaction of a compound of formula XXVIII as hereinbefore defined, with a compound of formula XIV as hereinbefore defined, for example under standard reaction conditions, e.g. such as those described in process (x) above;
(g) for compounds of formula II, wherein T is N and Q is O, cyclisation of a compound of formula XXXI,
Figure imgf000060_0002
wherein X and A1 to A5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example, the conditions described under process (xi) above; and
(h) for compounds of formula II, wherein T is N, G is O and Z is a bond, reaction of a compound of formula XXVII as hereinbefore defined with hydroxyguanidine, under reaction conditions known to those skilled in the art, for example, those described under process (b) above.
Compounds of formula V may be prepared by reaction of a compound of formula XXXII,
Figure imgf000060_0003
wherein Halo represents a halogen atom (e.g. iodo, bromo or chloro), the dotted lines, A1 to A5, X, T and G, are as hereinbefore defined, or, more preferably, T is S or O and G is N, with a compound of formula XII as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in a suitable solvent (e.g. tetrahydrofuran or diethyl ether) and subsequent reaction at reduced to elevated temperatures (e.g. from -780C to 1000C), or e.g. as described in Kurkjy et al. (1952) J. Am. Chem. Soc. (74), 6260-6262.
Compounds of formula Vl wherein L3 represents halo (e.g. chloro) may be prepared by reaction of a compound of formula Il with NaNO2 and a suitable halogen source (e.g. hydrochloric acid), under reaction conditions known to those skilled in the art, for example such as those described in Foroumadi et al. (1999) Arzneim. Forsch. 49, 1035- 1038 or Foroumadi et al (2005) Arch. Pharm. Chem. Life ScL , 338, 112-116, for example in the presence of a suitable metal (e.g. copper powder).
Compounds of formula Vl wherein L3 represents methylsulfonyl may be prepared by oxidation of a compound of formula XXXIII,
Figure imgf000061_0001
wherein the dotted lines, Ai to A5, X, T and G, are as hereinbefore defined, or, more preferably, T is S or O and G is N, under reaction conditions known to those skilled in the art, for example under standard oxidation conditions, e.g. such as those described in process (vi) above.
Compounds of formula IX may be prepared by:
(aa) reaction of a compound of formula Vl, wherein L3 is halo (e.g. chloro), with a source of SO2 (e.g. SO2 gas) followed by reaction of the intermediate compound with a suitable halogen source (e.g. Λ/-chlorosuccinamide or Λ/-bromosuccinamide), under reaction conditions known to those skilled in the art, for example such as those described in Naganawa et al. (2006) Biorg. Med. Chem. 14, 6628-6639, e.g. for the first step in the presence of a suitable base (e.g. n-butyllithium), in a suitable solvent (e.g. tetrahydrofuran) and at reduced to elevated temperatures (e.g. from -78°C to 1000C) and for the second step, in the presence of a suitable solvent (e.g. dichloromethane) and at reduced to elevated temperatures (e.g. from -78°C to 500C); or
(bb) reaction of a compound of formula XXXIV,
Figure imgf000062_0001
wherein dotted lines, Ai to A5, X, T and G, are as hereinbefore defined, or, more preferably, T is S or O and G is N, with a suitable chlorine source (e.g. chlorine gas), under reaction conditions known to those skilled in the art, for example such as those described in Naganawa et al. (2006) Biorg. Med. Chem. 14, 6628-6639, e.g. in the presence of a suitable solvent (e.g. 33% aqueous acetic acid) and at reduced to room temperatures (e.g. from -200C to 250C).
Compounds of formula Xl may be prepared by reaction of a compound of formula Vl, wherein L3 is halo (e.g. chloro), with hydrazine, under reaction conditions known to those skilled in the art, for example such as those described in Shafiee et al. (1976), J. Het. Chem. 13, 117-121 , e.g. in the presence of a suitable solvent (e.g. ethanol, methanol), optionally in the presence of a suitable base (e.g. triethylamine, Hunig's base) and at reduced to elevated temperatures (e.g. from -78°C to 1100C).
Compounds of formula XIII may be prepared by halogenation of a compound of formula XXXV,
Figure imgf000062_0002
wherein dotted lines, Di to Ds, X, T and G, are as hereinbefore defined, or, more preferably, T is S or O and G is N, with a halogen (bromine, chlorine or iodine), under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (e.g. acetic acid) and in the presence of a suitable base (e.g. NaOAc) as described in Pippich et al. J. Heterocyclic Chemistry (1997) 34, 823-828.
Compounds of formula XXII may be prepared by reaction of a compound of formula XXXVI,
XXXVI
Figure imgf000063_0001
with a hydrazine hydrate, under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (e.g. DMF, MeOH, EtOH, THF), and optionally at reduced to elevated temperatures (e.g. from O0C to 1000C).
Compounds of formula XXIV may be prepared by reaction of a compound of formula XXXVII,
Figure imgf000063_0002
Wherein A1 to A5, X and Ra are as hereinbefore defined, with Lawesson's reagent, under reaction conditions known to those skilled in the art, for example such as those described in Bradley et al. (2005), Liquid Crystals Today, 14, 15-18, e.g. in the presence of a suitable solvent (e.g. THF).
Compounds of formula XXVI may be prepared by reaction of a compound of formula XXVII, with a compound of formula XXXVIII,
^NH2
Q> N XXXVIII
H wherein G' is OH or NH2 and T is as hereinbefore defined or, more preferably, more preferably, T is S or O and G' is NH2, under reaction conditions known to those skilled in the art, for example such as those described in process step (b) above.
Compounds of formula XXIX may be prepared by reaction of a compound of formula XXVIII as defined hereinbefore, with a compound of formula XXXIX,
XXXIX
Figure imgf000064_0001
wherein E and A1 to A5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example with a suitable metal catalyst (e.g. Pd(OAc)2, Pd(dba)2, PdCI2, Pd(PPh3)4, Pd(OCOCF3)2(PPh3)2), a suitable base (e.g. NaOAc, K2CO3, Na2CO3, K3PO4, triethylamine, Hunig's base, LiCI), optionally in the presence of a suitable ligand (e.g. triethanolamine, Me4NCI, H-Bu4NBr, Λ/,Λ/-Dimethyl-β-alanine or those ligands described in A.-E. Wang, J.-H. Xie, L.-X. Wang, Q.-L. Zhou, Tetrahedron, 2005, 61, 259-266, L. R. Moore, K. H. Shaughnessy, Org. Lett., 2004, 6, 225-228 and references therein), in a suitable solvent (e.g. THF, DMF, acetonitrile, water, cyclohexene, benzene, tolune) and at reduced to elevated temperatures (e.g. from O0C to 1500C).
Compounds of formula XXX may be prepared by reaction of a compound of formula XL,
Figure imgf000064_0002
wherein the dotted lines, E, T and G are as defined hereinbefore or, more preferably, T is S or O and G is N1 with a compound of formula XLI,
Figure imgf000064_0003
wherein L9 represents a suitable leaving group (e.g. chloro, bromo or iodo) and Ai to A5 are as defined hereinbefore, under reaction conditions known to those skilled in the art, for example those described above for the preparation of a compound of formula XXIX.
Additionally, compounds of XXIX, XXX and XL may be prepared by synthetic methods analogous to those described in US 2,420,434 and US 2,511 ,371.
Compounds of formulae XXXII may be prepared by synthetic methods analogous to those described hereinbefore, or by analogy to those described by Kurkjy et at. (1952) J. Am. Chem. Soc. (74), 6260-6262.
Compounds of formulae XXXIII may be prepared by synthetic methods analogous to those described hereinbefore, or by analogy to those described by Boots et at. (1967) J. Het. Chem. 4, 274-283, Amtul et at. (2004) Biochem. Biophys. Commun. 319, 1053- 1063, Kramer et al. (1994) J. Het. Chem. 31, 1439-1443 or DE 2 652 121.
Compounds of formulae XXXIV may be prepared by synthetic methods analogous to those described hereinbefore, or by analogy to those described by Foroumadi et at. (2005) Arch. Pharm. Chem. Life. ScL 338, 112-116, Boots et at. (1967) J. Het. Chem. 4, 274-283, Amtul et al. (2004) Biochem. Biophys. Commun. 319, 1053-1063, Kramer et at. (1994) J. Het. Chem. 31, 1439-1443, DE 2 611 965 or DE 2 652 121.
Compounds of formula XV may be prepared by reaction of a compound of formula XVII as hereinbefore defined, with a compound of formula XXVII as hereinbefore defined, under reaction conditions known to those skilled in the art, for example, in an appropriate solvent (e.g. DCM, Et2θ or THF) and optionally in the presence of a base (e.g. Hunig's base, triethylamine, DMAP, pyridine) and at reduced to elevated temperatures (e.g. from 00C to 800C) and the uncyclised intermediate isolated.
Compounds of formula XVII may be prepared by way of synthetic procedures analogous to those described herein. For example, compounds of formula XVII wherein wherein Y represents -NHS(O)2-, T is NH and Q' is OH may be prepared by reaction of a compound of formula XLII,
Figure imgf000066_0001
wherein J represents Ci-4 alkyl, T represents NH and D1 to D5 are as defined hereinbefore, with hydroxylamine, under reaction conditions known to those skilled in the art, for example, in the presence of a suitable base (e.g. triethylamine, Hunig's base, DMAP), in a suitable solvent (e.g. diethyl ether, ethanol, methanol) and at reduced to elevated temperatures (e.g. from 00C to 1200C).
Compounds of formula XXXI may be prepared by reaction of a compound of formula XLIII,
*UΔΛ !TCN XLlIl
wherein X and Ai to A5 are as hereinbefore defined, with hydroxyamine, under reaction conditions known to those skilled in the art, for example, as described in US 3,720,685.
Compounds of formula XXXVI may be prepared by reaction of a compound of formula XLIV,
Figure imgf000066_0002
with morpholine and sulfur, under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (e.g. DMF, MeOH, EtOH, THF), and optionally at reduced to elevated temperatures (e.g. from 00C to 100°C).
Compounds of formula XXXVII may be prepared by reaction of a compound of formula XLV,
Figure imgf000067_0001
wherein A1 to A5 and X are as hereinbefore defined, with a compound of formula XLVI,
Figure imgf000067_0002
wherein Ra is as hereinbefore defined, under standard reaction conditions, e.g. such as those described in process (viii) above.
Compounds of formulae III, IV, VII, VIII, X, XII1 XIV1XVI, XVIII, XIX, XX, XXI, XXVII, XXVIII, XXXV, XXXVIII, XXXIX, XLI, XLII, XLIII1 XLIV1 XLV and XLVI are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein (or processes described in references contained herein), or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions.
Substituents, such as R1, R2, R3 and R4 in final compounds of formula I (or precursors thereto and other relevant intermediates) may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions (e.g. carbonyl bond reductions in the presence of suitable and, if necessary, chemoselective, reducing agents such as LiBH4 or NaBH4), oxidations, alkylations, acylations, hydrolyses, esterifications, and etherifications. The precursor groups can be changed to a different such group, or to the groups defined in formula I1 at any time during the reaction sequence.
Compounds of formula I may be isolated from their reaction mixtures using conventional techniques. It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups.
The protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.
The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis.
The use of protecting groups is fully described in "Protective Groups in Organic Chemistry", edited by J W F McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 3rd edition, T.W. Greene & P.G.M. Wutz, Wiley-lnterscience (1999).
As used herein, the term "functional groups" means, in the case of unprotected functional groups, hydroxy-, thiolo-, aminofunction, carboxylic acid and, in the case of protected functional groups, lower alkoxy, N-, O-, S- acetyl, carboxylic acid ester.
Medical and Pharmaceutical Uses
Compounds of formula I are indicated as pharmaceuticals.
Advantageously, compounds of formula I may be AMPK agonists, i.e. they may activate AMPK. By 'activate AMPK', we mean that the steady state level of phosphorylation of the Thr-172 moiety of the AMPK-α subunit is increased compared to the steady state level of phosphorylation in the absence of the agonist. Alternatively, or in addition, we mean that there is a higher steady state level of phosphorylation of any other proteins downstream of AMPK1 such as acetyl-CoA carboxylase (ACC). As the compounds of formula I may be AMPK activators, they may therefore be useful in the treatment of diseases such as those described herein, especially diabetes (e.g. type Il diabetes).
Compounds of formula I are therefore indicated for use in the treatment of a disorder or condition ameliorated by the activation of AMPK.
The terms "disorder or condition ameliorated by the activation of AMPK" will be understood by those skilled in the art to include lung disease, obesity, dry-type age- related macular degeneration, cardioprotection or, preferably, diabetes, hyperinsulinemia and associated conditions, cancer, a condition/disorder where fibrosis plays a role, sexual dysfunction, osteoporosis, inflammation, heart failure and neurodegenerative diseases.
Compounds of formula I may also be indicated for use in the treatment of a disorder or a condition caused by, linked to, or contributed to by, hyperinsulinemia.
According to a further aspect of the invention, there is provided the use of a compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, for the manufacture of a medicament for the treatment of a disorder or condition ameliorated by the activation of AMPK.
The terms "disorder or condition caused by, linked to, or contributed to by, hyperinsulinemia" or "treatment of hyperinsulinemia or an associated condition" will be understood by those skilled in the art to include hyperinsulinemia and associated conditions, such as cardiovascular disease or, preferably, type 2 diabetes, glucose intolerance, insulin resistance, metabolic syndrome, dyslipidemia, hyperinsulinism in childhood, hypercholesterolemia, high blood pressure, obesity, fatty liver conditions, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, atherosclerosis, cerebrovascular conditions such as stroke, systemic lupus erythematosus, neurodegenerative diseases such as Alzheimer's disease, and polycystic ovary syndrome. Other disease states include progressive renal disease such as chronic renal failure.
Preferred disorders include hyperinsulinemia and, particularly, type 2 diabetes. Certain compounds of formula I may also have the additional advantage that they exhibit partial agonist activity and may therefore be useful in conditions, such as late type 2 diabetes, in which stimulation of the production of insulin is required. By "agonist activity", we include direct and indirect-acting agonists.
According to a further aspect of the invention there is provided a method of treatment of a disorder or condition ameliorated by the activation of AMPK, which method comprises the administration of an effective amount of a compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, to a patient in need of such treatment.
Compounds of formula I may also be of use in the treatment of cancer (primary and metastatic cancers).
The term "cancer" will be understood by those skilled in the art to include one or more diseases in the class of disorders that is characterized by uncontrolled division of cells and the ability of these cells to invade other tissues, either by direct growth into adjacent tissue through invasion, proliferation or by implantation into distant sites by metastasis.
Compounds of formula I may reduce the rate of cell proliferation when tested in an assay using a human breast cancer cell line (e.g. MDA-MB-231 ). The compounds may thus possess a beneficial inhibitory effect on the ability of tumors of this type, and of cancers generally, to survive. Compounds of formula I may also reduce the rate of cell proliferation when tested in other cancer cells lines such as MCF-7, PC-3, Jurkat, Skov- 3, HL60, MV4-11 , HT29, K562, MDA-MB231 , HCT116wt, HCT116P53-/-, A-549, DU- 145, LOVO, HCT-116 and PANC-1.
In a preferred embodiment, compounds of formula I are capable of inhibiting the proliferation of cancer cells. By "proliferation" we include an increase in the number and/or size of cancer cells.
Alternatively, or preferably in addition, compounds of formula I are capable of inhibiting metastasis of cancer cells.
By "metastasis" we mean the movement or migration (e.g. invasiveness) of cancer cells from a primary tumor site in the body of a subject to one or more other areas within the subject's body (where the cells can then form secondary tumors). Thus, in one embodiment the invention provides compounds and methods for inhibiting, in whole or in part, the formation of secondary tumors in a subject with cancer. It will be appreciated by skilled persons that the effect of a compound of formula I on "metastasis" is distinct from any effect such a compound may or may not have on cancer cell proliferation.
Advantageously, compounds of formula I may be capable of inhibiting the proliferation and/or metastasis of cancer cells selectively.
By "selectively" we mean that the combination product inhibits the proliferation and/or metastasis of cancer cells to a greater extent than it modulates the function (e.g. proliferation) of non-cancer cells. Preferably, the compound inhibits the proliferation and/or metastasis of cancer cells only.
Compounds of formula I may be suitable for use in the treatment of any cancer type, including all tumors (non-solid and, preferably, solid tumors). For example, the cancer cells may be selected from the group consisting of cancer cells of the breast, bile duct, brain, colon, stomach, reproductive organs, thyroid, hematopoietic system, lung and airways, skin, gallbladder, liver, nasopharynx, nerve cells, kidney, prostate, lymph glands and gastrointestinal tract. Preferably, the cancer is selected from the group of colon cancer (including colorectal adenomas), breast cancer (e.g. postmenopausal breast cancer), endometrial cancer, cancers of the hematopoietic system (e.g. leukemia, lymphoma, etc), thyroid cancer, kidney cancer, oesophageal adenocarcinoma, ovarian cancer, prostate cancer, pancreatic cancer, gallbladder cancer, liver cancer and cervical cancer. More preferably, the cancer is selected from the group of colon, prostate and, particularly, breast cancer. Where the cancer is a non-solid tumor, it is preferably a hematopoietic tumor such as a leukemia (e.g. Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), Acute Lymphocytic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL).
Preferably, the cancer cells are breast cancer cells.
Compounds of formula I may also be of use in the treatment of a condition/disorder where fibrosis plays a role. Compounds of formula I may also be useful in the treatment of sexual dysfunction (e.g. the treatment of erectile dysfunction). A condition/disorder where fibrosis plays a role includes (but is not limited to) cystic fibrosis or, preferably, scar healing, keloids, scleroderma, pulmonary fibrosis (including idiopathic pulmonary fibrosis), nephrogenic systemic fibrosis, and cardiovascular fibrosis (including endomyocardial fibrosis), systemic sclerosis, liver cirrhosis, eye macular degeneration, retinal and vitreal retinopathy, Crohn's/inflammatory bowel disease, post surgical scar tissue formation, radiation and chemotherapeutic-drug induced fibrosis, and cardiovascular fibrosis.
Compounds of formula I may also be of use in the treatment of osteoporosis.
Compounds of formula I may also be of use in the treatment of inflammation.
Compounds of formula I may also be of use in the treatment of sexual dysfunction.
Compounds of formula I may also be of use in the treatment of heart failure.
Compounds of formula I may also be of use in the treatment of lung disease.
Compounds of formula I may also be of use in the treatment of obesity.
Compounds of formula I may also be of use in the treatment of dry-type age-related macular degeneration.
Compounds of formula I may also be of use as an agent for cardioprotection.
Compounds of formula I may also be of use in the treatment of neurodegenerative diseases (e.g. Alzheimer's disease, Parkinson's disease and Huntington's disease, amyotrophic lateral sclerosis, polyglutamine disorders, such as spinal and bulbar muscular atrophy (SBMA), dentatorubral and pallidoluysian atrophy (DRPLA), and a number of spinocerebellar ataxias (SCA)).
Preferebaly, compounds of formula I can be used in the treatment of diabetes, a disorder or condition where fibrosis plays a role, and hyperinsulinemia and associated conditions.
For the avoidance of doubt, in the context of the present invention, the terms "treatment", "therapy" and "therapy method" include the therapeutic, or palliative, treatment of patients in need of, as well as the prophylactic treatment and/or diagnosis of patients which are susceptible to, the relevant disease states.
"Patients" include mammalian (including human) patients.
The term "effective amount" refers to an amount of a compound, which confers a therapeutic effect on the treated patient (e.g. sufficient to treat or prevent the disease). The effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).
In accordance with the invention, compounds of formula I may be administered alone, but are preferably administered orally, intravenously, intramuscularly, cutaneously, subcutaneously, transmυcosally (e.g. sublingually or buccally), rectally, transdermal^, nasally, pulmonarily (e.g. tracheally or bronchially), topically, by any other parenteral route, in the form of a pharmaceutical preparation comprising the compound in a pharmaceutically acceptable dosage form. Preferred modes of delivery include oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal delivery.
