WO2009138799A1 - Utilisation thérapeutique de la 1-cyclopropyl-3-[3-(5-morpholin-4-ylméthyl-1h-benzoimidazol-2-yl)-lh-pyrazol-4-yl]-urée - Google Patents

Utilisation thérapeutique de la 1-cyclopropyl-3-[3-(5-morpholin-4-ylméthyl-1h-benzoimidazol-2-yl)-lh-pyrazol-4-yl]-urée Download PDF

Info

Publication number
WO2009138799A1
WO2009138799A1 PCT/GB2009/050520 GB2009050520W WO2009138799A1 WO 2009138799 A1 WO2009138799 A1 WO 2009138799A1 GB 2009050520 W GB2009050520 W GB 2009050520W WO 2009138799 A1 WO2009138799 A1 WO 2009138799A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
salts
formula
treatment
solvates
Prior art date
Application number
PCT/GB2009/050520
Other languages
English (en)
Inventor
Jayne Elizabeth Curry
John Francis Lyons
David Alexander Rawlins
Matthew Simon Squires
Neil Thomas Thompson
Nicola Gail Wallis
Original Assignee
Astex Therapeutics Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0808731A external-priority patent/GB0808731D0/en
Priority claimed from GB0809774A external-priority patent/GB0809774D0/en
Application filed by Astex Therapeutics Limited filed Critical Astex Therapeutics Limited
Publication of WO2009138799A1 publication Critical patent/WO2009138799A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to new therapeutic uses including the antibacterial use of 1 -cyclopropyl- 3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea and its salts and crystalline forms.
  • Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a wide variety of signal transduction processes within the cell (Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book. I and II, Academic Press, San Diego, CA).
  • the kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.). Sequence motifs have been identified that generally correspond to each of these kinase families (e.g., Hanks, S.
  • Protein kinases may be characterized by their regulation mechanisms. These mechanisms include, for example, autophosphorylation, transphosphorylation by other kinases, protein- protein interactions, protein- lipid interactions, and protein-polynucleotide interactions. An individual protein kinase may be regulated by more than one mechanism.
  • Kinases regulate many different cell processes including, but not limited to, proliferation, differentiation, apoptosis, motility, transcription, translation and other signalling processes, by adding phosphate groups to target proteins. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. Phosphorylation of target proteins occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stresses, etc. The appropriate protein kinase functions in signalling pathways to activate or inactivate (either directly or indirectly), for example, a metabolic enzyme, regulatory protein, receptor, cytoskeletal protein, ion channel or pump, or transcription factor.
  • Uncontrolled signalling due to defective control of protein phosphorylation has been implicated in a number of diseases, including, for example, inflammation, cancer, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system, and angiogenesis.
  • the c-Mer receptor tyrosine kinase is a member of the AxI RTK subfamily which is characterized by an N-CAM-like extracellular domain and a common ligand, Gas6 (growth arrest-specific protein 6). Protein S, another vitamin K-dependant ligand has also been observed to bind to Sky and Mer.
  • the family comprises of three members, AxI, Mer and Sky.
  • Human Mer, or c-Mer is so named after its original reported expression pattern (monocytes and epithelial and reproductive tissues).
  • Mer has been shown to be required for ingestion of apoptotic cells by professional phagocytes such as monocytes/macrophages, retinal pigment epithelial cells and dendritic cells.
  • Mer has also been shown to activate the STAT transcription factor pathway, which was associated with Mer- induced transformation. Upregulation of STATs is found in a wide range of cancer types.
  • AxI was initially identified as an NIH3T3 transforming gene, and Mer is the human ortholog of the transforming retroviral oncogene, v-eyk.
  • Overexpression of AxI, Mer, and Sky has been reported in various cancer types.
  • Mer overexpression has been found in solid tumours and leukaemias including prostate, acute lymphoblastic leukemia and mantle cell lymphoma.
  • Mice overexpressing Mer were found to develop adenopathy (lymphadenopathy), hepatosplenomegaly, and circulating lymphob lasts (Oncogene (2006) 25, 6092-6100).
  • Mitogen- and stress-activated kinase (MSK) 1 and MSK2 (also named RSKB or RLPK) belong to a family of dual protein kinases that are activated by either extracellular signal-regulated kinase (ERK) or p38 mitogen-activated protein kinases in response to stress or mitogenic extracellular stimuli.
  • MSKl and 2 have been shown to play key roles in the transcriptional regulation of immediate early genes including the inflammatory gene interleukin-6 and immediate early response genes, such as c-fos.
  • MSKl gene silencing in human tumour cells leads to severe mitotic aberrations and impaired proliferation. Persistent activation of the Ras-MAPK pathway and MSKl resulting in the elevation of phosphorylated H3 levels may contribute to the aberrant gene expression observed in oncogene-transformed cells (Strelkov and Davie Cancer Research 2002; 62(1): 75-78).
  • MSKl can enhance ER81 -dependent transcription, both through direct phosphorylation as well as indirectly by stimulating the co-activating factors CBP and p300.
  • ER81 has been shown to be involved in oncogenesis and breast tumour formation.
  • the oncogene HER2/Neu has been shown to trigger ER81 through MAPK pathways and is frequently overexpressed in breast tumours and correlates with adverse prognosis.
  • MSK-I and -2 may have a critical role in linking cellular signalling pathways to chromatin modification and modulation of transcription factor complexes and have potential therapeutic utility. Indeed, it has been demonstrated that MSK-I mediates excitotoxicity- induced death of hippocampal neurones and that inhibitors of MSK-I and -2 may, therefore, be of use in the treatment of diseases involving ischaemic injury (E.A. Irving and M. Bamford, J. Cereb. Blood Flow Metab. 22 (2002), p. 631). Since inhibitors of the p38 pathway and the ERK pathway are reported to be neuroprotectants, MSK-I and -2 inhibitors are also of interest in this regard. MSK inhibitors may also be of interest to pharmacologically precondition the heart against ischemia reperfusion injury so called cardioprotective effects or ischemic preconditioning (IPC).
  • IPC ischemic preconditioning
  • Inhibitors of kinases in the Erk MAPK cascade have been suggested for use in the treatment and/or prophylaxis of disorders associated with neuronal degeneration resulting from ischemic events, including cerebral ischemia after cardiac arrest, stroke and multi- infarct dementia and also after cerebral ischemic events such as those resulting from head injury, surgery and/or during childbirth. Since Msks are activated by Erk MARK, Msk inhibitors could serve a similar use. Inhibition of cytokines offers modest protection from injury in animal models of lung ischemia-reperfusion. Inhibition of MSK may also provide protection from injury and has the potential benefit of reducing lung reperfusion injury severity.
  • Msks are reported to be localized exclusively to the nucleus, and are responsible for the phosphorylation and activation of the transcription factor CREB in response to certain stress stimuli.
  • Mskl is involved in CREB-mediated transcriptional regulation of IL-I p and Cox2 in response to bacterial 25 lipopolysaccharide.
  • Msks are only one of a number of Erk substrates, CREB is involved in many different transcriptional activities, and Msk-mediated CREB phosphorylation could play a role in some cancers.
  • inhibitors of Msks could be of use in treatments for neuroinflammatory diseases such as stroke, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and inflammatory pain, as well as other inflammatory diseases such as rheumatoid arthritis, irritable bowel syndrome, inflammatory bowel disease and asthma.
  • DRAKl DAP kinase-r elated apoptosis-inducing protein kinase 1
  • DRAK2 DAP kinase-r elated apoptosis-inducing protein kinase 1
  • DRAK2 were first cloned by Sanjo et al. in 1998 as novel serine/threonine kinases and are novel members of the ser/thr protein kinase family, which mediate apoptosis through catalytic activity.
  • the kinase activity of DRAKl is significantly stronger than that of DRAK2.
  • DRAKl messenger RNA appears to be ubiquitously expressed in human tissues.
  • the DRAKl protein is located in the nucleus and the messenger RNA is ubiquitously expressed in human tissues. Overexpression of DRAKl induces apoptosis. Sanjo, et al.; J. Biol. Chem 1998; 273: 29066.
  • DRAKl may be a useful therapeutic target for the prevention of diseases involving cell death.
  • DAP -kinase expression is increased, thus defining this enzyme as a potential neuroprotective drug target for the treatment of CNS diseases.
  • a small molecule inhibitor with an IC 5 O of 13 ⁇ M has been reported, that showed neuroprotective effects in animal hypoxia- ischemia models, even when administered 6 hours following injury supporting the hypothesis that targeting protein kinases which function early in programmed cell death pathways could identify new therapeutic approaches to acute brain injury. (Velentza et al., Bio-org. Med. Chem. 2003; 13(20): 3465-3470.
  • DRAKl has also been found to be associated with rheumatoid arthritis (RA).
  • RA rheumatoid arthritis
  • DRAKl expression showed an age-associated ascending trend with significantly greater transcripts of RANKL and DRAKl in females (p ⁇ 0.01).
  • RA patients exhibited increased RANKL, PPAR-Gamma, and DRAKl mRNA levels (p ⁇ 0.05) (Jiang et al., J Orthop. Res. 2008; ePub).
  • DRAKl is strongly expressed in bone marrow tissues. Moreover, DRAKl is expressed weakly or not at all in osteoblasts; however, it is expressed strongly in osteoclasts, multinucleated giant cells with the resorbing activity of calcified tissues. These results suggest that DRAKl is closely involved in the regulation of osteoclastogenesis and osteoclast apoptosis. Patients with conditions resulting in excessive bone formation may derive therapeutic benefit from inhibition of osteoblast apoptosis and increased bone resorbtion. (Kojima et al., J. Biol. Chem. 2001; Vol. 276, (22): 19238-19243). SIK
  • Salt-inducible kinase belongs to a family of AMP-activated protein kinase, a serine/threonine protein kinase which plays important roles in regulating metabolism of cells under the stress.
  • SIK was identified as a specific kinase induced by Adrenocorticotropic hormone (ACTH) in the adrenal glands of rats fed a high-salt diet.
  • ACTH Adrenocorticotropic hormone
  • ACTH is the major stimulant for biosynthesis of steroid hormones in the adrenocortical cells.
  • SIKl adipose-specific isoform SIK2 that regulates the early phase of insulin-signaling in the adipose tissue of type2 diabetic animals
  • SIK3 a ubiquitously expressed isoform SIK3.
  • the Fms proto-oncogene is a protein tyrosine-kinase transmembrane receptor also known as macrophage colony-stimulating factor 1 receptor (M-CSF-IR) and belongs to the CSF-1/PDGF receptor subfamily. It is expressed in bone marrow and in differentiated blood mononuclear cells. Binding of the ligand CSF-I to this receptor induces receptor dimerisation, activation and autophosphorylation of cytoplasmic tyrosine residues used as docking sites for SH2- domain containing signalling proteins. There 5 major autophosphorylation sites including PY723 and PY809.
  • M-CSF-IR macrophage colony-stimulating factor 1 receptor
  • Imatinib has also been described as an effective inhibitor of the FMS receptor and that mutation of Asp 802 of FMS to VaI confers imatinib resistance. This suggests that Fms inhibitors may also prove effective for the treatment of diseases whose progression is dependent upon FMS receptor and ligand activity. These include inflammatory conditions such as rheumatoid arthritis and cancers such as breast and ovarian cancers. The FMS receptor and ligand have also been shown to be important in the biology of breast cancer and regulate tumor cell invasion by a urokinase-dependent mechanism in breast cancer.
  • FMS receptor has been associated with enhanced invasive and metastatic potential whilst expression of the FMS receptor and ligand together predict a highly significant decrease in survival and increased risk of recurrence which may serve to identify high-risk ovarian cancer patients.
  • Macrophage numbers present within target tissues have been strongly correlated with disease severity in rheumatoid arthritis and immune nephritis. In some solid tumors, such as breast cancer, elevated macrophage numbers are thought to contribute to disease progression and poor survivability. Binding of CSF-I to its exclusive receptor, colony-stimulating factor- 1 receptor (FMS), induces receptor dimerization and autophosphorylation which leads to the phosphorylation of downstream signaling proteins, and the subsequent differentiation and activation of cells in the macrophage lineage. Animal studies with CSF-I deficient mice suggest that CSF-I /FMS is a crucial component of a positive cycle that drives chronic inflammation.
  • FMS colony-stimulating factor- 1 receptor
  • Inhibitors of the c-Fms tyrosine kinase might also act as anti- inflammatory or anti-osteolytic agents against arthritis.
  • the 9OkDa ribosomal S6 kinases (RSKl -4) are a family of widely expressed serine/threonine kinases characterised by two functional kinase domains and a C-terminal docking site for ERKs. They are activated by ERK or PDKl and act as downstream effectors of mitogen- activated protein kinase (MAPK). Rsk has been shown to directly promote cell survival by regulating the expression and activation of pro-survival proteins such as CREB (cyclic adenosine monophosphate response element binding protein). The combination of promoting cell survival and prevention of apoptosis causes excessive cell survival, eventually leading to diseases such as cancer and autoimmune disorders. RSKs have been implicated in a number of cancer types including prostate and breast cancers, osteosarcomas and angiogenesis.
  • RSK2 regulates the expression of PSA, an important diagnostic marker for prostate cancer.
  • RSK regulates the growth and is elevated in some human prostate cancer cell lines such as LNCaP cells.
  • RSK levels are higher in 30% of human prostate tumors compared to normal prostate tissue suggest that RSK is an important drug target for prostate cancer.
  • RSK was shown to be overexpressed in 50% of human breast cancer tissue samples, suggesting that regulation of RSK has been compromised.
  • RSK has a role in proliferation of transformed cells and may be a useful new target for chemotherapeutic agents.
  • An RSK inhibitor was shown to inhibit proliferation of the human breast cancer cell line MCF-7 but not the normal human breast cell line MCF-IOA, although it still inhibited RSK in these cells. This further supports the proliferative requirement of RSK activity for some breast cancer cells. (Smith et al., Bioorg. Med. Chem. 2005; 15(4): 5018-5034).
  • RSK has also been suggested as a potential therapeutic target for liver fibrosis as it has a contributory role in the development of the disease.
  • RSK2 is important in normal development and has been associated with Coffm-Lowry syndrome.
  • the RSKs are implicated in a range of cancers in particular sarcomas, prostate cancer, and breast cancer. Furthermore, it is known that RSK levels are higher in human breast and prostate tumors compared to normal tissue. Evidence from other laboratories has demonstrated that RSK is involved in osteosarcoma formation and in non-small cell lung carcinoma. Taken together, these results suggest that RSK could serve as an important novel drug target in some types of cancers. In addition, inhibitors of Rsk can also be used as therapeutic interventions in non-terminal diseased states or neurological diseases such as epilepsy in which the MAPK signaling pathway is improperly regulated.
  • the PKC family of enzymes are serine-threonine kinases involved in multiple cell signaling pathways and the control of many cellular processes. Activation leads to a variety of cellular responses such as secretion, gene expression, proliferation and muscle contraction.
  • the family consists of at least 12 isozymes and are classified, based on their interactions with calcium and diacylglycerol as cofactors.
  • Conventional or classic isoforms including ⁇ , ⁇ l, ⁇ ll, and ⁇ require both calcium and diacylglycerol for activation.
  • Novel isoforms such as ⁇ , ⁇ , ⁇ , and ⁇ are independent of calcium but require diacylglycerol for activation.
  • AD Alzheimers Disease
  • PKC ⁇ (also known as Protein Kinase D or PKD) is implicated in the regulation of multiple cellular processes including Golgi organization and membrane transport in epithelial cells.
  • PKC ⁇ is phosphorylated on serine 742 in the activation loop in a PKC-dependent pathway by other PKC isoforms. This is critical for its catalytic activity, substrate phosphorylation and role in activating the ERKl MAP Kinase signalling cascade growth factor-induced signalling processes and proliferative effects in cells such as keratinocytes.
  • PKC ⁇ is thought to be involved in the function of invadopodia formed by breast cancer cells during invasion of the surrounding tissues.
  • PKC ⁇ and its upstream activating kinase PKC ⁇ seemed to be involved in triggering cellular adhesion processes.
  • Antiapoptotic effects have also been reported such as PKC ⁇ mediated pancreatic adenocarcinoma cell resistance. (Trauzold et al., Oncogene 2003; 22: 8939-8947)
  • PKC ⁇ -mediated signaling pathways in the cardiovascular system, particularly in the regulation of myocardial contraction, hypertrophy and remodeling.
  • HDACs histone deacetylases
  • Inhibitors of PCK-mu can therefore be used in the treatment of heart disease and its manifestations, including coronary artery disease, myocardial infarction, myocardial contraction, congestive heart failure, cardiac hypertrophy, cardiac remodelling, and heart failure such as congestive heart failure (CHF).
  • heart disease including coronary artery disease, myocardial infarction, myocardial contraction, congestive heart failure, cardiac hypertrophy, cardiac remodelling, and heart failure such as congestive heart failure (CHF).
  • CHF congestive heart failure
  • Decreasing PKD activity in the heart cells of a subject may serve as a treatment for myocardial infarct, prevention of cardiac hypertrophy and dilated cardiomyopathy, inhibition of progression of cardiac hypertrophy, treatment of heart failure, inhibition of progression of heart failure, increasing exercise tolerance in a subject with heart failure or cardiac hypertrophy, reducing hospitalization in a subject with heart failure or cardiac hypertrophy, improving quality of life in a subject with heart failure or cardiac hypertrophy, and decreasing morbidity or mortality in subjects with heart failure or cardiac hypertrophy.
  • Hypertension is a frequent precursor of congestive heart failure (CHF).
  • CHF congestive heart failure
  • the treatment may improve one or more symptoms of pathologic cardiac hypertrophy or heart failure such as providing increased exercise capacity, increased cardiac ejection volume, decreased left ventricular end diastolic pressure, decreased pulmonary capillary wedge pressure, increased cardiac output or cardiac index, lowered pulmonary artery pressures, decreased left ventricular end systolic and diastolic dimensions, decreased left and right ventricular wall stress, decreased wall tension and wall thickness, increased quality of life, and decreased disease-related morbidity and mortality.
  • PKC ⁇ chronic hypoxic pulmonary hypertension
  • SCAl 4 spinocerebellar ataxia type 14
  • PKCgamma has been found to have a role in pain.
  • inhibitors of PKC-gamma have use in the management and/or lessening of pain in particular chronic pain.
  • Chronic pain unlike normal pain, does not abate.
  • a number of physiological changes in the spinal cord, dorsal root ganglia (DRG), and the brain have been observed, which correspond to the state of chronic pain.
  • Chronic neuropathic pain results from aberrant sensory processing in either the peripheral and/or the central nervous system (CNS), typically caused by an initial inflammatory, immunological, or viral episode, or by ischemic or mechanical insult to a nerve.
  • CNS central nervous system
  • Neuropathic pain is characterized by an altered pain perception that can manifest as allodynia, a response to a normally non-noxious stimulus (e.g., the touch of clothing becomes painful), or as hyperalgesia, a decreased threshold to noxious stimuli (e.g., warm water on burned skin).
  • PKC ⁇ deficient mice show greatly reduced hyperalgesia following an inflammatory nerve injury.
  • PKC gamma along with two other isozymes ( ⁇ ll and ⁇ ) have been shown to participate in the sensation of pain (the nociception pathway) (Igwe O. J., et al., Neuroscience 104(3):875-890 (2001); Martin W.
  • Nociception is the term commonly used to refer to the perception of pain. Nociception is the unconscious afferent activity produced in the peripheral and central nervous system by stimuli that have the potential to damage tissue. As such compounds inhibiting PKC-mu will be useful for the treatment or prevention of pain. It is desirable to have an agent for the palliative treatment of pain, i.e. the direct relief of pain in addition to the relief of pain as the result of amelioration of the underlying disease or medical condition, which is the cause of the pain.
  • PKCgamma mediates ethanol withdrawal hyper-responsiveness in spinal motor neurons.
  • Inhibitory PKC-gamma-specific peptides attenuated mechanical allodynia and thermal hyperalgesia in EtOH-withdrawal rats (J Pain. 2005 Aug;6(8):535-49). Further, thermal hyperalgesia during spontaneous opiate withdrawal was inhibited by PKC gamma inhibitors (Pain. 2004 JuI; 110(1 -2):281-9).
  • PKC ⁇ gamma inhibitors allodynia and hyperalgesia, in particular in EtOH or opiate withdrawal-associated allodynia and hyperalgesia.
  • PKC ⁇ can contribute in several ways to tumor formation, with direct effects on tumor cells and with involvement in tumor host mechanisms such as inflammation and angiogenesis. PKC ⁇ is also involved in other disease areas. Hyperglycemia has been shown to lead to PKC ⁇ activation and contribute to diabetic microvascular complications. In vivo studies have shown that inhibition of PKC ⁇ can delay or even reverse diabetic retinopathy, nephropathy and neuropathy. Thus PKC ⁇ inhibitors are currently in clinical trials to treat diabetic induced vascular abnormalities.
  • PKC isoforms Small molecules that target specific sites within the PKC isoforms, including the diacyglycerol binding site are in development. These include inhibitors of single or multiple PKC isoforms. In addition peptide fragments that act as inhibitors or activators of translocation as well as antisense and siRNA approaches are also being pursued. The role of PKC in tumorigenesis and apoptosis suggests that combining PKC inhibitors with conventional cytotoxics may be also be an effective way to inhibit tumor growth.
  • the p21 activated kinase (PAK) family of kinases has become increasingly of interest as effectors of Rho family of small G proteins and as an upstream regulator of MAPK signalling pathways during cellular events such as re-arrangement of the cytoskeleton and apoptosis.
  • p21 -activated kinase 5 is an effector for the small GTPase Cdc42, known to activate cell survival signaling pathways but these GTPases do not regulate Pak5 kinase activity, which is constitutive and stronger than any other Pak.
  • PAK5 is highly expressed in mammalian brain and is not expressed in most other tissues. It is however found in some at lower levels such as prostate, testes and adrenal gland and at relatively high levels in the pancreas. (Li and Minden MoI Cell Biol. 2003; 23(20): 7134-7142). Over expression of PAK5 activates the JNK kinase pathway but not p38 or ERK pathways.
  • PAKs have also been shown to be upstream in pathways leading to activation of both the JNK (Bagrodia, S., et al. (1995) J. Biol. Chem. 270: 22731-22737) and ERK kinase pathways (Brown, J., et al. (1996). Curr Biol. 6: 598-605).
  • Pak5 has been shown to induce resistance to apoptosis by several mechanisms including phosphorylation of BAD on serine residues, in particular serine 112 as well as inhibition of PARP and caspase 3 cleavage. Over expression of the kinase dead mutant was shown not to protect against apoptosis. (Cotteret et al., MoI. Cell.
  • PAK5 may also have a mitogenic role, and be linked to cancer, based on its expression profile (elevated RNA and protein levels in a wide variety of tumor cell lines), its interaction with cdc42 via its PBD, and the ability of a kinase-dead allele (Lys350, 351 Ala) to block ras transformation of NIH3T3 cells.
  • a small molecule inhibitor of PAK5 kinase activity may yield compounds with therapeutic potential for intervention in cancer derived from a wide variety of tissue types.
  • PAK5 may also play a role in HIV pathogenesis as potential mediators of Nef signaling, since none of the known PAKs correspond to the PAK- like kinase shown to interact with, and be activated by, the HIV nef protein (Lu, X. et al. (1996) Current Biology 6: 1677-1684).
  • Inhibitors of PAK5 may have a role in the treatment of rheumatoid arthritis, atherosclerosis, autoimmune disorders, organ transplantation, myocardial infarction, cardiomyopathies, stroke, renal failure, oxidative stress-related neurodegenerative disorders, and cancer.
  • Inhibitors of PAK5 are also useful for the treatment of diabetic nephro- and neuropathy, and inhibition of dendritic spine formation and neurite outgrowth in primary neurons and neuroblastoma cells through the activation of Rac/Cdc42-PAK signaling pathways.
  • Brain serine/threonine kinase (BRSK, also known as brain-specific kinase) is a kinase expressed in the human brain in two isoforms (BRSKl and BRSK2).
  • Brain specific kinases 1 and 2 (BRSK1/2) are AMPK-related kinases that are highly expressed in mammalian forebrain. It is required for the polarization of forebrain neurons which endows axons and dendrites with distinct properties, possibly by locally regulating phosphorylation of microtubule-associated proteins.
  • AMPK-related kinases including BRSKl and BRS K2
  • phosphorylate Tau a microtubule-associated protein that regulates stability of the microtubule network.
  • AD Alzheimer's disease
  • AD Alzheimer's disease
  • Neuritic plaques are extracellular lesions, consisting mainly of deposits of ⁇ -amyloid peptide (A ⁇ ), surrounded by dystrophic (swollen, damaged and degenerating) neurites and glial cells activated by inflammatory processes.
  • a ⁇ ⁇ -amyloid peptide
  • NFTs neurofibrillary tangles
  • Tau is a soluble cytoplasmic protein which has a role in microtubule stabilisation. Excessive phosphorylation of this protein renders it insoluble and leads to its aggregation into paired helical filaments, which in turn form NFTs.
  • kinase inhibitors to control the hyperphosphorylation of Tau to treat or prevent AD other conditions involving Tau phosphorylation.
  • the microtubule affinity regulating kinase (MARK) is one such example since phosphorylation of Tau's microtubule-binding domain by the protein kinase MARK primes Tau for hyperphosphorylation by the kinases GSK-3 and Cdk5, which in turn triggers the aggregation of Tau into filaments and tangles. Toxic consequences for the neuron might be exacerbated by tangle formation but are already evident during the early steps of the process. (Drewes. Trends Biochem. Sci 2004; 29: 548-555).
  • the Tousled-like kinases are an evolutionarily conserved family of Serine/threonine protein kinases implicated in regulation of chromatin assembly in human cells named for their homology to the Tousled gene from Arabidopsis thaliana, essential for flower development.
  • Tlks are regulated in a cell cycle-dependent manner with maximal activity in S phase, and their link to chromatin assembly was established by the identification of the human chromatin assembly factors Asfla and Asflb (hAsfl) as TIk substrates.
  • the two known human Tlks, Tiki and Tlk2 are 84% similar at the amino acid sequence level, ubiquitously expressed.
  • Both kinases are inactivated by the generation of double strand breaks (DSBs), DNA-damaging agents and inhibitors of DNA replication, such as aphidicolin. This is dependent on intact checkpoints rather than inhibition of DNA synthesis itself, specifically the S-phase DNA damage checkpoint. DNA-damage during S-phase leads to ATM- and Chkl -dependent inhibition of TIk activity through phosphorylation.
  • TLKl has been found to be overexpressed in some breast cancers but not in benign breast specimens from non-cancer patients.
  • the degree of TLKl elevation is correlated with the degree of IF4E overexpression. (Norton et ah, J Surg Res. 2004; 116(1): 98-103).
  • TLKlB overexpression has been recently associated with resistance to radiation.
  • Antibiotic resistance arises following the introduction of every new drug and is seen as an inevitable result of the selective pressure that arises on widespread antibiotic use. It has been shown that bacterial pathogens can acquire resistance to multiple antibiotics and resistance can be transferred between unrelated bacterial species.
  • Ruart B. Levy The Challenge of Antibiotic Resistance, in Scientific American, 46-53 (March, 1998); Walsh, C. (2000) Nature 406, 775-781; Schluger, N. (2000) Int. J. Tuberculosis Lung Disease 4, S71 -S75; Raviglione et al., (2001) Ann. NYAcad. ScL 953, 88-97).
  • Gram-negative bacteria In general, bacterial pathogens may be classified as either Gram-positive or Gram-negative pathogens, so named because of their reaction to the Gram-stain, which stains the bacterial cell wall. Gram-negative bacteria have an extra outer membrane surrounding the cell wall which protects the cell wall from the stain. Gram-negative bacteria include pathogens such as Salmonella (e.g. Salmonella typhimurium), Escherichia (e.g. Escherichia col ⁇ ), Klebsiella (e.g. Klebsiella pneumoniae), Actinobacteria (including Br achy bacterium, Actinomyces, Corynebacterium, Micrococcus, monocytogenes, and Streptomyces species), Helicobacter (e.g.
  • Salmonella e.g. Salmonella typhimurium
  • Escherichia e.g. Escherichia col ⁇
  • Klebsiella e.g. Klebsiella pneumoniae
  • Actinobacteria including
  • Helicobacter pylori Legionella (e.g. L. pneumophila), Moraxella (e.g. Moraxella catarrhalis), Neisseria (e.g. Neisseria meningitidis, Neisseria gonorrhoeae), Haemophilus (e.g. Haemophilus influenzae, H. ducreyi), Enterobacter (e.g. Enterobactericeae pneumococci, Enter obacter faecalis), Pseudomonas (e.g. Pseudomonas aeruginosa, P. pseudomallei), Proteus (e.g. Proteus mirabilis) and Shigella (e.g. Shigella dysenteriae).
  • the additional protective cell membrane in Gram-negative bacteria often results in them being less susceptible to conventional, topical antibacterial actives.
  • Gram-positive bacteria include pathogens such as Staphylococci (e.g. Staphylococcus aureus, Staphylococcus epidermidis), Streptococci (e.g. Streptococcus diogenes, Streptococcus pneumoniae, Streptococcus mutans, Streptococcus gordonii, S. pyogenes), Enterococci (e.g. Enterococcus faecium), Clostridium (e.g. Clostridium perfringens , Clostridium difficile, Clostridium botulinum), Bacillus (e.g. Bacillus anthracis), Listeria (e.g. Listeria monocytogenes) and Mycobacteria (e.g. Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium leprae).
  • Staphylococci e.g. Staphylococcus aureus, Staphy
  • Resistance to antibiotics can arise due to a number of different mechanisms including blocking the antibiotic's accumulation (e.g. efflux pumps), modification of the antibiotic (e.g. beta- lactamases) or changes in the antibacterial target itself (e.g. ribosomal modification (erm) strains). Resistance can be inherent to the organism or acquired due to mutation or transfer of genes from other microorganisms.
  • Resistant strains of Gram-positive and Gram-negative bacteria are prevalent in hospital environments and are both difficult to treat and to eradicate, this being a treatment problem especially in intensive care units. They are also increasingly found as community-acquired infections.
  • Gram-positive resistant strains are methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), methicillin resistant coagulase negative staphylococci (MRCNS), penicillin resistant Streptococcus pneumoniae, vancomycin-resistant enterococcus (VRE), and multiply resistant Enterococcus faecium.
  • Gram- negative bacteria can have intrinsic resistance due to their outer membrane barrier and multidrug efflux pumps, which can lead to resistance to almost all antibiotics.
  • the resistant strains also often use enzymes to breakdown antibiotics, e.g. the extended spectrum beta- lactamases, which are often found in Klebsiella pneumoniae, Escherichia coli and
  • Staphylococcus aureus Enter obacteriaceae. Pseudomonas aeruginosa, K pneumoniae and Acinetobacter can be resistant to all clinically available antibiotics due to a combination of these mechanisms. Staphylococcus aureus
  • Staphylococcus aureus (also known as golden staph), is the most common cause of staphylococcal infections.
  • S. aureus is an aerobic and opportunistic Gram-positive coccus, which appears as grape-like clusters and has large, round, golden-yellow colonies, often causing hemolysis, when grown on blood agar plates.
  • the golden appearance is the etymological root of the bacteria's name: aureus means "golden" in Latin.
  • S. aureus frequently lives on the skin or in the nose of a person and is commensal on the skin of 20-30% of the general population.
  • S. aureus causes two types of disease, invasive and toxigenic. Invasive infections are characterised by abcess formation of varying severity from minor skin infections, such as pimples, impetigo, boils, cellulitis, folliculitis, furuncles (boils), carbuncles (a collection of furuncles), to life-threatening diseases, such as, osteomyelitis, endocarditis, septic arthritis, pneumonia and meningitis. Toxigenic diseases include Toxic shock syndrome (TSS), food poisoning and scalded skin syndrome (Staphylococcal scalded skin syndrome or SSSS). S. aureus can affects skin, soft tissue, respiratory, bone, joint, endovascular and wound infections. It is a major cause of nosocomial infections, causing infection of surgical wounds and sites of indwelling medical devices (e.g. prosthetic joints), which may lead to sepsis and septicemia.
  • TSS Toxic shock syndrome
  • S. aureus (including Methicillin-resistant Staphylococcus aureus or MRSA) is spread through human-to-human contact.
  • the bacterium is able to transport itself on the hands of medical staff who, for instance, get the bacteria from a seemingly healthy patient carrying a "benign" or commensal strain of the pathogen, and then go into surgery and infect the open incision with staphylococcus.
  • S. aureus infections can be spread through contact with pus from an infected wound, skin-to- skin contact with an infected person and contact with objects such as towels, sheets, clothing, or athletic equipment used by an infected person. Deeply situated S. aureus infections can be very severe.
  • S. aureus can also cause disease in animals. For example, it is one of the causal agents of mastitis in dairy cows and can also cause bumblefoot in chickens.
  • an appropriate specimen is obtained accordingly and sent to the laboratory for definitive identification by using biochemical or enzyme-based tests.
  • a Gram stain is first performed, which should show typical Gram-positive bacteria, cocci, in clusters.
  • the organism is cultured in Mannitol Salt Agar, which is a selective medium with 7-9% NaCl that allows S. aureus to grow producing yellow-colored colonies as a result of salt utilization and subsequent drop in the medium's pH.
  • catalase positive for all species
  • coagulase fibrin clot formation
  • DNAse zone of clearance on nutrient agar
  • lipase a yellow color and rancid odor smell
  • phosphatase a pink color
  • Recent genetic advances have enabled reliable and rapid techniques for the identification and characterization of clinical isolates of S. aureus in real-time which is important in identifying outbreaks and new strains of S. aureus. These are used in infection control strategies to limit bacterial spread and ensure the appropriate use of antibiotics. These techniques include Real- time PCR and Quantitative PCR and are increasingly being employed in clinical laboratories.
  • S. aureus may occur as a commensal on human skin in particular in the nose or throat.
  • the occurrence of S. aureus under these circumstances does not always indicate infection and therefore may not require treatment.
  • As such bacteria play a fundamental role in preventing the colonisation of other, more harmful bacteria and fungi, treatment under these circumstances may be undesirable.
  • S. aureus has become resistant to many commonly used antibiotics. Staphylococcal infection that is not antibiotic resistant can be treated in about a month (depending on severity) using appropriate antibiotics.
  • Methicillin-resistant S. aureus MRSA is one of the most common resistant bacteria found in hospitals and is a treatment concern especially in intensive care units. When penicillin was first introduced more than 95% of S. aureus were susceptible, now less than 10% are, due to the acquisition of beta-lactamases by the bacteria which break down the beta-lactam ring of the penicillin molecule. Methicillin (a penicillin resistant to beta- lactamases) was introduced to overcome this resistance, but now more than 40% of infections are resistant to this antibiotic in some hospitals.
  • mecA The mechanism of resistance to methicillin is by the acquisition of the mecA gene, which codes for an altered penicillin-binding protein (PBP) that has a lower affinity for binding ⁇ -lactams (penicillins, cephalosporins and carbapenems).
  • PBP penicillin-binding protein
  • ⁇ -lactams penicillins, cephalosporins and carbapenems.
  • MRSA Methicillin-resistant S. aureus
  • the glycopeptides vancomycin and teicoplanin are increasingly the major clinically effective antibiotics for such infections and MRSA with intermediate resistance to vancomycin has already been reported. Glycopeptide resistance is mediated by acquisition of the vanA gene.
  • the vanA gene originates from the enterococci and codes for an alternative peptidoglycan to which vancomycin will not bind.
  • MRSA infections in both the hospital and community setting are commonly treated with non- ⁇ -lactam antibiotics such as clindamycin (a lincosamine) and co-trimoxazole (also commonly known as trimethoprim/sulfamethoxazole). Resistance to these antibiotics has also led to the use of a new class of broad-spectrum anti-Gram-positive antibiotics the oxazolidinones, e.g. linezolid, but resistance to this new class of antibiotics has already been reported.
  • non- ⁇ -lactam antibiotics such as clindamycin (a lincosamine) and co-trimoxazole (also commonly known as trimethoprim/sulfamethoxazole).
  • clindamycin a lincosamine
  • co-trimoxazole also commonly known as trimethoprim/sulfamethoxazole
  • glycopeptide antibiotics vancomycin and teicoplanin
  • VRSA glycopeptide antibiotics
  • Pseudomonas aeruginosa is a Gram-negative, aerobic, rod-shaped bacterium with unipolar motility. Adaptation to microaerobic or anaerobic environments is necessary for certain lifestyles of P. aeruginosa, for example lung infections in cystic fibrosis patients.
  • An opportunistic pathogen of immunocompromised individuals, P. aeruginosa typically infects the pulmonary tract, urinary tract, burns, wounds, and also causes blood infections. It is the most common cause of burn and external ear infections, and is the most frequent colonizer of medical devices (e.g.catheters). Pseudomonas can in rare circumstances cause community acquired pneumonias, as well as ventilator-associated pneumonias.
  • P. aeruginosa induces symptoms of soft rot with Arabidopsis thaliana (Thale cress) and Letuca sativa (Lettuce). It is a powerful pathogen with Arabidopsis and with some animals: Caenorhabditis elegans, Drosophila and Galleria mellonella. The associations of virulence factors are the same for vegetal and animal infections
  • a Gram stain is performed, which should show Gram-negative rods with no particular arrangement. If the specimen is pure, the organism is grown on MacConkey agar plate to produce colorless colonies (as it doesn't ferment lactose), but if the specimen is not pure, then the use of a selective plate is essential. Cetrimide agar has been traditionally used for this purpose. When grown on it, P. aeruginosa expresses the exopigment pyocyanin, which is blue- green in color, and the colonies will appear flat, large, and oval. It also has a characteristic fruity smell. P.
  • aeruginosa is catalase, oxidase, nitrase, and lipase positive.
  • TSI medium When grown on TSI medium it has a K/K/g-/H2S- profile, meaning that the medium will not change color.
  • serology could help which is based on H & O antigens.
  • P. aeruginosa is frequently isolated from non-sterile sites (mouth swabs, sputum, and so forth) and under these circumstances, it often represents colonisation and not infection.
  • the advice of a microbiologist or infectious diseases physician is usually sought prior to starting treatment upon isolation of P. aeruginosa from non-sterile specimens. Often no treatment is needed.
  • P. aeruginosa When P. aeruginosa is isolated from a sterile site (blood, bone, deep collections), it almost always requires treatment. It is sometimes possible to guide treatment according to laboratory sensitivities, rather than choosing an antibiotic empirically. If antibiotics are started empirically, then cultures should be obtained and the choice of antibiotic used should be reviewed when the culture results are available. A range of antibiotics have activity against P.
  • aeruginosa [aminoglycosides (gentamicin, amikacin, tobramycin); quinolones (ciprofloxacin and levofloxacin but not moxifloxacin); cephalosporins (ceftazidime, cefepime, cefpirome, but not cefuroxime, ceftriaxone, cefotaxime); ureidopenicillins (piperacillin, ticarcillin: P.
  • aeruginosa is intrinsically resistant to all other penicillins); carbapenems (meropenem, imipenem, but not ertapenem); polymyxins (polymyxin B and colistin) and monobactams (aztreonam)] but these antibiotics, with the exception of fluoroquinolones, must all be given by injection. For this reason, in some hospitals, fluoroquinolone use is severely restricted in order to avoid the development of resistant strains of P. aeruginosa. In the rare occasions where infection is superficial and limited (for example, ear infections or nail infections) topical gentamicin or colistin may be used.
  • P. aeruginosa has inherent resistance to a large range of antibiotics due to low membrane permeability and may also readily acquire resistance after unsuccessful treatment, particularly through multidrug efflux pumps. This evolving resistance has led to clinical isolates emerging that are only susceptible to one class of antibiotic, the polymxyins, an old class of polypeptide cationic antibiotics. Furthermore there are also reports of pan-drug resistant strains of P. aeruginosa.
  • an object of the present invention to provide pharmaceutical compounds which have broad antibacterial activity including activity against Gram-positive and Gram- negative organisms. It is a further object of the present invention to provide pharmaceutical compounds having antibacterial activity that can be used in animal medicine (for example in the treatment of mammals such as humans), or in the treatment of plants (e.g. in agriculture and horticulture), or as general antibacterial agents, for example as preservatives and disinfectants.
  • the antibacterial activity of the compound of the present invention thus comprises an important contribution to therapy for treating infections caused by these difficult to control pathogens.
  • WO 03/035065 & WO 03/035644 discloses a broad class ofbenzimidazole derivatives as protein kinase inhibitors.
  • WO 03/066629 discloses benzimidazolylpyrazole amines as kinase inhibitors.
  • WO 2005/028624 discloses molecular scaffolds for compounds having activity against protein kinases.
  • the invention provides a compound of Formula (I), or salts, solvates or tautomers thereof, for use in the prophylaxis or treatment of a disease state or condition mediated by a kinase, or a mutated form thereof, which is:
  • AXL family such as AxI, Mer and Sky, in particular Mer.
  • MSK 1 and MSK2 a member of the Mitogen- and stress-activated kinase family such as MSK 1 and MSK2, in particular MSK2
  • DRAKl a member of the DAP kinase-r elated apoptosis-inducing protein kinase family, such as DRAKl and DRAK2, in particular DRAKl
  • M-CSF-IR macrophage colony- stimulating factor 1 receptor
  • RSKl -4 a member of the 9OkDa ribosomal S6 kinase family such as RSKl -4, in particular RSK2, RSK3, RSK4
  • ⁇ a member of the PKC family known as alpha, beta-I, beta-II, gamma, delta, epsilon, zeta, eta, theta, iota, lambda and mu ( ⁇ , ⁇ ( ⁇ l and ⁇ ll), ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ ), in particular PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ )
  • PAK5 a member of the p21 activated kinase (PAK) family in particular PAK5
  • ⁇ a member of the Brain specific kinase family, Brain specific kinases 1 and 2 (BRSKl /2), in particular BrSK2, or
  • TLK Tousled- like kinase
  • the invention provides a compound of Formula (I), or salts, solvates or tautomers thereof, for use as an antibacterial agent, wherein the compound of Formula (I) is:
  • the compound of formula (I) corresponds to the structure of Examples 24, 65 and 66 disclosed in our International patent application number PCT/GB2005/005097 (WO 2006/070195), the contents of which are incorporated herein by reference.
  • the invention provides a compound of Formula (I) or salts, solvates or tautomers thereof, for use in the prophylaxis or treatment of a disease state or condition mediated by a kinase, or a mutated form thereof, wherein the kinase is:
  • AXL family such as AxI, Mer and Sky, in particular Mer.
  • MSK 1 and MSK2 a member of the Mitogen- and stress-activated kinase family such as MSK 1 and MSK2, in particular MSK2
  • DRAKl a member of the DAP kinase-r elated apoptosis-inducing protein kinase family, such as DRAKl and DRAK2, in particular DRAKl
  • M-CSF-IR macrophage colony- stimulating factor 1 receptor
  • RSKl -4 a member of the 9OkDa ribosomal S6 kinase family such as RSKl -4, in particular RSK2, RSK3, RSK4
  • ⁇ a member of the PKC family known as alpha, beta-I, beta-II, gamma, delta, epsilon, zeta, eta, theta, iota, lambda and mu ( ⁇ , ⁇ ( ⁇ l and ⁇ ll), ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ ), in particular PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ )
  • PAK5 a member of the p21 activated kinase (PAK) family in particular PAK5
  • TLK Tousled- like kinase
  • the invention provides a compound of Formula (I) or salts, solvates or tautomers thereof, for use as an antibacterial agent.
  • a further aspect of the invention is a compound of Formula (I) or salts, solvates or tautomers thereof, for use in the prophylaxis or treatment of a disease or condition selected from the following:
  • ⁇ pain ⁇ coronary artery disease, myocardial contraction, cardiomyopathy (e.g. dilated cardiomyopathy), cardiac remodelling, and heart failure such as congestive heart failure (CHF), hypertension including chronic hypoxic pulmonary hypertension (PHTN) disorders, systemic vascular diseases and a range of lung conditions such as bronchiolitis, interstitial lung disease, lung injury; ⁇ disease states or conditions resulting in excessive bone formation, Paget's disease, and other diseases in which bone resorption mediates morbidity including prosthesis failure, osteolytic sarcoma, and tumor metastasis to bone; osteolytic disease associated with bone metastasis and other bone diseases in patients;
  • proliferative vitreoretinopathy liver fibrosis, renal failure, irritable bowel syndrome (IBS), oxidative stress-related neurodegenerative disorders and diabetic nephro- and neuropathy;
  • IBS irritable bowel syndrome
  • ⁇ cerebral ischemia Coffin-Lowry syndrome, Borna disease, spinocerebellar ataxia type 14 (SCA14), schizophrenia, transplant rejection, organ transplantation, resistance to transplantation, in graft vs. host disease, pancreatitis and metal (e.g.lead) poisoning;
  • ⁇ pancreatic adenocarcinoma gastric adenocarcinomas; invasive and/or metastatic breast cancer; metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia, in particular bone metastases;
  • ⁇ adenopathy (lymphadenopathy), hepatosplenomegaly, and circulating lymphoblasts;
  • the invention provides a compound of Formula (I) or salts, solvates or tautomers thereof, for use as a neuroprotective agent, as an immunosuppressive agent or as an anti- osteolytic agent.
  • the invention provides: " A compound of Formula (I) or salts, solvates or tautomers thereof, for use: a) in the prophylaxis or treatment of a disease state or condition mediated by a kinase, or a mutated form thereof, which is a member of the AXL family, or the PKC family, or the CSF-1/PDGF receptor subfamily, or the Mitogen- and stress-activated kinase family, or the DAP kinase-related apoptosis-inducing protein kinase family; or is a Salt-inducible kinase; or is a member of the 9OkDa ribosomal S6 kinase family, or the p21 activated kinase (PAK) family, or the Brain specific kinase family, or the Tousled- like kinase (TLK) family; or b) as an antibacterial agent; or c) as a neuroprotective
  • pancreatitis and metal poisoning pancreatic adenocarcinoma, gastric adenocarcinomas; invasive and/or metastatic breast cancer; metastasis from various cancers; adenopathy, hepatosplenomegaly, and circulating lymphoblasts; and allodynia and hyperalgesia.