Compounds of formula I will generally be administered as a pharmaceutical formulation in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which may be selected with due regard to the intended route of administration and standard pharmaceutical practice. Such pharmaceutically acceptable carriers may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use. Suitable pharmaceutical formulations may be found in, for example, Remington The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995). For parenteral administration, a parenterally acceptable aqueous solution may be employed, which is pyrogen free and has requisite pH, isotonicity, and stability. Suitable solutions will be well known to the skilled person, with numerous methods being described in the literature. A brief review of methods of drug delivery may also be found in e.g. Langer, Science (1990) 249, 1527.
Otherwise, the preparation of suitable formulations may be achieved non-inventively by the skilled person using routine techniques and/or in accordance with standard and/or accepted pharmaceutical practice. Another aspect of the present invention includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, in combination with a pharmaceutically acceptable excipient, such as an adjuvant, diluent or carrier.
The amount of compound of formula I in the formulation will depend on the severity of the condition, and on the patient, to be treated, as well as the compound(s) which is/are employed, but may be determined non-inventively by the skilled person.
Depending on the disorder, and the patient, to be treated, as well as the route of administration, compounds of formula I may be administered at varying therapeutically effective doses to a patient in need thereof.
However, the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe. One skilled in the art will recognize that the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease.
Administration may be continuous or intermittent (e.g. by bolus injection). The dosage may also be determined by the timing and frequency of administration. In the case of oral or parenteral administration the dosage can vary from about 0.01 mg to about 1000 mg per day of a compound of formula I (or, if employed, a corresponding amount of a pharmaceutically acceptable salt or prodrug thereof).
In any event, the medical practitioner, or other skilled person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient. The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention. The compounds of formula I may also be used or administered in combination with one or more additional drugs useful in the treatment of a disorder or condition ameliorated by the activation of AMPK, in combination therapy.
According to a further aspect of the invention, there is provided a combination product comprising:
(A) a compound of formula I; and
(B) another therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK, wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
Other therapeutic agents useful in the treatment of a disorder or condition ameliorated by the activation of AMPK will be well known to those skilled in the art and include biguanides, glitazones (i.e. thiazolidinediones), oligomycins, AICAR (aminoimidazole carboxamide ribonucleotide), insulin, insulin secretagogues (such as sulphonylureas), peroxisome proliferator-activated receptor (PPAR) agonists (which also include thiazolidinediones), α-glucosidase inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, exenatide, inhibitors of 11-β hydroxysteroid dehydrogenase type 1 , inhibitors of stearoyl- CoA desaturase 1 (SCD-1), A-769662, D942 (5-(3-(4-(2-(4-Fluorophenyl)ethoxy)- phenyl)propyl)furan-2-carboxylic acid), cilostazol, AM251 (a CBi receptor antagonist), SIRT1 activators (e.g. resveratrol) and salidroside. By "agonist" we include direct and indirect-acting agonists. By "agonist" we include direct and indirect-acting agonists.
In one embodiment, the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise a biguanide. For example, the agent may be selected from the group consisting of phenformin, buformin, and, most preferably, metformin.
In an alternative embodiment, the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise glitazones. For example, the agent may be selected from the group consisting of troglitazone, pioglitazone and rosiglitazone.
In an alternative embodiment, the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise an oligomycin. For example, the agent may be selected from the group consisting of oligomycin A, oligomycin B, oligomycin C, oligomycin D (rutamycin A), oligomycin E, oligomycin F, rutamycin B, 44-homooligomycin A and 44-homooligomycin B.
In an alternative embodiment, the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise AICAR.
In one embodiment, the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise GLP-1 or a biologically active fragment, variant, fusion of derivative thereof. For example, the agent may be selected from the group consisting of Exendin-4 (exenatide; Byetta), exenatide long acting release (LAR), exenatide derivatives (such as ZP10 developed by Zealand Pharmaceuticals), native GLP-1, human GLP-1 derivatives (such as BIM51077 (Ipsen and Roche)), DPP-IV resistant GLP-1 analogues (for example LY315902 and LY30761 SR (Lilly)), long acting GLP-1 derivatives (such as NN2211 (Liraglutide; Novo Nordisk)) and complex proteins (such as the GLP-1 -albumin complex CJC-1131).
In an alternative embodiment, the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise a dipeptidyl peptidase IV (DPP-IV) inhibitor. For example, the agent may be selected from the group consisting of Vildagliptin (LAF237), MK-0431-Sitagliptin and Saxagliptin.
In a further alternative embodiment, the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise gastric inhibitory polypeptide (GIP), or a biologically active fragment, variant, fusion of derivative thereof. GIP, also known as glucose-dependent insulinotropic polypeptide, is a 42-amino acid peptide hormone synthesised in and secreted from K cells in the intestinal epithelium. An important determinant of GIP action is the N-terminal cleavage of the peptide to the inactive GIP (3-42). The enzyme DPP-4, which also cleaves GLP-1 and GLP-2, rapidly inactivates GIP both in vitro and in vivo. Hence, it may be desirable to administer GIP in combination with a DPP-4 inhibitor.
In a further alternative embodiment, the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise a selective inhibitor of 11-β hydroxysteroid dehydrogenase type 1 (11β-HSD1), an enzyme associated with conversion of cortisone to Cortisol in the liver and adipose tissue. Examples of suitable 11β-HSD1 inhibitors/antagonists include AMG221 (developed by
Amgen) and BVT83370 (developed by Biovitrum).
In one embodiment, the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise an inhibitor of stearoyl- CoA desaturase 1 (SCD-1). Examples of suitable SCD-1 inhibitors include those described in US 2005/0019251 (e.g. 6-[4-(2-bromo-4-methoxy-benzoyl)-piperazin-1-yl]- N-(3-phenyl-propyl)-nicotinamide), those described in WO 2006/130986 (e.g. 2-[4-(2- trifluoromethyl-benzoyl)-piperazin-1-yl]-thiazole-5-carboxylic acid amide), those described in WO 2008/029266 and WO 2008/062276 (e.g. GRC 9332), those described in Freeman, J. et al. (2007) Discovery of phenoxypiperidines as novel Stearoyl-CoA desaturase inhibitors: From Assay Validation to Lead Development, 233rd ACS National Meeting, 25-29 March 2007, Chicago, IL, USA (MEDI-383) (e.g. 4-(2-chloro-5-fluoro- phenoxy)-1-(5-methyl-[1 ,3,4]oxadiazol-2-yl)-piperidine), those described in Xin et al. Bioorg. Med. Chem. Lett. (2008), 18(15), 4298-4302 (e.g. 4-(2-chlorophenoxy)-Λ/-[3- (methylcarbamoyl)phenyl]piperidine-1-carboxamide) and those described in Liu et al. J. Med. Chem. (2007), 50(13), 3086-3100. Without wishing to be bound by theory, it is proposed that inhibition of SCD-1 results in the activation of AMPK (Dobrzyn et al. Proceedings of the National Academy of Sciences (2004), 101(17), 6409-6414.
In yet a further alternative embodiment, the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise a SIRT1 (also known as sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)) activator. Examples of suitable SIRT1 activators include resveratrol and SRT-1720 (N-[2-[3-(piperazin-1-ylmethyl)imidazo[2,1-b][1 ,3]thiazol-6-yl]phenyl]quinoxal- ine-2-carboxamide).
Combination products as described herein provide for the administration of compound of formula I in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises compound of formula I1 and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including compound of formula I and the other therapeutic agent).
Thus, there is further provided: (1) pharmaceutical formulations including a compound of formula I; another therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK; and a pharmaceutically-acceptable adjuvant, diluent or carrier; and
(2) kits of parts comprising components:
(a) a pharmaceutical formulation including a compound of formula I in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and
(b) a pharmaceutical formulation including another therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
Components (a) and (b) of the kits of parts described herein may be administered simultaneously or sequentially.
According to a further aspect of the invention, there is provided a method of making a kit of parts as defined above, which method comprises bringing component (a), as defined above, into association with a component (b), as defined above, thus rendering the two components suitable for administration in conjunction with each other.
By bringing the two components "into association with" each other, we include that components (a) and (b) of the kit of parts may be:
(i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or
(ii) packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy.
Thus, there is further provided a kit of parts comprising:
(I) one of components (a) and (b) as defined herein; together with
(II) instructions to use that component in conjunction with the other of the two components. The kits of parts described herein may comprise more than one formulation including an appropriate quantity/dose of compound of formula I1 and/or more than one formulation including an appropriate quantity/dose of the other therapeutic agent, in order to provide for repeat dosing. If more than one formulation (comprising either active compound) is present, such formulations may be the same, or may be different in terms of the dose of either compound, chemical composition(s) and/or physical form(s).
With respect to the kits of parts as described herein, by "administration in conjunction with", we include that respective formulations comprising compound of formula I and the other therapeutic agent are administered, sequentially, separately and/or simultaneously, over the course of treatment of the relevant condition.
Thus, in respect of the combination product according to the invention, the term "administration in conjunction with" includes that the two components of the combination product (compound of formula I and the other therapeutic agent) are administered (optionally repeatedly), either together, or sufficiently closely in time, to enable a beneficial effect for the patient, that is greater, over the course of the treatment of the relevant condition, than if either a formulation comprising compound of formula I, or a formulation comprising the other therapeutic agent, are administered (optionally repeatedly) alone, in the absence of the other component, over the same course of treatment. Determination of whether a combination provides a greater beneficial effect in respect of, and over the course of treatment of, a particular condition will depend upon the condition to be treated or prevented, but may be achieved routinely by the skilled person.
Further, in the context of a kit of parts according to the invention, the term "in conjunction with" includes that one or other of the two formulations may be administered (optionally repeatedly) prior to, after, and/or at the same time as, administration with the other component. When used in this context, the terms "administered simultaneously" and "administered at the same time as" include that individual doses of compound of formula I and the other therapeutic agent are administered within 48 hours (e.g. 24 hours) of each other.
The compounds/combinations/methods/uses described herein may have the advantage that, in the treatment of the conditions described herein, they may be more convenient for the physician and/or patient than, be more efficacious than, be less toxic than, have better selectivity, have a broader range of activity than, be more potent than, produce fewer side effects than, or may have other useful pharmacological properties over, similar compounds, combinations, methods (treatments) or uses known in the prior art for use in the treatment of those conditions or otherwise.
Further, such advantages may stem from the compounds of formula I being AMPK activators (e.g. especially where it is stated that the compounds described herein may have better selectivity, and may produce fewer side effects, e.g. gastrointestinal side effects).
Preferred, non-limiting examples which embody certain aspects of the invention will now be described, with reference to the following figures:
Figure 1a, which shows the effect of the compound of Example 1 on AMPK phosphorylation. PC3 cells were cultured in serum-free medium overnight (16 h) and subsequently incubated with 5 μM (5) or 10 μM (10) of the compound of Example 1 or 0.1% DMSO (-) for 6 h. Equal amounts of protein from total cell lysates were separated by 4-12% Bis-Tris polyacrylamide gel and the phosphorylation of AMPK was immunoblotted with a specific anti-phospho-Thr-172 AMPKα antibody as described under "Experimental Procedures".
Figure 1b, which shows the effect of the compound of Example 3 and compounds (j) and (k) of Example 4 on eEF2 phosphorylation. After starvation of PC3 cells in serum-free medium for 5 h, 1 μM or 5 μM of the compound of Example 3 and compounds (j) and (k) of Example 4 were added and incubated for an additional 4 h. The figure provides representative immunoblots of eEF2 phosphorylation (p) by the compound of Example 3 and compounds (j) and (k) of Example 4. The compound of Example 3 and Compounds (j) and (k) of Example 4 stimulate AMPK and eEF2 phosphorylation in PC3 cells.
Figure 1 c, which shows the effect of the compounds of Example 4 on AMPK and eEF2 phosphorylation. After starvation of PC3 cells in serum-free medium for 5 h, 5 μM of the compounds (a) to (i) of Example 4 were added and incubated for an additional 1 h. The figure provides representative immunoblots of AMPK and eEF2 phosphorylation (p) by compounds (a) to (i) of Example 4. Compounds (a) to (i) of Example 4 stimulate AMPK and eEF2 phosphorylation in PC3 cells. Figure 1d, which shows the effect of the compounds of Example 4 on AMPK and eEF2 phosphorylation. After starvation of PC3 cells in serum-free medium for 5 h, 1 μM or 5 μM of the compounds (j) and (k) of Example 4 were added and incubated for an additional 4 h. The figure provides representative immunoblots of AMPK and eEF2 phosphorylation (p) by compounds (j) and (k) of Example 4. Compounds Q) and (k) of Example 4 stimulate AMPK and eEF2 phosphorylation in PC3 cells.
Figure 2, which shows the effect of compound of Example 1 on blood glucose levels in ob/ob mice. Ob/ob mice were administered compound of Example 1 (30 mg/kg, gray bars) or vehicle (black bars) by oral gavage twice daily for 20 days. Blood sampling was made on fed mice at day 0, 16 hours post dose of day 12 and day 20 of dosing.
Figure 3a, which shows that treatment of tumor cell lines with Example 2 generates a dose dependent reduction in proliferation in MDA-MB-231 human breast cancer cell lines as measured by BrdU incorporation.
Figure 3b, which shows that treatment of tumour cell lines with Example 1 generates a dose dependent reduction in proliferation in PC3 human prostate cancer cell lines as measured by BrdU incorporation.
Figure 4, which shows that the compound of Example 1 inhibits TGF-β-induced secretion of collagen IV in human primary mesangial cells, as indicated by the measurement of absorbance using the ELISA procedure.
Figure 5, which shows that the compound of Example 1 (referred to as L201 in the Figure) does not affect plasma insulin levels in C57BL/6JBomTac mice after acute administration. Blood samples were analyzed for plasma insulin prior to administration of the compound of Example 1 and 10, 30 and 60 min after drug administration.
Figure 6a, which shows the effect of TGF-β1 or TGF-β1 and the compound of Example 3 on EDA-fibronectin expression and αSMA expression in WI-38 lung fibroblast cells. Wl- 38 cells were incubated with TGF-β1 (1 ng/mL) or TGF-β1 (1 ng/mL) and the compound of Example 3 at 0.125 and 0.625 μM respectively) for 24 h.
Figure 6b, which shows the effect of TGF-β1 or TGF-β1 and the compound of Example 3 on AMPK and SMAD2 phosphorylation in WI-38 lung fibroblast cells. WI-38 cells were incubated with TGF-β1 (1 ng/mL) or TGF-β1 (1 ng/mL) and the compound of Example 3 at 0.125 and 0.625 μM respectively) for 24 h. The figure shows that the compound of Example 3 increases the phopshorylation of AMPK and decreases SMAD2 phosphorylation.
Figure 7, which shows that the compound of Example 5 suppress PP2C mediated dephosphorylation of p-T172 of AMPK in a cell free system, as measured by the relative levels of p-T172 of AMPK.
Figure 8, which showns that the treatment of normal human fibroblast cell line WI-38 with the compound of Example 5 increases steady state levels of phosphorylated AMPK and ACC.
Examples
The invention is illustrated by the following examples, in which the following abbreviations may be employed:
BrdU 5-bromo-2-deoxyuridine
CoA co-enzyme A
DCM dichloromethane
DMF dimethylformamide
DMSO dimethylsulfoxide
ES electro spray
Et2O diethyl ether
EtOAc ethyl acetate
EtOH ethanol
LC liquid chromatography
MeOH methanol
MS mass spectrometry
MTBE methyl tert-butyl ether
NMR nuclear magnetic resonance
THF tetrahydrofuran Where no preparative routes are included, the relevant intermediate is commercially available (e.g. from Chemical Diversity, San Diego, CA, USA or other available commercial sources).
General Procedures
LC-MS was performed on a Sciex API 150 LC/ES-MS equipped with an ACE 3 C8 column (30 x 3.0 mm) using a flow of 1 ml_/min. Two gradient systems of acetonitrile in water (with 0.1% TFA) are used for elution: A) 5-100% under 10 min, then 2 min 100% isocratic or B) 90-100% under 2 min, then 2 min 100% isocratic. Direct inlet ES-MS was also performed on a Bruker Esquire LC/ES-MS. 1H nuclear magnetic resonance was recorded on a Bruker Avance DRX 400 spectrometer at 400.01 MHz using residual solvent as internal standard.
Example 1 3,4-Dichloro-N-r5-(3-trrfluoromethylbenzyl)-f1 ,3,41thiadiazol-2-yll-benzenesulfonamide
(a) 3-Trifluoromethyl phenyl acetyl chloride
To a solution of 3-Trifluoromethyl phenyl acetic acid (20 g) in 200 mL toluene was added thionyl chloride (15 mL) and DMF (0.4 mL) at room temperature. The reaction mixture was then heated to 500C for about 1 h. The resultant mixture was then cooled to room temperature and the solvent evaporated under reduced pressure. The majority of the residual thionyl chloride was then removed by repeated co-evaporation with toluene (200 mL) under reduced pressure. The resultant product was formed as a yellow solid in almost quantitative yield and was used without further purification.
(b) N-Thiourea-(3-trifluoromethylphenyl)-acetamide
3-Trifluoromethyl phenyl acetyl chloride (21.8 g) was dissolved in DCM (400 mL) and was slowly added to a flask containing Thiosemicarbazide (10 g) in DCM (400 mL) and DMF (100 mL) and the reaction mixture stirred at room temperature overnight. The reaction mixture was then evaporated to give a yellow liquid. Ice cold water (400 mL) was added to the liquid under stirring to produce a white precipitate. The solid was filtered and then triturated by stirring it in Et2O (150 mL) for 2 h. The solid was then collected, washed with Et2O and dried under high-vacuum to provide the product as a white solid. Yield: 9.71 g (36%). (c) 5-(3-Trifluoromethylbenzyl)-π ,3,41thiadiazol-2-ylamine
N-Thiourea-(3-trifluoromethylphenyl)-acetamicle (4.71 g) and methanesulfonic acid (1.2 ml_, 1.1 eq.) were added to toluene (100 mL) and the resultant mixture refluxed. After 3 h the reaction was complete according to LC-MS analysis indicate and the solvent was evaporated to give the crude methanesulfonic acid salt as a white solid (>90% purity). The salt was then triturated by stirring in EtOAc (150 mL) for about 40 min and was then collected by filtration (4.71 g (100% purity) 78% yield). The salt was dissolved in EtOAc (200 mL) and 2M NaOH (75 mL) and the layers separated. The organic phase was washed twice with 2M NaOH (75 mL) and the combined water phase extracted with 4x150 mL EtOAc. The combined organic phase was washed with water (150 mL) followed by brine (150 mL), dried (MgSO4) and the solvent removed under reduced pressure to give the desired product as a white solid (2.8 g, 64% yield).
1H NMR (500 MHz, DMSO-d6) ppm 7.66 (br. s, 1H), 7.54-7.65 (m, 3H), 7.06 (s. 2H), 4.28 (S, 2H).