  • CSF-IR or FMS a member of the 9OkDa ribosomal S6 kinase family such as RSKl -4, in particular RSK2, RSK3, RSK4; PKC family known as alpha, beta-I, beta-II, gamma, delta, epsilon, zeta, eta, theta, iota, lambda and mu ( ⁇ , ⁇ ( ⁇ l and ⁇ ll), ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ ), in particular PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ ); a member of the p21 activated kinase (PAK) family in particular PAK5; a member of the Brain specific kinase family, Brain specific kinases 1 and 2 (BRSK1/2), in particular BrSK2, and a member of the Tousled- like kinase (TLK) family such as TLK
  • DRAKl Salt-inducible kinase
  • SIK Salt-inducible kinase
  • M-CSF-IR or FMS macrophage colony-stimulating factor 1 receptor
  • 9OkDa ribosomal S6 kinase family in particular RSKl -4, in particular RSK2, RSK3, RSK4
  • PKC family e.g. PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ )
  • PKC ⁇ PKC-mu
  • PKC ⁇ PKC-gamma
  • PAK p21 activated kinase
  • PAK5 p21 activated kinase
  • PAK5 p21 activated kinase
  • PAK5 p21 activated kinase
  • PAK5 p21 activated kinase
  • PAK5 p21 activated kinase
  • BNK Brain specific kinase
  • TLK Tousled-like kinase
  • DRAKl Salt-inducible kinase
  • SIK Salt-inducible kinase
  • M-CSF-IR or FMS macrophage colony-stimulating factor 1 receptor
  • 9OkDa ribosomal S6 kinase family in particular RSKl- 4, in particular RSK2, RSK3, RSK4
  • PKC family e.g. PKC-mu (PKC ⁇ ) or PKC- gamma (PKC ⁇ )
  • PKC e.g. PKC-mu (PKC ⁇ ) or PKC- gamma (PKC ⁇ )
  • PKC p21 activated kinase
  • PAK p21 activated kinase
  • PAK Brain specific kinase family
  • BrSK2 Brain specific kinase family
  • TLK Tousled-like kinas
  • PKC-mu PKC-mu
  • PKC-gamma PKC-gamma
  • PAK PAK5
  • BrSK2 BrSK2 and TLK2.
  • a kinase which is a mutated form of a kinase selected from PKC e.g. PKC gamma, FMS, RSK e.g. RSK2 and PAK5.
  • dilated cardiomyopathy cardiac remodeling
  • heart failure such as congestive heart failure (CHF); hypertension including chronic hypoxic pulmonary hypertension (PHTN) disorders; systemic vascular diseases; bronchiolitis; interstitial lung disease; lung injury; disease state or condition results in excessive bone formation; Paget's disease; prosthesis failure; osteolytic sarcoma; tumor metastasis to bone; osteolytic disease associated with bone metastasis; proliferative vitreoretinopathy; liver fibrosis; renal failure; irritable bowel syndrome (IBS); oxidative stress-related neurodegenerative disorders; diabetic nephro- and neuropathy; cerebral ischemia; Coffm-Lowry syndrome; Borna disease; spinocerebellar ataxia type 14 (SCA14); schizophrenia; transplant rejection; organ transplantation; resistance to transplantation; in graft vs.
  • CHF congestive heart failure
  • PHTN chronic hypoxic pulmonary hypertension
  • PHTN chronic hypoxic pulmonary hypertension
  • pancreatitis pancreatitis
  • metal e.g. lead
  • pancreatic adenocarcinoma gastric adenocarcinomas
  • invasive and/or metastatic breast cancer metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia, in particular bone metastases
  • adenopathy lymphadenopathy
  • hepatosplenomegaly circulating lymphoblasts
  • allodynia including mechanical allodynia and EtOH or opiate withdrawal-associated allodynia
  • hyperalgesia in particular thermal hyperalgesia and hyperalgesia during EtOH or opiate withdrawal (also known as EtOH or opiate withdrawal-associated hyperalgesia)
  • pancreatitis metal (e.g. lead) poisoning
  • pancreatic adenocarcinoma gastric adenocarcinomas
  • invasive and/or metastatic breast cancer metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia, in particular bone metastases
  • adenopathy lymphadenopathy
  • hepatosplenomegaly circulating lymphoblasts
  • allodynia including mechanical allodynia and EtOH or opiate withdrawal-associated allodynia
  • hyperalgesia in particular thermal hyperalgesia and hyperalgesia during EtOH or opiate withdrawal (also known as EtOH or opiate withdrawal-associated hyperalgesia).
  • the disease state or condition is gastric adenocarcinoma or adenopathy (lymphadenopathy), hepatosplenomegaly, and circulating lymphoblasts, in particular gastric adenocarcinoma.
  • MSK in particular Msk2; and wherein the disease state or condition is irritable bowel syndrome (IBS).
  • IBS irritable bowel syndrome
  • IBS irritable bowel syndrome
  • a method of preventing or reducing damage or injury in a patient in need comprises administering to the patient an effective neuroprotective amount of a compound of the formula (I) or salts, solvates or tautomer thereof.
  • RSKl 2, 3, or 4 in particular RSK2, 3 or 4.
  • a kinase which is RSKl, 2, 3, or 4, in particular RSK2, 3 or 4
  • the disease state or condition is selected from liver fibrosis, cardiomyopathy, Coffm-Lowry syndrome, Borna disease and lead poisoning.
  • a compound of the formula (I) or salts, solvates or tautomers thereof, for use in the treatment or prophylaxis of a disease state or condition mediated by PKC in particular PKC-gamma or PKC-mu.
  • CHF congestive heart failure
  • PHTN chronic hypoxic pulmonary hypertension
  • lung conditions such as bronchiolitis, interstitial lung disease and lung injury.
  • PHTN chronic hypoxic pulmonary hypertension
  • lung conditions such as bronchiolitis, interstitial lung disease and lung injury
  • ⁇ A compound of the formula (I) or salts, solvates or tautomers thereof, for use in the treatment or prophylaxis of a disease state or condition mediated by PKC-gamma, and wherein the disease state or condition is allodynia including mechanical allodynia and EtOH or opiate withdrawal-associated allodynia, and hyperalgesia, in particular thermal hyperalgesia and hyperalgesia during EtOH or opiate withdrawal (also known as EtOH or opiate withdrawal-associated hyperalgesia).
  • ⁇ A compound of the formula (I) or salts, solvates or tautomers thereof, for use in the treatment or prophylaxis of a disease state or condition mediated by PAK5.
  • AXL family e.g. Mer
  • Mitogen- and stress-activated kinase family e.g. MSK2
  • DAP kinase-related apoptosis-inducing protein kinase family e.g. DRAKl
  • CSF-1/PDGF receptor subfamily in particular macrophage colony-stimulating factor 1 receptor (M-CSF-IR or FMS), 9OkDa ribosomal S6 kinase family (in particular RSKl- 4, in particular RSK2, RSK3, RSK4), PKC family (e.g. PKC-mu (PKC ⁇ ) or PKC- gamma (PKC ⁇ )), p21 activated kinase (PAK) family (e.g. PAK5), Brain specific kinase family (e.g. BrSK2) or Tousled-like kinase (TLK) family (e.g. TLK2) or mutated form thereof; and wherein the disease state or condition is cancer.
  • PKC e.g. PKC-mu (PKC ⁇ ) or PKC- gamma (PKC ⁇ )
  • PKC p21 activated kinase
  • PAK p21 activated kinase
  • PAK Brain specific kina
  • DRAKl Salt-inducible kinase
  • SIK Salt-inducible kinase
  • M-CSF-IR or FMS macrophage colony-stimulating factor 1 receptor
  • 9OkDa ribosomal S6 kinase family in particular RSKl- 4, in particular RSK2, RSK3, RSK4
  • PKC family e.g. PKC-mu (PKC ⁇ ) or PKC- gamma (PKC ⁇ )
  • PKC p21 activated kinase
  • PAK p21 activated kinase
  • PAK Brain specific kinase family
  • TLK2 Tha specific kinase family
  • TLK2 Tha specific kinase family
  • TLK2 Tha specific kinase family
  • TLK2 Tha specific kinase family
  • TLK2
  • DRAKl Salt-inducible kinase
  • SIK Salt-inducible kinase
  • M-CSF-IR or FMS macrophage colony-stimulating factor 1 receptor
  • 9OkDa ribosomal S6 kinase family in particular RSKl- 4, in particular RSK2, RSK3, RSK4
  • PKC family e.g. PKC-mu (PKC ⁇ ) or PKC- gamma (PKC ⁇ )
  • PKC p21 activated kinase
  • PAK p21 activated kinase
  • PAK Brain specific kinase family
  • BrSK2 Brain specific kinase family
  • TLK Tousled-like kinase
  • TLK2 tumor necrosis adenocarcinomas in particular pancreatic adenocarcinomas and gastric adenocarcinomas; invasive and/or metastatic breast cancer; metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia, in particular bone metastases.
  • a compound of the formula (I) or salts, solvates or tautomers thereof, for use in the treatment or prophylaxis of a cancer wherein the cancer is selected from pancreatic adenocarcinoma, gastric adenocarcinoma; invasive and/or metastatic breast cancer; metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia, in particular bone metastases.
  • DRAKl Salt-inducible kinase
  • SIK Salt-inducible kinase
  • M-CSF-IR or FMS macrophage colony-stimulating factor 1 receptor
  • 9OkDa ribosomal S6 kinase family in particular RSKl -4, in particular RSK2, RSK3, RSK4
  • PKC family e.g. PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ )
  • PKC p21 activated kinase
  • PAK p21 activated kinase
  • PAK Brain specific kinase family
  • BrSK2 Brain specific kinase family
  • TLK Tousled-like kinase
  • a mutated kinase which is a mutated form of kinase selected from PKC gamma or PKC-mu, RSK e.g. RSK2, PAK5, BrSK2 and FMS.
  • PKC e.g. PKC gamma
  • FMS e.g. RSK2 or PAK5
  • the malignancy is selected from pancreatic adenocarcinoma, gastric adenocarcinoma; invasive and/or metastatic breast cancer; and metastasis from
  • TLK Tousled- like kinase
  • AXL family such as AxI, Mer and Sky, in particular Mer
  • a member of the Mitogen- and stress-activated kinase family such as MSK 1 and MSK2, in particular MSK2
  • a member of the DAP kinase-r elated apoptosis-inducing protein kinase family such as DRAKl and DRAK2, in particular DRAKl
  • SIK Salt-inducible kinase
  • M-CSF-IR or FMS macrophage colony-stimulating factor 1 receptor
  • a member of the 9OkDa ribosomal S6 kinase family such as RSKl -4, in particular RSK2, RSK3, RSK4
  • a compound of formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the prophylaxis or treatment of a disease state or condition mediated by a kinase which is a member of the AXL family, such as AxI, Mer and Sky, in particular Mer; a member of the Mitogen- and stress-activated kinase family such as MSK 1 and MSK2, in particular MSK2; a member of the DAP kinase- related apoptosis-inducing protein kinase family, such as DRAKl and DRAK2, in particular DRAKl ; a Salt-inducible kinase (SIK); a member of the CSF-1/PDGF receptor subfamily in particular macrophage colony-stimulating factor 1 receptor (M- CSF-IR or FMS); a member of the 9OkDa ribosomal S6 kinase family such as RSKl
  • a compound of Formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the prophylaxis or treatment of a disease state or condition mediated by a kinase which is a mutated form of a kinase selected from AXL family, such as AxI, Mer and Sky, in particular Mer; a member of the Mitogen- and stress-activated kinase family such as MSK 1 and MSK2, in particular MSK2; a member of the DAP kinase-r elated apoptosis-inducing protein kinase family, such as
  • DRAKl and DRAK2 in particular DRAKl; a Salt-inducible kinase (SIK); a member of the CSF-1/PDGF receptor subfamily in particular macrophage colony-stimulating factor 1 receptor (M-CSF-IR or FMS); a member of the 9OkDa ribosomal S6 kinase family such as RSKl -4, in particular RSK2, RSK3, RSK4; PKC family known as alpha, beta-I, beta-II, gamma, delta, epsilon, zeta, eta, theta, iota, lambda and mu ( ⁇ , ⁇
  • PKC-mu PKC-mu
  • PKC-gamma PKC-gamma
  • PAK PKC-mu
  • PAK ⁇ PKC-gamma
  • PAK5 p21 activated kinase
  • BRSKl /2 Brain specific kinases 1 and 2
  • BrSK2 BrSK2
  • TLK Tousled- like kinase
  • a compound of Formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for theprophylaxis or treatment of a disease state or condition mediated by a kinase which is AXL family (e.g. Mer), Mitogen- and stress- activated kinase family (e.g. MSK2), DAP kinase-r elated apoptosis-inducing protein kinase family (e.g.
  • AXL family e.g. Mer
  • Mitogen- and stress- activated kinase family e.g. MSK2
  • DAP kinase-r elated apoptosis-inducing protein kinase family e.g.
  • DRAKl Salt-inducible kinase
  • SIK Salt-inducible kinase
  • M-CSF-IR or FMS macrophage colony-stimulating factor 1 receptor
  • 9OkDa ribosomal S6 kinase family in particular RSKl -4, in particular RSK2, RSK3, RSK4
  • PKC family e.g. PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ )
  • PKC p21 activated kinase
  • PAK p21 activated kinase
  • PAK Brain specific kinase family
  • BrSK2 Brain specific kinase family
  • TLK Tousled-like kinase
  • TLK2 TLK2 ⁇
  • a compound of Formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the prophylaxis or treatment of a disease state or condition mediated by a kinase which is a mutated form of a kinase selected from AXL family (e.g. Mer), Mitogen- and stress-activated kinase family (e.g. MSK2), DAP kinase-related apoptosis-inducing protein kinase family (e.g.
  • AXL family e.g. Mer
  • Mitogen- and stress-activated kinase family e.g. MSK2
  • DAP kinase-related apoptosis-inducing protein kinase family e.g.
  • DRAKl Salt-inducible kinase
  • SIK Salt-inducible kinase
  • M-CSF-IR or FMS macrophage colony- stimulating factor 1 receptor
  • 9OkDa ribosomal S6 kinase family in particular RSKl -4, in particular RSK2, RSK3, RSK4
  • PKC family e.g. PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ )
  • PKC p21 activated kinase
  • PAK p21 activated kinase
  • PAK Brain specific kinase family
  • BrSK2 Brain specific kinase family
  • TLK Tousled- like kinase
  • a compound of Formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the prophylaxis or treatment of a disease state or condition mediated by a kinase selected from Mer, MSK2, DRAKl, SIK, FMS, RSKl- 4 (in particular RSK2, RSK3, RSK4, PKC-mu (PKC ⁇ ), PKC-gamma (PKC ⁇ ), PAK5,
  • a compound of Formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the prophylaxis or treatment of a disease state or condition mediated by a kinase which is a mutated form of a kinase selected from Mer, MSK2, DRAKl , SIK, FMS, RSKl -4 (in particular RSK2, RSK3, RSK4), PKC-mu
  • PKC ⁇ PKC-gamma
  • PAK5 BrSK2 and TLK2
  • a compound of Formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the in the prophylaxis or treatment of a disease state or condition mediated by a kinase selected from PKC gamma or PKC-mu, RSK e.g. RSK2, PAK5, BrSK2 and FMS
  • a kinase selected from PKC gamma or PKC-mu, RSK e.g. RSK2, PAK5, BrSK2 and FMS
  • a compound of Formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for theprophylaxis or treatment of a disease state or condition mediated by a kinase which is a mutated form of a kinase selected from PKC gamma or PKC-mu, RSK e.g. RSK2, PAK5, BrSK2 and FMS ⁇
  • a compound of Formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the prophylaxis or treatment of a disease state or condition mediated by a kinase selected from PKC-mu, BrSK2 and FMS
  • a compound of Formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the prophylaxis or treatment of a disease state or condition mediated by a kinase selected from PKC e.g. PKC gamma, FMS, RSK e.g.
  • a compound of Formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for theprophylaxis or treatment of a disease state or condition mediated by a kinase which is a mutated form of a kinase selected from PKC e.g. PKC gamma, FMS, RSK e.g. RSK2 and PAK5.
  • a kinase which is a member of the AXL family, such as AxI, Mer and Sky, in particular Mer; a member of the Mitogen- and stress-activated kinase family such as MSK 1 and MSK2, in particular MSK2; a member of the DAP kinase- related apoptosis-inducing protein kinase family, such as DRAKl and DRAK2, in particular DRAKl; a Salt-inducible kinase (SIK); a member of the CSF-1/PDGF receptor subfamily in particular macrophage colony-stimulating factor 1 receptor (M- CSF-IR or FMS); a member of the 9OkDa ribosomal S6 kinase family such as RSKl
  • TLK2 wherein the disease or condition is selected from from pain; coronary artery disease; myocardial contraction; cardiomyopathy (e.g. dilated cardiomyopathy); cardiac remodeling; heart failure such as congestive heart failure (CHF); hypertension including chronic hypoxic pulmonary hypertension (PHTN) disorders; systemic vascular diseases; bronchiolitis; interstitial lung disease; lung injury; disease state or condition results in excessive bone formation; Paget's disease; prosthesis failure; osteolytic sarcoma; tumor metastasis to bone; osteolytic disease associated with bone metastasis; proliferative vitreoretinopathy; liver fibrosis; renal failure; irritable bowel syndrome (IBS); oxidative stress-related neurodegenerative disorders; diabetic nephro- and neuropathy; cerebral ischemia; Coffm-Lowry syndrome; Borna disease; spinocerebellar ataxia type 14 (SCA14); schizophrenia; transplant rejection; organ transplantation; resistance to transplantation; in graft vs.
  • pancreatitis metal (e.g. lead) poisoning
  • pancreatic adenocarcinoma gastric adenocarcinomas
  • invasive and/or metastatic breast cancer metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia, in particular bone metastases
  • adenopathy lymphadenopathy
  • hepatosplenomegaly circulating lymphob lasts
  • allodynia including mechanical allodynia and EtOH or opiate withdrawal-associated allodynia, and hyperalgesia, in particular thermal hyperalgesia and hyperalgesia during EtOH or opiate withdrawal (also known as EtOH or opiate withdrawal-associated hyperalgesia).
  • a compound of Formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the prophylaxis or treatment of a disease selected from pain; coronary artery disease; myocardial contraction; cardiomyopathy (e.g.
  • dilated cardiomyopathy cardiac remodeling
  • heart failure such as congestive heart failure (CHF); hypertension including chronic hypoxic pulmonary hypertension (PHTN) disorders; systemic vascular diseases; bronchiolitis; interstitial lung disease; lung injury; disease state or condition results in excessive bone formation; Paget's disease; prosthesis failure; osteolytic sarcoma; tumor metastasis to bone; osteolytic disease associated with bone metastasis; proliferative vitreoretinopathy; liver fibrosis; renal failure; irritable bowel syndrome (IBS); oxidative stress-related neurodegenerative disorders; diabetic nephro- and neuropathy; cerebral ischemia;
  • CHF congestive heart failure
  • PHTN chronic hypoxic pulmonary hypertension
  • PHTN chronic hypoxic pulmonary hypertension
  • systemic vascular diseases bronchiolitis
  • interstitial lung disease lung injury
  • disease state or condition results in excessive bone formation
  • Paget's disease prosthesis failure
  • osteolytic sarcoma tumor met
  • Coffm-Lowry syndrome Borna disease; spinocerebellar ataxia type 14 (SCAl 4); schizophrenia; transplant rejection; organ transplantation; resistance to transplantation; in graft vs. host disease; pancreatitis; metal (e.g.
  • pancreatic adenocarcinoma gastric adenocarcinomas; invasive and/or metastatic breast cancer; metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia, in particular bone metastases; adenopathy (lymphadenopathy); hepatosplenomegaly; circulating lymphob lasts; allodynia including mechanical allodynia and EtOH or opiate withdrawal-associated allodynia, and hyperalgesia, in particular thermal hyperalgesia and hyperalgesia during EtOH or opiate withdrawal (also known as EtOH or opiate withdrawal-associated hyperalgesia).
  • ⁇ The use of a compound of the formula (I) or salts, solvates or tautomers thereof, for the manufacture of a medicament for thetreatment or prophylaxis of a disease state or condition mediated by Mer.
  • ⁇ The use of a compound of the formula (I) or salts, solvates or tautomers thereof, for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition mediated by Mer; wherein the disease state or condition is gastric adenocarcinoma or adenopathy (lymphadenopathy), hepatosplenomegaly, and circulating lymphoblasts, in particular gastric adenocarcinoma.
  • the disease state or condition is gastric adenocarcinoma or adenopathy (lymphadenopathy), hepatosplenomegaly, and circulating lymphoblasts, in particular gastric adenocarcinoma.
  • a compound of the formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition mediated by FMS; and wherein the disease state or condition is selected from metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia; treatment of invasive and metastatic breast cancer; pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; Paget's disease, and other diseases in which bone resorption mediates morbidity including prosthesis failure, osteolytic sarcoma, and tumor metastasis to bone; osteolytic disease associated with bone metastasis and other bone diseases in patients and as anti-osteolytic agents and in proliferative vitreoretinopathy.
  • a compound of the formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition selected from metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia; treatment of invasive and metastatic breast cancer; pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain;
  • Paget's disease, and other diseases in which bone resorption mediates morbidity including prosthesis failure, osteolytic sarcoma, and tumor metastasis to bone; osteolytic disease associated with bone metastasis and other bone diseases in patients and as anti-osteolytic agents and in proliferative vitreoretinopathy.
  • a compound of the formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition mediated by a kinase which is RSKl, 2, 3, or 4, in particular RSK2, 3 or 4; and wherein the disease state or condition is selected from liver fibrosis, cardiomyopathy, Coffm-Lowry syndrome, Borna disease and lead poisoning.
  • a compound of the formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the treatment or prophylaxis of liver fibrosis, Coffin- Lowry syndrome, Borna disease and lead poisoning.
  • a compound of the formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition mediated by PKC-mu, and wherein the disease state or condition is selected from coronary artery disease, myocardial contraction, cardiomyopathy (e.g. dilated cardiomyopathy), cardiac remodelling, and heart failure such as congestive heart failure (CHF)
  • a disease state or condition is selected from coronary artery disease, myocardial contraction, cardiomyopathy (e.g. dilated cardiomyopathy), cardiac remodelling, and heart failure such as congestive heart failure (CHF)
  • a compound of the formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition mediated by PKC-mu, and wherein the disease state or condition is selected from hypertension including chronic hypoxic pulmonary hypertension (PHTN) disorders, systemic vascular diseases and a range of lung conditions such as bronchiolitis, interstitial lung disease and lung injury.
  • PHTN chronic hypoxic pulmonary hypertension
  • lung conditions such as bronchiolitis, interstitial lung disease and lung injury.
  • ⁇ The use of a compound of the formula (I) or salts, solvates or tautomers thereof, for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition mediated by PKC-gamma, and wherein the disease state or condition is allodynia including mechanical allodynia and EtOH or opiate withdrawal-associated allodynia, and hyperalgesia, in particular thermal hyperalgesia and hyperalgesia during EtOH or opiate withdrawal (also known as EtOH or opiate withdrawal-associated hyperalgesia).
  • PAK5 The use of a compound of the formula (I) or salts, solvates or tautomers thereof, for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition mediated by PAK5.
  • a compound of the formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition mediated by PAK5, and wherein the disease state or condition is organ transplantation, cardiomyopathies, renal failure, oxidative stress-related neurodegenerative disorders and diabetic nephro- and neuropathy.
  • AXL family e.g. Mer
  • Mitogen- and stress-activated kinase family e.g. MSK2
  • DAP kinase-related apoptosis-inducing protein kinase family e.g.
  • DRAKl Salt-inducible kinase
  • SIK Salt-inducible kinase
  • 9OkDa ribosomal S6 kinase family in particular RSKl -4, in particular RSK2, RSK3, RSK4
  • PKC family e.g. PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ )
  • PKC p21 activated kinase
  • PAK p21 activated kinase
  • PAK Brain specific kinase family
  • BrSK2 Brain specific kinase family
  • TLK Tousled-like kinase
  • AXL family e.g. Mer
  • Mitogen- and stress-activated kinase family e.g. MSK2
  • DAP kinase-related apoptosis-inducing protein kinase family e.g.
  • DRAKl Salt-inducible kinase
  • SIK Salt-inducible kinase
  • M-CSF-IR or FMS macrophage colony-stimulating factor 1 receptor
  • 9OkDa ribosomal S6 kinase family in particular RSKl -4, in particular RSK2, RSK3, RSK4
  • PKC family e.g. PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ )
  • PKC p21 activated kinase
  • PAK p21 activated kinase
  • PAK Brain specific kinase family
  • BrSK2 Brain specific kinase family
  • TLK Tousled-like kinase
  • TLK2 TLK2
  • the disease state or condition is selected from cancer.
  • AXL family e.g. Mer
  • Mitogen- and stress-activated kinase family e.g. MSK2
  • DAP kinase-related apoptosis-inducing protein kinase family e.g.
  • DRAKl Salt-inducible kinase
  • SIK Salt-inducible kinase
  • M-CSF-IR or FMS macrophage colony-stimulating factor 1 receptor
  • 9OkDa ribosomal S6 kinase family in particular RSKl -4, in particular RSK2, RSK3, RSK4
  • PKC family e.g. PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ )
  • PKC p21 activated kinase
  • PAK p21 activated kinase
  • PAK Brain specific kinase family
  • BrSK2 Brain specific kinase family
  • TLK Tousled-like kinase
  • TLK2 tumor necrosis adenocarcinomas in particular pancreatic adenocarcinomas and gastric adenocarcinomas; invasive and/or metastatic breast cancer; metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia, in particular bone metastases.
  • a compound of the formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the treatment or prophylaxis of a cancer, wherein the cancer is selected from pancreatic adenocarcinoma, gastric adenocarcinoma; invasive and/or metastatic breast cancer; metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia, in particular bone metastases.
  • a mutated kinase which is a mutated form of kinase selected from AXL family, such as AxI, Mer and Sky, in particular Mer
  • AXL family such as AxI, Mer and Sky, in particular Mer
  • a member of the Mitogen- and stress-activated kinase family such as MSK 1 and MSK2, in particular MSK2
  • MSK 1 and MSK2 a member of the DAP kinase-related apoptosis-inducing protein kinase family, such as DRAKl and DRAK2, in particular DRAKl
  • a Salt-inducible kinase (SIK) a member of the CSF-1/PDGF receptor subfamily in particular macrophage colony-stimulating factor 1 receptor (M-CSF-IR or FMS); a member of the 9OkDa ribosomal S6 kin
  • a compound of Formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the prophylaxis or treatment of a cancer which expresses a mutated kinase which is a mutated form of kinase selected from AXL family (e.g. Mer), Mitogen- and stress-activated kinase family (e.g. MSK2), DAP kinase-related apoptosis-inducing protein kinase family (e.g.
  • DRAKl Salt-inducible kinase
  • SIK Salt-inducible kinase
  • M-CSF-IR or FMS macrophage colony- stimulating factor 1 receptor
  • 9OkDa ribosomal S6 kinase family in particular RSKl -4, in particular RSK2, RSK3, RSK4
  • PKC family e.g. PKC-mu
  • PKC ⁇ PKC-gamma
  • PKC ⁇ PKC-gamma
  • PAK p21 activated kinase family
  • PAK5 p21 activated kinase family
  • BrSK2 Brain specific kinase family
  • TLK Tousled- like kinase
  • a compound of Formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the prophylaxis or treatment of a cancer which expresses a mutated kinase which is a mutated form of kinase selected from Mer, MSK2, DRAKl, SIK, FMS, RSKl -4 (in particular RSK2, RSK3, RSK4, PKC-mu (PKC ⁇ ), PKC-gamma (PKC ⁇ ), PAK5, BrSK2 and TLK2.
  • a mutated kinase which is a mutated form of kinase selected from Mer, MSK2, DRAKl, SIK, FMS, RSKl -4 (in particular RSK2, RSK3, RSK4, PKC-mu (PKC ⁇ ), PKC-gamma (PKC ⁇ ), PAK5, BrSK2 and TLK2.
  • a compound of Formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the prophylaxis or treatment of a cancer which expresses a mutated kinase which is a mutated form of kinase selected from PKC gamma or PKC-mu, RSK e.g. RSK2, PAK5, BrSK2 and FMS.
  • a compound of Formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the prophylaxis or treatment of a cancer which expresses a mutated kinase which is a mutated form of kinase selected from PKC e.g. PKC gamma, FMS, RSK e.g. RSK2 and PAK5.
  • a compound of the formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition which is a malignancy driven by a mutated form of PKC e.g. PKC gamma, FMS, RSK e.g. RSK2 or PAK5 and wherein the malignancy is selected from pancreatic adenocarcinoma, gastric adenocarcinoma; invasive and/or metastatic breast cancer; and metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia, in particular bone metastases.
  • PKC e.g. PKC gamma
  • FMS e.g. RSK2 or PAK5
  • the malignancy is selected from pancreatic adenocarcinoma, gastric adenocarcinoma; invasive and/or metastatic breast cancer; and
  • a compound of the formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the treatment or prophylaxis of a cancer which expresses a mutated kinase which is a mutated form of Mer, PKC-mu, or FMS, and wherein the cancer is selected from pancreatic adenocarcinoma, gastric adenocarcinoma; invasive and/or metastatic breast cancer; metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia, in particular bone metastases.
  • a disease or condition e.g. cancer
  • a disease or condition e.g. cancer
  • a disease or condition e.g. cancer
  • a disease or condition e.g. cancer
  • a member of the AXL family such as AxI, Mer and Sky, in particular Mer
  • a member of the Mitogen- and stress- activated kinase family such as MSK 1 and MSK2, in particular MSK2
  • a member of the DAP kinase-r elated apoptosis-inducing protein kinase family such as DRAKl and DRAK2, in particular DRAKl
  • a Salt-inducible kinase SIK
  • 1/PDGF receptor subfamily in particular macrophage colony-stimulating factor 1 receptor M-CSF-IR or FMS
  • M-CSF-IR macrophage colony-stimulating factor 1 receptor
  • RSKl -4 a member of the 9OkDa ribosomal S6 kinase family such as RSKl -4, in particular RSK2, RSK3, RSK4
  • a kinase which is a member of the AXL family, such as AxI, Mer and Sky, in particular Mer; a member of the Mitogen- and stress-activated kinase family such as MSK 1 and MSK2, in particular MSK2; a member of the DAP kinase-related apoptosis-inducing protein kinase family, such as DRAKl and DRAK2, in particular DRAKl; a Salt-inducible kinase (SIK); a member of the CSF-1/PDGF receptor subfamily in particular macrophage colony-stimulating factor 1 receptor (M-CSF-IR or FMS); a member of the 9OkDa ribosomal S6 kinase family such as RSKl -4, in particular RSK2, RSK3, RSK4; PKC family
  • a method for the prophylaxis or treatment of a disease state or condition in a patient wherein the disease state or condition is mediated by a kinase which is a mutated form of a kinase selected from AXL family, such as AxI, Mer and Sky, in particular Mer; a member of the Mitogen- and stress-activated kinase family such as MSK 1 and MSK2, in particular MSK2; a member of the DAP kinase-related apoptosis-inducing protein kinase family, such as DRAKl and DRAK2, in particular DRAKl; a Salt-inducible kinase (SIK); a member of the CSF-1/PDGF receptor subfamily in particular macrophage colony-stimulating factor 1 receptor (M-CSF-IR or FMS); a member of the 9OkDa ribosomal S6 kinase family such as RSKl -4, in particular RSK2,
  • PAK PAK
  • BRSKl /2 Brain specific kinases 1 and 2
  • BrS K2 BrS K2
  • TLK Tousled-like kinase
  • AXL family e.g. Mer
  • Mitogen- and stress-activated kinase family e.g. MSK2
  • DAP kinase- related apoptosis-inducing protein kinase family e.g.
  • DRAKl Salt-inducible kinase
  • CSF-1/PDGF receptor subfamily in particular macrophage colony-stimulating factor 1 receptor (M-CSF-IR or FMS) 9OkDa ribosomal S6 kinase family (in particular RSKl -4, in particular RSK2, RSK3, RSK4), PKC family (e.g. PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ )), p21 activated kinase (PAK) family (e.g. PAK5), Brain specific kinase family (e.g. BrSK2) and Tousled-like kinase (TLK) family (e.g. TLK2) , which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • PKC family e.g. PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇
  • AXL family e.g. Mer
  • Mitogen- and stress-activated kinase family e.g. MSK2
  • DAP kinase-related apoptosis-inducing protein kinase family e.g.
  • DRAKl Salt-inducible kinase
  • SIK Salt-inducible kinase
  • M-CSF-IR or FMS macrophage colony-stimulating factor 1 receptor
  • 9OkDa ribosomal S6 kinase family in particular RSKl -4, in particular RSK2, RSK3, RSK4
  • PKC family e.g. PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ )
  • PAK protein kinase
  • TLK Tousled-like kinase
  • ⁇ A method for the prophylaxis or treatment of a disease state or condition in a patient, wherein the disease state or condition is mediated by a kinase selected from Mer,
  • MSK2, DRAKl, SIK, FMS, RSKl -4 (in particular RSK2, RSK3, RSK4, PKC-mu (PKC ⁇ ), PKC-gamma (PKC ⁇ ), PAK5, BrSK2 and TLK2, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the prophylaxis or treatment of a disease state or condition in a patient wherein the disease state or condition is mediated by a kinase which is a mutated form of a kinase selected from Mer, MSK2, DRAKl, SIK, FMS, RSKl -4 (in particular RSK2, RSK3, RSK4, PKC-mu (PKC ⁇ ), PKC-gamma (PKC ⁇ ), PAK5, BrSK2 and TLK2, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a kinase which is a mutated form of a kinase selected from Mer, MSK2, DRAKl, SIK, FMS, RSKl -4 (in particular RSK2, RSK3, RSK4, PKC-mu (PKC ⁇ ), PKC-gamma (PKC ⁇ ), PAK5, BrSK2 and TLK2, which method comprises
  • a kinase selected from PKC gamma or PKC-mu, RSK e.g. RSK2, PAK5, BrSK2 and FMS
  • a kinase which is a mutated form of a kinase selected from PKC gamma or PKC-mu, RSK e.g. RSK2, PAK5, BrSK2 and FMS
  • ⁇ A method for the prophylaxis or treatment of a disease state or condition in a patient, wherein the disease state or condition is mediated by a kinase which is a mutated form of a kinase selected from PKC-mu, BrSK2 and FMS, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • ⁇ A method for the prophylaxis or treatment of a disease state or condition in a patient, wherein the disease state or condition is mediated by a kinase selected from PKC e.g. PKC gamma, FMS, RSK e.g. RSK2 and PAK5, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • DRAKl and DRAK2 in particular DRAKl; a Salt-inducible kinase (SIK); a member of the CSF-1/PDGF receptor subfamily in particular macrophage colony-stimulating factor 1 receptor (M-CSF-IR or FMS); a member of the 9OkDa ribosomal S6 kinase family such as RSKl -4, in particular RSK2, RSK3, RSK4; PKC family known as alpha, beta-I, beta-II, gamma, delta, epsilon, zeta, eta, theta, iota, lambda and mu ( ⁇ , ⁇
  • PKC-mu PKC-mu
  • PKC-gamma PKC-gamma
  • PAK PKC-mu
  • PAK ⁇ PKC-gamma
  • PAK5 PKC-mu
  • BRSK1/2 Brain specific kinases 1 and 2
  • TLK Tousled- like kinase
  • dilated cardiomyopathy cardiac remodeling
  • heart failure such as congestive heart failure (CHF); hypertension including chronic hypoxic pulmonary hypertension (PHTN) disorders; systemic vascular diseases; bronchiolitis; interstitial lung disease; lung injury; disease state or condition results in excessive bone formation; Paget's disease; prosthesis failure; osteolytic sarcoma; tumor metastasis to bone; osteolytic disease associated with bone metastasis; proliferative vitreoretinopathy; liver fibrosis; renal failure; irritable bowel syndrome (IBS); oxidative stress-related neurodegenerative disorders; diabetic nephro- and neuropathy; cerebral ischemia; Coffm-Lowry syndrome; Borna disease; spinocerebellar ataxia type 14 (SCA14); schizophrenia; transplant rejection; organ transplantation; resistance to transplantation; in graft vs.
  • CHF congestive heart failure
  • PHTN chronic hypoxic pulmonary hypertension
  • PHTN chronic hypoxic pulmonary hypertension
  • pancreatitis metal (e.g. lead) poisoning
  • pancreatic adenocarcinoma gastric adenocarcinomas
  • invasive and/or metastatic breast cancer metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia, in particular bone metastases
  • adenopathy lymphadenopathy
  • hepatosplenomegaly circulating lymphob lasts
  • allodynia including mechanical allodynia and EtOH or opiate withdrawal-associated allodynia
  • hyperalgesia in particular thermal hyperalgesia and hyperalgesia during EtOH or opiate withdrawal (also known as EtOH or opiate withdrawal-associated hyperalgesia)
  • method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the prophylaxis or treatment of a disease or condition in a patient wherein the disease or condition is selected from pain; coronary artery disease; myocardial contraction; cardiomyopathy (e.g. dilated cardiomyopathy); cardiac remodeling; heart failure such as congestive heart failure (CHF); hypertension including chronic hypoxic pulmonary hypertension (PHTN) disorders; systemic vascular diseases; bronchiolitis; interstitial lung disease; lung injury; disease state or condition results in excessive bone formation; Paget's disease; prosthesis failure; osteolytic sarcoma; tumor metastasis to bone; osteolytic disease associated with bone metastasis; proliferative vitreoretinopathy; liver fibrosis; renal failure; irritable bowel syndrome (IBS); oxidative stress-related neurodegenerative disorders; diabetic nephro- and neuropathy; cerebral ischemia; Coffm-Lowry syndrome; Borna disease; spinocerebellar ataxia type 14 (SCA14); schizophrenia; transplant rejection; transplant rejection
  • pancreatitis metal (e.g. lead) poisoning
  • pancreatic adenocarcinoma gastric adenocarcinomas
  • invasive and/or metastatic breast cancer metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia, in particular bone metastases
  • adenopathy lymphadenopathy
  • hepatosplenomegaly circulating lymphob lasts
  • allodynia including mechanical allodynia and EtOH or opiate withdrawal-associated allodynia
  • hyperalgesia in particular thermal hyperalgesia and hyperalgesia during EtOH or opiate withdrawal (also known as EtOH or opiate withdrawal-associated hyperalgesia)
  • method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the treatment or prophylaxis of a disease state or condition in a patient, wherein the disease state or condition is mediated by Mer comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) and salts, solvates or tautomers thereof.
  • lymphoblasts in particular gastric adenocarcinoma
  • a method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof
  • a method for the treatment or prophylaxis of a disease state or condition in a patient wherein the disease state or condition is mediated by a kinase which is MSK, in particular Msk2, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the treatment or prophylaxis of a disease state or condition in a patient wherein the disease state or condition is mediated by a kinase which is MSK, in particular Msk2; and wherein the disease state or condition is irritable bowel syndrome (IBS), which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the treatment or prophylaxis of irritable bowel syndrome (IBS) in a patient comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • ⁇ A method for the treatment or prophylaxis of a disease state or condition in a patient, wherein the disease state or condition is mediated by a kinase which is MSK, in particular Msk2; wherein the use is as neuroprotective agents, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • ⁇ A method for the treatment or prophylaxis of a disease state or condition in a patient, wherein the disease state or condition is mediated by DRAK, in particular DRAK2, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the treatment or prophylaxis of a disease state or condition in a patient, wherein the disease state or condition is mediated by DRAK, in particular DRAK2; and wherein the disease state or condition results in excessive bone formation comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the treatment or prophylaxis of a disease state or condition in a patient, wherein the disease state or condition is mediated by FMS comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the treatment or prophylaxis of a disease state or condition in a patient wherein the disease state or condition is mediated by FMS; and is selected from metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia; treatment of invasive and metastatic breast cancer; pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; Paget's disease, and other diseases in which bone resorption mediates morbidity including prosthesis failure, osteolytic sarcoma, and tumor metastasis to bone; osteolytic disease associated with bone metastasis and other bone diseases in patients and as anti-osteolytic agents and in proliferative vitreoretinopathy, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the treatment or prophylaxis of a disease state or condition in a patient wherein the disease state or condition is selected from metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia; treatment of invasive and metastatic breast cancer; pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; Paget's disease, and other diseases in which bone resorption mediates morbidity including prosthesis failure, osteolytic sarcoma, and tumor metastasis to bone; osteolytic disease associated with bone metastasis and other bone diseases in patients and as anti-osteolytic agents and in proliferative vitreoretinopathy, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • ⁇ A method for the for the treatment or prophylaxis of a disease state or condition in a patient, wherein the disease state or condition is mediated by a kinase which is RSKl,
  • RSK2, 3 or 4 which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • ⁇ A method for the treatment or prophylaxis of a disease state or condition in a patient, wherein the disease state or condition is mediated by a kinase which is RSKl, 2, 3, or
  • the disease state or condition is selected from liver fibrosis, cardiomyopathy, Coffm-Lowry syndrome, Borna disease and lead poisoning, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the treatment or prophylaxis of a disease state in a patient, wherein the disease state is selected from liver fibrosis, Coffm-Lowry syndrome, Borna disease and lead poisoning which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • ⁇ A method for the treatment or prophylaxis of a disease state or condition in a patient, wherein the disease state or condition is mediated by PKC-mu, and is selected from coronary artery disease, myocardial contraction, cardiomyopathy (e.g.
  • dilated cardiomyopathy dilated cardiomyopathy
  • cardiac remodelling CAD
  • heart failure congestive heart failure (CHF)
  • method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof ⁇
  • PHTN chronic hypoxic pulmonary hypertension
  • lung conditions such as bronchiolitis, interstitial lung disease and lung injury
  • a method for the treatment or prophylaxis of a disease state or condition in a patient, wherein the disease state or condition is mediated by PKC-mu, and is pancreatic adenocarcinoma which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the treatment or prophylaxis of spinocerebellar ataxia type 14 (SCAl 4) in a patient comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the treatment or prophylaxis of a disease state or condition in a patient, wherein the disease state or condition is mediated by PKC-gamma, and wherein the disease state or condition is pain comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the treatment or prophylaxis of a disease state or condition in a patient wherein the disease state or condition is mediated by PKC-gamma, and wherein the disease state or condition is allodynia including mechanical allodynia and EtOH or opiate withdrawal-associated allodynia, and hyperalgesia, in particular thermal hyperalgesia and hyperalgesia during EtOH or opiate withdrawal (also known as EtOH or opiate withdrawal-associated hyperalgesia), which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the treatment or prophylaxis of renal failure, oxidative stress-related neurodegenerative disorders and diabetic nephro- and neuropathy in a patient comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the treatment or prophylaxis of transplant rejection, organ transplantation, resistance to transplantation, in graft vs. host disease, and pancreatitis in a patient comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • ⁇ A method for the treatment or prophylaxis of a disease state or condition in a patient, wherein the disease state or condition is mediated by BrSKl and 2, in particular BRSK2, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • ⁇ A method for the treatment or prophylaxis of a disease state or condition in a patient, wherein the disease state or condition is mediated by BrSKl and 2, in particular BRSK2, and wherein the disease state or condition is schizophrenia or cerebral ischemia, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the treatment or prophylaxis of schizophrenia or cerebral ischemia in a patient comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the treatment or prophylaxis of a disease state or condition in a patient wherein the disease state or condition is mediated by AXL family (e.g. Mer), Mitogen- and stress-activated kinase family (e.g. MSK2), DAP kinase-related apoptosis-inducing protein kinase family (e.g.
  • DRAKl Salt-inducible kinase
  • CSF-1/PDGF receptor subfamily in particular macrophage colony-stimulating factor 1 receptor (M- CSF-IR or FMS) 9OkDa ribosomal S6 kinase family (in particular RSKl -4, in particular RSK2, RSK3, RSK4), PKC family (e.g. PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ )), p21 activated kinase (PAK) family (e.g. PAK5), Brain specific kinase family (e.g. BrSK2) or Tousled-like kinase (TLK) family (e.g. TLK2) or a mutated form thereof; and wherein the disease state or condition is selected from cancer, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • PKC family e.g. P
  • AXL family e.g. Mer
  • Mitogen- and stress-activated kinase family e.g. MSK2
  • DAP kinase-related apoptosis-inducing protein kinase family e.g.
  • DRAKl Salt-inducible kinase
  • SIK Salt-inducible kinase
  • 9OkDa ribosomal S6 kinase family in particular RSKl -4, in particular RSK2, RSK3, RSK4
  • PKC family e.g. PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ )
  • PKC p21 activated kinase
  • PAK p21 activated kinase
  • PAK Brain specific kinase family
  • BrSK2 Brain specific kinase family
  • TLK Tousled-like kinase
  • a method for the treatment or prophylaxis of a disease state or condition in a patient comprising administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • AXL family e.g. Mer
  • Mitogen- and stress-activated kinase family e.g. MSK2
  • DAP kinase-related apoptosis-inducing protein kinase family e.g. DRAKl
  • CSF-1/PDGF receptor subfamily in particular macrophage colony-stimulating factor 1 receptor (M-
  • CSF-IR or FMS 9OkDa ribosomal S6 kinase family (in particular RSKl -4, in particular RSK2, RSK3, RSK4), PKC family (e.g. PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ )), p21 activated kinase (PAK) family (e.g. PAK5), Brain specific kinase family (e.g. BrSK2) or Tousled-like kinase (TLK) family (e.g.