(d) S^-Dichloro-N-rδ-O-trifluoromethylbenzylHI .SΛlthiadiazol-Σ-vn-benzene-sulfon- amide
5-(3-Trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-ylamine (1.1 g) was dissolved in dry THF (70 mL) and the resultant solution was added over 15 min to a slurry of solid NaH in THF (20 mL) at 00C in a 3-necked round bottomed flask under an inert atmosphere. After the addition was complete, a solution of 3,4-dichlorophenylsulfonyl chloride in THF (30 mL) was added to the mixture over 5 min at 0°C. The resultant mixture was stirred and the reaction followed by LC-MS. After 40 min an additional 50 mg NaH was added. After 1 h the reaction was quenched (5-10% starting material still remained) slowly with water. More water (50 mL) was added and the aqueous solution was extracted using 4xEtOAc (100 mL). The organic phase was washed with 1x aq. Sat. NaHCO3 (100 mL), 2xH2O (100 mL), 2x 2M HCI (aq.) (100 mL), 1x H2O (100 mL) and 1x brine (100 mL), dried (MgSO4) and the solvent evaporated under reduced pressure. MeOH was added to the slightly brownish crude product and the mixture subjected to ultrasonication for up to five minutes and the mixture was then put in the refrigerator for 30 min. The solvent was removed with a Pasteur pipette. The sonication/refrigeration procedure was repeated three times to give the product as a light yellow solid (597 mg, 30% yield. 95% purity). 1 H NMR (500 MHz, DMSO-d6) δ ppm 14.28 (br. s., 1 H) 7.92 (d, J=2.20 Hz, 1 H) 7.82 (d, J=8.30 Hz, 1 H) 7.74 (br. s., 1 H) 7.73 (dd, J=6.35, 2.20 Hz, 1 H) 7.66 (t, J=8.30 Hz, 2H) 7.57 - 7.63 (m, 1 H) 4.35 (s, 2 H).
Example 2 3,4-Dichloro-N-F5-(3-trifluoromethylbenzyl)-H .2,41oxadiazol-3-vn-benzenesulfonarnide
(a) N-H -Amino-1 -methylsulfanyl-methylidenei-S^-dichlorobenzenesulfonamide 2,3-Dichlorobenzenesulfonyl chloride (491 mg, 2 mmol) and 2-methyl-2-thiopseudourea hemisulfate salt (557 mg, 4 mmol) were mixed in acetonitrile (100 mL), stirred at reflux for 2 hours and then at room temperature over for 72 hours. Water (200 mL) and diethyl ether (200 mL) were then added to the reaction mixture and the organic phase washed with 1 M Na2CO3 (2x50 mL), brine (50 mL), dried over MgSO4, filtered and then concentrated to give a colorless oil (553 mg, 80% yield). The product solidifies on standing.
(b) N-f1 -Amino-1 -hvdroxyaminomethylidenel-3,4-dichlorobenzenesulfonamide
To N-[1 -amino-1 -methylsulfanylmethylideneJ-S^-dichloro-benzenesulfonamide (553 mg) in ethanol (100 mL) was added triethylamine (405mg, 4 mmol) and hydroxylamine (2 mL 50% aq, 32 mmol) and heated at 70°C for 2 hours. Diethyl ether (200 mL) and 1 M NazCO3 (200 ml) were then added to the reaction mixture and the aqueous phase washed with diethyl ether (2x100 mL), acidified to pH 3 with o-phosphoric acid and extracted with diethyl ether (2x100 mL). The combined organic phases were dried over MgSO4, filtered and concentrated to provide the product as a white solid (85% purity, 189 mg, 0.66 mmol, 33% yield).
(c) 3,4-Dichloro-N-f5-(3-trifluoromethylbenzyl)-f1 ,2,41oxadiazol-3-vn- benzenesulfonamide
Carbonyl-diimidazole (324 mg, 2 mmol) and 3-(trifluoromethyl)phenylacetic acid (408 mg, 2 mmol) were mixed in acetonitrile (10 mL). After 30 minutes 3.3 ml (0.66 mmol, 1 eq) of the mixture was added to a solution of N-[1 -Amino-1 -hydroxyaminomethylidene]-3,4- dichlorobenzenesulfonamide (189 mg at 85% purity) in acetonitrile (20 mL) and the temperature raised to 8O0C. After 1 hour was the reaction complete and the reaction was quenched by the addition of diethyl ether (200 ml) and water (200 ml) and the phases separated. The aqueous phase was washed with 1 M Na2CO3 (2x50 ml), of 1 M H3PO4 (2x50 ml) and brine (50 ml), dried over MgSO4, filtered and concentrated. The residue was dissolved in ethyl acetate (10 ml) and heptane (100 ml) was added and a white precipitate formed. After being allowed to settle overnight, the solid was collected by suction to give the product (60 mg, 0.13 mmol, 20% yield (95% purity)).
MS m/z= 452; 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.88 (d, 1 H) 7.54-7.68 (m, 6 H) 4.15 (s, 2 H).
Example 3
3,4-Dichloro-N-r5-π-(4-chlorophenyl)cyclopropyπ-1 ,3.4-thiadiazol-2-vnbenzene- sulfonamide
(a) ff 1 -(4-Chlorophenyl)cvclopropanecarbonyl1amino1thiourea
1-(4-Chlorophenyl)-cyclopropanecarboxylic acid (2 g, 10.2 mmol) was dissolved in 20 mL dry toluene. Thionyl chloride (2.42 g, 20.4 mmol) was added dropwise at room temperature and a catalytic amount of dry DMF was added. The resultant mixture was stirred at 50 0C for 2 hours. The reaction mixture was concentrated under high vacuum at 60 0C, the residue was dissolved in 10 ml_ DCM and thiosemicarbazide (1.12 g, 10.224 mmol) in a mixture of DMF: DCM (1 :4, 50 ml_) was added at 5-10 0C. The mixture was stirred at room temperature overnight under a nitrogen atmosphere and then the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 200 ml. EtOAc and extracted with water (2x200mL), NaHCO3 (2x200 ml_) and brine (1x200 ml_). After concentration the product was precipitated by petroleum ether to give [[1-(4-chlorophenyl) cyclopropane-carbonyl]amino]thiourea in 32.7 % yield (900 mg)
MS: m/z 270 (M+H) HPLC purity: 99.0%, NMR (300 MHz, DMSO-d6) δ ppm 1.01 (t, 2 H), 1.1.4 (m, 2H), 7.35 (d, 2 H) 7.45 (d, 2 H).
(b) 5-f 1 -(4-Chlorophenyl)cvclopropyn-1 ,3.4-thiadiazol-2-amine
[[1-(4-Chlorophenyl)cyclopropanecarbonyl]amino]thiourea (0.9 g, 3.3 mmol; from step (a) above) was dissolved in 18 mL toluene and 0.23 ml_ methane sulfonic acid was added. The mixture was refluxed overnight. After cooling to room temperature, 2M NaOH solution (50 mL) was added. The mixture was extracted with EtOAc (100 mL), followed by water and brine (100 mL). The crude material was purified by recrystallisation (petroleum ether) to give the product 5-[1-(4-chlorophenyl)cyclopropyl]-1 ,3,4-thiadiazol-2- amine in 72% yield (600 mg). MS: m/z 251.8 (M+H) HPLC purity: 93.0%, NMR (300 MHz, DMSO-d6) δ ppm 1.35 (t, 2 H), 1.73 (m, 2H), 7.28-7. 38 (m, 4 H).
(c) 3.4-Dichloro-N-r5-H -(4-chlorophenyl)cyclopropyπ-1 ,3,4-thiadiazol-2-yl1benzene- sulfonamide
5-[1-(4-Chlorophenyl)cyclopropyl]-1 ,3,4-thiadiazol-2-amine (0.4 g, 1.6 mmol; from step (b) above) and dimethylaminopyridine (0.235, 1.9 mmol) were dissolved in 8 mL dry DCM. The mixture was cooled to 10 0C and 3,4 -Dichlorobenzenesulfonyl chloride (0.43 g, 1.75 mmol) was added slowly dropwise. The mixture was stirred overnight at room temperature and the the reaction was quenched with ice water (20 mL) and extracted with DCM (25 mL). The organic phase was extracted with saturated NaHCO3 (aq.), water and brine (20 mL each) and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (60-120 silica gel, 0.1 % MeOH in DCM) to give the product as a white solid in 13.5% yield (100 mg).
MS: m/z 461.5 (M+H) HPLC purity: 98.0%, NMR (300 MHz, DMSO-d6) δ ppm 1.45 (t, 2 H), 1.69 (m, 2H), 7.37 (t, 2 H) 7.52 (d, 1 H), 7.69 (d, 1 H), 7.96 (s, 1 H)
Example 4
The following compounds were obtained from either VitasM-Laboratories or
Interbioscreen.
(a) 1 -[5-(4-Chlorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-3-(3,4-dichlorophenyl)-urea;
(b) 1 -[5-(2,4-dichlorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-3-(3,4-dichlorophenyl)-urea;
(c) 1 -[5-(2-fluorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-3-(3,4-dichlorophenyl)-urea;
(d) 1 -(3,4-dichlorophenyl)-3-[5-(1 -phenylethyl)-[1 ,3,4]thiadiazol-2-yl]-urea;
(e) 1 -[5-(4-fluorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-3-(3,4-dichlorophenyl)-urea; (T) 1 -(3,4-dichlorophenyl)-3-(5-phenethyl-[1 ,3,4]thiadiazol-2-yl)-urea;
(9) 1 -[5-(2,4-dichlorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-3-(2,4-dichlorophenyl)-urea;
(h) 1 -(5-benzhydryl-[1 ,3,4]thiadiazol-2-yl)-3-(2,4-dichlorophenyl)-urea;
(i) 1 -(3,4-dichlorophenyl)-3-[5-[(3,4-dimethoxyphenyl)methyl]-1 ,3,4-thiadiazol-2- yljurea;
Q) 1 -(3,4-dichlorophenyl)-3-[5-(4-fluorobenzylsulfanyl)-[1 ,3,4]thiadiazol-2-yl]-urea;
(k) 1-(3,4-dichlorophenyl)-3-(5-phenylsulfanylmethyl-[1 ,3,4]thiadiazol-2-yl)-urea;
(I) N-[4-[[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]sulfamoyl]phenyl] acetamide; (m) N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]benzenesulfonamide;
(n) N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-1 -phenyl- methanesulfonamide;
(o) 1 -phenyl-N-[5-(phenylsulfanylmethyl)-1 ,3,4-thiadiazol-2-yl]methanesulfonamide;
(p) N-[5-(3-phenoxypropyl)-1 ,3,4-thiadiazol-2-yl]-1 -phenyl-methanesulfonamide;
(q) N-[5-[2-(4-methoxyphenyl)ethyl]-1 ,3,4-thiadiazol-2-yl]-1 -phenyl-methane sulfonamide;
(r) 4-bromo-N-[5-[(4-methoxyphenyl)methyl]-1 ,3,4-thiadiazol-2-yl]benzene sulfonamide;
(s) 3,4-dichloro-N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]benzamide;
(t) 3,4-dichloro-N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]benzamide;
(u) 2-(4-chlorophenyl)-N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl] acetamide;
(v) N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-2-(4-chlorophenyl) acetamide;
(w) 2-(4-chlorophenoxy)-N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2- yljacetamide;
(x) 1 -[5-[(4-chloro-2-methyl-phenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-3-(3,4- dichlorophenyl)urea;
(y) 1 -(3,4-dichlorophenyl)-3-[5-[(2-fluorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]urea;
(z) 1 -(3,4-dichlorophenyl)-3-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2- yljurea;
(a1 ) 1 -[5-[(4-tert-butylphenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-3-(3,4-dichlorophenyl) urea;
(b1) 1-(3,4-dichlorophenyl)-3-[5-(1-phenoxyethyl)-1 ,3,4-thiadiazol-2-yl]urea; and
(c1 ) 1 -(3,4-dichlorophenyl)-3-[5-(2-fluorophenyl)-1 ,3,4-thiadiazol-2-yl]urea.
Example 5
3,4-Dichloro-N-r5-rf4-(trifluoromethyl)phenvnmethyll-1 ,3,4-thiadiazol-2-ynbenzene- sulfonamide
The title compound was prepared using an analogous technique to that described in Example 1.
Purity: 97.8%; MS: m/z 468.1 , 1H NMR (300 MHz, DMSOd6) ppm 7.93 (s, 1 H), 7.82 (d, 1 H), 7.74 (m, 3H), 7.57 (d, 2H), 4.35 (s. 2H). Example 6 3,4-Dichloro-N-[5-[4-(trifluoromethyl)benzoyl]-1 ,3,4-thiadiazol-2-yl]benzenesulfonamide
0.8 g of S^-dichloro-N-^-I^^trifluoromethyOphenylJmethylJ-I.S^-thiadiazol^-yl]- benzenesulfonamide (1.7 mM; see Example 5 above) was mixed with 1O mL water in a sealed tube. 0.68 g of potassium permanganate was added. The mixture was refluxed for 12 hours. The residue was filtered and washed with ethyl acetate (3 times). The organic phase was dried over Na2SO4, filtered and concentrated in a rotary evaporator. The product was purified by column chromathography and recrystallized using isopropyl alcohol and n-hexane to give the title product as a yellow solid in 37% yield (300 mg). Purity: 96.5 %; MS: m/z 482.1 , 1H NMR (300 MHz, DMSO-de) ppm 8.34 (d, 2H), 7.95 (d, 3H), 7.80 (m, 2H).
Example 7 1-(3,4-Dichlorophenyl)-3-[5-[[4-(trifluoromethyl)phenyl]methyl]-1 ,3,4-thiadiazol-2-yl]urea
100 mg of 5-(4-trifluoromethylbenzyl)-[1,3,4]thiadiazol-2-ylamine (prepared according to the method described in Example 1 , steps (a) to (c); 0.4 mM) was dissolved in 2 ml_ of CH2CI2 and cooled to 00C. 10 mg of DMAP (0.2 eq.) and 38 μl_ pyridine (1.2 eq.) was added at 00C. 113 mg of 3,4-dichloroisocyanatebenzene (1.2 eq.) was added and the mixture was stirred at room temperature for 12 hours. The reaction was quenched by additions of water. The residue was extracted with EtOAc and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in a rotary evaporator. The product was purified by column chromatography using EtOAc and petroleum ether as eluent to give 140 mg of the title product (78% yield).
Purity: 95.5%; MS: m/z 447.0 (M+H), 1H NMR (300 MHz, DMSO-d6) ppm 7.87 (s, 1H), 7.73 (d, 2H), 7.56 (dd, 3H), 7.42 (d, 1 H), 4.42 (s. 2H).
Example 8
The compounds of Example 8 are formed in a one step reaction from commercially available 2-amino-1 ,3,4-thiodiazoles and commercially available sulfonylchloride derivatives using the following method : 50 mg of the 2-amino-1,3,4-thiodiazole is dissolved in 2 mL dichloromethane (DCM) and chilled to 0 0C. 0.4 equiv dimethylaminopyridine (DMAP) and 1.2 equiv. pyridine is added and stirred for 5 min. 1.2 equiv. of the sulfonylchloride is added dropwise to the mixture. The reaction mixture is stirred for 12 h at rt. The reaction mixture is then quenched with 2 mL NaHCO3 (aq.) followed by 2 mL water and extracted twice with DCM (2 mL). The residue is dried over Na2SO4 and concentrated. The product was purified by column chromatography using silica and petroleum ether and EtOAc as eluting solvent
(i) 3,4-dichloro-N-[5-[2-(p-tolylsulfonyl)ethyl]-1 ,3,4-thiadiazol-2- yljbenzenesulfonamide;
Purity: 96.8 %; MS: m/z 492.5, 1H NMR (300 MHz, DMSO-d6) ppm 7.92 (s, 1 H), 7,90 (d, 1 H), 7,75 (m, 3H), 7.41 (d, 2H), 3.74 (t, 2H), 3.15 (t, 2H), 2.38 (s, 3H);
(ii) 3-chloro-N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]-4-fluoro-benzene sulfonamide;
Purity: 96.2 %; MS: m/z 418,3, 1H NMR (300 MHz, DMSO-d6) ppm 7.92 (d, 1 H), 7.80 (m,1 H), 7.60 (t, 1 H), 7.40 (q, 4H), 4.23 (s, 2H);
(iii) N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-1 -(4-chlorophenyl)methane sulfonamide;
Purity: 96.7 %; MS: m/z 430.6, 1H NMR (300 MHz, DMSO-d6) ppm 7.38 (m, 6H), 7.05 (dd, 2H), 5.25 (s, 2H), 4.43 (s, 2H);
(iv) N-[5-[1 -(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-4-(trifluoromethoxy)benzene sulfonamide;
Purity: 95.1 %; MS: m/z 480, 1H NMR (300 MHz, DMSO-d6) ppm 7.92 (d, 2H), 7.55 (d, 2H), 7.36 (d, 2H), 7.08 (d, 2H), 5.80 (q, 1 H)1 1.63 (d, 3H);
(v) 3,4-dichloro-N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2- yljbenzenesulfonamide; Purity: 96.0 %; MS: m/z 434.4;
(vi) 3,4-dichloro-N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]ben2ene sulfonamide;
Purity: 92.3 %; MS: m/z 450.3;
(vii) 3,4-dichloro-N-[5-[2-(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]benzene sulfonamide;
Purity: 99.4 %; MS: m/z 464,3;
(viii) 3,4-dichloro-N-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2- yl]benzenesulfonamide;
Purity: 97.3 %; MS: m/z 450. 2;
(ix) N-(5-benzhydryl-1 ,3,4-thiadiazol-2-yl)-1-[4-(trifluoromethyl)phenyl]methane sulfonamide;
Purity: 97.2 %; MS: m/z 490, 1H NMR (300 MHz, DMSO-d6) ppm 7.70 (d, 2H), 7.59 (d, 2H), 7.35 (m, 6H), 7.24 (d, 4H), 5.78 (s, 1 H), 4.51 (s, 2H);
(x) N-(5-benzhydryl-1 ,3,4-thiadiazol-2-yl)-3,4-dichloro-benzenesulfonamide; Purity: 98.3 %; MS: m/z 476.1 ;
(xi) 3-chloro-4-fluoro-N-[5-[2-(p-tolylsulfonyl)ethyl]-1 ,3,4-thiadiazol-2-yl]benzene sulfonamide;
Purity: 97.7 %; MS: m/z 482.1 , 1H NMR (300 MHz, DMSOd6) ppm 7.92 (d, 1 H), 7.79 (m, 3H), 7.62 (t, 1 H), 7.42 (d, 2H), 3.7 (t, 2H), 3.15 (t, 2H), 2.38 (s, 3H); (xii) 1 -(4-chlorophenyl)-N-[5-[2-(p-tolylsulfonyl)ethyl]-1 ,3,4-thiadiazol-2-yl]methane sulfonamide;
Purity: 91.2%; MS: m/z 472.2;
(xiii) N-[5-[2-(p-tolylsulfonyl)ethyl]-1,3,4-thiadiazol-2-yl]-4-(trifluoromethoxy)benzene sulfonamide,
Purity: 97.4%; MS: m/z 506.1 ;
(xiv) N-[5-[2-(p-tolylsulfonyl)ethyl]-1 ,3,4-thiadiazol-2-yl]-1 -[4-(trifluoromethyl)phenyl] methanesulfonamide,
Purity: 96.4%; MS: m/z 504.0;
(xv) N-[5-[2-(p-tolylsulfonyl)ethyl]-1 ,3,4-thiadiazol-2-yl]-6-(trifluoromethyl)pyridine-3- sulfonamide,
Purity: 98.4%; MS: m/z 491.0;
(xvi) 1 -(4-chlorophenyl)-N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2- yljmethanesulfonamide,
Purity: 98.8%; MS: m/z 414.5;
(xvii) N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]-4- (trifluoromethoxy)benzenesulfonamide;
Purity: 93.6 %; MS: m/z 448.3, 1H NMR (300 MHz, DMSOd6) ppm 7.88 (dd, 2H), 7.53 (d, 2H), 7.42 (m, 4H), 4.21 (s, 2H); (xviii) N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]-1 -[4-(trifluoromethyl)phenyl] methanesulfonamide;
Purity: 95.0%; MS: m/z 446.2;
(xix) N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]-6-(trifluoromethyl)pyridine-3- sulfonamide;
Purity: 99.2 %; MS: m/z 433.2, 1H NMR (300 MHz, DMSOd6) ppm 9.11 (s, 1H), 8.44 (d, 1 H), 8.10 (d, 1 H), 7.42 (m, 4H), 4.24 (s, 2H);
(xx) N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-6-(trifluoromethyl)pyridine-3- sulfonamide,
Purity: 93.0%; MS: m/z 450.8;
(xxi) 3,4-dichloro-N-[5-[1-(4-chlorophenoxy)ethyl]-1,3,4-thiadiazol-2- yljbenzenesulfonamide,
Purity: 99.8%; MS: m/z 463.1 ;
(xxii) 3-chloro-N-[5-[1 -(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-4-fluoro- benzenesulfonamide,
Purity: 98.4%; MS: m/z 446.5;
(xxiii) N-[5-[1 -(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-1 -(4- chlorophenyl)methanesulfonamide,
Purity: 81.3%; MS: m/z 442.9; (xxiv) N-[5-[1 -(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-1 -[4 (trifluoromethyl)phenyl] methanesulfonamide,
Purity: 97.6%; MS: m/z 476.3;
(xxv) N-[5-[1 -(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-6-(trifluoromethyl)pyridine-3- sulfonamide;
Purity: 98.3 %; MS: m/z 463.2, 1H NMR (300 MHz, DMSO-d6) ppm 9.14 (d, 1 H), 8.44 (d, 1 H), 8.10 (d, 1 H), 7.36 (d, 2H), 7.08 (d, 2H), 5.80 (q, 1 H), 1.63 (d, 1 H);
(xxvi) N-(5-benzhydryl-1 ,3,4-thiadiazol-2-yl)-3-chloro-4-fluoro-benzenesulfonamide, Purity: 92.9%; MS: m/z 460.0;
(xxvii) N-(5-benzhydryl-1 , 3 ,4-thiad iazol-2-y l)-1 -(4-chlorophenyl)methanesulfonamide, Purity: 90.5%; MS: m/z 456.3;
(xxviii) N-CS-benzhydryl-I .S^-thiadiazol^-ylJ^-CtrifluoromethoxyJbenzenesulfonamide, Purity: 98.3%; MS: m/z 490.0;
(xxix) N-(5-benzhydryl-1 ,3,4-thiadiazol-2-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide,
Purity: 99.7 %; MS: m/z 475.0, 1H NMR (300 MHz, DMSOd6) ppm 9.12 (d, 1 H), 8.44 (d, 1 H), 8.10 (d, 1 H), 7.27-7.40 (m, 10H), 5.9 (s, 1 H);
(xxx) 3-chloro-N-[5-[2-(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-4-fluoro-benzene sulfonamide,
Purity: 98.2%; MS: m/z 446.7; (xxxi) N-[5-[2-(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-1 -(4-chlorophenyl)methane sulfonamide,
Purity: 91.4%; MS: m/z 442.5;
(xxxii) N-[5-[2-(4-chlorophenoxy)ethyI]-1 ,3,4-thiadiazol-2-yl]-4-(trifluoromethoxy) benzene sulfonamide,
Purity: 98.5%; MS: m/z 478.3;
(xxxiii) N-[5-[2-(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-1 -[4-(trifluoromethyl)phenyl] methanesulfonamide,
Purity: 95.0%; MS: m/z 476.2;
(xxxiv) N-[5-[2-(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-6-(trifluoromethyl)pyridine-3- sulfonamide,
Purity: 92.2%; MS: m/z 463.4;
(xxxv) 3-chloro-4-fluoro-N-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2- yljbenzene sulfonamide,
Purity: 97.9%; MS: m/z 434.1 ;
(xxxvi) N-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2-yl]-4-(trifluoromethoxy) benzenesulfonamide,
Purity: 98.5%; MS: m/z 464.0; (xxxvii) N-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2-yl]-1 -[4- (trifluoromethyl)phenyl]methanesulfonamide,
Purity: 93.9 %; MS: m/z 463.6;
(xxxviii) N-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2-yl]-6-
(trifluoromethyl)pyridine-3-sulfonamide,
Purity: 93.0 %; MS: m/z 450.7; and
(xxxix) 3,4-dichloro-N-[5-[3-(trifluoromethyl)benzoyl]-1,3,4-thiadiazoI-2- yljbenzenesulfonamide;
Purity: 99.4 %; MS: m/z 483.8, 1H NMR (300 MHz1 DMSO-d6) ppm 8.48 (s, 1 H), 8.41 (d, 1 H), 8.11 (d, 1 H), 8.01 (s, 1 H) 7.83 (m, 3H).