  • the cancer is selected from adenocarcinomas in particular pancreatic adenocarcinomas and gastric adenocarcinomas; invasive and/or metastatic breast cancer; metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia, in particular bone metastases, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the treatment or prophylaxis of a cancer in a patient wherein the cancer is selected from pancreatic adenocarcinoma, gastric adenocarcinoma; invasive and/or metastatic breast cancer; metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia, in particular bone metastases, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the prophylaxis or treatment of a cancer in a patient wherein the cancer is one which expresses a mutated kinase which is a mutated form of kinase selected from AXL family, such as AxI, Mer and Sky, in particular Mer; a member of the
  • Mitogen- and stress-activated kinase family such as MSK 1 and MSK2, in particular MSK2; a member of the DAP kinase-related apoptosis-inducing protein kinase family, such as DRAKl and DRAK2, in particular DRAKl; a Salt-inducible kinase (SIK); a member of the CSF-1/PDGF receptor subfamily in particular macrophage colony- stimulating factor 1 receptor (M-CSF-IR or FMS); a member of the 9OkDa ribosomal
  • S6 kinase family such as RSKl -4, in particular RSK2, RSK3, RSK4; PKC family known as alpha, beta-I, beta-II, gamma, delta, epsilon, zeta, eta, theta, iota, lambda and mu ( ⁇ , ⁇ ( ⁇ l and ⁇ ll), ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , i, ⁇ , and ⁇ ), in particular PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ ); a member of the p21 activated kinase (PAK) family in particular PAK5; a member of the Brain specific kinase family, Brain specific kinases 1 and 2 (BRSK1/2), in particular BrSK2, or a member of the Tousled-like kinase (TLK) family such as TLKl or TLK2 in particular TLK2, which method comprises administering to the patient a therapeutically effective
  • a method for the prophylaxis or treatment of a cancer in a patient wherein the cancer is one which expresses a mutated kinase which is a mutated form of kinase selected from AXL family (e.g. Mer), Mitogen- and stress-activated kinase family (e.g. MSK2), DAP kinase-related apoptosis-inducing protein kinase family (e.g.
  • DRAKl SaIt- inducible kinase
  • SIK SaIt- inducible kinase
  • 9OkDa ribosomal S6 kinase family in particular RSKl -4, in particular RSK2, RSK3, RSK4
  • PKC family e.g. PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ )
  • PKC-mu (PKC ⁇ ) PKC-gamma
  • PAK p21 activated kinase
  • PAK Brain specific kinase family
  • BrSK2 Brain specific kinase family
  • TLK Tousled-like kinase
  • a method for the prophylaxis or treatment of a cancer in a patient wherein the cancer is one which expresses a mutated kinase which is a mutated form of kinase selected from Mer, MSK2, DRAKl, SIK, FMS, RSKl -4 (in particular RSK2, RSK3, RSK4, PKC-mu (PKC ⁇ ), PKC-gamma (PKC ⁇ ), PAK5, BrSK2 and TLK2, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a mutated kinase which is a mutated form of kinase selected from Mer, MSK2, DRAKl, SIK, FMS, RSKl -4 (in particular RSK2, RSK3, RSK4, PKC-mu (PKC ⁇ ), PKC-gamma (PKC ⁇ ), PAK5, BrSK2 and TLK2, which method comprises administering
  • a method for the prophylaxis or treatment of a cancer in a patient wherein the cancer is one which expresses a mutated kinase which is a mutated form of kinase selected from PKC gamma or PKC-mu, RSK e.g. RSK2, PAK5, BrSK2 and FMS, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • RSK2 or PAK5 wherein the malignancy is selected from pancreatic adenocarcinoma, gastric adenocarcinoma; invasive and/or metastatic breast cancer; and metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia, in particular bone metastases, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the treatment or prophylaxis of a cancer in a patient wherein the cancer is one which expresses a mutated kinase which is a mutated form of Mer, PKC-mu, or FMS, and wherein the cancer is selected from pancreatic adenocarcinoma, gastric adenocarcinoma; invasive and/or metastatic breast cancer; metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia, in particular bone metastases, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • PKC ⁇ PKC-mu
  • PKC ⁇ PKC- gamma
  • PAK5 BrSK2 or TLK2; for example PKC e.g. PKC gamma, FMS, RSK e.g. RSK2 or PAK5, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the prophylaxis or treatment of a disease state or condition (e.g. cancer) in a patient wherein the disease state or condition (e.g. cancer) is characterized by overexpression of any one or more kinases selected from a member of the AXL family, such as AxI, Mer and Sky, in particular Mer; a member of the Mitogen- and stress- activated kinase family such as MSK 1 and MSK2, in particular MSK2; a member of the DAP kinase-r elated apoptosis-inducing protein kinase family, such as DRAKl and DRAK2, in particular DRAKl; a Salt-inducible kinase (SIK); a member of the CSF- 1/PDGF receptor subfamily in particular macrophage colony-stimulating factor 1 receptor (M-CSF-IR or FMS); a member of the 9OkDa ribosomal S6 kinase family
  • BrSK2 or a member of the Tousled- like kinase (TLK) family such as TLKl or TLK2 in particular TLK2, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • TLK Tousled- like kinase
  • a method for the diagnosis and treatment of a disease state or condition mediated by a kinase which is AXL family, such as AxI, Mer and Sky, in particular Mer; a member of the Mitogen- and stress-activated kinase family such as MSK 1 and MSK2, in particular MSK2; a member of the DAP kinase-related apoptosis-inducing protein kinase family, such as DRAKl and DRAK2, in particular DRAKl; a Salt-inducible kinase (SIK); a member of the CSF-1/PDGF receptor subfamily in particular macrophage colony-stimulating factor 1 receptor (M-CSF-IR or FMS); a member of the 9OkDa ribosomal S6 kinase family such as RSKl -4, in particular RSK2, RSK3, RSK4; PKC family known as alpha, beta-I, beta-II, gamma, delta, e
  • PAK Brain specific kinase family
  • BRSK1/2 Brain specific kinases 1 and 2
  • BrSK2 BrSK2
  • TLK Tousled- like kinase
  • TLKl TLK2 in particular TLK2
  • method comprises (i) screening a patient to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound having activity against the kinase; and (ii) where it is indicated that the disease or condition from which the patient is thus susceptible, thereafter administering to the patient a compound compound of the formula (I) or salt, solvates and tautomers thereof.
  • the invention also provides: ⁇ A compound of Formula (I), or salts, solvates or tautomers thereof, for use in the prophylaxis or treatment of a disease state or condition described herein.
  • a compound of the formula (I) or salts, solvates and tautomers thereof for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition in a patient who has been screened and has been determined as suffering from, or being at risk of suffering from, a disease or condition which would be susceptible to treatment with a compound having activity against a kinase which is AXL family, such as AxI, Mer and Sky, in particular Mer; a member of the Mitogen- and stress-activated kinase family such as MSK 1 and MSK2, in particular MSK2; a member of the DAP kinase-r elated apoptosis-inducing protein kinase family, such as DRAKl and DRAK2, in particular DRAKl; a Salt-inducible kinase (SIK); a member of the CSF-1/PDGF receptor subfamily in particular macrophage colony-stimulating factor 1 receptor
  • DRAKl a Salt-inducible kinase (SIK); a member of the CSF-1/PDGF receptor subfamily in particular macrophage colony-stimulating factor 1 receptor (M-CSF-IR or FMS); a member of the 9OkDa ribosomal S6 kinase family such as RSKl -4, in particular RSK2, RSK3, RSK4; PKC family known as alpha, beta-I, beta-II, gamma, delta, epsilon, zeta, eta, theta, iota, lambda and mu ( ⁇ , ⁇ ( ⁇ l and ⁇ ll), ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ ), in particular PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ ); a member of the p21 activated kinase (PAK) family in particular PAK5; a member of
  • TLK2 which method comprises (i) screening a patient to determine whether a cancer from which the patient is or may be suffering is one in which the cancer cells thereof contain the drug resistant kinase mutation; and (ii) where it is indicated that the cancer cells do contain the drug resistant mutation, thereafter administering to the patient a compound of the formula (I) or salts, solvates or tautomers thereof.
  • AXL family such as AxI, Mer and Sky, in particular Mer
  • a member of the Mitogen- and stress-activated kinase family such as MSK 1 and MSK2, in particular MSK2
  • MSK 1 and MSK2 a member of the Mitogen- and stress-activated kinase family
  • MSK 1 and MSK2 a member of the Mitogen- and stress-activated kinase family
  • MSK 2 a member of the DAP kinase-related apoptosis-inducing protein kinase family, such as DRAKl and DRAK2, in particular DRAKl
  • a Salt-inducible kinase SIK
  • a member of the CSF-1/PDGF receptor subfamily in particular macrophage colony-stimulating factor 1 receptor (M-CSF-IR or FMS
  • AXL family such as AxI, Mer and Sky, in particular Mer
  • 1/PDGF receptor subfamily in particular macrophage colony-stimulating factor 1 receptor M-CSF-IR or FMS
  • M-CSF-IR macrophage colony-stimulating factor 1 receptor
  • RSKl -4 a member of the 9OkDa ribosomal S6 kinase family such as RSKl -4, in particular RSK2, RSK3, RSK4
  • PKC e.g. PKC gamma
  • FMS e.g. RSK2 or PAK5.
  • a compound of the formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the treatment or prophylaxis of a cancer in a patient who has been screened and has been determined as suffering from, or being at risk of suffering from a cancer which expresses a mutated molecular target which is a mutated form of PKC e.g. PKC gamma, FMS, RSK e.g. RSK2 or PAK5.
  • a method for the diagnosis and treatment of a cancer which expresses a mutated molecular target which is a mutated form of PKC e.g. PKC gamma, FMS, RSK e.g.
  • RSK2 or PAK5 which method comprises (i) screening a patient to determine whether a cancer from which the patient is or may be suffering is one which expresses the said mutated molecular target; and (ii) where it is indicated that the cancer cells do express the said mutated molecular target, thereafter administering to the patient a compound of the formula (I) or salts, solvates or tautomers thereof.
  • DRAKl Salt-inducible kinase
  • SIK Salt-inducible kinase
  • M- CSF-IR or FMS macrophage colony-stimulating factor 1 receptor
  • 9OkDa ribosomal S6 kinase family in particular RSKl -4, in particular RSK2, RSK3, RSK4
  • PKC family e.g. PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ )
  • PKC p21 activated kinase
  • PAK p21 activated kinase
  • PAK Brain specific kinase family
  • TLK Tousled-like kinase
  • a method of modulating a cellular process for example cell division
  • modulating e.g. inhibiting
  • DRAKl Salt-inducible kinase
  • SIK Salt-inducible kinase
  • 9OkDa ribosomal S6 kinase family in particular RSKl -4, in particular RSK2, RSK3, RSK4
  • PKC family e.g. PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ )
  • PKC p21 activated kinase
  • PAK p21 activated kinase
  • PAK Brain specific kinase family
  • BrSK2 Brain specific kinase family
  • TLK Tousled-like kinase
  • a compound of the formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for modulating (e.g. inhibiting) the activity of a kinase selected from AXL family (e.g. Mer), Mitogen- and stress-activated kinase family (e.g. MSK2), DAP kinase-related apoptosis-inducing protein kinase family (e.g. DRAKl),
  • AXL family e.g. Mer
  • Mitogen- and stress-activated kinase family e.g. MSK2
  • DAP kinase-related apoptosis-inducing protein kinase family e.g. DRAKl
  • Salt-inducible kinase (SIK), CSF-1/PDGF receptor subfamily in particular macrophage colony-stimulating factor 1 receptor (M-CSF-IR or FMS), 9OkDa ribosomal S6 kinase family (in particular RSKl -4, in particular RSK2, RSK3, RSK4), PKC family (e.g. PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ )), p21 activated kinase (PAK) family (e.g. PAK5), Brain specific kinase family (e.g. BrSK2) and Tousled- like kinase (TLK) family (e.g. TLK2).
  • SIK Salt-inducible kinase
  • 9OkDa ribosomal S6 kinase family in particular R
  • a compound of the formula (I) or salts, solvates or tautomers thereof, for use in the treatment of pain for use in the treatment of pain.
  • somatic pain somatic pain, visceral pain, acute pain, chronic pain, hyperalgesia, allodynia, post operative pain, pain due to hypersensivity, headache, inflammatory pain (e.g. rheumatic, dental, dys
  • somatic pain e.g. rheumatic, dental, dysmenorrhoea or infection
  • neurological pain e.g. rheumatic, dental, dysmenorrhoea or infection
  • neurogenic pain e.g. caused by tumour metatasis or osteoarthritis
  • skeletal pain e.g. caused by tumour metatasis or osteoarthritis
  • musculoskeletal pain
  • ⁇ The use of a compound of the formula (I) or salts, solvates or tautomers thereof, for the manufacture of a medicament for the treatment of pain.
  • a compound of the formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for the treatment of any one or more of nociception, somatic pain, visceral pain, acute pain, chronic pain, hyperalgesia, allodynia, post operative pain, pain due to hypersensivity, headache, inflammatory pain (e.g. rheumatic, dental, dysmenorrhoea or infection), neurological pain, neurogenic pain, skeletal pain (e.g.caused by tumour metatasis or osteoarthritis), musculoskeletal pain, cancer related pain or vascular pain.
  • somatic pain e.g. rheumatic, dental, dysmenorrhoea or infection
  • neurological pain e.g. rheumatic, dental, dysmenorrhoea or infection
  • neurological pain e.g. rheumatic, dental, dysmenorrhoea or infection
  • neurogenic pain e.g.caused by tumour me
  • a method of treating pain in a patient such as a mammal (e.g. human), which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the reduction or elimination of pain in a patient e.g. a mammal such as a human
  • which method comprises administering to the patient an effective pain-reducing or pain-eliminating amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the treatment of pain including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory and neurogenic pain, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof. It has now been found that compound of the formula (I) have good activity against PKC-mu and/or RSK and/or PAK5 kinases and, on the basis of such activity, the compounds will be useful in the treatment of certain heart conditions. Therefore, the invention also provides:
  • heart disease including coronary artery disease, cardiomyopathy, myocardial contraction, congestive heart failure, cardiac hypertrophy, cardiac remodelling, and heart failure such as congestive heart failure (CHF).
  • CHF congestive heart failure
  • CHF congestive heart failure
  • a compound of the formula (I) or salts, solvates or tautomers thereof, for use in the treatment of cardiomyopathy including Dilated cardiomyopathy, Restrictive cardiomyopathy, Hypertrophic cardiomyopathy, Coronary artery disease; Congenital heart disease; Ischemic (or ischaemic) cardiomyopathy; Hypertensive cardiomyopathy,
  • Valvular cardiomyopathy Inflammatory cardiomyopathy; Cardiomyopathy secondary to a systemic metabolic disease and Alcoholic cardiomyopathy, in particular dilated cardiomyopathy.
  • a compound of the formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for use in the treatment of heart disease and its manifestations, including coronary artery disease, cardiomyopathy, myocardial contraction, congestive heart failure, cardiac hypertrophy, cardiac remodelling, and heart failure such as congestive heart failure (CHF).
  • heart disease including coronary artery disease, cardiomyopathy, myocardial contraction, congestive heart failure, cardiac hypertrophy, cardiac remodelling, and heart failure such as congestive heart failure (CHF).
  • CHF congestive heart failure
  • a compound of the formula (I) or salts, solvates or tautomers thereof for the manufacture of a medicament for use in the treatment of cardiomyopathy including Dilated cardiomyopathy, Restrictive cardiomyopathy, Hypertrophic cardiomyopathy, Coronary artery disease; Congenital heart disease; Ischemic (or ischaemic) cardiomyopathy; Hypertensive cardiomyopathy, Valvular cardiomyopathy; Inflammatory cardiomyopathy; Cardiomyopathy secondary to a systemic metabolic disease and Alcoholic cardiomyopathy, in particular dilated cardiomyopathy.
  • cardiomyopathy including Dilated cardiomyopathy, Restrictive cardiomyopathy, Hypertrophic cardiomyopathy, Coronary artery disease; Congenital heart disease; Ischemic (or ischaemic) cardiomyopathy; Hypertensive cardiomyopathy, Valvular cardiomyopathy; Inflammatory cardiomyopathy; Cardiomyopathy secondary to a systemic metabolic disease and Alcoholic cardiomyopathy, in particular dilated cardiomyopathy.
  • a method for the treatment of heart disease and its manifestations, including coronary artery disease, cardiomyopathy, myocardial contraction, congestive heart failure, cardiac hypertrophy, cardiac remodelling, and heart failure such as congestive heart failure (CHF) in a patient comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • CHF congestive heart failure
  • a method for the treatment of any one or more of coronary artery disease, cardiomyopathy, myocardial contraction, congestive heart failure, cardiac hypertrophy, cardiac remodelling, and heart failure such as congestive heart failure (CHF), in a patient comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • CHF congestive heart failure
  • a method for the treatment of cardiomyopathy including Dilated cardiomyopathy, Restrictive cardiomyopathy, Hypertrophic cardiomyopathy, Coronary artery disease; Congenital heart disease; Ischemic (or ischaemic) cardiomyopathy; Hypertensive cardiomyopathy, Valvular cardiomyopathy; Inflammatory cardiomyopathy;
  • Cardiomyopathy secondary to a systemic metabolic disease and Alcoholic cardiomyopathy, in particular dilated cardiomyopathy, in a patient which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the treatment of congestive heart failure in a patient which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • Paget's disease, and other diseases in which bone resorption mediates morbidity including prosthesis failure, osteolytic sarcoma, and tumor metastasis to bone; osteolytic disease associated with bone metastasis and other bone diseases in patients.
  • a method of treating a bone disorder in a patient in need thereof comprises administering to the patient a therapeutically effective antiosteolytic amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • a method for the treatment of hypercalcemia, osteoarthritis, or sympomatic treatment of bone metastasis in a patient comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) and salts, solvates or tautomers thereof.
  • a method for the treatment of condition that results in excessive bone formation in a patient comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or salts, solvates or tautomers thereof.
  • Streptococcus diogenes Streptococcus pneumoniae, Streptococcus mutans, Streptococcus gordonii, Streptococcus pyogenes, Enterococcus faecium, Clostridium perfringens, Clostridium difficile, Clostridium botulinum, Bacillus anthracis, Listeria monocytogenes , Mycobacterium tuberculosis, Mycobacterium avium or Mycobacterium leprae infection.
  • a compound of Formula (I) or salts, solvates or tautomers thereof, for use in the prophylaxis or treatment of a Staphylococcus aureus infection A compound of Formula (I) or salts, solvates or tautomers thereof, for use in the prophylaxis or treatment of a drug resistant Staphylococcus aureus infection (e.g. MRSA)
  • a compound of Formula (I) or salts, solvates or tautomers thereof, for use in the prophylaxis or treatment of a Gram-negative bacterial infection for use in the prophylaxis or treatment of an Escherichia spp., Salmonella spp., Pseudomonas spp., Helicobacter app., Legionella spp., Moraxella spp., Neisseria spp., Hemophilus spp., Klebsiella spp., Actinobacteria spp., Proteus, Shigella or Enterobacter spp. infection.
  • Neisseria meningitidis Neisseria gonorrhoeae, Haemophilus influenzae, Haemophilus ducreyi, Enterobactericeae pneumococci, Enterobacter faecalis, Pseudomonas aeruginosa, Pseudomonas pseudomallei, Proteus mirabilis or Shigella dysenteriae infection.
  • a compound of Formula (I) or salts, solvates or tautomers thereof for use in the prophylaxis or treatment of a disease state or condition caused by Gram-positive bacteria.
  • Enterobacter faecalis Enterobacter faecalis, Pseudomonas aeruginosa, Pseudomonas pseudomallei, Proteus mirabilis or Shigella dysenteriae, or drug resistant strains thereof.
  • a compound of the formula (I) or salts, solvates or tautomers thereof, for use in the treatment or prophylaxis of infection such as streptococcal infection including strep throat, impetigo, erysipelas, scarlet fever, infections from surgical procedures, hospital acquired lung infection, skin infection, diabetic foot infections, soft tissue infection, bone infection, joint infection, ear infection including otitis media, eye infection including conjunctivitis and blepharoconjunctivitis, urinary tract infection including catheter infection, venous catheter insertions, prosthesis infection, respiratory tract infection including upper respiratory tract infection, lower respiratory tract infection; tonsillitis; meningitis; cellulitis; diverticulitis; endocarditis; osteomyelitis; pseudomembranous colitis; bronchitis e.g.
  • streptococcal infection including strep throat, impetigo, erysipelas, scarlet fever, infections from surgical procedures, hospital acquired lung infection, skin infection,
  • tracheobronchitis sinusitis; laryngitis; pneumonia including community acquired pneumonia, bronchopneumonia and legionellosis (Legionnaires' disease); sepsis; septic arthritis; cellulitis; osteomyelitis; epiglottitis; exacerbation of existing chronic obstructive pulmonary disease (COPD); botulism; food poisoning; gonorrhoea; septicemia including meningococcal septicaemia; typhoid fever; paratyphoid fever; foodborne illness including food poisoning; toxic shock syndrome (TSS); gastrointestinal diseases including diarrhoea, dysentery- like conditions; ankylosing spondylitis; scalded skin syndrome; peptic ulcers; chronic gastritis; duodenitis; gas gangrene; enterotoxemia; tetanus; anthrax; listeriosis; necrotizing fascitis; tuberculosis; bacter
  • an infection such as urinary tract infection, or streptococcal infection including strep throat, impetigo, erysipelas, scarlet fever; tonsillitis; meningitis; cellulitis; diverticulitis; endo
  • tracheobronchitis sinusitis; laryngitis; pneumonia including bronchopneumonia and legionellosis (Legionnaires' disease); sepsis; cellulitis; osteomyelitis; epiglottitis; exacerbation of existing chronic obstructive pulmonary disease (COPD); gonorrhoea; bacterial meningitis; septicemia including meningococcal septicaemia; typhoid fever; paratyphoid fever; foodborne illness; gastrointestinal diseases including diarrhoea, dysentery-like conditions; ankylosing spondylitis; peptic ulcers; chronic gastritis; duodenitis; bacteremia, chancroid, shigellosis or dysentery.