Example 9
The compound of Example 9 was formed in a one step reaction from commercially available 2-amino-1 ,3,4-thiodiazoles and commercially available chloroformate derivatives using the method as described for Example 1d.
(4-chlorophenyl) N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]carbamate;
Purity: 97.5 %; MS: m/z 380.3, 1H NMR (300 MHz, DMSOd6) ppm 7.49 (d, 2H), 7.28- 7.42 (m, 6H)1 4.35 (s, 3H).
Example 10
1 ,3.4-Thiadiazol-2-yl]-5-benzohvdrazide derivatives
Compounds of Example 10 are formed in the following way:
The 5-substituted 1 ,3,4-thiadiazol-2-ylhydrazines are formed from the corresponding 2- amino- 1 ,3,4-thiadiazole via the 2-chloro-1 ,3,4-thiadiazole using methods well-known to the person skilled in the art. For example methods described in Potts et al {J. Org. Chem. 1966, 31 , 3528-3531). General protocol for the formation of benzohydrazides: The hydrazine derivative (45 mg) was dissolved in 2 mL DCM and 2 equiv. of 1 -ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDC), 0.05 equiv. of hydroxybenzo- triazole (HOBt) and 3 equiv. triethylamine were added and stirred for 5 min. The phenyl carboxylic derivative (1.2 equiv.) was then added under N2 atmosphere. The reaction mixture was stirred for approx. 3 h. The reaction mixture was quenched with water, followed by 10% NaHCO3 (aq.) and extracted in to DCM. The organic phase was dried over dry Na2SO4 and concentrated. The products were purified by column chromatography using petroleum ether and ethylacetate as eluting system on silica.
(a) N'-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-5-fluoro-2-(trifluoromethyl) benzohydrazide; Purity: 96.3%; MS: m/z 510.3, 1H NMR (300 MHz, DMSO-d6) ppm 7.74 (d, 2H), 7.58 (d, 2H), 7.10 (s, 2H), 5.77 (s, 2H), 4.54 (s, 2H), 4.00 (m, 6H, -CH2-, 1.33 (t, 6H, -CH3-), 1.24 (t, 3H, -CH3-);
(b) 5-fluoro-2-(trifluoiOmethyl)-N'-[5-[[4-(trifluoromethyl)phenyl]methyl]-1 ,3,4- thiadiazol-2-yl]benzohydrazide, Purity: 97.1%; MS: m/z 464.4;
(c) 2-methoxy-5-methyl-N'-[5-[[4-(trifluoromethyl)phenyl]methyl]-1 ,3,4-thiadiazol-2- yljbenzohydrazide Purity: 97.8%; MS: m/z 422.4, 1H NMR (300 MHz, DMSO-d6) ppm 7.75 (d, 2H), 7.60 (d, 2H), 7.24 (d, 1 H), 7.09 (s, 1 H), 6.97 (d, 1 H), 5.55 (s, 2H), 4.54 (s, 2H), 3.71 (s, 3H, -OCH3-), 2.25 (s, 3H, -CH3-);
(d) 3-methylsulfanyl-N'-[5-[[4-(trifluoromethyl)phenyl]methyl]-1 ,3,4-thiadiazol-2- yljbenzohydrazide, Purity: 94.9%; MS: m/z 424.7;
(e) 2-methylamino-N'-[5-[[4-(trifluoromethyl)phenyl]methyl]-1 ,3,4-thiadiazol-2- yljbenzohydrazide, Purity: 96.6%; MS: m/z 407.8;
(f) 4-methoxy-N'-[5-[[4-(trifluoromethyl)phenyl]methyl]-1 ,3,4-thiadiazol-2- yl]benzohydrazide, Purity: 96.8%; MS: m/z 408.7, 1H NMR (300 MHz, DMSO-d6) ppm 7.88 (d, 2H)1 7.73 (d, 2H), 7.59 (d, 2H), 7.00 (d, 2H), 5.78 (s, 2H), 4.53 (s, 2H), 3.82 (s, 3H, -OCH3-);
(g) 3-bromo-4-fluoro-N'-[5-[[4-(trifluoromethyl)phenyl]methyl]-1 ,3,4-thiadiazol-2- yl]benzohydrazide, Purity: 95.5%; MS: m/z 474.8, 1H NMR (300 MHz, DMSO-d6) ppm 8.18 (d, 1 H), 7.84 (m, 1 H), 7.74 (d, 2H)1 7.59 (d, 2H), 7.49 (t, 1 H), 5.78 (s, 2H), 4.55 (s, 2H); (h) 2-methoxy-N'-[5-[[4-(trifluoromethyl)phenyl]methyl]-1 I3,4-thiadiazol-2- yljbenzohydrazide, Purity: 96.8%; MS: m/z 408.8, 1H NMR (300 MHz, DMSOd6) ppm 7.74 (d, 2H), 7.60 (d, 2H), 7.45 (m, 1 H), 7.28 (d, 1 H), 7.08 (d,1 H), 6.99 (t, 1 H), 5.56 (S, 2H), 4.54 (s, 2H), 3.77(s, 3H);
(i) N'-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-3,4,5-triethoxy- benzohydrazide, Purity: 96.2 %; MS: m/z 492.6;
(j) N'-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-5-fluoro-2-(trifluoromethyl) benzohydrazide, Purity: 95.2%; MS: m/z 446.7, 1H NMR (300 MHz, DMSOd6) ppm 7.95 (dd, 1 H), 7.63 (d, 1 H)1 7.57 (t, 1 H), 7.39 (d, 2H), 7.14 (d,2H), 5.78 (s, 2H), 5.62 (s, 2H);
(k) 3,5-dimethoxy-4-methyl-N'-[5-[[4-(trifluoromethyl)phenyl]methyl]-1 ,3,4-thiadiazol- 2-yl]benzohydrazide, Purity:96.5 %; MS:m/z 452.6, 1H NMR (300 MHz, DMSO-d6) ppm 7.74 (d, 2H), 7.59 (d, 2H), 7.05 (s, 2H), 5.78 (s, 2H), 4.55 (d,2H), 3.79 (s, 6H), 2.04 (s, 3H);
(I) 2,5-bis(trifluoromethyl)-Nl-[5-[[4-(trifluoromethyl)phenyl]methyl]-1 ,3,4-thiadiazol-2- yl]benzohydrazide Purity:92.2 %; MS:m/z 514.2;
(m) 2-methylsulfanyl-N'-[5-[[4-(trifluoromethyl)phenyl]methyl]-1 ,3,4-thiadiazol-2- yl]benzohydrazide, Purity:94.9 %; MS:m/z 424.7;
(n) N'-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-2-methoxy-5-methyl- benzohydrazide, Purity:94.3 %; MS:m/z 405.1 ;
(o) N'-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-3-methylsulfanyl- benzohydrazide, Purity:94.0 %; MS:m/z 407.0, 1H NMR (300 MHz, DMSO-d6) ppm 7.67 (s, 1 H), 7.52 (m, 1 H), 7.39 (m, 4H), 7.12 (dd, 2H), 5.82 (s,2H), 5.58 (s, 2H), 2.50 (s, 3H); and
(p) N'-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-2-methylamino- benzohydrazide, Purity:90.1 %; MS:m/z 390.3.
Example 11
[1 ,3,4-thiadiazol-2-yl]-5-benzenesulfonohydrazide derivatives.
1 ,3,4-thiadiazol-2-yl)hydrazine (formed as described in Example 10) is treated with sulfonic acid chlorides derivatives as described in Example 8 but with the use of potassium carbonate as base and acetonitrile as solvent to form the 1 ,3,4-thiadiazol-2- yl]-5- benzenesulfonohydrazide derivatives . (a) 4-chloro-N45-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-3-fluoro-benzene sulfonohydrazide, Purity:90.2 %; MS:m/z 466.1 , 1H NMR (300 MHz1 DMSO-d6) ppm 8.22 (s, 1H), 7.97 (s, 1H)1 7.35 (d, 2H), 7.07 (d, 2H), 6.48 (s,2H), 5.42 (s, 2H);
(b) 3-chloro-N'-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-4-fluoro-benzene sulfonohydrazide, Purity:98.7 %; MS:m/z 448.9; and
(c) N'-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-4-(trifluoromethoxy)benzene sulfonohydrazide, Purity:98.8 %; MS:m/z 480.5, 1H NMR (300 MHz, DMSO-d6) ppm 8.16 (d, 2H), 7.66 (d, 2H), 7.36 (d, 2H), 7.09 (d, 2H), 6.37 (s,2H), 5.43 (s, 2H).
Example 12
The following compounds may be prepared using procedures described in the specification above.
(i) 1 -(3,4-dichlorophenyl)-3-[5-(3-trif luoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-urea;
(ii) 1 -(3,4-dimethoxyphenyl)-3-[5-(3-chlorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-urea;
(iii) 1 -(4-carboxyphenyl)-3-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-urea ethyl ester; (iv) [5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-carbamic acid 3,4-dichloro- phenyl ester;
(v) [5-(2-chlorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-carbamic acid 3,5-dichlorophenyl ester; (vi) [5-pyridin-4-ylmethyl-[1 ,3,4]thiadiazol-2-yl]-carbamic acid 3,4-dichlorophenyl ester; (vii) 1 -(4-acetamidophenyl)-3-[5-(2,3-dihydrobenzo[1 ,4]dioxin-6-ylmethyl)-
[1 ,3,4]thiadiazol-2-yl]-sulfonamide; (viii) 1-(3,4-dimethylphenyl)-3-[5-(3-moφholin-4-ylbenzyl)-[1,3,4]thiadiazol-2-yl]- sulfonamide;
(ix) 2-(3,4-dichlorophenylsulfanyl)-5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazole; (x) 2-(3,4-dichlorophenylsulfanyl)-5-(3,4-dimethylbenzyl)-[1 ,3,4]thiadiazole; (xi) 2-(phenylsulfanyl)-5-(4-carboxybenzyl)-[1 ,3,4]thiadiazole ethyl ester; (xii) 2-(3,4-dichlorophenoxy)-5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazole; (xiii) 2-(3,5-dichlorophenoxy)-5-(3-methanthiolbenzyl)-[1 ,3,4]thiadiazole; (xiv) 2-(3,4-dimethylphenoxy)-5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazole; (xv) 2-(3,4-dichlorobenzenesulfonyl)-5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazole; (xvi) 2-(4-chlorobenzenesulfonyl)-5-(1 ,2,3,4-tetrahydroquinolin-6-ylmethyl)-
[1 ,3,4]thiadiazole; (xvii) 2-(2,6-dichlorobenzenesulfonyl)-5-(3-difluoromethoxybenzyl)-[1,3,4]thiadiazole; (xviii) (3,4-dichlorophenyl)-[5-(3-trifluoromethylbenzyl)-[1,3,4]thiadiazol-2-yl]- methanone;
(xix) (2-methoxyphenyl)-[5-(3-fluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-methanone; (xx) (4-acetamidophenyl)-[5-(3,4-dimethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-methanone; (xxi) 5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazole-2-sulfonic acid (3,4-dichlorophenyl)- amide; (xxii) 5-(4-trifluoromethylbenzyl)-[1,3,4]thiadiazole-2-sulfonic acid (3-difluoromethoxy- phenyl)-amide; (xxiii) 5-(4-fluorobenzyl)-[1,3,4]thiadiazole-2-sulfonic acid (4-difluoromethoxyphenyl)- amide; (xxiv) N-[1-(3,4-dichlorophenyl)-meth-(E)-ylidene]-NI-[5-(3-trifluoronnethylbenzyl)-
[1 ,3,4]thiadiazol-2-yl]-hydrazine; (xxv) N-[1-(3,4-diacetophenyl)-meth-(E)-ylidene]-N'-[5-(3-trifluoromethylbenzyl)-
[1 ,3,4]thiadiazol-2-yl]-hydrazine; (xxvi) 1 -^-(δ^N'-li -(3,4-dichlorophenyl)-meth-(E)-ylidene]-hydrazinoH1 ,3,4]thiadiazoi-
2-ylmethyl)-phenyl]-ethanone; (xxvii) 3,4-dichlorobenzoic acid N'-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiodiazol-2-yl]- hydrazide; (xxviii) 3,4-dichlorophenylsulfonyl N'-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiodiazol-2-yl]- hydrazide;
(xxix) acetic acid 4-[(5-benzyl-[1 ,3,4]thiadiazol-2-yl)-hydrazonomethyl]-phenyl ester; (xxx) methanesulfonic acid 4-{[5-(4-ethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-hydrazono- methyl}-phenyl ester; (xxxi) 3,4-dichloro-N-{5-[1 -(4-chlorophenyl)-ethyl]-[1 ,3,4]thiadiazol-2-yl}- benzenesulfonamide; (xxxii) 3,4-dichloro-N-{5-[1 -methyl-1 -(3-trifluoromethylphenyl)-ethyl]-[1 ,3,4]thiadiazol-2- yl}-benzenesulfonamide; (xxxiii) 3,4-dichloro-N-[5-(3-trifluoromethylphenoxymethyl)-[1 ,3,4]thiadiazol-2- yl]benzenesulfonamide; (xxxiv) C-(3,4-dichlorophenyl)-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- methanesulfonamide; (xxxv) 1 -(3,4-dichlorophenyl)-3-[5-(3-trifluoromethylbenzylsulfanyl)-[1 ,3,4]thiadiazol-2-yl]- urea;
(xxxvi) 1 -(3,4-dichlorophenyl)-3-[5-(3-trifluoromethylbenzoyl)-[1 ,3,4]thiadiazol-2-yl]-urea; (xxxviiJ S^-dichloro-N-tS-CS-trifluoromethylbenzyO-fi.S^lthiadiazol^-yl]- benzenesulfonamide (xxxviii)4-chloro-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesu If on a m ide ; (xxxix) 2,4-dichloro-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzene sulfonamide;
(xl) 3,4-dichloro-N-[5-(2-methoxybenzyl)-[1,3,4]thiadiazol-2-yl]-benzenesulfonamide; (xli) 4-chloro-N-[5-(2-methoxybenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide; (xlii) 2,4-dichloro-N-[5-(2-methoxybenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide; (xliii) 3,4-dichloro-N-[5-(4-fluorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonannide; (xliv) 4-chloro-N-[5-(4-fluorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide; (xlv) 2,4-dichloro-N-[5-(4-fluorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide; (xlvi) 3,4-dichloro-N-[5-(4-dimethylaminobenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide; (xlvii) 4-chloro-N-[5-(4-dimethylaminobenzylH1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide; (xlviii) 2,4-dichloro-N-[5-(4-dimethylaminobenzyl)-[1,3,4]thiadiazol-2-yl]- benzenesulfonamide; (xlix) 4-methoxy-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide; (I) 3,4-dimethoxy-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzene sulfonamide; (Ii) 3,4,5-trimethoxy-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzene sulfonamide;
(Ni) N-[5-(3-trifluoromethylbenzyl)-[1,3,4]thiadiazol-2-yl]-benzenesulfonamide; (liii) 4-cyano-N-[5-(3-trifluorornethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide; (Hv) 4-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-ylsulfamoyl]-benzoic acid ethyl ester;
(Iv) 3,4-dichloro-N-(5-phenethyl-[1 ,3,4]thiadiazol-2-yl)-benzenesulfonamide; (Ivi) 3,4-dichloro-N-{5-[2-(2-methoxyphenyl)-ethylH1 ,3,4]thiadiazol-2-yl}- benzenesulfonamide; (Ivii) 3,4-dichloro-N-{5-[2-(3-trifluoromethylphenyl)-ethyl]-[1 ,3,4]thiadiazol-2-yl}- benzenesulfonamide;
(Iviii) 4-fluoro-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide; (Nx) 2,4-difluoro-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide; (Ix) 3,4-difluoro-N-[5-(2-methoxybenzyl)-[1 ,3,4]thiadiazol-2-yI]-benzenesulfonamide; (Ixi) 4-cyano-N-[5-(2-methoxybenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide; (Ixii) 4-[5-(4-fluorobenzyl)-[1 ,3,4]thiadiazol-2-ylsulfamoyl]-benzoic acid ethyl ester; (Ixiii) 4-cyano-N-[5-(4-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide; (Ixiv) 4-[5-(4-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-ylsulfamoyl]-benzoic acid ethyl ester; (Ixv) 3,4-dichloro-N-[5-(3-difluoromethoxybenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide; (Ixvi) 4-chloro-N-[5-(3-difluoromethoxybenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(Ixvii) 3,4-dichloiO-N-(5-pyridin-4-ylmethyl)-[1 ,3,4]thiadiazol-2-yl)-benzenesulfonamide; (Ixviii) 3,4-dichloro-N-[5-[(4-chlorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2-yl]benzene- sulfonamide; (Ixix) 3,4-dichloro-N-[5-[1-(4-chlorophenoxy)cyclopropyl]-1,3,4-thiadiazol-2-yl]benzene- sulfonamide; (Ixx) 3,4-dichloro-N-[5-[1 -[3-(trifluoromethyl)phenoxy]cyclopropyl]-1 ,3,4-thiadiazol-2- yl]benzenesulfonamide; (Ixxi) 3,4-dichloro-N-[5-[1 -[4-fluorophenyl)cyclopropyl]-1 ,3,4-thiadiazol-2-yl]benzene- sulfonamide; (Ixxii) 1 -(3,4-dichlorophenyl)-3-[5-[1 -[4-(trifluoromethyl)phenyl]cyclopropyl]-1 ,3,4-thiadia- zol-2-yl]urea; (Ixxiii) 3-chloro-N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-4-fluoro- benzenesulfonamide; (Ixxiv) N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-4-
(trifluoromethoxy)benzenesulfonamide; (Ixxv) N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-1 -[4-
(trifluoromethyl)phenyl]methanesulfonamide; (Ixxvi) 1 -(4-chlorophenyl)-N-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2- yl]methanesulfonamide; (Ixxvii) 3-chloro-N'-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]-4-fluoro- benzenesulfonohydrazide; (Ixxviii) 3,4-dichlorobenzoic acid N'-[5-(2,3-dihydrobenzo[1 ,4]dioxin-6-ylmethyl)-
[1 ,3,4]thiadiazol-2-yl]-hydrazide; and (Ixxix) 4-acetylbenzoic acid N'-[5-(3-methoxybenzyl)-[1 ,3,4]thiadiazol-2-yl]-hydrazide. Example 13
The data presented in Table 1 below indicates the potency for a number of compounds of the examples that were tested in Tests A, I and J below. The potency of the compounds to stimulate the phosphorylation of Thr-172 on the AMPK-α subunit was estimated by comparing the relative intensity of the Western blot for the compound in question to the Western blot obtained using the solvent vehicle as a control. A "+" indicates a compound that is more potent than the control compound (with "+++" representing compounds that were significantly more potent).