  • COPD chronic obstructive pulmonary disease
  • a compound of the formula (I) or salts, solvates or tautomers thereof, for use in the treatment or prophylaxis of an infection such as infection from surgical procedures, soft tissue infection, joint infection, ear infection including otitis media, eye infection including conjunctivitis and blepharoconjunctivitis, urinary tract infection including venous catheter insertions, respiratory tract infection including upper respiratory tract infection, and lower respiratory tract infection; bronchitis e.g. tracheobronchitis; sinusitis; laryngitis; pneumonia including bronchopneumonia and legionellosis
  • an infection such as infection from surgical procedures, soft tissue infection, joint infection, ear infection including otitis media, eye infection including conjunctivitis and blepharoconjunctivitis, urinary tract infection including venous catheter insertions, respiratory tract infection including upper respiratory tract infection, and lower respiratory tract infection; bronchitis e.g. tracheobronchitis; sinusitis; la
  • S. aureus methicillin- susceptible and -resistant strains
  • Streptococcus pneumoniae including multidrug- resistant strains (MDRSP)
  • complicated skin and skin structure infections including diabetic foot infections, without concomitant osteomyelitis, caused by S. aureus (methicillin- susceptible and -resistant strains), Strepto
  • skin infections in particular pimples, impetigo, boils, cellulitis, folliculitis, furuncles, carbuncles
  • endocarditis osteomyelitis
  • septic arthritis pneumonia
  • meningitis meningitis
  • TSS toxic shock syndrome
  • SSSSSS scalded skin syndrome
  • a compound of the formula (I) or salts, solvates or tautomers thereof, for use in the treatment or prophylaxis of skin infections in particular pimples, impetigo, boils, cellulitis, folliculitis, furuncles, carbuncles), endocarditis, osteomyelitis, septic arthritis, pneumonia, meningitis, toxic shock syndrome (TSS), food poisoning or scalded skin syndrome (Staphylococcal scalded skin syndrome or SSSS).
  • indwelling medical devices e.g. prosthetic joints and catheters.
  • a method for the diagnosis and treatment of a disease state or condition caused by bacteria comprises (i) screening a patient to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound having antibacterial activity; and (ii) where it is indicated that the disease or condition from which the patient is thus susceptible, thereafter administering to the patient a compound of the formula (I) or salt, solvates and tautomers thereof.
  • bacteria e.g. a Gram-positive or Gram-negative bacteria
  • a method for the diagnosis and treatment of a disease state or condition caused by bacteria comprises (i) screening a patient to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound having activity against bacteria (e.g. a Gram-positive or Gram-negative bacteria); and (ii) where it is indicated that the disease or condition from which the patient is thus susceptible, thereafter administering to the patient a compound of the formula (I) or salt, solvates and tautomers thereof.
  • bacteria e.g. Gram-positive and/or Gram-negative bacteria
  • a method for the prophylaxis of a disease state or condition as defined herein which method comprises administering to a patient in need thereof, an effective amount of 1- cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]- urea or salts, solvates or tautomers thereof.
  • a method for the prophylaxis of a disease state or condition as defined herein which method comprises administering to a patient in need thereof, an effective amount of 1- cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]- urea or salts, solvates or tautomers thereof.
  • ⁇ A method for the prophylaxis of a disease state or condition as defined herein, which method comprises administering to a patient in need thereof, an effective amount of 1- cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]- urea lactate or citrate salt (in particular Lactate salt) including crystalline forms thereof.
  • ⁇ A compound of the formula (I) and salts, solvates and tautomers thereof, as for use in alleviating or reducing the incidence of a disease state or condition as defined herein.
  • a method for alleviating or reducing the incidence of a disease state or condition as defined herein comprises administering to a patient (e.g. a patient in need thereof) a compound (e.g. in a therapeutically effective amount) of the formula (I) and salts, solvates and tautomers thereof.
  • a method for alleviating or reducing the incidence of a disease state or condition as defined herein comprises administering to a patient (e.g. a patient in need thereof) a compound (e.g. in a therapeutically effective amount) of the formula (I) or salts, solvates and tautomers thereof.
  • the salt is the lactate or citrate salt or mixtures thereof, in particular the lactate salt.
  • the salt is in a crystalline form.
  • the crystalline form is as described herein and in WO 2006/070195.
  • a lactate (particularly the L-lactate) or citrate salt of a compound of the formula (I) for the manufacture of a medicament for the prophylaxis or treatment of a disease state or condition described herein.
  • treatment and the related terms “treat” and “treating” refer to both prophylactic or preventative treatment as well as curative or palliative treatment of the condition (e.g. pain or infection).
  • condition e.g. pain or infection
  • treatment also cover both complete and partial reduction or prevention of the condition.
  • the term encompasses inhibiting or killing bacteria.
  • the compound of the invention may prevent an existing condition from worsening, assist in the management of the condition or reduce or even eliminate the condition.
  • the compound may prevent any condition from developing or it may lessen the extent of condition that may develop.
  • the term means treatment only (i.e. excludes prophylaxis).
  • modulation As used herein, the term "modulation", as applied to the activity of a kinase, is intended to define a change in the level of biological activity of the protein kinase. Thus, modulation encompasses physiological changes which effect an increase or decrease in the relevant protein kinase activity. In the latter case, the modulation may be described as "inhibition”.
  • the modulation may arise directly or indirectly, and may be mediated by any mechanism and at any physiological level, including for example at the level of gene expression (including for example transcription, translation and/or post-translational modification), at the level of expression of genes encoding regulatory elements which act directly or indirectly on the levels of kinase activity.
  • modulation may imply elevated/suppressed expression or over- or under-expression of a kinase, including gene amplification (i.e. multiple gene copies) and/or increased or decreased expression by a transcriptional effect, as well as hyper- (or hypo-) activity and (de)activation of the protein kinase(s) (including (de)activation) by mutation(s).
  • gene amplification i.e. multiple gene copies
  • hyper- (or hypo-) activity i.e. multiple gene copies
  • de deactivation of the protein kinase(s) (including (de)activation) by mutation(s).
  • modulated modulating
  • modulate are to be interpreted accordingly.
  • kinase activity (and in particular aberrant levels of kinase activity, e.g.
  • kinase over-expression need not necessarily be the proximal cause of the disease, state or condition: rather, it is contemplated that the kinase mediated diseases, states or conditions include those having multifactorial aetiologies and complex progressions in which the kinase in question is only partially involved.
  • the role played by the kinase may be direct or indirect and may be necessary and/or sufficient for the operation of the treatment, prophylaxis or outcome of the intervention.
  • a disease state or condition mediated by a kinase includes the development of resistance to any particular cancer drug or treatment.
  • upregulation of a kinase is defined as including elevated expression or over-expression of the kinase, including gene amplification (i.e. multiple gene copies) and increased expression by a transcriptional effect, and hyperactivity and activation of the kinase, including activation by mutations and stabilisation.
  • overexpression means elevated levels of a kinase in the cell compared to normal levels. This can be due to gene amplification or upregulation of the pathway comprising the gene, or due to elevated levels of the protein in the cell due to stabilisation of the protein or reduction in the rate of destruction of the protein.
  • the term "caused by”, as used e.g. in conjunction with a bacteria as described herein (and applied for example to various physiological processes, diseases, states, conditions, therapies, treatments or interventions) is intended to operate limitatively so that the various processes, diseases, states, conditions, treatments and interventions to which the term is applied are those in which the bacteria plays a biological role.
  • the biological role played by the bacteria may be direct or indirect and may be necessary and/or sufficient for the manifestation of the symptoms of the disease, state or condition (or its aetiology or progression).
  • bacterial activity need not necessarily be the proximal cause of the disease, state or condition: rather, it is contemplated that the diseases, states or conditions caused by the bacteria include those contributed to by bacteria, and those having multifactorial aetiologies and complex progressions in which the bacteria in question is only partially involved or to which the bacteria only contributes to the diseases state or condition.
  • the role played by the bacteria may be direct or indirect and may be necessary and/or sufficient for the operation of the treatment, prophylaxis or outcome of the intervention.
  • a disease state or condition mediated by a bacterium includes the development of resistance to any particular drug or treatment.
  • references to compound of the invention include the compound of Formula (I) and/or salts (e.g. lactate or citrate salts) thereof.
  • references to the prophylaxis or treatment of a disease state or condition such as cancer include within their scope alleviating or reducing the incidence of that disease e.g. cancer.
  • the hydrogen atom may not be explicitly shown. However, in such cases, it is to be understood that the hydrogen atom is present.
  • a hydrogen atom is not explicitly shown at the 1 -position of the the pyrazole ring - i.e. the pyrazole ring appears thus:
  • the compound of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea includes its salts, solvates, and tautomers. References to salts include crystalline forms thereof, in particular as described herein. In another embodiment the compound of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea includes its salts and crystalline forms thereof.
  • the compound of the formula (I) may be referred to in this application by its chemical name, 1- cyclopropyl-3 - [3 -(5-morpholin-4-ylmethyl- 1 H-benzoimidazol-2-yl)- 1 H-pyrazol-4-yl] -urea, or, for convenience, as "the compound I", or "the compound of formula (I)".
  • Each of these synonyms refers to the compound shown in formula (I) above and having the chemical name 1- cyclopropyl-S-fS ⁇ S-morpholin ⁇ -ylmethyl-lH-benzoimidazol ⁇ -y ⁇ -lH-pyrazol ⁇ -yll-urea.
  • references to the compound l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol- 2-yl)-l H-pyrazol-4-yl] -urea free base and its acid addition salts include within their scope all solvates, tautomers and isotopes thereof and, where the context admits, N-oxides, other ionic forms and prodrugs. Therefore a reference to the alternative tautomer of formula (I), 1- cyclopropyl-3-[3-(6-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea is to be understood to refer to compound (I).
  • the compound for the new therapeutic uses of the invention is l-cyclopropyl-3-[3-(5- morpholin-4-ylmethyl- 1 H-benzoimidazol-2-yl)- 1 H-pyrazol-4-yl] -urea.
  • the compound for the new therapeutic uses of the invention is 1- cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea or salts (e.g. the lactate or citrate salts or mixtures thereof), solvates and tautomers thereof.
  • the compound for the new therapeutic uses of the invention is 1- cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea and salts (e.g. the lactate or citrate salts or mixtures thereof), solvates and tautomers thereof.
  • the invention further provides therapeutic uses of the compound l-cyclopropyl-3-[3-(5- morpholin-4-ylmethyl-l H-benzoimidazol-2-yl)- 1 H-pyrazol-4-yl] -urea and its salts.
  • the invention provides inter alia the lactate and citrate salts of the compound l-cyclopropyl-3- [3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea and crystalline forms thereof for the new uses defined herein.
  • the invention provides for the novel uses described herein, a salt of 1- cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea selected from the lactate, citrate and mixtures thereof.
  • the acid addition salt of formula (I) may be selected from salts formed with a wide variety of acids, both inorganic and organic.
  • acid addition salts include salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), aspartic (e.g. L-aspartic), benzenesulphonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric (e.g.
  • L-glutamic L-glutamic
  • ⁇ -oxoglutaric glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, isobutyric
  • lactic e.g. (+)-L-lactic and , (-)-D-lactic
  • lactobionic laurylsulphonic, maleic, malic, (-)-L-malic, malonic, ( ⁇ )-DL-mandelic, methanesulphonic, mucic, naphthalenesulphonic (e.g.
  • naphthalene-2-sulphonic naphthalene-2-sulphonic
  • naphthalene- 1,5-disulphonic 1- hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulphuric, tannic, tartaric (e.g. (+)-L-tartaric), thiocyanic, toluenesulphonic (e.g. />-toluenesulphonic), undecylenic and valeric and xinafoic acids, as well as acylated amino acids and cation exchange resins.
  • salicylic 4-amino-salicylic, sebacic, stearic, succinic, sulph
  • salts consist of salts formed from hydrochloric, hydriodic, phosphoric, nitric, sulphuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulphonic, toluenesulphonic, methanesulphonic, ethanesulphonic, naphthalenesulphonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids.
  • salts formed from hydrochloric, acetic, adipic, L-aspartic and D- or L-lactic acids.
  • Another sub-group of salts consists of the acetate, mesylate, ethanesulphonate, D- or L-lactate, adipate, D-glucuronate, D-gluconate and hydrochloride salts.
  • the preferred acid addition salts are mesylate, ethanesulphonate, D- or L-lactate, and hydrochloride salts.
  • the acid addition salt is the DL-lactate, in particular the L-lactate or D-lactate, preferably the L-lactate.
  • the salt of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea may be the acetate, mesylate, ethanesulphonate, DL-lactate, adipate, D-glucuronate, D-gluconate or hydrochloride salt.
  • the free base or salt of the compound of Formula (I) is selected from the L-lactate salt, free base dehydrate, esylate salt, free base and hydrochloride salt.
  • the salt of the compound of Formula (I) is selected from the lactate and citrate salts and mixtures thereof, and more preferably is selected from the L- lactate and citrate salts and mixtures thereof, with the L-lactate salt being particularly preferred.
  • Particular and preferred embodiments of the invention relating to the L-lactate and citrate salts of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea are set out and described in more detail below.
  • the compound of Formula (I) is a free base.
  • the salts of the present invention can be synthesized from the parent compound l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor),
  • such salts can be prepared by reacting the parent compound l-cyclopropyl-3-[3-(5- morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea with the appropriate acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • an acid addition salt of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea such as the the lactate (e.g. L-lactate) and citrate salts
  • lactate e.g. L-lactate
  • citrate salts can be formed by preparing a solution of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl- lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea free base in a solvent (typically an organic solvent) or mixture of solvents, and treating the solution with an acid to form a precipitate of the acid addition salt.
  • a solvent typically an organic solvent
  • the acid may be added as a solution in a solvent which is miscible with the solvent in which the free base is dissolved.
  • the solvent in which the free base is initially dissolved may be one in which the acid addition salt thereof is insoluble.
  • the solvent in which the free base is initially dissolved may be one in which the acid addition salt is at least partially soluble, a different solvent in which the acid addition salt is less soluble subsequently being added such that the salt precipitates out of solution.
  • an acid addition salt such as the lactate (e.g. L-lactate) and citrate salts
  • a solvent comprising a volatile acid and optionally a co-solvent
  • a solution of the acid addition salt with the volatile acid and the resulting solution is then concentrated or evaporated to isolate the salt.
  • an acid addition salt that can be made in this way is the acetate salt.
  • the salt is typically precipitated from the organic solvent as it is formed and hence can be isolated by separation of the solid from the solution, e.g. by filtration.
  • One salt form of the invention can be converted to the free base and optionally to another salt form by methods well known to the skilled person.
  • the free base can be formed by passing the salt solution through a column containing an amine stationary phase (e.g. a Strata-NH 2 column).
  • a solution of the salt in water can be treated with sodium bicarbonate to decompose the salt and precipitate out the free base.
  • the free base may then be combined with another acid by one of the methods described above or elsewhere herein.
  • the preferred salts such as acid addition salts e.g. the lactate (e.g. L-lactate) and citrate salts, have a number of advantages.
  • the salts will enjoy one or more of the following advantages in that they:
  • • may have improved anti-cancer activity; and • may have an improved therapeutic index.
  • the lactate (e.g. L-lactate) salt of the invention is particularly advantageous as it has good solubility in water, and gives better solubility in buffer systems.
  • Preferred salts for use in the preparation of liquid (e.g. aqueous) pharmaceutical compositions are acid addition salts (such as the lactates) having a solubility in a given liquid carrier (e.g. water) of greater than 1 mg/ml, typically greater than 5 mg/ml of the liquid carrier (e.g. water), more typically greater than 15 mg/ml, more typically greater than 20 mg/ml and preferably greater than 25 mg/ml.
  • Aqueous solutions of the salts represent a further aspect of the invention.
  • Such solutions may be buffered or unbuffered.
  • the salts will typically dissociate to form l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea in protonated form together with one or more counter ions.
  • the invention also provides an aqueous solution of 1- cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea in protonated form together with one or more counter ions and optionally one or more further counter ions (for example counter ions derived from other salts such as sodium chloride or buffering agents).
  • salts of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol- 4-yl]-urea are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. ScL, Vol. 66, pp. 1-19. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms therefore also form part of the invention.
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm.
  • the benzoimidazole group may take either of the following two tautomeric forms A and B.
  • the general formula (I) illustrates forms A but the formula is to be taken as embracing all four tautomeric forms.
  • the pyrazole ring may also exhibit tautomerism and can exist in the two tautomeric forms C and D below.
  • references to 1 -cyclopropyl-3 - [3 -(5-morpholin-4-ylmethyl- 1 H-benzoimidazol-2-yl)- 1 H- pyrazol-4-yl]-urea and its salts also include variants with one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element.
  • a reference to hydrogen includes within its scope 1 H, 2 H (D), and 3 H (T).
  • references to carbon and oxygen include within their scope respectively 12 C, 13 C and 14 C and 16 O and 18 O.
  • the isotopes may be radioactive or non-radioactive.
  • the compounds contain no radioactive isotopes. Such compounds are preferred for therapeutic use.
  • the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in a diagnostic context.
  • references to l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea and its salts are any polymorphic forms, solvates (e.g. hydrates), complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) thereof.
  • solvates for example with water (i.e., hydrates) or common organic solvents.
  • solvate means a physical association of the compounds of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • solvate is intended to encompass both solution-phase and isolatable solvates.
  • Non- limiting examples of suitable solvates include compounds on the invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine and the like.
  • the compounds of the invention may exert their biological effects whilst they are in solution.
  • Solvates are well known in pharmaceutical chemistry. They can be important to the processes for the preparation of a substance (e.g. in relation to their purification, the storage of the substance (e.g. its stability) and the ease of handling of the substance and are often formed as part of the isolation or purification stages of a chemical synthesis.
  • a person skilled in the art can determine by means of standard and long used techniques whether a hydrate or other solvate has formed by the isolation conditions or purification conditions used to prepare a given compound. Examples of such techniques include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (e.g.
  • the skilled person can deliberately form a solvate using crystallisation conditions that include an amount of the solvent required for the particular solvate. Thereafter the standard methods described above, can be used to establish whether solvates had formed.
  • the compounds of the present invention may have one or more polymorph or amorphous crystalline forms and as such are intended to be included in the scope of the invention.
  • preferred salts of Compound (I) are the acid addition salts formed with lactic acid (more preferably L-lactic acid), citric acid or mixtures thereof.
  • lactic acid more preferably L-lactic acid
  • citric acid or mixtures thereof.
  • the salts formed from L-lactic acid, and citric acid may be referred to herein as the L-lactate salts and citrate salts respectively.
  • the salt is the L-lactate or D-lactate, preferably L-lactate.
  • the salt is a salt formed with citric acid.
  • the salts are a mixture of the L-lactate salts and citrate salts.
  • the lactate (particularly the L-lactate) or citrate salts of the invention can be crystalline or amorphous or a mixture thereof.
  • the lactate (particularly the L-lactate) or citrate salts are amorphous.
  • amorphous solid In an amorphous solid, the three dimensional structure that normally exists in a crystalline form does not exist and the positions of the molecules relative to one another in the amorphous form are essentially random, see for example Hancock et al. J. Pharm. ScL (1997), 86, 1).
  • the lactate (particularly the L-lactate) or citrate salts are substantially crystalline i.e. they may be from 50% to 100% crystalline, and more particularly they may be at least 50% crystalline, or at least 60% crystalline, or at least 70% crystalline, or at least 80% crystalline, or at least 90% crystalline, or at least 95% crystalline, or at least 98% crystalline, or at least 99% crystalline, or at least 99.5% crystalline, or at least 99.9% crystalline, for example 100% crystalline.
  • the lactate or citrate salts are selected from the group consisting of lactate (particularly the L-lactate) or citrate salts that are from 50% to 100% crystalline, for example at least 50% crystalline, at least 60% crystalline, at least 70% crystalline, at least 80% crystalline, at least 90% crystalline, at least 95% crystalline, at least 98% crystalline, at least 99% crystalline, at least 99.5% crystalline, and at least 99.9% crystalline, for example 100% crystalline.
  • the lactate (particularly the L-lactate) or citrate salts may be those (or may be selected from the group consisting of those) that are 95% to 100 % crystalline, for example at least 98% crystalline, or at least 99% crystalline, or at least 99.5% crystalline, or at least 99.6% crystalline or at least 99.7% crystalline or at least 99.8% crystalline or at least 99.9% crystalline, for example 100% crystalline.
  • a substantially crystalline salt is a crystalline salt formed with L-lactic acid.
  • a substantially crystalline salt is a crystalline salt formed with citric acid.
  • the salts of the invention in the solid state, can be solvated (e.g. hydrated) or non-solvated (e.g. anhydrous).
  • the salts are non-solvated (e.g. anhydrous).
  • a further example of a non-solvated salt is the crystalline salt formed with lactic acid (particularly L-lactic acid) as defined herein.
  • the crystalline form of the salt of Formula (I) is selected from L-lactate salt and citrate salt, in particular the L-lactate salt.
  • anhydrous does not exclude the possibility of the presence of some water on or in the salt (e.g. a crystal of the salt). For example, there may be some water present on the surface of the salt (e.g. salt crystal), or minor amounts within the body of the salt (e.g. crystal).
  • an anhydrous form contains fewer than 0.4 molecules of water per molecule of compound, and more preferably contains fewer than 0.1 molecules of water per molecule of compound, for example 0 molecules of water.
  • the lactate (particularly the L-lactate) or citrate salts are solvated.
  • the salts can contain, for example, up to three molecules of water of crystallisation, more usually up to two molecules of water, e.g. one molecule of water or two molecules of water.
  • Non-stoichiometric hydrates may also be formed in which the number of molecules of water present is less than one or is otherwise a non- integer. For example, where there is less than one molecule of water present, there may be for example 0.4, or 0.5, or 0.6, or 0.7, or 0.8, or 0.9 molecules of water present per molecule of compound.
  • solvates include alcoholates such as ethanolates and isopropanolates.
  • the lactic acid salt (particularly the L-lactate) is solvated for example with water and/or ethanol.
  • lactate (particularly the L-lactate) or citrate salts of the present invention can be synthesized from the parent compound l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.
  • such salts can be prepared by reacting the parent compound l-cyclopropyl-3-[3-(5- morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea with the appropriate acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • a method of preparing a lactate (particularly the L-lactate) or citrate salt of l-cyclopropyl-3- [3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea comprises forming a solution of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)- lH-pyrazol-4-yl]-urea free base in a solvent (typically an organic solvent) or mixture of solvents, and treating the solution with an acid to form a precipitate of the salt.
  • a solvent typically an organic solvent
  • the acid may be added as a solution in a solvent which is miscible with the solvent in which the free base is dissolved.
  • the solvent in which the free base is initially dissolved may be one in which the salt thereof is insoluble.
  • the solvent in which the free base is initially dissolved may be one in which the salt is at least partially soluble, a different solvent in which the salt is less soluble subsequently being added such that the salt precipitates out of solution.
  • l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea is dissolved in a solvent comprising a volatile acid and optionally a co-solvent, thereby to form a solution of the salt with the volatile acid, and the resulting solution is then concentrated or evaporated to isolate the salt.
  • a method of forming a lactate (particularly the L-lactate) or citrate salt of l-cyclopropyl-3-[3- (5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea as defined herein comprises treating a compound of the formula (I): with an organic or inorganic acid as defined herein in an organic solvent, and optionally isolating the salt thus formed.
  • the lactate (particularly the L-lactate) or citrate salt is typically precipitated from the organic solvent as it is formed and hence can be isolated by separation of the solid from the solution, e.g. by filtration.