Table 1
Figure imgf000103_0001
Figure imgf000103_0002
Figure imgf000104_0001
Figure imgf000104_0002
Biological Tests
Descriptions of the cancer cell lines including source, tumor type, and morphology may be obtained from the American Type Culture Collection (ATCC) or its website (www.atcc.org).
Test A
Activation of AMPK and eEF2
Test compound
The compounds of Examples 1 and 3 were obtained as described above and Compounds (a) to (k) and (I) to (n), (q), (x), (a1) and (b1), of Example 4 were obtained from VitasM-Laboratories or Interbioscreen. A stock solution of 10 mM was prepared by dissolving the compounds in 100% DMSO.
Cell line and cell culture
Human PC3 cells were purchased from LGC Promochem-ATCC (ATCC catalog no CRL- 1435). PC3 cells were maintained in Dulbecco's modified Eagle's medium (Gibco 21885) containing 5% fetal bovine serum (Gibco 10500-064), 25 ug/ml Gentamicin (Gibco 15750) and 1x non essential amino acids (Gibco 11140). The cells were incubated in a humidified atmosphere of 5% CO2 at 37°C and passaged every 3 days by trypsinization. For experiments, PC3 cells were cultured in complete medium with 10% fetal bovine serum in 60-mm-diameter dishes, grown to 70-80% confluence and cultured in serum-free Dulbecco's modified Eagle's medium for 5 h. Cells were then treated for 1 h with the compounds of Examples 1 , 3 and compounds (a) to (i) of Example 4 or for 4h with compounds (j) and (k) of Example 4 that were dissolved in DMSO at the concentrations indicated in Figures 1a to 1d or above. Cells treated with compounds (I), (m), (n), (q), (x), (a1) and (b1), of Example 4 were handled in a corresponding manner to cells treated with compounds (j) and (k) of Example 4. The final concentration of DMSO did not exceed 0.1%, which did not affect AMPK or eEF2 phosphorylation. 0.1% DMSO was used as control.
Western Blot analysis
PC3 cells were lysed in buffer (10OmM TRIS pH 6,8, 2%w/v Sodium dodecylsulfate (SDS), 1OmM NaF, 1OmM β-glycerophosphate, 1mM Na Vanadate). Cell debris is removed by centrifugation at 14,000 X g for 15 min at 40C and the resulting supernatant is used for Western blotting. Protein concentrations of the lysates were measured using a BCA protein assay kit (Pierce #23225). For Western blotting, 15 ug protein was loaded in each well of a 4-12% bis/tris gel for AMPK or eEF2 detection (Criterion precast gel Bio-Rad #345-0117) and run according to manufacturers recommendation. Gels were blotted onto a nitrocellulose filters (Hybond-C extra Amersham #RPN203E). Filters were blocked in 2OmM TRIS pH 7,5, 137mM NaCI, 25%v/v Tween20 and 5%w/v fat free powdered milk for 30 min. Filters were incubated overnight in blocking solution with phospho-AMPKα (Thr172) or phospho-eEF2 (Thr56) (Cell signalling #2531 and #2331). Filters were washed in 2OmM TRIS pH 7.5, 137mM NaCI, 25%v/v Tween20 for 3x5min. Filters were incubated in blocking solution with secondary antibody, peroxidase- conjugated Goat anti-rabbit IgG (Jackson immunoResearch #111-035-003) at room temperature for 1 h. Filters were washed as above for 3x10 min. Signal was developed with SuperSignal West Dura ECL kit (Pierce #1859024) and exposed to Hyperfilm ECL (Amersham #28906837).
Results
To investigate whether AMPK is activated by the compounds of Examples 1 , 3 and compounds (a) to (k) of Example 4 in PC3 cells, the phosphorylation of AMPK and its downstream target, eEF2 were used as indicators of AMPK activation.
The Western blot result showed that the compound of Example 1 stimulated the phosphorylation of Thr-172 of the AMPK α subunit (see Figure 1a).
The Western blot result showed that the compound of Example 3 stimulated the phosphorylation of Thr-172 of the AMPK α subunit. Moreover, AMPK activation by the compound of Example 3 in PC3 cells was further confirmed by enhanced phosphorylation of eEF2. These results indicate that the compound of Example 3 stimulated AMPK phosphorylation and downstream activity (see Figures 1b). The Western blot result showed that compounds (a) to (k) of Example 4 stimulated the phosphorylation of Thr-172 of the AMPK α subunit. Moreover, AMPK activation by compounds (a) to (k) of Example 4 in PC3 cells was further confirmed by enhanced phosphorylation of eEF2. These results indicate that compounds (a) to (i) of Example 4 stimulate AMPK phosphorylation and downstream activity (see Fig 1c), as do compounds (j) and (k) of Example 4 (see Figures 1 b and 1d).
In addition to the Western blots provided as Figures 1a to 1c, the potency of the compounds of Examples 1 , 3, 4(a), 4(b), 4(d), 4(e), 4(f), 4(h), 40), 4(k), 4(I), 4(m), 4(n), 4(q), 4(x), 4(a1), and 4(b1) to stimulate the phosphorylation of Thr-172 on the AMPK-α subunit was estimated by comparing the relative intensity of the Western blot obtained for the vehicle control to the Western blot obtained for the compound in question. As indicated in Table 1 of Example 13, the compounds were generally more potent than the control compound.
Test B
Blood glucose measurement study in diabetic ob/ob mice
Aim
The aim of this study was to verify the efficacy of the compound of Example 1 in diabetic ob/ob mouse with regard to correction of the metabolic disorder hyperglycemia. Ob/ob mice were gavaged twice daily with the compound of Example 1 and the effect of the compound on levels of blood glucose were assessed and the results were compared to a concurrent control group gavaged with vehicle.
EXPERIMENTAL PROCEDURES
Animals
Male B6.V-Lepob/JBomTac (model number OB-M) mice were bred and delivered by Taconic. Animals were housed in Umea University animal facility in transparent polycarbonate cages, with wood chip bedding at a 12 h light/darkness cycle, a temperature of ~21°C, and a relative humidity of ~50% throughout the accommodation and dosing periods. Five animals were housed in each cage with free access to standard rodent chow (CRM(E)Rodent, Special Diets Services, Scanbur BK, Sweden) and tap water. All animal experiments were approved by the Local Ethics Review
Committee on Animal Experiments, Umea Region.
Animal experimental procedures
In vivo potency and efficacy were determined in groups of 10 mice. Male ob/ob mice, 18 to 19 weeks of age were administered compound of Example 1 (30 mg/kg body weight) or vehicle (0.5% methylcellulose and 1% DMSO in PBS) by oral gavage twice daily (8:00-9:00 A.M. and 4:00-5:00 P.M.) for 20 days. Mice were administered 5 ml/kg body weight of each emulsion using a teflon needle with silicone tip (Agnthos AB, Lidingδ, Sweden). Blood samples were drawn from the tail vein from fed animals 16 h post dose of day 12 and 20 of dosing for analysis of blood glucose.
Analytic methods
Blood glucose levels were measured by using a Glucometer Elite (Bayer) according to the manufacturer's recommendations.
Data analysis
Data in the figure is presented as means ± SEM. P values were calculated using the Student's Mest. Values of P < 0.05 (*) were considered to be statistically significant (P < 0.01 ** and P < 0.001 ***). Statistical analyses were performed using Microsoft Office Excel 2003.
Results
The compound of Example 1 was evaluated in diabetic ob/ob mice to test the effect of the compound of Example 1 on hyperglycemia. As shown in Figure 2, on day 12 of the treatment, the group treated with the compound of Example 1 showed a noticeable decrease in fed blood glucose when compared to mice treated with vehicle. At the end of the experiment (day 20), fed blood glucose levels in vehicle treated ob/ob mice were higher than those in the ob/ob mice treated with the compound of Example 1.
Test C
BrdU incorporation assay.
Cells growing in logarithmic phase in DMEM (Gibco 212885) supplemented with Non essential amino acids (Gibco 11140) Penicillin/streptomycin (Gibco 15140-122) and 10% Foetal Calf Serum (FBS; Gibco 10500-064) at 37*C and 5% CO2 were plated in 96 well plates (NUNC Nunclon) with between 10-15000 cells/well (depending on cell line) in propagation media. After 24h incubation the media is changed to propagation media (FBS). After a further 24h incubation the culture media was then changed to serum free DMEM containing either 0.2 % DMSO as vehicle control or 10, 5, 1, 0.1 μM of the compound . of Example 2 in 0.2% DMSO in quadruplicate. After 18 h incubation, BrdU was added according to manufacturer's recommendations. After 6 h incubation in the presence of BrdU, the culture media was removed and BrdU incorporation was measured using "Cell Proliferation ELISA, BrdU colorimetric11 Roche (11647229001) according to manufacturer's recommendations.
The above method was repeated using 10, 5, 1 , 0.1 μM of the compound of Example 1.
Results (for the compound of Example 2)
Proliferation rate of MDA-MB-231 cells are reduced by relevant concentrations of the test compounds as measured by BrdU incorporation (see Figure 3a).
For example, in the above assay, the compound of Example 2, relative to the vehicle control (which displayed a BrdU incorporation of 1 unit) displayed the following (approximate) units of BrdU incorporations at different concentrations:
10 μM: 0. 7
5 μM: 0. 95
1 μM: 1
0.5 μM: 1. 1
These results are depicted in Figure 3a.
Results (for the compound of Example 1 )
Proliferation rate of PC-3 cells are reduced by relevant concentrations of the test compounds as measured by BrdU incorporation (see Figure 3b). For example, in the above assay, the compound of Example 1, relative to the vehicle control (which displayed a BrdU incorporation of 1 unit) displayed the following (approximate) units of BrdU incorporations at different concentrations:
10 μM: 0 .51
5 μM: 0 .58
1 μM: 0 .85
0.5 μM: 0 .95
These results are depicted in Figure 3b.
Test D
Amelioration of TGFβ dependent collagen IV secretion
Methods and Materials
Cell culture and treatment:
Human primary mesangial cells (Lonza) were seeded at a density of 5700 cells per well in a 24 well plate in DMEM (Gibco 212885) supplemented with Non essential amino acids (Gibco 11140) Penicillin/streptomycin (Gibco 15140-122) and 10% Foetal Calf Serum (FBS) (Gibco 10500-064).
After 24h incubation, media was changed to DMEM (Gibco 212885) supplemented with non essential amino acids (Gibco 11140) Penicillin/streptomycin (Gibco 15140-122) and 0,5% Foetal Calf Serum (FBS)(Gibco 10500-064) as the experimental media. After 24h incubation, media was changed to experimental media containing either vehicle or TGFβ (0,5ng/ml), compound of Example 1 (2,5μM), or TGFβ (0,5ng/ml) and compound of Example 1 (2,5μM) in combination.
After 48h of exposure the supernatant from each well was collected and subjected to ELISA analysis.
ELISA procedure:
Using Nunc Maxisorp microtiter plates, duplicate samples of conditioned cell culture medium (diluted 1 :10) was used for coating (100 μl/well, 18h, +4 0C). After 3x washing in ELISA buffer (PBS (Gibco) + 0.01% Triton X-100 (Sigma)) Collagen IV rabbit polyclonal primary antibody (Rockland) diluted 1 :4000 in ELISA buffer was incubated at +4 0C for 24 h. After 3x washing HRP-conjugated anti-rabbit polyclonal antibody (Jackson Immunochemicals) diluted 1 :10000 in ELISA buffer was incubated at room temp for 2h. After 3x washing in ELISA buffer, reactions were visualised using 100 μl/well TMB liquid substrate system for ELISA (Sigma) After maximum 30 min reactions were stopped by addition of 25 μl 1 M H2SO4 and immediately analysed at 450 nm using a Multiskan EX plate reader (Thermo Labsystems).
Results
As shown by Figure 4, compound of Example 1 can ameliorate the TGFβ dependent collagen IV secretion in human primary mesangial cells.
Test E
Insulin measurement study in C57BU6JBomTac mice
Aim
The aim of this study was to verify the acute effect of compound of Example 1 in the C57BL/6JBomTac mouse. Female C57BL/6JBomTac mice were gavaged one time with the compound of Example 1 and the acute effect of the compound on levels of plasma insulin were assessed and the results were compared to a concurrent control group gavaged with vehicle.
Test compound
The compound of Example 1 was obtained from Anthem, BloScience India. A stock solution of 6 mg/ml was prepared by dissolving the compound in PBS, pH 7.4, 1 % DMSO and 0.5% methyl cellulose. Animals
Female C57BL/6JBomTac mice were bred and delivered by Taconic. Animals were housed in Umea University animal facility in transparent polycarbonate cages, with wood chip bedding at a 12 h light/darkness cycle, a temperature of ~21 °C, and a relative humidity of ~50% throughout the accommodation and dosing periods. Five animals were housed in each cage with free access to standard rodent chow (CRM(E)Rodent, Special Diets Services, Scanbur BK, Sweden) and tap water. All animal experiments were approved by the Local Ethics Review Committee on Animal Experiments, Umea Region.
Animal experimental procedures
In vivo efficacy was determined in groups of five mice. Female C57BlJ6JBomTac mice, 13 weeks of age were administered acutely with compound of Example 1 (30 mg/kg body weight) or vehicle (0.5% methylcellulose and 1 % DMSO in PBS) by oral gavage. Mice were administered 5 ml/kg body weight of each emulsion using a teflon needle with silicone tip (Agnthos AB, Lidingό, Sweden). Blood samples were drawn from the tail vein from overnight fasted animals (12 h) prior to administration of the compound of Example 1 and 10, 30 and 60 min after drug administration.
Analytic methods
Plasma insulin levels were determined according to the manufacturer's recommendations with a rat insulin ELISA kit using mouse insulin standard (Crystal Chem Inc).
Data analysis
Data in the figure is presented as means ± SEM. P values were calculated using the Student's Mest. Values of P < 0.05 (*) were considered to be statistically significant (P < 0.01 ** and P < 0.001 ***). Statistical analyses were performed using Microsoft Office Excel 2003.
Results
The compound of Example 1 was evaluated in C57BL/6JBomTac mice to acutely test the effect of compound of Example 1 on plasma insulin levels. As shown in Figure 5, there was no significantly difference in plasma insulin levels at any time point between animals treated with compound of Example 1 or vehicle control. Test F
Epithelial-mesenchymal transition in HepG2 cells inhibition
Test compound
A stock solution of 10 mM of the compound of Example 3 was prepared by dissolving the compound in 100% DMSO. rhTGF-βl was purchased from R&D Systems (240-B).
Cell line and cell culture
WI-38 lung fibroblast cells were purchased from LGC Promochem-ATCC (Cat. Nr. CCL- 75). The cells were maintained in Dulbecco's modified Eagle's medium (DMEM Gibco21885) containing 10% fetal bovine serum (Gibco 10500-064), 25μg/ml Gentamicin (Gibco 15750) and 1x Non Essentioal Amino Acids (NEAA Gibco 11140). The cells were incubated in a humified athsosphere of 5% CO2 at 370C and passaged every 3 days by trypinization. For experiments, Wi-38 lung fibroblast cells were plated at 180000 cells per 60-mm-diameters dishs in maintenance DMEM, incubated for 24 hours and thereafter incubated in serum-free DMEM for 4 hours. Cells were then treated with TGF- β1 (1ng/ml), the compound of Example 3 (0.625 or 1.25μM) or the compound of Example 3 (0.625 or 1.25μM) + TGFβ (1 ng/ml), each dissolved in DMSO. The final concentration of DMSO did not exceed 0.1%, which did not affect expression of EDA-FN, β-Aktin, αSMA, p-T172 AMPK and p-S 245/250/255 Smad2. 0.1% DMSO is used as control.
Western Blot analysis
Cells were lysed in 10OmM TRIS ph 6,8, 2% WVv Sodium dodecylsulfate (SDS), 1OmM NaF, 1OmM Z-glycerophosphate, 1 mM Na Vanadate. Protein concentration of the lysates was measured by BCA protein assay kit (Pierce#23225) and then 20ug protein is loaded in each well of a 4-12% Bis/Tris gel for detection of EDA-FN, β-Aktin, αSMA, p-T172 AMPK and p-S 245/250/255 Smad2 (Criterion precast gel Bio-Rad # 345-0117) and run according to manufactures recommendation. Gels were blotted onto a nitrocellulose filters (Hybond-C extra Amersham #RPN203E). Filters were blocked in 2OmM TRIS pH 7.5, 137mM NaCI, 25v/v Tween20 and 5% w7v fat free powdered milk for 30 minutes. Filters were incubated overnight in blocking solution with Fibronectin [IST9] (Abeam # ab6328-280), β-Actin (Abeam # 4967), αSMA (AbCam # ab5694), p-T172 AMPK (Cellsignal # 2531) and β-Actin (Cell signal #4967). Filters were washed 2OmM TRIS ph 7.5, 137mM NaCI, 25%v/v Tween20 for 4x5 minutes. Filters were incubated in blocking solutions with secondary antibody, peroxidase-conjugated Goat anti-mouse IgG (Pierce #1858413) for EDA-FN and peroxidase-conjugated Affini-pure Goat Anti-Rabbit IgG
(H+L) ( Jackson IR # 111-035-003) for β-Actin, αSMA, p-T172 AMPK and p-S 245/250/255 Smad2, in room temperature for 1h. Filters were washed as above for 4x5 minutes. Signal was developed with SuperSignal West Dura ECL kit (Pierce#1859024) and exposed to Hyperfilm ECL ( Amersham #28906837).