  • One salt form of the invention can be converted to the free base and optionally to another salt form by methods well known to the skilled person.
  • the free base can be formed by passing the salt solution through a column containing an amine stationary phase (e.g. a Strata-NH 2 column).
  • a solution of the salt in water can be treated with sodium bicarbonate to decompose the salt and precipitate out the free base.
  • the free base may then be combined with another acid by one of the methods described above or elsewhere herein.
  • lactate particularly the L-lactate
  • citrate salts have a number of advantages over the corresponding free base.
  • the salts will enjoy one or more of the following advantages over the free base in that they:
  • the crystalline lactate salt (particularly the L-lactate) of the invention is particularly advantageous as it is:
  • the term 'stable' or 'stability' as used herein includes chemical stability and solid state (physical) stability.
  • the term 'chemical stability' means that the compound can be stored in an isolated form, or in the form of a formulation in which it is provided in admixture with for example, pharmaceutically acceptable carriers, diluents or adjuvants as described herein, under normal storage conditions, with little or no chemical degradation or decomposition.
  • 'Solid- state stability' means the compound can be stored in an isolated solid form, or the form of a solid formulation in which it is provided in admixture with, for example, pharmaceutically acceptable carriers, diluents or adjuvants as described herein, under normal storage conditions, with little or no solid-state transformation (e.g. hydration, dehydration, solvatisation, desolvatisation, crystallisation, recrystallisation or solid-state phase transition).
  • Preferred salts for use in the preparation of liquid (e.g. aqueous) pharmaceutical compositions are the salts of the invention (i.e. the lactate or citrate or mixtures thereof as defined herein) having a solubility in a given liquid carrier (e.g. water or buffered systems) of greater than 1 mg/ml, typically greater than 5 mg/ml of the liquid carrier (e.g. water), more typically greater than 15 mg/ml, more typically greater than 20 mg/ml and preferably greater than 25 mg/ml.
  • a given liquid carrier e.g. water or buffered systems
  • a pharmaceutical composition comprising an aqueous solution containing the lactate salt (particularly the L- lactate) or citrate salt or mixtures thereof of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea (such as) in a concentration of greater than 1 mg/ml, typically greater than 5 mg/ml of the liquid carrier (e.g. water or buffered systems), more typically greater than 15 mg/ml, more typically greater than 20 mg/ml and preferably greater than 25 mg/ml.
  • the liquid carrier e.g. water or buffered systems
  • the pharmaceutical composition comprises an aqueous solution containing the L-lactate salt of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea in a concentration of greater than 1 mg/ml, typically greater than 5 mg/ml of the liquid carrier (e.g. water), more typically greater than 15 mg/ml, typically greater than 20 mg/ml and preferably greater than 25 mg/ml.
  • the liquid carrier e.g. water
  • the invention provides, for the novel uses as defined herein, an aqueous solution of the lactate salt (particularly the L-lactate) or citrate salt or mixtures thereof of 1 - cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea, wherein the aqueous solution has a pH of 2 to 6, for example 2 to 5, and more particularly 4 to 6 such as 4 to 5.
  • the salt may be any of the salts described herein but, in one preferred embodiment is the L-lactate salt. In one preferred embodiment, the salt is a mixture of L-lactate and citrate salts.
  • the invention also provides, for the novel uses as defined herein, an aqueous solution of 1 - cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea in protonated form together with one or more counter ions and optionally one or more further counter ions.
  • one of the counter ions is selected from lactate and citrate.
  • one of the counter ions is from the formulation buffer as described herein such as citrate.
  • there may be one or more further counter ions such as a chloride ion (e.g. from saline).
  • the invention therefore provides, for the novel uses as defined herein, an aqueous solution of 1 - cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea in protonated form together with one or more counter ions selected from L-lactate and citrate, and optionally one or more further counter ions such as a chloride ion.
  • the aqueous solution of 1 - cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea in protonated form will potentially contain a mixture of counter ions for example a mixture of L- lactate and citrate counter ions and optionally one or more further counter ions such as a chloride ion.
  • the invention therefore provides, for the novel uses as defined herein, an aqueous solution of 1 - cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea in protonated form together with one or more counter ions selected from L-lactate and citrate and optionally one or more further counter ions such as a chloride ion, and a mixture thereof.
  • the invention also provides, for the novel uses as defined herein, an aqueous solution of 1 - cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea in protonated form together with one or more counter ions and optionally one or more IV excipients for dilution to achieve isotonic formulation.
  • one of the counter ions is selected from L-lactate and citrate.
  • one of the counter ions is from the formulation buffer as described herein such as citrate.
  • the invention therefore provides an aqueous solution of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea in protonated form together with one or more counter ions selected from L-lactate and citrate, and optionally one or more IV excipients such as dextrose.
  • the aqueous solution of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea in protonated form will potentially contain a mixture of counter ions for example a mixture of lactate and citrate counter ions and optionally one or more further IV excipients such as a dextrose.
  • the invention therefore provides an aqueous solution of l-cyclopropyl-3-[3-(5- morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea in protonated form together with one or more counter ions selected from L-lactate and citrate and optionally one or more further IV excipients such as a dextrose, and a mixture thereof.
  • the aqueous solutions can be formed inter alia by dissolving a lactate salt in a solution of citrate ions (e.g a citrate buffer) or by dissolving a citrate salt in a solution of lactate ions.
  • the lactate and citrate ions may be present in the solution in a lactate:citrate ratio of from 10:1 or less, for example 10:1 to 1 :10, more preferably less then 8:1, or less than 7:1, or less than 6:1, or less than 5:1 or less than 4:1 or less than 3:1 or less than 2:1 or less than 1 :1, more particularly from 1 : 1 to 1 : 10.
  • the lactate and citrate ions are present in the solution in a lactate: citrate ratio of from 1 :1 to 1 :10, for example 1 :1 to 1 :8, or 1 :1 to 1 :7 or 1 :1 to 1 :6 or 1 :1 to 1 :5, e.g. approximately 1 :4.4.
  • aqueous solutions of the salts may be buffered or unbuffered but in one embodiment are buffered.
  • a pharmaceutical composition comprising a lyophilised formulation containing the lactate salt or citrate salt or mixtures thereof of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea, wherein the formulation has a pH of 2 to 6, for example 2 to 5, and more particularly 4 to 6 such as 4 to 5.
  • the salt is the L- lactate.
  • the invention also provides, for the novel uses of the invention as defined herein, a lyophilised formulation of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH- pyrazol-4-yl]-urea in protonated form together with one or more counter ions.
  • one of the counter ions is L-lactate.
  • one of the counter ions is from the formulation buffer as described herein such as citrate.
  • the invention therefore provides, for the novel uses of the invention as defined herein, a lyophilised formulation of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2- yl)-lH-pyrazol-4-yl]-urea in protonated form together with one or more counter ions selected from L- lactate and citrate.
  • the aqueous solution of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH- pyrazol-4-yl]-urea in protonated form will potentially contain a mixture of counter ions for example a mixture of L-lactate and citrate counter ions.
  • the invention therefore provides, for the novel uses of the invention as defined herein, a lyophilised formulation of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2- yl)-lH-pyrazol-4-yl]-urea in protonated form together with one or more counter ions selected from lactate, citrate and a mixture thereof.
  • the salt is a L-lactate and the buffer salt is citrate.
  • the lactate and citrate ions are present in the lyophilised formulation in a lactate :citrate ratio of from 10:1 or less, for example 10:1 to 1 :10, more preferably less then 8:1, or less than 7:1, or less than 6:1, or less than 5:1 or less than 4:1 or less than 3:1 or less than 2:1 or less than 1 :1, more particularly from 1 : 1 to 1 : 10, for example 1 :1 to 1 :8, or 1 : 1 to 1 :7 or 1 : 1 to 1 :6 or 1 :1 to 1 :5, e.g. approximately 1 :4.4.
  • the lyophilised formulation of the salts may be buffered or unbuffered but in one embodiment are buffered.
  • a preferred buffer is a buffer formed from citric acid and corrected with NaOH or HCl to the correct pH, for example at a solution pH of approximately 4.5. At this pH and in the citrate buffer, the free base has a solubility of about 80 mg/ml respectively.
  • the lyophilised formulation is then reconstituted into a sterile aqueous solution containing an IV excipient such as saline or dextrose, preferably dextrose.
  • an IV excipient such as saline or dextrose, preferably dextrose.
  • the lactate or citrate salts of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl- lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea can be amorphous or substantially crystalline.
  • the lactate or citrate salts are substantially crystalline, the term "substantially crystalline" having the meaning defined above.
  • the lactate salt of 1 - cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea is substantially crystalline.
  • lactate salt particularly the L-lactate
  • lactate salt of l-cyclopropyl-3-[3-(5-morpholin-4- ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea is substantially crystalline, one single crystalline form may predominate, although other crystalline forms may be present in minor and preferably negligible amounts.
  • the crystalline forms of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)- lH-pyrazol-4-yl]-urea contain less than or equal to about 5% by weight other crystalline forms of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea, in particular containing less than or equal to about 1% by weight of other crystalline forms.
  • the invention provides a substantially crystalline salt (e.g. a lactate salt (particularly the L-lactate) as defined herein) of l-cyclopropyl-3-[3-(5-morpholin-4- ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea containing a single crystalline form of the salt and no more than 5% by weight of any other crystalline forms of the salt.
  • a substantially crystalline salt e.g. a lactate salt (particularly the L-lactate) as defined herein) of l-cyclopropyl-3-[3-(5-morpholin-4- ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea containing a single crystalline form of the salt and no more than 5% by weight of any other crystalline forms of the salt.
  • the single crystalline form is accompanied by less than 4%, or less than 3%, or less than 2% of other crystalline forms, and in particular contains less than or equal to about 1% by weight of other crystalline forms. More preferably, the single crystalline form is accompanied by less than 0.9%, or less than 0.8%, or less than 0.7%, or less than 0.6%, or less than 0.5%, or less than 0.4%, or less than 0.3%, or less than 0.2%, or less than 0.1%, or less than 0.05%, or less than 0.01%, by weight of other crystalline forms, for example 0% by weight of other crystalline forms.
  • the crystals and their crystal structures can be characterised using a number of techniques including single crystal X-ray crystallography, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infra red spectroscopy, e.g. Fourier Transform infra-red spectroscopy (FTIR).
  • XRPD single crystal X-ray crystallography
  • DSC differential scanning calorimetry
  • FTIR Fourier Transform infra-red spectroscopy
  • the behaviour of the crystals under conditions of varying humidity can be analysed by gravimetric vapour sorption studies and also by XRPD.
  • Determination of the crystal structure of a compound can be performed by X-ray crystallography which can be carried out according to the conventional methods such as those described herein and in Fundamentals of Crystallography, C. Giacovazzo, H. L. Monaco, D. Viterbo, F. Scordari, G. Gilli, G. Zanotti and M. Catti, (International Union of Crystallography/Oxford University Press, 1992 ISBN 0-19-855578-4 (p/b), 0-19-85579-2 (h/b)).
  • This technique involves the analysis and interpretation of the X-ray diffraction of single crystal.
  • Tables 2 and 4 of Examples 69 and 71 of WO 2006/070195 (at pages 203 and 207) give coordinate data for crystals of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol- 2-yl)-lH-pyrazol-4-yl]-urea in Crystallographic Information File (CIF) Format (see Hall, Allen and Brown, Acta Cryst. (1991). A47, 655-685; http://www.iucr.ac.uk/iucr-top/cif/home.html).
  • Alternative file formats such as a PDB file format (e.g.
  • the invention provides, for the novel uses of the invention as defined herein, a lactate salt (particularly the L-lactate) of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl- lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea which is crystalline and has a crystal structure as defined by the coordinates in Table 4 of WO 2006/070195 (at page 207).
  • the invention provides, for the novel uses of the invention as defined herein, a lactate salt (particularly the L-lactate) of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl- lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea which is crystalline and has a crystal structure as set out in Figures 4 and 5 of WO 2006/070195.
  • the invention provides, for the novel uses of the invention as defined herein, a lactate salt (particularly the L-lactate) of l-cyclopropyl-3-[3-(5-morpholin- 4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea which is crystalline and:
  • (b) has a crystal structure as defined by the coordinates in Table 4 of WO 2006/070195; and/or
  • (e) has a crystal structure that belongs belong to an orthorhombic space group
  • the substantially crystalline salts preferably are substantially free of residual organic solvent used, e.g. to recrystallise or otherwise purify the salt, or other solvent such as water.
  • the crystals of the lactate salt (particularly the L-lactate) of the compounds of Formula (I) and (V), in particular lactate salt of l-cyclopropyl-3-[3-(5-morpholin-4- ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea are crystals which contain less than 10% by weight of residual solvent (e.g. water or an organic solvent), for example less than 5% residual solvent.
  • residual solvent e.g. water or an organic solvent
  • the crystalline salts e.g. the lactate salts -particularly the L-lactate
  • the term "anhydrous" having the meaning defined above.
  • the crystalline lactate salt of l-cyclopropyl-3-[3-(5-morpholin-4- ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea contains residual organic solvent e.g. ethanol in the range of about 0 to 5% by weight for example about 2 % ethanol.
  • XRPD X-ray Powder Diffraction
  • XRPD can be carried out according to the conventional methods such as those described herein (see Examples 70 and72 of WO 2006/070195) and in Introduction to X-ray Powder Diffraction, Ron Jenkins and Robert L.
  • interplanar spacings, diffraction angle and overall pattern are important for identification of crystal in the X-ray powder diffraction, due to the characteristics of the data.
  • the relative intensity should not be strictly interpreted since it may be varied depending on the direction of crystal growth, particle sizes and measurement conditions.
  • the diffraction angles usually mean ones which coincide in the range of 2 ⁇ 0.2°.
  • the peaks mean main peaks and include peaks not larger than medium at diffraction angles other than those stated above.
  • Tables 3, 5 and 6 in Examples 70 and 72 of WO 2006/070195 show the interplanar spacing (d) values of the X-ray diffraction spectrum that correspond to the diffraction angle values of the free base, lactate salt and dihydrate free base forms of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4- yl]-urea.
  • the invention therefore provides, for the novel uses of the invention as defined herein, crystals of salts (e.g. lactate - particularly the L-lactate) of l-cyclopropyl-3-[3-(5-morpholin-4- ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea having an X-ray powder diffraction patterns which are substantially as in Figure 3, 6, 7 or 8 of WO 2006/070195.
  • salts e.g. lactate - particularly the L-lactate
  • the compound of the present invention is a compound which exhibits peaks at the same diffraction angles as those of the X-ray powder diffraction pattern shown in Figure 3, 6, 7 or 8 and/or Table 3 and/or Table 5 and/or Table 6 of WO 2006/070195and optionally has same the relative intensity.
  • the invention further provides, for the novel uses of the invention as defined herein, a crystal of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea lactic acid salt (particularly the L-lactate) which has an X-ray powder diffraction pattern essentially as shown in Figure 6 of WO 2006/070195.
  • the invention provides, for the novel uses of the invention as defined herein, a substantially crystalline lactate salt (particularly the L-lactate) of l-cyclopropyl-3-[3-(5-morpholin-4- ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea which exhibits peaks at the same diffraction angles as those of the X-ray powder diffraction pattern shown in Figure 6 of WO 2006/070195.
  • the peaks have the same relative intensity as the peaks in Figure 6 of WO 2006/070195.
  • the invention provides, for the novel uses of the invention as defined herein, a substantially crystalline lactic acid salt (particularly the L-lactate) of 1- cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea having an X-ray powder diffraction pattern substantially as shown in Figure 6 of WO 2006/070195.
  • the X-ray powder diffraction pattern of the lactate salt may be characterised by the presence of peaks at the diffraction angles (2 ⁇ ) and interplanar spacings (d), and preferably the intensities shown in Table 5 in Example 72 of WO 2006/070195.
  • the invention provides, for the novel uses of the invention as defined herein, a crystal of cyclopropyl-3-[3-(6-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea lactate (particularly the L-lactate), which shows an X-ray powder diffraction pattern having characteristic peaks at a diffraction angle (2 ⁇ 1.0 degree such as ⁇ 0.2 degree, in particular ⁇ 0.1 degree) of Table 5 of Example 72 of WO 2006/070195.
  • the invention also provides, for the novel uses of the invention as defined herein, crystals of cyclopropyl-3-[3-(6-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea lactate salt (particularly the L-lactate) having an X-ray powder diffraction pattern showing major peaks of diffraction angles 2 ⁇ of 17.50, 18.30, 19.30, 19.60, and 21.85 ⁇ 1.0 degree such as ⁇ 0.2 degree, in particular ⁇ 0.1 degree.
  • the invention provides, for the novel uses of the invention as defined herein, a crystalline form of cyclopropyl-3-[3-(6-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea lactate salt (particularly the L-lactate) characterized by peaks in the X-ray diffraction pattern at 12.40, 15.20, 15.60, 17.50, 18.30, 18.50, 19.30, 19.60, 21.85, and 27.30 ⁇ 1.0 degrees two-theta.
  • the crystal of cyclopropyl-3 - [3 -(6-morpholin-4-ylmethyl- 1 H-benzoimidazol-2-yl)- 1 H-pyrazol- 4-yl]-urea lactate salt (particularly the L-lactate) is also characterised in that the characterisitic X-ray powder diffraction pattern is represented by the spacings between lattice planes , d (A) of Table 5 of Example 72 of WO 2006/070195.
  • the invention provides, for the novel uses of the invention as defined herein, a crystal of cyclopropyl-3-[3-(6-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH- pyrazol-4-yl]-urea lactate salt (particularly the L-lactate), which possess an X-ray powder diffraction pattern whose characteristic peaks appear as the lattice spacing (d) of the powder X- ray diffraction at 5.06, 4.85, 4.60, 4.53, and 4.07, more particularly lattice spacing (d) of the powder X-ray diffraction at 7.13, 5.83, 5.68, 5.06, 4.85, 4.79, 4.60, 4.53, 4.07, and 3.26 angstrom.
  • the invention provides, for the novel uses of the invention as defined herein, a substantially crystalline L-lactate salt (particularly the L-lactate) of 1- cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea having an X-ray powder diffraction pattern characterised by the presence of major peaks at the diffraction angles (2 ⁇ ) of 17.50, 18.30, 19.30, 19.60, and 21.85 degrees, more particularly 12.40, 15.20, 15.60, 17.50, 18.30, 18.50, 19.30, 19.60, 21.85, and 27.30 degrees, and interplanar spacings (d) of 5.06, 4.85, 4.60, 4.53, and 4.07, more particularly 7.13, 5.83, 5.68, 5.06, 4.85, 4.79, 4.60, 4.53, 4.07, and 3.26 angstrom.
  • the invention provides, for the novel uses of the invention as defined herein, a substantially crystalline L-lactate salt of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl- lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea having an X-ray powder diffraction pattern characterised by the presence of peaks at the diffraction angles (2 ⁇ ) and interplanar spacings (d), and preferably the intensities shown in Table 5 of Example 72 of WO 2006/070195.
  • the crystalline salts of the invention can also be characterised by differential scanning calorimetry (DSC).
  • the lactate salt has been analysed by DSC and exhibits onset at 190 0 C and a peak at 194-197 0 C.
  • the invention provides, for the novel uses of the invention as defined herein, a lactate salt (particularly the L-lactate) of which is anhydrous and exhibits onset at 190 0 C and/or an endothermic peak at 194-197 0 C when subjected to DSC.
  • onset refers to the start of an endothermic peak in the DSC scan, where the peak is the point of maximum heat output.
  • a further aspect of the invention concerns the novel uses of the lactate salt (particularly the L-lactate) of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol- 2-yl)-lH-pyrazol-4-yl]-urea which exhibits peaks at the same diffraction angles as those of the X-ray powder diffraction pattern shown in Figure 6, 7 or 8 of WO 2006/070195 and further exhibits onset at 190 0 C and/or an endothermic peak accompanying decomposition in the vicinity of a peak at 194-197 0 C according to thermal analysis (DSC).
  • DSC thermal analysis
  • the lactate salt can exist in a stable anhydrous crystalline form in conditions of high relative humidity does not undergo changes in crystal structure under such conditions.
  • the salts of the invention can be further characterised by infra-red spectroscopy, e.g. FTIR.
  • the infra-red spectrum of the lactate salt (KBr disc method) contains characteristic peaks at 3229, 2972 and 1660 cm 1 .
  • the invention provides, for the novel uses of the invention as defined herein, a (preferably substantially crystalline) lactic acid salt (particularly the L-lactate) of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH- pyrazol-4-yl]-urea that exhibits an infra-red spectrum, when analysed using the KBr disc method , that contains characteristic peaks at 3229, 2972 and 1660 cm "1 .
  • the lactate salt (particularly the L-lactate) of the invention can be characterised by a number of different physicochemical parameters. Accordingly, in a preferred embodiment, the invention provides a L-lactate salt (particularly the L-lactate) of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH- pyrazol-4-yl]-urea which is crystalline and is characterised by any one or more (in any combination) or all of the following parameters, namely that the salt:
  • (f) has an X-ray powder diffraction pattern characterised by the presence of major peaks at the diffraction angles (2 ⁇ ) of 17.50, 18.30, 19.30, 19.60, and 21.85 degrees, more particularly 12.40, 15.20, 15.60, 17.50, 18.30, 18.50, 19.30, 19.60, 21.85, and 27.30 degrees, and/or interplanar spacings (d) of 5.06, 4.85, 4.60, 4.53, and 4.07, more particularly 7.13, 5.83, 5.68, 5.06, 4.85, 4.79, 4.60, 4.53, 4.07, and 3.26 angstrom; and/or
  • (h) has an X-ray powder diffraction pattern substantially as shown in Figure 6 of WO 2006/070195; and/or (i) is anhydrous and exhibits onset at 190 0 C and/or an endothermic peak at 194-
  • (j) exhibits an infra-red spectrum, when analysed using the KBr disc method , that contains characteristic peaks at 3229, 2972 and 1660 cm “1 .
  • the free base of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH- pyrazol-4-yl]-urea can also be amorphous or substantially crystalline.
  • the free base is substantially crystalline, the term "substantially crystalline" having the meaning defined above.
  • the free base of l-cyclopropyl-3-[3-(5- morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea exists in a dihydrate crystalline form.
  • the invention provides, for the novel uses of the invention as defined herein, crystals of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2- yl)-lH-pyrazol-4-yl]-urea free base exhibiting X-ray powder diffraction patterns containing peaks at the same diffraction angles as those of the X-ray powder diffraction pattern shown in Figure 3, 6, 7 or 8 and/or Table 3 and/or Table 5 and/or Table 6 of WO 2006/070195 and wherein the peaks optionally have the same relative intensity.
  • the invention also provides, for the novel uses of the invention as defined herein, a crystal of 1- cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea free base, which shows an X-ray powder diffraction pattern having characteristic peaks at a diffraction angle (2 ⁇ 1.0 degree such as ⁇ 0.2 degree, in particular ⁇ 0.1 degree) of Table 2 of Example 69 of WO 2006/070195.