Results
To determine if a compound of Example 3 could prevent the epithelial-mesenchymal transition (EMT) induced by the fibrogenic cytokine TGF-βl in WI-38 lung fibroblast cells. EMT was assessed in WI-38 lung fibroblast treated with TGF-βl or the compound of Example 3 alone and also TGF-βl + the compound of Example 3 by Western blot analysis of cell lysates for expression of mesenchymal phenotypic markers such as extra type III domain A fibronectin (EDA-fn) and α-SMA.
In Western blot studies the expression of the mesenchymal phenotype marker EDA-fn and the expression of α-SMA was determined following treatment of WI-38 lung fibroblast cells with TGF-βl (1 ng/ml), the compound of Example 3 (0.625 or 0.125 μM) or the compound of Example 3 (0.625 or 0.125 μM) +TGF-βl (1 ng/ml) for 24 h. WI-38 lung fibroblast cells incubated with TGF- βl alone significantly induced expression of the mesenchymal marker EDA-fn and α-SMA (Fig. 6a), while cells incubated with the compound of Example 3 did not induce expression of the mesenchymal marker EDA-fn or α-SMA (Fig. 6a) and TGF-βl+ the compound of Example 3 inhibited the epithelialmesenchymal transition as shown in Figure 6a. These results indicate that the compound of Example 3 is a plausible compound for the treatment of pathologic fibroproliferative disorders. The immune blots in Fig 6b show the effect of TGF-β1 or TGF-β1 and the compound of Example 3 on AMPK and SMAD2 phosphorylation in the WI-38 lung fibroblast cells. Figure 6b shows that the compound of Example 3 increases the phopshorylation of AMPK and decreases SMAD2 phosphorylation
Test G
Induction of autophagy
Test compound
A stock solution of a compound of the Examples of 10 mM is prepared by dissolving the compound in 100% DMSO. Cell line and cell culture
Human breast cancer cell line MDA-MB-231 cells are purchased from LGC Promochem- ATCC (ATCC catalog no HTB-26). MDA-MB-231 cells are maintained in Dulbecco's modified Eagle's medium (Gibco 21885) containing 5% fetal bovine serum (Gibco 10500- 064), 25 ug/ml Gentamicin (Gibco 15750) and 1x non essential amino acids (Gibco 11140). The cells are incubated in a humidified atmosphere of 5% CO2 at 37°C and passaged every 3 days by trypsinization. For experiments, 0.6 million MDA-231 cells are cultured in complete medium with 5% fetal bovine serum in 060 mm dishes overnight then incubated in serum-free Dulbecco's modified Eagle's medium for 24h. Cells are then treated for 24h with a compound of the Examples is dissolved in DMSO is added to the medium. The final concentration of DMSO did not exceed 0.1%, which did not affect AMPK phosphorylation.
Western Blot analysis
Cells are lysed in 10OmM TRIS pH 6,8, 2%w/v Sodium dodecylsulfat (SDS), 1OmM NaF, 1OmM β-glycerophosphate, 1 mM Na Vanadate. Protein concentration of the lysates is measured by BCA protein assay kit (Pierce #23225). 25 ug protein is loaded in each well of a 12% bis/tris gel (Criterion precast gel Bio-Rad #345-0117) and run according to manufacturers recommendation. Gels are blotted onto a nitrocellulose filters (Hybond-C extra Amersham #RPN203E). Filters are blocked in 2OmM TRIS pH 7,5, 137mM NaCI, 25%v/v Tween20 and 5%w/v fat free powdered milk for 30 min. Filters are incubated overnight in blocking solution with rabbit anti-LC3B antibody (Novus Biologicals #2775). Filters are washed in 2OmM TRIS pH 7,5, 137mM NaCI, 25%v/v Tween20 for 3x5min. Filters are incubated in blocking solution with secondary antibody, peroxidase- conjugated Goat anti-rabbit IgG (Jackson immunoResearch #111-035-003) in room temperature for 1h. Filters are washed as above for 3x10 min. Signal is developed with SuperSignal West Dura ECL kit (Pierce #1859024) and exposed to Hyperfilm ECL (Amersham #28906837).
Test H Dephosphorylation Assay
Test compound
A stock solution of 10 mM of the compound of Example 5 was prepared by dissolving the compound in 100% DMSO. Assay
10 ng hyperphosphorylated AMPK trimer (α1/β1/γ1) (Recombinant Human AMP- activated protein kinase, PV4672, Invitrogen) and 1.25 ng recombinant PP2Cα (PPM1A protein (His tag) ab51205, Abeam) were incubated with drug compound of Example 5 at a concentration of 1.25-10 μM in a buffer containing 40 mM Hepes (pH 7.45), 2 mM MnCI2 (Manganese chloride tetrahydrate, M8054, Sigma), 0.5 mM DTT (1 ,4-Dithio-DL- threitol, 43815, Fluka). The concentration of DMSO in the dephosphorylation reactions was 0.1 or 0.2%.
The reaction volume was 10 μL All components were diluted in the buffer above. The components were kept and mixed on ice and the reactions carried out in 30°C for 20 minutes. The reactions were terminated by addition of 45 μL stop solution containing 1% BSA (Albumine, Bovine, 105033, MP Biochemicals, LLC), 10 mM EDTA and anti Phospho-AMPKα (ThM 72) Antibody (#2531 Cell signaling) at a dilution of 1/1000 in PBS. The samples were transferred to glutathione coated wells (#15140 Glutathione coated plate (8 well strips), Pierce) and incubated O/N at +4°C. The wells were washed three times in 200 μl PBS/ 0.05% Triton X-100 and incubated with horse radish peroxidase conjugated goat-anti rabbit antibody (#111-035-003, Jackson lmmunoresearch Laboratories Inc.) at a dilution of 1/10 000 in PBS/ 1% BSA/ 1OmM EDTA for 2h in room temperature. After incubation wells were washed three times in 200 μl PBS/ 0.05% Triton X-100. The assay was developed by addition of 100 μl Liquid Substrate System for ELISA (T0440, Sigma) until colour development was sufficient for photometric detection, typically 5-30 minutes. The developing reactions were terminated by addition of 25 μl 1 M H2SO4. Absorbance was measured at 450 nm in a plate reader (Multiskan EX, Thermo Labsystems), using Ascent Software version 2.6. The absorbance correlates to the amount of P-T172 AMPK.
Result
Compound of Example 5 suppress PP2C mediated dephosphorylation of p-T172 of
AMPK in a cell free system as depicted by Figure 7. Test I
Activation of AMPK and S-79 ACC
Test compound
A stock solution of 10 mM of the compound of Example 5 was prepared by dissolving the compound in 100% DMSO.
Cell line and cell culture
Human WI-38 cells were purchased from LGC Promochem-ATCC (ATCC catalog no CCL-75). WI-38 cells were maintained in Dulbecco's modified Eagle's medium (Gibco 21885) containing 5% fetal bovine serum (Gibco 10500-064), 25μg/ml Gentamicin (Gibco 2015750) and 1x non essential amino acids (Gibco 11140). The cells were incubated in a humidified atmosphere of 5% CO2 at 37°C and passaged every 3 days by trypsinization. For experiments, WI-38 cells were cultured in complete medium with 10% fetal bovine serum in 60-mm-diameter dishes, grown to 70-80% confluence and cultured in serumfree Dulbecco's modified Eagle's medium for 5 h. Cells were then treated with 10 μM of the compound of Example 1 for 24 h. The final concentration of DMSO did not exceed 0.1 %, which did not affect AMPK or ACC phosphorylation (0.1 % DMSO was used as control).
Western Blot analysis
WI-38 cells were lysed in buffer (10OmM TRIS pH 6,8, 2%w/v Sodium dodecylsulfate (SDS), 1OmM NaF, 1OmM β-glycerophosphate, 1mM Na Vanadate). Cell debris is removed by centrifugation at 14,000 X g for 15 min at 4°C and the resulting supernatant is used for Western blotting. Protein concentrations of the lysates were measured using a BCA protein assay kit (Pierce #23225). For Western blotting, 15 μg protein was loaded in each well of a 4-12% bis/tris gel for AMPK or S-79 ACC detection (Criterion precast gel Bio-Rad #345-0117) and run according to manufacturers recommendation. Gels were blotted onto a nitrocellulose filters (Hybond-C extra Amersham #RPN203E). Filters were blocked in 2OmM TRIS pH 7.5, 137 mM NaCI, 25%v/v Tween20 and 5%w/v fat free powdered milk for 30 min. Filters were incubated overnight in blocking solution with phospho-AMPK (Thr172) or phospho-acetyl CoA carboxylase (Cell signalling #2531 and #3661) or with a pan-AMPK antibody (Cell signalling #2532). Filters were washed in 2OmM TRIS pH 7.5, 137 mM NaCI, 25%v/v Tween20 for 3x5min. Filters were incubated in blocking solution with secondary antibody, peroxidase conjugated Goat anti-rabbit IgG (Jackson immunoResearch #111-035-003) at room temperature for 1h. Filters were washed as above for 3x10 min. Signal was developed with SuperSignal West Dura ECL kit (Pierce #1859024) and exposed to Hyperfilm ECL Amersham #28906837).
Results
The Western blot result showed that the compounds of Examples 5 stimulated the phosphorylation of ThM 72 of the AMPK ε-20 subunit (in comparison to control) and increased production of phosphorylated acetyl coenzymeA (a substrate of AMPK), as depicted by Figure 8 and by Table 1 of Example 13.
Test J
Activation of AMPK
Test compounds
Stock solution of 10 mM of the compounds of Examples 7, 8(i), 8(vi), 8(vii), 8(viii), 8(x), 8(xi), 8(xii), 8(xiii), 8(xiv), 8(xv), 8(xvi), 8(xvii), 8(xviii), 8(xix), 8(xx), 8(xxi), 8(xxii), 8(xxiii), 8(xxiv), 8(xxvi), 8(xxvii), 8(xxviii), 8(xxix), 8(xxx), 8(xxxi), 8(xxxii), 8(xxxiii), 8(xxxiv), δ(xxxvi), δ(xxxvii), δ(xxxviii), 9, 10(a) to 100) were prepared by dissolving the compounds in 100% DMSO.
Cell line and cell culture
Human WI-38 cells were purchased from LGC Promochem-ATCC (ATCC catalog no CCL-75). WI-38 cells were maintained in Dulbecco's modified Eagle's medium (Gibco 21885) containing 10% fetal bovine serum (Gibco 10500-064), 25μg/ml Gentamicin (Gibco 2015750) and 1x non essential amino acids (Gibco 11140). The cells were incubated in a humidified atmosphere of 5% CO2 at 37°C and passaged every 3-5 days by trypsinization. For experiments 350 000 cells/ 60-mm-diameter dish were seeded and cultured in Dulbecco's modified Eagle's medium with10% fetal bovine serum. After 24 hours incubation cells were cultured in serumfree Dulbecco's modified Eagle's medium for 4 h. Cells were then treated with 2.5 and 5 μM of the compounds indicated above for 20 h, except for compound of Example 10(a) to 10(j) which were treated with 2.5 and 5 μM of the compounds in serumfree medium for 4h. The final concentration of DMSO did not exceed 0.05%, which did not affect AMPK (0.05% DMSO was used as control). Western Blot analysis
WI-38 cells were lysed in buffer (10OmM TRIS pH 6,8, 2%w/v Sodium dodecylsulfate (SDS), 1OmM NaF, 1OmM β-glycerophosphate, 1 mM Na Vanadate) and the resulting supernatant was used for Western blotting. Protein concentrations of the lysates were measured using a BCA protein assay kit (Pierce #23225). For Western blotting, 5μl sample buffer (no. 161-0791 , Bio-Rad) containing 2% 2-mercaptoethanol (M3148, SIGMA) were added and the samples were heated for 3 min at 1000C. 10 μg protein was loaded in each well of a 4-12% bis/tris gradient gel for AMPK detection (Criterion precast gel Bio-Rad #345-0124) and run in XT MES Running Buffer (Cat No. 161-0789) for 60 min at 200 V and electroblotted onto nitrocellulose filters (Hybond-C extra Amersham #RPN203E). After blocking the membranes in TBS-Tween (20 mmol/l Tris-HCI, 137 mmol/l NaCI and 0.1% Tween-20, pH 7.5) and 5% bovine serum albumin (Cat No. 105033, MP Biomedicals) for 1 h at room temperature, the membranes were incubated overnight at 40C with phospho-AMPK (Thr172) (Cell signalling #2535) or with a pan- AMPK antibody (Cell signalling #2532). Filters were washed in 2OmM TRIS pH 7.5, 137 mM NaCI, 25%v/v Tween20 for 3x5min. Filters were incubated with horseradish- peroxidase-labeled anti-rabbit antibody (Cat no. 111-035-003, Jackson ImmunoResearch) in TBS-Tween and 5% non-fat dried milk for 1 h at room temperature. Filters were washed as above for 3x10 min. Signal was developed with SuperSignal West Dura ECL kit (Pierce #1859024) and exposed to Hyperfilm ECL Amersham #28906837).
Results
The potency of the compounds of Examples 7, 8(i), 8(vi), 8(vii), 8(viii), 8(x), 8(xi), 8(xii), 8(xiii), 8(xiv), 8(xv), 8(xvi), 8(xvii), 8(xviii), 8(xix), 8(xx), 8(xxi), 8(xxii), 8(xxiii), 8(xxiv), 8(xxvi), 8(xxvii), 8(xxviii), 8(xxix), 8(xxx), 8(xxxi), 8(xxxii), 8(xxxiii), 8(xxxiv), 8(xxxvi), δ(xxxvii), 8(XXXVNi), 9, 10(a) to 100) to stimulate the phosphorylation of Thr-172 on the AMPK-α subunit was estimated by comparing the relative intensity of the Western blot obtained for the vehicle control to the Western blot obtained for the compound in question. As indicated in Table 1 of Example 13, the compounds were generally more potent than the control compound.

Claims

Claims
1. A compound of formula I,
Figure imgf000119_0001
wherein:
X represents -Q-[CRxRy]π-Z- or -C(O)-;
T represents N, S or O;
G represents O or N; when G is N, the dotted line between the point of attachment of X to the ring and G is a double bond and the dotted line between the point of attachment of X to the ring and T is a single bond; when T is N, the dotted line between the point of attachment of X to the ring and T is a double bond and the dotted line between the point of attachment of X to the ring and G is a single bond;
Y represents -NHC(O)-[CH2]r-B-, -C(O)NH-[CH2]rB-, -C(O)-, -NHS(O)2-[CH2]q-,
-NHN=CH-, -NHNHS(O)2-, -NHNHC(O)-, -NHC(O)NH-, -NHC(O)O-, -NHS(O)2NH-,
-S-[CH2]q-, -0-[CH2]q-, -S(O)2-, -S(O)2NH-;
A1 to A5 respectively represent C(R1), C(R2), C(R3), C(R4) and C(R5), or, alternatively, up to two of Ai to A5 may independently represent N;
D1 to D5 each respectively represent C(R6a), C(R6b), C(R60), C(R6d) and C(R6e), or, alternatively, up to two of D1 to D5 may independently represent N;
Q and Z independently represent S(O)2, a bond, S, or O;
B represents S(O)2, or more preferably, a bond, S, or O; one of Rx and Ry is Cy1 or Het1 (which latter two groups are optionally substituted by one or more R6f substituents) and the other is H or, more preferably,
Rx and Ry are independently selected from H, halo, C1-6 alkyl (optionally substituted by one or more halo atoms), or Rx and Ry are linked to form, along with the carbon atom to which they are attached, a non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or C1-6 alkyl (optionally substituted by one or more halo atoms); Cy1 represents a 5- to 8-membered aromatic, fully saturated or partially unsaturated carbocyclic ring;
Het1 represents a 5- to 8-membered heterocyclic group that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N;
R1 to R5 independently represent H, halo, -R7, -CF3, -CN, -NO2, -C(O)R7, -C(O)OR7,
-N(R7a)R7b, -N(RV, -SR7, -OR7, -NH(O)R7 or -SO3R7, or any two of R1 to R5 which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I1 an aromatic or non-aromatic 3- to
8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo,
-R7, -OR7 and =0;
R6a to R6e independently represents H, cyano, -NO2, halo, -R8, -OR8, -N(R8JC(O)R8, -
NR9R10, -SR11, -Si(R12)3, -OC(O)R13, -C(O)OR13, -C(O)R14, -C(O)NR15aR15b, -
S(O)2NR15cR15d, aryl or heteroaryl (which aryl and heteroaryl groups are themselves optionally and independently substituted by one or more groups selected from halo and
R16), or any two R6a to R6e groups which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula
I1 an aromatic or non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo, -R7, -OR7 and =0;
R6f independently represents H, halo, -R7, -CF3, -CN, -NO2, -C(O)R7, -C(O)OR7,
-N(R7a)R7b, -N(R7)3 +, -SR7, -OR7, -NH(O)R7 or -SO3R7, or any two R6f substituents which are adjacent to each other are optionally linked to form, along with two atoms of the essential ring to which they are attached, an aromatic or non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo, -R7, -OR7 and =0;
R7 is selected from H or C1-C6 alkyl, C1-C6 cycloalkyl, aryl and heteroaryl (wherein the latter four groups are optionally substituted by one or more halo atoms);
R7a and R7b are independently selected from H, or C1-C6 alkyl, C1-C6 cycloalkyl, aryl and heteroaryl, or R7a and R7b are optionally linked to form, along with the nitrogen atom to which they are attached, an aromatic or non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo, -R7, -OR7 and =0;
R8, R9, R10, R11, R12, R13, R14, R15a, R15b, R15c and R15d independently represent H or R16; R16 represents Ci.6 alkyl optionally substituted by one or more halo atoms; n represents 1 , 2 or 3; q represents 0, 1 or 2; r represents O1 1 , 2 or 3; or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof for use in the treatment of a condition or disorder ameliorated by the activation of AMPK.
2. A compound of formula I as defined in Claim 1 , provided that: (i) when T represents O, X represents -Q-[CRXRVZ- and Rx and Ry are independently selected from H, halo or C-i.6 alkyl (optionally substituted by one or more halo atoms), then Y represents -NHC(O)NH-, -C(O)-, -NHS(O)2-[CH2Jq-, -NHN=CH-, -NHNHS(O)2-, -NHNHC(O)-, -NHC(O)O-, -NHS(O)2NH-, -O-[CH2]q-, -S(O)2-, -S(O)2NH-; (ii) when T represents S, X represents -Q-[CR51R^n-Z-, Z represents S, Q represents a bond and R* and Ry are independently selected from H, halo or Ci-6 alkyl (optionally substituted by one or more halo atoms), then Y represents -C(O)-, -NHS(O)2-[CH2]q-, -NHN=CH-, -NHNHS(O)2-, -NHNHC(O)-, -NHC(O)NH-, -NHC(O)O-, -NHS(O)2NH-, -O-[CH2]q-, -S(O)2-, -S(O)2NH-;
(iii) when T represents S, X represents -Q-[CRxRy]n-Z- and Rx and Ry are independently selected from H, halo or C1-6 alkyl (optionally substituted by one or more halo atoms), then Y represents -C(O)-, -NHS(O)2-[CH2Jq-, -NHN=CH-, -NHNHS(O)2-, -NHC(O)O-, -NHS(O)2NH-, -S-[CH2Jq-, -0-[CH2Jq-, -S(O)2-, -S(O)2NH-; (iv) when T represents S, X represents -Q-[CRWJn-Z-, Z represents a bond, Q represents O or S, Rx and Ry are independently selected from H, halo or Ci-6 alkyl (optionally substituted by one or more halo atoms), C(R1) to C(R4) are all H, C(R5) represents H, OCH3 or Cl and when:
(a) C(Ra), C(Rb), C(Rd) and C(Re) represent H and C(RC) represents C(H) or ' C(CI);
(b) C(R6a) represents C(CH3), C(R6b) represents C(CI) and C(R6c) to C(R6e) represent C(H); or
(C) C(R6e) represents C(CH3), C(R6d) represents C(CI) and C(R6a) to C(R6c) represent C(H), then
Y represents -C(O)-, -NHN=CH-, -NHNHS(O)2-, -NHC(O)O-, -NHS(O)2NH-, -S-[CH2Jq-, -0-[CH2Jq-, -S(O)2-, -S(O)2NH-; (v) when T represents S, X represents -Q-[CRxRy]n-Z-, Z represents a bond, Q represents a bond, Rx and Ry are independently selected from H, halo or C1-6 alkyl (optionally substituted by one or more halo atoms) and when:
(a) C(R1) to C(R4) are all C(H), C(R5) represents C(H), C(OCH3) or C(CI), C(Ra), C(R"), C(Rd) and C(Re) represent C(H) and C(R0) represents C(H), C(CI), C(Br), C(F), C(CH3), C(OCH3), C(NHC(O)CH3);
(b) C(R1) to C(R4) are all C(H), C(R5) represents C(OCH3), C(Rb) and C(Rd) represent H and C(Ra), C(RC) and C(Re) represent C(CH3);
(C) C(R1) and C(R3) are C(H), C(R5) represents C(OCH3), one of C(R2) and
C(R4) represents C(OCH3) while the other represents C(H) and C(RC) represents C(CI) or C(OCH3); or (d) one of C(R1) or C(R3) represents C(OCH3), while the other represents
C(H), C(R2), C(R4) and C(R5) represent H, and C(Ra) to C(Rd) represent
H, then
Y represents -C(O)-, -NHN=CH-, -NHNHS(O)2-, -NHC(O)O-, -NHS(O)2NH-, -S-[CH2Jq-, -0-[CH2Jq-, -S(O)2-, -S(O)2NH-; and
(vi) when T represents S, X represents -Q-[CRxRy]n-Z-, Z represents a bond, Q represents a bond, Rx and Ry are independently selected from H, Ci.6 alkyl (optionally substituted by one or more halo atoms), C(R6a) represents C(CH3), C(R6b) represents C(CI) and C(R6c) to C(R6e) represent C(H) or C(R6e) represents C(CH3), C(R6d) represents C(CI) and C(R6a) to C(R6c) represent C(H) and when:
(a) C(R1) to C(R5) are all H;
(b) C(R5) represents C(CI), C(F) or C(NO2) and C(R1) to C(R4) are all H;
(c) one of C(R1) or C(R3) represents C(F) or C(OCH3), while the other represents C(H) and C(R2), C(R4) and C(R5) represent C(H); or
(d) one of A2 or A4 represents N, the other represents C(H) and C(R1), C(R3) and C(R5) represent C(H), then
Y represents -C(O)-, -NHN=CH-, -NHNHS(O)2-, -NHC(O)O-, -NHS(O)2NH-, -S-[CH2]q-, -0-[CH2Jq-, -S(O)2-, -S(O)2NH-, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof.
3. A compound of formula I as defined in Claim 1 , provided that when T represents S, G represents N, X represents -Q-[CR^n-Z- and Rx and Ry are independently selected from H, halo, Ci-6 alkyl (optionally substituted by one or more halo atoms), then a) Y represents -C(O)-, -NHS(O)2-[CH2Jq-, -NHN=CH-, -NHNHS(O)2-, -NHC(O)O-, -NHS(O)2NH-, -S-[CH2]q-, -0-[CH2I0 -S(O)2-, -S(O)2NH-; and b) further, when Rx and Ry are independently selected from H or C1-6 alkyl, Y represents -NHS(O)2-[CH2Jq- and Z represents a bond, then Q represents a bond, A2 represents C(R2), A4 represents C(R4), at least one of R1 to R5 is not H, at least one R6 group is not H, and R5, when present, represents H, Br, I, F, -CF3, -CN, -C(O)R7, -C(O)OR7 or -N(R7J3 +, or any two of R1 to R5 which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I1 an aromatic or non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof.
4. The compound as claimed in any one of Claims 1 to 3, wherein each -[CR^1']- unit may be independently selected from:
(a) a unit wherein Rx and Ry are independently selected from H, halo, Ci-6 alkyl (optionally substituted by one or more halo atoms);
(b) a unit wherein Rx and Ry are linked to form, along with the carbon atom to which they are attached, a non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or C1-6 alkyl (optionally substituted by one or more halo atoms); and
(c) a unit wherein -[CR^- may represent -[CH(Cy3)]- or -[CH(Hetc)]-, which Cy3 and Hetc groups are optionally substituted by one or more R5 substituents), provided that no more than one unit is selected from (b) or (c).
5. The compound as claimed in any one of Claims 1 to 4, wherein Rx and Ry are linked to form, along with the carbon atom to which they are attached, a cyclobutyl, cyclopentyl, cyclohexyl or cyclopropyl ring which ring is itself optionally substituted by one or more substituents selected from halo or Ci-6 alkyl (optionally substituted by one or more halo atoms).
6. The compound as claimed in any one of Claims 1 to 4, wherein R* and Ry are independently selected from halo, C1-6 alkyl (optionally substituted by one or more halo atoms).
7. The compound of any one of Claims 1 to 6, wherein Q represents S(O)2, O or a bond; or Z represents S, O or a bond.
8. The compound of any one of Claims 1 to 7, wherein Y represents -C(O)-, -NHS(O)HCH2Iq-, -NHNHS(O)2-, -NHS(O)2NH-, -S(O)2- Or -S(O)2NH-.
9. The compound of any one of Claims 1 to 8, wherein Y represents -C(O)-, -NHN=CH-, -NHNHS(O)2-, -NHNHC(O)-, -NHC(O)O-, -NHS(O)2NH, -S-[CH2]q-, -CHCH2Jq-, -S(O)2- Or -S(O)2NH-.
10. The compound of any one of Claims 1 to 9, wherein Y represents -C(O)-, -NHNHS(O)2-, -NHS(O)2NH-, -S(O)2- or -S(O)2NH-.
11. The compound of any one of Claims 1 to 10, wherein T represents O or S.
12. The compound of any one of Claims 1 to 11, wherein at least one of R1 to R5 is not H.
13. The compound of any one of Claims 1 to 12, wherein at least one of R1 to R5, when present, represents R7, -OR7, halo, -CF3, -CN or -N(R7J3 +.
14. The compound of any one of Claims 1 to 13, wherein at least one of R1 to R4, when present, represents -OR7, halo, -CF3, -CN or -N(R7)3 +.
15. The compound of any one of Claims 1 to 14, wherein R5, when present, represents CH3, Cl, H, Br1 1, F, -CF3, -CN -C(O)R7, -C(O)OR7 or -N(R7J3 +.
16. The compound of any one of Claims 1 to 15, wherein R6 independently represents -C(O)NR15aR15b, H, cyano, -NO2, -Br, -Cl, -F, -R8, -OR8, -NR9R10, -SR11, -C(O)OR13, -C(O)R14, -S(O)2NR15cR15d, aryl or heteroaryl (which aryl and heteroaryl groups are themselves optionally and independently substituted by one or more groups selected from halo and R16).
17. The compound of any one of Claims 1 to 16, wherein R6 independently represents H, -Br, -F or -Cl.
18. The compound of any one of Claims 1 to 17, wherein Di to D3 each independently represent C(H);
D4 and D5 both represent C(R6); R6 represents Cl.
19. The compound of any one of Claims 1 to 17, wherein at least two of R6a to R6e are selected from Cl, F and OCH3 with the remainder each representing H, and Y represents -S-[CH2Jq-, -C(O)-, -NHS(O)2-[CH2Jq-, -NHN=CH-, -NHNHS(O)2-, -NHC(O)O-, -NHS(O)2NH-, -0-[CH2Jq-, -S(O)2-, -S(O)2NH- or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof.
20. The compound of Claim 19, wherein R6c represents Cl or F; one of R6b or R6d represents Cl and the other represents H; and
Y represents -S-[CH2Jq-, -C(O)-, -NHS(O)2-[CH2Jq-, -NHN=CH-, -NHNHS(O)2-, -NHC(O)O-, -NHS(O)2NH-, -0-[CH2Jq-, -S(O)2-, -S(O)2NH- or a pharmaceutically- acceptable salt or solvate, or a pharmaceutically functional derivative thereof.
21. A compound as claimed in Claim 1 , which is selected from the group:
(i) 1 -(3,4-dichlorophenyl)-3-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-urea; (ii) 1 -(3,4-dimethoxyphenyl)-3-[5-(3-chlorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-urea; (iii) 1 -(4-carboxyphenyl)-3-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-urea ethyl ester;
(iv) [5-(3-trifluoromethylbenzyl)-[1 ,3,4Jthiadiazol-2-yl]-carbamic acid 3,4-dichloro- phenyl ester;
(v) [5-(2-chlorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-carbamic acid 3,5-dichlorophenyl ester; (vi) [5-pyridin-4-ylmethyl-[1 ,3,4Jthiadiazol-2-yl]-carbamic acid 3,4-dichlorophenyl ester;
(vii) 1 -(3,4-dichlorophenyl)-3-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-ylJ- sulfonamide;
(viii) 1 -(4-acetamidophenyl)-3-[5-(2,3-dihydrobenzo[1 ,4]dioxin-6-ylmethyl)- [1 ,3,4]thiadiazol-2-yl]-sulfonamide; (ix) 1 -(3,4-dimethylphenyl)-3-[5-(3-moφholin-4-ylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- sulfonamide;
(x) 2-(3,4-dichlorophenylsulfanyl)-5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazole;
(xi) 2-(3,4-dichlorophenylsulfanyl)-5-(3,4-dimethylbenzyl)-[1 ,3,4]thiadiazole;
(xii) 2-(phenylsulfanyl)-5-(4-carboxybenzyl)-[1 ,3,4]thiadiazole ethyl ester;
(xiii) 2-(3,4-dichlorophenoxy)-5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazole;
(xiiii) 2-(3,5-dichlorophenoxy)-5-(3-methanthiolbenzyl)-[1 ,3,4]thiadiazole;
(xiv) 2-(3,4-dimethylphenoxy)-5-(3-trifluoromethylbenzylH1 >3,4]thiadiazole;
(xv) 2-(3,4-dichlorobenzenesulfonyl)-5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazole;
(xvi) 2-(4-chlorobenzenesulfonyl)-5-(1 ,2,3,4-tetrahydroquinolin-6-ylmethyl)-
[1 ,3,4]thiadiazole;
(xvii) 2-(2,6-dichlorobenzenesulfonyI)-5-(3-difluoromethoxydbenzyl)-[1 ,3,4]thiadiazole;
(xviii) (3,4-dichlorophenyl)-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- methanone;
(xix) (2-methoxyphenylH5-(3-fluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-methanone;
(xx) (4-acetamidophenyl)-[5-(3,4-dimethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-methanone;
(xxi) 5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazole-2-sulfonic acid (3,4-dichlorophenyl)- amide;
(xxii) 5-(4-trifluoromethylbenzyl)-[1 ,3,4]thiadiazole-2-sulfonic acid (3-difluoromethoxy- phenyl)-amide;
(xxiii) 5-(4-fluorobenzyl)-[1,3,4]thiadiazole-2-sulfonic acid (4-difluoromethoxyphenyl)- amide;
(xxiv) N-[1-(3,4-dichlorophenyl)-meth-(E)-ylidene]-N'-[5-(3-trifluoromethylbenzyl)-
[1 ,3,4]thiadiazol-2-yl]-hydrazine;
(xxv) N-[1-(3I4-diacetophenyl)-meth-(E)-ylidene]-N'-[5-(3-trifluoromethylbenzyl)-
[1 ,3,4]thiadiazol-2-yl]-hydrazine;
(xxvi) 1 -[3-(5-{N'-[1 -(3,4-dichlorophenyl)-meth-(E)-ylidene]-hydrazino}-[1 ,3,4]thiadiazol-
2-ylmethyl)-phenyl]-ethanone;
(xxvii) 3,4-dichlorobenzoic acid N'-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiodiazol-2-yl]- hydrazide;
(xxviii) 3,4-dichlorobenzoic acid N'-[5-(2,3-dihydrobenzo[1 ,4]dioxin-6-ylmethyl)-
[1 ,3,4]thiadiazol-2-yl]-hydrazide;
(xxix) 4-acetyibenzoic acid N'-[5-(3-methoxybenzyl)-[1 ,3,4]thiadiazol-2-yi]-hydrazide;
(xxx) 3,4-dichlorophenylsulfonyl N'-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiodiazol-2-yl]- hydrazide;
(xxxi) acetic acid 4-[(5-benzyl-[1 ,3,4]thiadiazol-2-yl)-hydrazonomethyl]-phenyl ester; (xxxii) methanesulfonic acid 4-{[5-(4-ethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-hydrazono- methyl}-phenyl ester;
(xxxiii)3,4-dichloro-N-{5-[1-(4-chlorophenyl)-ethyl]-[1 ,3,4]thiadiazol-2-yl}- benzenesulfonamide;
(xxxiv)3,4-dichloro-N-{5-[1-(4-chlorophenyl)-cyclopropylH1-3,4]thiadiazol-2-yl}- benzenesulfonamide;
(xxxv) 3,4-dichloro-N-{5-[1 -methyl-1 -(3-trifluoromethylphenyl)-ethyl]-[1 ,3,4]thiadiazol-2- yl}-benzenesulfonamide;
(xxxvi) 3,4-dichloro-N-[5-(3-trifluoromethylphenoxymethyl)-[1 ,3,4]thiadiazol-2- yljbenzenesulfonamide;
(xxxvii)C-(3,4-dichlorophenyl)-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- methanesulfonamide;
(xxxviii) 1 -(3,4-dichlorophenyl)-3-[5-(3-trifluoromethylbenzylsulfanylH1 ,3,4]thiadiazol-2- yl]-urea;
(xxxix) i-CS^-dichlorophenyO-S-fδ-CS-trifluoromethylbenzoyO-II .SΛJthiadiazol^-ylJ-urea;
(xl) 1 -[5-(4-chlorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-3-(3,4-dichlorophenyl)-urea;
(xli) 1 -[5-(2,4-dichlorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-3-(3,4-dichlorophenyl)-urea;
(xlii) 1 -[5-(2-fluorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-3-(3,4-dichlorophenyl)-urea;
(xliii) 1 -(3,4-dichlorophenyl)-3-[5-(1 -phenylethyl)-[1 ,3,4]thiadiazol-2-yl]-urea;
(xliv) 1 -[5-(4-fluorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-3-(3,4-dichlorophenyl)-urea;
(xlv) 1 -[5-(2,4-dichlorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-3-(2,4-dichlorophenyl)-urea;
(xlvi) 1-(3,4-dichlorophenyl)-3-(5-phenethyl-[1 ,3,4]thiadiazol-2-yl)-urea;
(xlvii) 1 -(5-benzhydryl-[1 ,3,4]thiadiazol-2-yl)-3-(3,4-dichlorophenyl)-urea;
(xlviii) 1 -(3,4-dimethoxyphenyl)-3-[5-(1 -phenylethyl)-[1 ,3,4]thiadiazol-2-yl]-urea;
(xlix) 1-(3,4-dichlorophenyl)-3-[5-(4-fluorobeπzylsulfanyl)-[1 ,3,4]thiadiazol-2-yl]-urea;
(I) 1-(3,4-dichlorophenyl)-3-(5-phenylsulfanylmethyl-[1 ,3,4]thiadiazol-2-yl)-urea;
(Ii) 3,4-dichloro-N-[5-(3-trifluoromethylbenzyl)-[1,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(lii) 4-chloro-N-[5-(3-trifluoromethylbenzyl)-[1,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(INi) 2,4-dichloro-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(liv) 3,4-dichloro-N-[5-(2-methoxybenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide;
(Iv) 4-chloro-N-[5-(2-methoxybenzyl)-[1,3,4]thiadiazol-2-yl]-benzenesulfonamide;
(Ivi) 2,4-dichloro-N-[5-(2-methoxybenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide;
(Ivii) 3,4-dichloro-N-[5-(4-fluorobenzyl)-[1 ,3,4lthiadiazol-2-yl]-benzenesulfonamide; (Iviii) ^chloro-N-fδ^-fluorobenzyO-li .S^Jthiadiazol-Z-yll-benzenesulfonamide;
(lix) 2,4-dichloro-N-[5-(4-fluorobenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide;
(Ix) 3,4-dichloro-N-[5-(4-dimethylaminobenzyi)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(Ixi) 4-chloro-N-[5-(4-dimethylaminobenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(IxN) 2,4-dichloro-N-[5-(4-dimethylaminobenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(Ixiii) 4-methoxy-N-[5-(3-trifluoromethylbenzyl)-[1,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(Ixiv) 3,4-dimethoxy-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(Ixv) 3,4,5-trimethoxy-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(Ixvi) N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide;
(Ixvii) 4-cyano-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(Ixviii) 4-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-ylsulfamoyl]-beπzoic acid ethyl ester;
(Ixix) 3,4-dichloro-N-(5-phenethyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamide;
(Ixx) 3,4-dichloro-N-{5-[2-(2-methoxyphenyl)-ethyl]-[1 ,3,4]thiadiazol-2-y^ benzenesulfonamide;
(Ixxi) S^-dichloro-N^δ-p-CS-trifluoromethylphenyO-ethyO-fi .S^Jthiadiazol^-yl}- benzenesulfonamide;
(Ixxii) 4-fluoro-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide;
(Ixxiii) 2,4-difluoro-N-[5-(3-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(Ixxiv) 3,4-difluoro-N-[5-(2-methoxybenzyl)-[1 ,3,4]thiadiazol-2-yl]-benzenesulfonamide;
(Ixxv) 4-cyano-N-[5-(2-methoxybenzyl)-[1,3,4]thiadiazol-2-yl]-benzenesulfonamide;
(Ixxvi) 4-[5-(4-fluorobenzyl)-[1 ,3,4]thiadiazol-2-ylsulfamoyl]-benzoic acid ethyl ester;
(Ixxvii) 4-cyano-N-[5-(4-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide;
(Ixxviii) 4-[5-(4-trifluoromethylbenzyl)-[1 ,3,4]thiadiazol-2-ylsulfamoyl]-benzoic acid ethyl ester;
(Ixxix) 3,4-dichloro-N-[5-(3-difluoromethoxybenzyl)-[1 ,3,4]thiadiazol-2-yl]- benzenesulfonamide; (Ixxx) 4-chloro-N-[5-(3-difluoromethoxybenzylH1 A4]thiadiazol-2-yl]- benzenesulfonamide;
(Ixxxi) 3,4-dichloro-N-(5-pyridin-4-yImethyl)-[1 ,3,4]thiadiazol-2-yl)-benzenesulfonamide; and
(Ixxxii) 3,4-dichloro-N-[5-(3-trifluoromethylbenzylH1,2,4]oxadiazol-3-yI]- benzenesulfonamide;
(lxxxiii) 3,4-dichloro-N-[5-[(4-chlorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2-yl]benzene- sulfonamide;
(Ixxxiv) 3,4-dichloro-N-[5-[1 -(4-chlorophenoxy)cyclopropy!]-1 ,3,4-thiadiazol-2-yl]benzene- sulfonamide;
(Ixxxv) 3,4-dichioro-N-[5-[1 -^-(trifluoromethyOphenoxylcyclopropylJ-i ,3,4-thiadiazol-2- yljbenzenesulfonamide;
(Ixxxvi) 1 -[5-[(4-tertbutylphenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-3-(3,4-dichlorophenyl) urea;
(Ixxxvii) N-[5-(3-phenoxypropyl)-[1 ,3,4]thiadiazol-2-yl]-C-phenyl-methanesulfonamide;
(Ixxxviii) N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-1 -phenyl-methanesulfon- amide;
(Ixxxix) N-[5-[2-(4-methoxyphenyl)ethyl]-1 ,3,4-thiadiazol-2-yl]-1 -phenyl-methanesulfon- amide;
(xc) 1 -[5-(4-chloro-2-methylphenoxymethyl)-[1 ,3,4]thiadiazol-2-yl]-3-(3,4-dichlorophen- yl)-urea;
(xci) 1-(3,4-dichlorophenyl)-3-[5-(2-fluorobenzylsulfanyl)-[1 ,3,4]thiadiazol-2-yl]-urea;
(xcii) 1 -(3,4-dichlorophenyl)-3-[5-(2-fluorophenoxymethyl)-[1 ,3,4]thiadiazol-2-yl]-urea;
(xciii) 1 -(3,4-dichlorophenyl)-3-[5-(1 -phenoxyethyl)-[1 ,3,4]thiadiazol-2-yl]-urea;
(xciv) N-(5-benzhydryl-1 ,3,4-thiadiazol-2-yl)-1 -[4-(trifluoromethyl)phenyl]methane- sulfonamide;
(xcv) N-Cδ-benzhydryl-I.S^-thiadiazol^-yO-S^-dichloro-benzenesulfonamide;
(xcvi) N-(5-benzhydryl-1 ,3,4-thiadiazol-2-yl)-3-chloro-4-fluoro-benzenesulfonamide;
(xcvii) N-(5-benzhydryl-1 ,3,4-thiadiazol-2-yl)-1 -(4-chlorophenyl)methanesulfonamide;
(xcviii) N-(5-benzhydryl-1 ,3,4-thiadiazol-2-yl)-4-(trifluoromethoxy)benzenesulfonamide;
(xcix) N-CS-benzhydryl-I.S^-thiadiazol^-yO-δ-CtrifluoromethylJpyridine-S-sulfonamide;
(c) 3,4-dichloro-N-[5-[[4-(trifluoromethyl)phenyl]methyl]-1 ,3,4-thiadiazol-2- yljbenzenesulfonamide;
(ci) 3,4-dichloro-N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2- yl]benzenesulfonamide;
(cii) N-[4-[[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]sulfamoyl]phenyl]acetamide; (ciii) N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]benzenesulfonamide;
(civ) 1 -phenyl-N-[5-(phenylsulfanylmethyl)-1 ,3,4-thiadiazol-2-yl]methanesulfonamide;
(cvJ S^-dichloro-N-^-^^p-tolylsulfonyOethyll-I.S^-thiadiazol^-ylJbenzenesulfonamide;
(cvi) 3-chloro-N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]-4-fluoro- benzenesulfonamide;
(cvii) N-[5-[1-(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-4-
(trifluoromethoxy)beπzenesulfonamide;
(cviii) 3,4-dichloro-N-[5-[4-(trifluoromethyl)benzoyl]-1 ,3,4-thiadiazol-2- yl]benzenesulfonamide;
(cix) 3-chloro-4-fluoro-N-[5-[2-(p-tolylsulfonyl)ethyl]-1 ,3,4-thiadiazol-2- yl]benzenesulfonamide;
(ex) 1 -(4-chlorophenyl)-N-[5-[2-(p-tolylsulfonyl)ethyl]-1 ,3,4-thiadiazol-2- yl]methanesulfonamide;
(cxi) N-[5-[2-(p-tolylsulfonyl)ethyl]-1 ,3,4-thiadiazol-2-yl]-4-
(trifluoromethoxy)benzenesulfonamide;
(cxii) N-[5-[2-(p-tolylsulfonyl)ethyl]-1 ,3,4-thiadiazol-2-yl]-1 -[4-
(trifluoromethyl)phenyl]methanesulfonamide;
(cxiii) N-[5-[2-(p-tolylsulfonyl)ethyl]-1 ,3,4-thiadiazol-2-yl]-6-(trifluoromethyl)pyridine-3- sulfonamide;
(cxiv) 3,4-dichloro-N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2- yljbenzenesulfonamide;
(cxv) N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]-4-
(trifluoromethoxy)benzenesulfonamide;
(CXVi) N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]-1 -[4-
(trifluoromethyl)phenyl]methanesulfonamide;
(cxvii) N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]-6-(trifluoromethyl)pyridine-3- sulfonamide;
(cxviii) 3-chloro-N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-4-fluoro- benzenesulfonamide;
(cxix) N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-4-
(trifluoromethoxy)benzenesulfonamide;
(cxx) N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-1 -[4-
(trifluoromethyl)phenyl]methanesulfonamide;
(cxxi) N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-6-(trifluoromethyl)pyridine-3- sulfonamide; (cxxii) S^-dichloro-N-tS-fi^-chlorophenoxyJethylJ-I .S^-thiadiazol-Σ- yl]benzenesulfonamide;
(cxxiii) 3-chloro-N-[5-[1 -(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-4-fluoro- benzenesulfonamide;
(cxxiv) N-[5-[1 -(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-1 -(4- chlorophenyl)methanesulfonamide;
(cxxv) N-[5-[1 -(4-chiorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-1 -[4-
(trifluoromethyl)phenyl]methanesulfonamide;
(cxxvi) N-[5-[1 -(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-6-(trifluoromethyl)pyridine-3- sulfonamide;
(cxxvii) 3,4-dichloro-N-[5-[2-(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2- yl]benzenesulfonamide;
(cxxviii) 3-chloro-N-[5-[2-(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-4-fluoro- benzenesulfonamide;
(cxxix) N-[5-[2-(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-1-(4- chlorophenyl)methanesulfonamide;
(cxxx) N-[5-[2-(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-4-
(trifluoromethoxy)benzenesulfonamide;
(cxxxi) N-[5-[2-(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-1 -[4-
(trifluoromethyl)phenyl]methanesulfonamide;
(cxxxii) N-[5-[2-(4-chlorophenoxy)ethyl]-1 ,3,4-thiadiazol-2-yl]-6-(trifluoromethyl)pyridine-
3-sulfonamide;
(cxxxiii) 3,4-dichloro-N-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2- yljbenzenesulfonamide;
(cxxxiv) 3-chloro-4-fluoro-N-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2- yljbenzenesulfonamide;
(cxxxv) 1 -(4-chlorophenyl)-N-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2- yljmethanesulfonamide;
(cxxxvi) N-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2-yl]-4-
(trifluoromethoxy)benzenesulfonamide;
(cxxxvii) N-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2-yl]-1 -[4-
(trifluoromethyl)phenyl]methanesulfonamide;
(cxxxviii) N-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2-yl]-6-
(trifluoromethyl)pyridine-3-sulfonamide;
(cxxxixJ S^-dichloro-N-fS-tS-ltrifluoromethylJbenzoyll-I .S^-thiadiazol^- yljbenzenesulfonamide; (cxl) 4-bromo-N-[5-[(4-methoxyphenyl)methyl]-1,3,4-thiadiazol-2-yl]benzenesulfonamide;
(cxli) 1 -(5-benzhydryl-1 ,3,4-thiadiazol-2-yl)-3-(2,4-dichlorophenyl)urea; (cxlii) 1 -(3,4-dichlorophenyl)-3-[5-[(3,4-dimethoxyphenyl)methyl]-1 ,3,4-thiadiazol-2- yljurea;
(cxliii) 2-[(4-chlorophenyl)methylsulfanyl]-5-[(3,4-dichlorophenyl)methylsulfanyl]-1 ,3,4- thiadiazole;
(cxliv) (4-chlorophenyl) N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]carbamate; (cxlv) 3-chloro-N'-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]-4-fluoro- benzenesulfonohydrazide;
(cxlvi) 3,4-dichloro-N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]benzamide; (cxlvii) 3,4-dichtoro-N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]benzamide; (cxlviii) 2-(4-chlorophenyl)-N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]acetamide; (cxlix) N-[5-[(4-chlorophenoxy)methyl]-1,3,4-thiadiazol-2-yl]-2-(4-chlorophenyl)acetamide; (cl) 2-(4-chlorophenoxy)-N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]acetamide; (cli) S^-dichloro-N-Iδ-I^-^rifluoromethylJphenylJmethylJ-I .S^-thiadiazol^-ylJbenzene- sulfonamide;
(cliiJ S^-dichloro-N-Iδ-^-^rifluoromethyObenzoyll-I .S^-thiadiazol^-ylJbenzenesulfon- amide;
(cliii) ^(S^-dichlorophenylJ-S-tδ-tμ^trifluoromethyOphenylJmethylJ-I .SΛ-thiadiazol^-yl]- urea
(clivJ S^-dichloro-N-fS-p-Cp-tolylsulfonyOethylJ-I .S^-thiadiazol^-ylJbenzenesulfon- amide;
(civ) 3-chloro-N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2-yl]-4-fluorobenzene- sulfonamide;
(clvi) N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]-1 -(4-chlorophenyl)methane- sulfonamide;
(clvii) N-[5-[1-(4-chlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl]-4-(trifluoromethoxy)benzene- sulfonamide;
(clviii) 3,4-dichloro-N-[5-[(4-chlorophenyl)methyl]-1 ,3,4-thiadiazol-2- yljbenzenesulfonamide;
(clix) 3,4-dichloro-N-[5-[(4-chlorophenoxy)methyl]-1 ,3,4-thiadiazol-2-yl]benzenesulfon- amide;
(clx) S^-dichloro-N-Iδ-p^-chlorophenoxyJethylJ-I .S^-thiadiazol^-ylJbenzenesulfon- amide;
(clxi) 3,4-dichloro-N-[5-[(2-fluorophenyl)methylsulfanyl]-1 ,3,4-thiadiazol-2-yl]benzene- sulfonamide; (clxii) 3,4-dichloro-N-[5-[1 -[4-trifluoromethylphenyl)cyclopropyl]-1 ,3,4-thiadiazol-2- yl]benzene-sulfonamide; and
(clxiii) 1 -(3,4-dichlorophenyl)-3-[5-[1 -[4-(trifluoromethyl)phenyl]cyclopropyl]-1 ,3,4-thiadia- zol-2-yl]urea.
22. Any one of compounds (i) to (xxxix), (Ii) to (xxxv), (xciv) to (ci), (cv) to (cxxxix), (cxliv), (cxlv) or (cli) to (clxiii) as defined in Claim 21 or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof.
23. A combination product comprising:
(A) a compound of formula I as defined in any one of Claims 1 to 22, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof; and
(B) another therapeutic agent useful in the treatment of a condition or disorder ameliorated by the activation of AMPK, wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
24. A combination product as claimed in Claim 23 which comprises a pharmaceutical formulation including a compound of formula I as defined in any one of Claims 1 to 22, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof; another therapeutic agent useful in the treatment of a condition or disorder ameliorated by the activation of AMPK; and a pharmaceutically-acceptable adjuvant, diluent or carrier.
25. A combination product as claimed in Claim 23, which comprises a kit of parts comprising components:
(a) a pharmaceutical formulation including a compound of formula I as defined in any one of Claims 1 to 22, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, in admixture with a pharmaceutically- acceptable adjuvant, diluent or carrier; and
(b) a pharmaceutical formulation including another therapeutic agent useful in the treatment of a condition or disorder ameliorated by the activation of AMPK in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
26. A kit of parts as claimed in Claim 25, wherein components (a) and (b) are suitable for sequential, separate and/or simultaneous use in the treatment of a condition or disorder ameliorated by the activation of AMPK.
27. A combination product as claimed in any one of Claims 23 to 26, wherein the other therapeutic agent is selected from biguanides, glitazones, oligomycins, AICAR, insulin, insulin secretagogues, peroxisome proliferator-activated receptor agonists, α- glucosidase inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, exenatide, inhibitors of 11-β hydroxysteroid dehydrogenase type 1 , inhibitors of stearoyl-CoA desaturase 1, A-769662, D942, cilostazol, AM251 , SIRT1 activators and salidroside.
28. The use of a compound of formula I as defined in any one of Claims 1 to 22, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, or a combination product as defined in any one of Claims 23 to 27, for the manufacture of a medicament for the treatment of a condition or disorder ameliorated by the activation of AMPK.
29. A combination product as defined in any one of Claims 23 to 27, for use in the treatment of a condition or disorder ameliorated by the activation of AMPK.
30. A method of treatment of a condition or disorder ameliorated by the activation of AMPK, which method comprises the administration of an effective amount of a compound of formula I as defined in any one of Claims 1 to 22, or a pharmaceutically- acceptable salt or solvate, or a pharmaceutically functional derivative thereof, or a combination product as defined in any one of Claims 23 to 27, to a patient in need of such treatment.
31. A compound as defined in any one of Claims 2 to 22 or a pharmaceutically- acceptable salt or solvate, or a pharmaceutically functional derivative thereof for use in the treatment of a condition or disorder ameliorated by the activation of AMPK.
32. A compound for use as defined in any one of Claims 1 and 4 to 22, a combination product as defined in any one of Claims 23 to 27, a kit of parts, use, compound, combination or method as claimed in Claim 28 or 30, the use as defined in Claim 29, and a compound for use as defined in Claim 31, wherein the condition is selected from skin diseases, lung disease, obesity, dry-type age-related macular degeneration, cardioprotection, diabetes, hyperinsulinemia and associated conditions, cancer, a disorder or condition where fibrosis plays a role, sexual dysfunction, osteoporosis, heart failure, inflammation and neurodegenerative diseases.
33. A kit of parts, use or method as claimed in Claim 32, wherein the condition is diabetes, a disorder or condition where fibrosis plays a role, inflammation and hyperinsulinemia and associated conditions.
34. A kit of parts comprising:
(I) one of components (a) and (b) as defined in Claim 25, or any one of Claims 26, 27, 30 or 31 (as dependent on Claim 25); together with
(II) instructions to use that component in conjunction with the other of the two components.
35. A method of making a kit of parts as defined in Claim 25, or any one of Claims 26, * 27, 30 or 31 (as dependent on Claim 25), which method comprises bringing a component (a) into association with a component (b), thus rendering the two components suitable for administration in conjunction with each other.
36. A process for the preparation of a compound of formula I as defined in Claim 1 , Claim 2 or Claim 3, which process comprises:
(i) for compounds of formula I wherein Y represents -NHC(O)-[CH2JrB-, -NHC(O)NH-, -NHC(O)O-, -NHS(O)2NH- or -NHS(O)2-[CH2]q-, reaction of a compound of formula II,
Figure imgf000135_0001
wherein the dotted lines, Ai to A5, X, T and G are as hereinbefore defined, with a compound of formula III,
Figure imgf000135_0002
wherein Y* represents -C(O)-[CH2JrB-, -C(O)NH-, -C(O)O-, -S(O)2NH-, or -S(O)2-[CH2Jq-, L2 represents a suitable leaving group, and D1 to D5 are as defined in Claim 1; (ii) for compounds of formula I wherein Y represents -NHC(O)NH-, reaction of a compound of formula Il with a compound of formula IV,
Figure imgf000136_0001
wherein D1 to D5 are as defined in Claim 1 ;
(iii) for compounds of formula I wherein Y represents -C(O)-, oxidation of a compound of formula V,
Figure imgf000136_0002
wherein the dotted lines, Ai to A5, X, T, G and D1 to D5 are as defined in Claim 1 ;
(iv) for compounds of formula I wherein Y represents -C(O)-, reaction of a compound of formula Vl,
Figure imgf000136_0003
wherein L3 represents a suitable leaving group, and the dotted lines, A1 to A5, X, T and G are as defined in Claim 1 , with a compound of formula VII,
Figure imgf000136_0004
wherein D1 to D5 are as defined in Claim 1 ;
(v) for compounds of formula I where Y represents -S-[CH2]q- or -O-[CH2]q-, reaction of a compound of formula Vl as hereinbefore defined, with a compound of formula VIII,
Figure imgf000136_0005
wherein AA represents HO- or HS-, q and Di to D5 are as defined in Claim 1 ;
(vi) for compounds of formula I wherein Y represents -S(O)2-, oxidation of a compound of formula I wherein Y represents -S-;
(vii) for compounds of formula I wherein Y represents -S(O)2NH-, reaction of a compound of formula IX,
Figure imgf000137_0001
wherein L5 represents a suitable leaving group, the dotted lines, Ai to A5, X, T and G are as defined in Claim 1 , with a compound of formula X1
Figure imgf000137_0002
wherein Di to D5 are as defined in Claim 1 ;
(viii) for compounds of formula I wherein Y represents -NHNHC(O)- or -NHNHS(O)2-, reaction of a compound of formula Xl,
Figure imgf000137_0003
wherein the dotted lines, Ai to A5, X, T and G are as defined in Claim 1 , with a compound corresponding to a compound of formula III, but wherein Yx instead represents -C(O)- or
-S(O)2-;
(ix) for compounds of formula I wherein Y represents -NHN=CH-, reaction of a compound of formula Xl as defined above, with a compound of formula XII,
Figure imgf000137_0004
wherein Di to D5 are as defined in Claim 1 ;
(x) for compounds of formula I wherein Z is O or S, reaction of a compound of formula XIII,
Figure imgf000138_0001
wherein L5a represents a halogen atom and wherein the dotted lines, D1 to D5, T and G are as defined in Claim 1 , with a compound of formula XIV,
Figure imgf000138_0002
wherein, Za is O or S and A1 to A5, Q, Rx, Ry and n are as defined in Claim 1; (xi) cyclisation of a compound of formula XV,
Figure imgf000138_0003
wherein T' represents S, NH or O and G, X, Y, A1 to A5 and D1 to D5 are as defined in
Claim 1 ;
(xii) reaction of a compound of formula XVI,
Figure imgf000138_0004
wherein X and A1 to A5 are as defined in Claim 1 and L6a represents a suitable leaving group or OH, with a compound of formula XVII,
Figure imgf000138_0005
wherein G' represents NH2 or OH, T' is as defined above and D1 to D5 are as defined in
Claim 1 ;
(xiii) for compounds of formula I wherein Z is a bond, reaction of a compound of formula
XVIII,
Figure imgf000139_0001
XVIII wherein L7a represents a halogen atom and the dotted lines, Y, T, G and Di to D5 are as defined in Claim 1 , with a compound of formula XIX,
Figure imgf000139_0002
wherein L8 represents a halogen atom, Xaa is -Q-[CR^n- and Q, Rx, Ry and A1 to A5 are as defined in Claim 1 ;
(xiv) for compounds of formula I, wherein X is -[CH2]2- or -[CH2]3-, Q and Z both represent bonds and Y is -NHS(O)2-, hydrogenation of a compound of formula XX or XXI,
Figure imgf000139_0003
wherein E represents CH2 or a bond and the dotted lines, T, G, A1 to A5 and D1 to D5 are as defined in Claim 1 ;
(xv) for compounds of formula I in which X represents -C(O)-, oxidation of a corresponding compound of formula I in which X represent -CH2-;
(xvi) for compounds of formula I in which Y represents -C(O)NH-[CH2]r-B-, reaction of a compound of formula XXII,
Figure imgf000139_0004
wherein r, B and D1 to D5 are as defined in Claim 1 , with a compound of formula XVI as defined above; (xvii) for compounds of formula I in which Y represents -C(O)NH-[CH2JrB-, reaction of a compound of formula XXII, as defined above, with a compound of formula XXIIl,
XXIII
Figure imgf000140_0001
wherein Ai to A5 and X are as defined in Claim 1 , followed by oxidation of the resulting intermediate; and
(xviii) for compounds of formula I in which Y represents -C(O)NH-[CH2Jr-B-, reaction of a compound of formula XXIV,
Figure imgf000140_0002
wherein A1 to A5, X, T and G are as defined in Claim 1 and R3 represents a linear or branched Ci to C6 alky! group, with a compound of formula XXV,
Figure imgf000140_0003
wherein r, B and D1 to D5 are as defined in Claim 1.
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