  • the invention for the novel uses of the invention as defined herein, provides a crystal of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH- pyrazol-4-yl]-urea free base, which possess an X-ray powder diffraction pattern whose characteristic peaks appear as the lattice spacing (d) of Table 3 of Example 69 of WO 2006/070195.
  • the free base of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH- pyrazol-4-yl]-urea exhibits peaks at the same diffraction angles as those of the X-ray powder diffraction pattern shown in Figure 3 and/or Table 3 of WO 2006/070195 and further exhibits an exothermic peak accompanying decomposition in the vicinity of 193° C according to thermal analysis (DSC).
  • DSC thermal analysis
  • ⁇ a member of the AXL family, such as AxI, Mer and Sky, in particular Mer.
  • M-CSF-IR macrophage colony- stimulating factor 1 receptor
  • MSK 1 and MSK2 a member of the Mitogen- and stress-activated kinase family such as MSK 1 and MSK2, in particular MSK2
  • DRAKl a member of the DAP kinase-r elated apoptosis-inducing protein kinase family, such as DRAKl and DRAK2, in particular DRAKl - a Salt-inducible kinase (SIK)
  • RSKl -4 a member of the 9OkDa ribosomal S6 kinase family such as RSKl -4, in particular RSK2, RSK3, RSK4
  • PAK5 a member of the p21 activated kinase (PAK) family in particular PAK5
  • ⁇ a member of the Brain specific kinase family, Brain specific kinases 1 and 2 (BRSKl /2), in particular BrSK2, or
  • TLK Tousled- like kinase
  • a neuroprotective agent as an immunosuppressive agent or as anti-osteolytic agent
  • a disease selected from the following:
  • cardiomyopathy e.g. dilated cardiomyopathy
  • cardiac remodelling e.g. dilated cardiomyopathy
  • CHF congestive heart failure
  • PHTN systemic vascular diseases and a range of lung conditions such as bronchiolitis, interstitial lung disease, lung injury;
  • ⁇ disease state or condition results in excessive bone formation, Paget's disease, and other diseases in which bone resorption mediates morbidity including prosthesis failure, osteolytic sarcoma, and tumor metastasis to bone; osteolytic disease associated with bone metastasis and other bone diseases in patients;
  • ⁇ proliferative vitreoretinopathy liver fibrosis, renal failure, irritable bowel syndrome (IBS), oxidative stress-related neurodegenerative disorders and diabetic nephro- and neuropathy
  • IBS irritable bowel syndrome
  • oxidative stress-related neurodegenerative disorders and diabetic nephro- and neuropathy
  • SCA14 spinocerebellar ataxia type 14
  • pancreatic adenocarcinoma gastric adenocarcinomas
  • invasive and/or metastatic breast cancer metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia, in particular bone metastases;
  • ⁇ adenopathy hepatosplenomegaly, and circulating lymphoblasts
  • ⁇ allodynia including mechanical allodynia and EtOH or opiate withdrawal-associated allodynia, and hyperalgesia, in particular thermal hyperalgesia and hyperalgesia during EtOH or opiate withdrawal (also known as EtOH or opiate withdrawal-associated hyperalgesia).
  • the compound of Formula (I) and the lactate or citrate salts of compound of the formula (I) are inhibitors of kinases selected from:
  • AXL family such as AxI, Mer and Sky, in particular Mer.
  • Mitogen- and stress-activated kinase family such as MSK 1 and MSK2, in particular MSK2 ⁇ DAP kinase-related apoptosis-inducing protein kinase family, such as DRAKl and
  • CSF-1/PDGF receptor subfamily in particular macrophage colony-stimulating factor 1 receptor (M-CSF-IR or FMS) ⁇ 9OkDa ribosomal S6 kinase family such as RSKl -4, in particular RSK2, RSK3, RSK4
  • ⁇ a member of the PKC family known as alpha, beta-I, beta-II, gamma, delta, epsilon, zeta, eta, theta, iota, lambda and mu ( ⁇ , ⁇ ( ⁇ l and ⁇ ll), ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ ), in particular PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ )
  • PAK ⁇ p21 activated kinase
  • PAK5 ⁇ Brain specific kinase family
  • BRSK1/2 Brain specific kinases 1 and 2
  • TLK Tousled-like kinase family
  • TLKl TLKl
  • TLK2 TLK2 in particular TLK2.
  • the compound of Formula (I) and the lactate or citrate salts of compound of the formula (I) are inhibitors of kinases selected from AXL family (e.g. Mer), Mitogen- and stress- activated kinase family (e.g. MSK2), DAP kinase-related apoptosis-inducing protein kinase family (e.g.
  • DRAKl Salt-inducible kinase
  • SIK Salt-inducible kinase
  • M-CSF-IR or FMS macrophage colony-stimulating factor 1 receptor
  • 9OkDa ribosomal S6 kinase family in particular RSKl -4, in particular RSK2, RSK3, RSK4
  • PKC family e.g. PKC-mu (PKC ⁇ ) or PKC-gamma (PKC ⁇ )
  • PKC p21 activated kinase
  • PAK p21 activated kinase
  • PAK Brain specific kinase family
  • BrSK2 Brain specific kinase family
  • TLK Tousled-like kinase
  • the compound of Formula (I) and the lactate or citrate salts of compound of the formula (I) are inhibitors of kinases selected from Mer, MSK2, DRAKl, SIK, FMS, RSKl -4 (in particular RSK2, RSK3, RSK4), PKC- PKC e.g. PKC gamma or PKC-mu, RSK e.g. RSK2, PAK5, BrSK2 and FMS.
  • kinases selected from Mer, MSK2, DRAKl, SIK, FMS, RSKl -4 (in particular RSK2, RSK3, RSK4), PKC- PKC e.g. PKC gamma or PKC-mu, RSK e.g. RSK2, PAK5, BrSK2 and FMS.
  • the compound of Formula (I) and the lactate or citrate salts of compound of the formula (I) are inhibitors of kinases selected from PKC e.g. PKC gamma or PKC-mu, RSK e.g. RSK2, PAK5, BrSK2 and FMS.
  • PKC e.g. PKC gamma or PKC-mu
  • RSK e.g. RSK2, PAK5, BrSK2 and FMS.
  • the compound of Formula (I) and the lactate or citrate salts of compound of the formula (I) are inhibitors of kinases selected from PKC-mu, BrSK2 and FMS.
  • the compound of Formula (I) and the lactate or citrate salts of compound of the formula (I) are inhibitors of kinases selected from PKC e.g. PKC gamma, FMS, RSK e.g. RSK2 and PAK5.
  • the compound of the invention will be useful in treating conditions such as cancer which are mediated by the kinases described herein or mutated forms thereof.
  • One sub-group of disease states and conditions where the compound of formula I or the lactate or citrate salts thereof will be useful consists of pain, heart conditions and bone disorders.
  • cancers which may be inhibited include, but are not limited to, a carcinoma, for example a carcinoma of the bladder, breast, colon (e.g. colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, epidermis, liver, lung, for example adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, oesophagus, gall bladder, ovary, pancreas e.g.
  • a carcinoma for example a carcinoma of the bladder, breast, colon (e.g. colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, epidermis, liver, lung, for example adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, oesophagus, gall bladder, ovary, pancreas e.g.
  • exocrine pancreatic carcinoma, stomach, cervix, thyroid, prostate, or skin for example squamous cell carcinoma
  • a hematopoietic tumour of lymphoid lineage for example leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma
  • a hematopoietic tumour of myeloid lineage for example acute and chronic myelogenous leukemias, myelodysplastic syndrome, or promyelocytic leukemia
  • thyroid follicular cancer a tumour of mesenchymal origin, for example fibrosarcoma or rhabdomyosarcoma
  • a tumour of the central or peripheral nervous system for example astrocytoma, neuroblastoma, glioma or schwannoma
  • the cancers may be cancers which are sensitive to inhibition of kinases, including mutated forms of the kinases, outlined herein.
  • the cancer is a leukaemia or lymphoma, in particular leukemia.
  • the cancer is leukaemia or lymphoma including chronic lymphocytic leukaemia, mantle cell lymphoma , B-cell lymphoma (such as diffuse large B cell lymphoma), acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non- Hodgkin's lymphoma, hairy cell lymphoma, Burkett's lymphoma, acute myelogenous leukemias, chronic myelogenous leukemias, myelodysplastic syndrome, or promyelocytic leukaemia.
  • chronic lymphocytic leukaemia mantle cell lymphoma
  • B-cell lymphoma such as diffuse large B cell lymphoma
  • acute lymphocytic leukemia B-cell lymphoma
  • T-cell lymphoma T-cell lymphoma
  • Hodgkin's lymphoma non- Hodgkin'
  • the cancer is leukaemia including chronic lymphocytic leukaemia, acute lymphocytic leukemia, acute myelogenous leukemias, chronic myelogenous leukemias, myelodysplastic syndrome, or promyelocytic leukaemia.
  • Whether or not a particular cancer is one which is sensitive to inhibition by a kinase outlined herein may be determined by means of a cell growth assay as set out in the examples below or by a method as set out in the section headed "Methods of Diagnosis”.
  • the kinases are also known to play a role in apoptosis, proliferation, differentiation and transcription and therefore inhibitors of the kinases could also be useful in the treatment of the following diseases other than cancer; viral infections, for example herpes virus, pox virus, Epstein-Barr virus, Sindbis virus, adenovirus, HIV, HPV, HCV and HCMV; prevention of AIDS development in HIV-infected individuals; chronic inflammatory diseases, for example systemic lupus erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus; cardiovascular diseases for example cardiac hypertrophy, restenosis, atherosclerosis; neurodegenerative disorders, for example Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotropic lateral sclerosis, retinitis pigmentosa, spinal muscular atropy and cerebellar degeneration; glomerulonephriti
  • adenocarcinomas in particular pancreatic adenocarcinomas and gastric adenocarcinomas.
  • Another sub-set of cancers includes invasive and/or metastatic breast cancer
  • the compound is also anticicpated for use in the treatment of metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, and hairy cell leukemia, in particular bone metastases.
  • the compounds of Formula (I) and the lactate (particularly the L-lactate) or citrate salts of the compound of the formula (I), are inhibitors of Mer activity.
  • Mer is overexpressed in a range of cancers and as such, they will be useful in providing a means of preventing the growth or inducing apoptosis of neoplasias. It is therefore anticipated that the compound will prove useful in treating or preventing proliferative disorders such as cancers in particular gastric adenocarcinoma. In particular tumours with overexpression, upregulation or activating mutants of Mer may be particularly sensitive to the inhibitors.
  • Mer inhibitors may be useful in the treatment of adenopathy (lymphadenopathy), hepatosplenomegaly, and circulating lymphoblasts.
  • the compounds of Formula (I) and the lactate (particularly the L-lactate) or citrate salts of the compound of the formula (I), are inhibitors of Mskl or Msk 2 activity.
  • MSKl and MSK2 are activated by either extracellular signal-regulated kinase (ERK) or p38 mitogen-activated protein kinases in response to stress or mitogenic extracellular stimuli.
  • ERK extracellular signal-regulated kinase
  • p38 mitogen-activated protein kinases in response to stress or mitogenic extracellular stimuli.
  • As such inhibitors of MSK family have a role as neuroprotectants.
  • Inhibitors of MSKl or 2 kinases may be useful in the treatment and/or prophylaxis of, or protection from, disorders associated with neuronal degeneration resulting from ischemic events, including cerebral ischemia after cardiac arrest, stroke and multi-infarct dementia, lung ischemia-rep erfusion and reducing lung reperfusion injury severity and also after cerebral ischemic events such as those resulting from head injury, surgery and/or during childbirth.
  • the compounds may be used as neuroprotective agents to prevent or reduce the damage to tissue following an injury.
  • the compounds of the invention may be administered to provide a neuroprotective effect to prevent or reduce the extent of damage to the appropriate issue.
  • the invention therefore provides the use of a compound of the formula (I) for the manufacture of a medicament for use as a neuroprotective agent.
  • Msks are also involved in inflammation and and such may be useful in the treatment and/prophylaxis of inflammatory conditions such as irritable bowel syndrome (IBS).
  • the invention therefore provides the use of a compound of the formula (I) for the manufacture of a medicament for treatment and/prophylaxis of irritable bowel syndrome (IBS).
  • the compounds of Formula (I) and the lactate (particularly the L-lactate) or citrate salts of the compound of the formula (I), are inhibitors of DRAK activity.
  • DRAK is involved in a range of bone related disorders and is strongly expressed in bone marrow tissues.
  • the invention therefore provides the use of a compound of the formula (I) for the manufacture of a medicament for treatment and/prophylaxis of conditions resulting in excessive bone formation.
  • the compounds of Formula (I) and the lactate (particularly the L-lactate) or citrate salts of the compound of the formula (I), are inhibitors of FMS activity.
  • FMS plays a role in mammary gland development and are important in osteolytic processes.
  • FMS inhibitors may tbe useful in the treatment of invasive and metastatic breast cancer, osteolytic disease associated with bone metastasis and other bone diseases in patients and as anti-osteolytic agents for example in the treatment of arthritis.
  • FMS inhibitors may be useful in methods of treating autoimmune diseases; and diseases with an inflammatory component; treating metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia; and treating pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; as well as osteoporosis, Paget's disease, and other diseases in which bone resorption mediates morbidity including rheumatoid arthritis, and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone.
  • c-Fms has also been linked to diseases such as atherosclerosis, fibrosis and proliferative vitreoretinopathy.
  • the invention therefore provides the use of a compound of the formula (I), salts or crystalline forms thereof as defined herein, for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition mediated by a FMS; and wherein the disease state or condition is selected from autoimmune diseases; and diseases with an inflammatory component; treating metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia; and treating pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; as well as osteoporosis, Paget's disease, and other diseases in which bone resorption mediates morbidity including rheumatoid arthritis, and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma, myeloma; tumor metastasis to bone; treatment of invasive and metastatic breast cancer; osteolytic disease associated with bone metastasis
  • the compound of formula (I) may be useful in the treatment of metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia; treatment of invasive and metastatic breast cancer; and treating pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; as well as Paget's disease, and other diseases in which bone resorption mediates morbidity including prosthesis failure, osteolytic sarcoma, and tumor metastasis to bone; osteolytic disease associated with bone metastasis and other bone diseases in patients and as anti-osteolytic agents and proliferative vitreoretinopathy.
  • the compounds of Formula (I) and the lactate (particularly the L-lactate) or citrate salts of the compound of the formula (I), are inhibitors of RSK activity including RSKl, RSK2, RSK3 and RSK4 (in particular RSK2, 3, and 4).
  • RSK has also been suggested as a potential therapeutic target for liver fibrosis as it has a contributory role in the development of the disease.
  • inappropriate RSK activity has been implicated in the etiology of a number of other diseases including cardiomyopathy, infection, and metal poisoning. There is evidence to show that the pathway is involved upon exposure to lead.
  • RSK2 is also important in normal development and has been associated with Coffin-Lowry syndrome.
  • a compound of the formula (I), salts or crystalline forms thereof as defined herein for the manufacture of a medicament for the treatment or prophylaxis of liver fibrosis, cardiomyopathy, Coffin-Lowry syndrome, Borna disease and lead poisoning.
  • the compounds of Formula (I) and the lactate (particularly the L-lactate) or citrate salts of the compound of the formula (I), are inhibitors of PKC activity, in particular PKC-mu and PKC- gamma.
  • PKC-mu and PKC- gamma are inhibitors of PKC activity, in particular PKC-mu and PKC- gamma.
  • the PKC family is involved in multiple cell signaling pathways and the control of many cellular processes, and therefore compounds acting on this family are useful in the treatment of a range of conditions.
  • PKC-mu plays a role in heart diseases and inhibitors of PCK-mu can therefore be used in the treatment of heart disease and its manifestations, including coronary artery disease, cardiomyopathy (e.g. dilated cardiomyopathy), myocardial infarction, myocardial contraction, congestive heart failure, cardiac hypertrophy, cardiac remodelling, and heart failure such as congestive heart failure (CHF).
  • cardiomyopathy e.g. dilated cardiomyopathy
  • myocardial infarction myocardial contraction
  • congestive heart failure e.g. dilated cardiomyopathy
  • cardiac hypertrophy e.g. CAD
  • cardiac remodelling e.g. CAD
  • CHF congestive heart failure
  • the invention therefore provides the use of a compound of the formula (I), salts or crystalline forms thereof as defined herein, for the manufacture of a medicament for the treatment or prophylaxis of coronary artery disease, myocardial contraction, cardiomyopathy (e.g. dilated cardiomyopathy), cardiac remodelling, and heart failure such as congestive heart failure (CHF).
  • a compound of the formula (I), salts or crystalline forms thereof as defined herein for the manufacture of a medicament for the treatment or prophylaxis of coronary artery disease, myocardial contraction, cardiomyopathy (e.g. dilated cardiomyopathy), cardiac remodelling, and heart failure such as congestive heart failure (CHF).
  • cardiomyopathy e.g. dilated cardiomyopathy
  • cardiac remodelling e.g. dilated cardiomyopathy
  • CHF congestive heart failure
  • An inhibitor of PKC may also provide a method of preventing pathologic heart failure by identifying a patient at risk of developing pathologic heart failure; and administering (via intravenous, oral, transdermal, sustained release, delayed release, controlled release, suppository, sublingual administration, or direct injection into cardiac tissue) to the patient compound (I).
  • the patient at risk may exhibit one or more of a list of risk factors comprising long standing uncontrolled hypertension, uncorrected valvular disease, chronic angina, or recent myocardial infarction, or a patient at risk maybe identified by measuring an indicative parameters such as right ventricular ejection fraction, left ventricular ejection fraction, ventricular wall thickness, heart weight/body weight ratio, right or left ventricular weight body weight ratio, or cardiac weight normalization measurement.
  • the patient at risk my also have a congenital, familiar, or genetic predisposition to heart disease, heart failure or cardiac hypertrophy.
  • Heart failure or symptoms thereof may comprise ischemia, cardiomyopathy, aortic stenosis, or other heart muscle diseases
  • the invention also provides the use of a compound of the formula (I), salts or crystalline forms thereof as defined herein, for the manufacture of a medicament for the treatment or prophylaxis of diseases such as hypertension including chronic hypoxic pulmonary hypertension (PHTN) disorders, systemic vascular diseases and a range of lung conditions such as bronchiolitis, interstitial lung disease and lung injury.
  • Inhibitors of PKC ⁇ may be useful in the treatment of pancreatic adenocarcinoma and PKC ⁇ - mediated cell resistance.
  • the invention therefore provides the use of a compound of the formula (I), salts or crystalline forms thereof as defined herein, for the manufacture of a medicament for the treatment or prophylaxis of pancreatic adenocarcinoma and PKC ⁇ - mediated cell resistance.
  • PKC ⁇ mutations resulting in increased kinase activity have been found in neurodegenerative disorders such spinocerebellar ataxia type 14 (SCA14).
  • the invention therefore provides the use of a compound of the formula (I), salts or crystalline forms thereof as defined herein, for the manufacture of a medicament for the treatment or prophylaxis of spinocerebellar ataxia type 14 (SCA14).
  • PKC-gamma has also been found to have a role in pain. Therefore invention therefore provides the use of the compound of formula I, salts or crystalline forms thereof as defined herein, for the treatment of pain.
  • a further aspect of the invention is the use of compounds of formula (I) and inhibitors thereof in the treatment and/or prohpylaxis of allodynia including mechanical allodynia and EtOH or opiate withdrawal-associated allodynia, and hyperalgesia, in particular thermal hyperalgesia and hyperalgesia during EtOH or opiate withdrawal (also known as EtOH or opiate withdrawal- associated hyperalgesia).
  • PKC ⁇ inhibitors are currently in clinical trials to treat diabetic induced vascular abnormalities. Therefore a further aspect of the invention is the compound of formula (I) for use in the treatment of diabetic retinopathy, nephropathy and neuropathy
  • the compound of formula I is also an inhibitor of PAK5.
  • Inhibitors of PAK5 may have a role in the treatment of organ transplantation, cardiomyopathies, renal failure, oxidative stress- related neurodegenerative disorders.
  • Inhibitors of PAK5 are also useful for the treatment of diabetic nephro- and neuropathy, and inhibition of dendritic spine formation and neurite outgrowth in primary neurons and neuroblastoma cells through the activation of Rac/Cdc42- PAK signaling pathways. Therefore a further aspect of the invention is the compound of formula (I) for use in the treatment of organ transplantation, cardiomyopathies, renal failure, oxidative stress-related neurodegenerative disorders and diabetic nephro- and neuropathy.
  • the compounds are also expected to be useful in the treatment of transplant rejection and are expected to be immunosuppressive agents.
  • the compounds of this invention are therefore useful in the treatment of resistance to transplantation, in transplant rejection, in graft vs. host disease, and pancreatitis.
  • a compound of this invention may be used either prophylactically or in response to an adverse reaction by the human subject to a transplanted organ or tissue.
  • a compound of this invention is administered to the patient or to the tissue or organ to be transplanted in advance of the transplantation operation.
  • Prophylactic treatment may also include administration of the medication after the transplantation operation but before any signs of adverse reaction to transplantation are observed.
  • a compound of this invention When administered in response to an adverse reaction, a compound of this invention is administered directly to the patient in order to treat resistance to transplantation after outward signs of the resistance have been manifested. Therefore a further aspect of the invention is the compound of formula (I) for use in the treatment of organ transplantation, resistance to transplantation, in transplant rejection, in graft vs. host disease, and pancreatitis
  • the compound of formula I is also an inhibitor of BrSKl and 2, in particular 2.
  • BrSK2 is primarily expressin the brain and as such its modulation will have an effect in a range of brain diseases and disorders, including pyschotic and neurological conditions.
  • Inhibitors of BrSK may have a role in the treatment of schizophrenia and cerebral ischemia.
  • Crohn's disease also known as granulomatous colitis and regional enteritis
  • Crohn's disease is an autoimmune disease causing inflammation of the GI tract.
  • risk factors for Crohn's disease have been identified in recent genome-wide association studies some of which are kinases.
  • a further aspect of the invention therefore provides a compound of the formula (I) or salts, solvates or tautomers thereof, for use in the treatment or prophylaxis of Crohn's disease.
  • lactate or citrate salts of compound of formula (I) are used to treat the conditions or diseases described herein.
  • the activity of the compound of formula I and/or the lactate or citrate salts of compound of the invention as inhibitors of the kinases described herein can be measured using the assays set forth in the examples below and the level of activity exhibited by a given compound can be defined in terms of the IC 50 value.
  • Bone Disorders The compound of formula I has activity against a number of kinases implicated bone disorders.
  • Paget's Disease also known as osteitis deformans
  • Paget's Disease can start in any bone in the body. It is rare before the age of 60. The disease involves the thickening of the bones but instead of becoming tougher and stronger the bones, paradoxically, become softer and tend to deform easily. If Paget's Disease affects the bone of the spine, nerves are often compressed producing pain.
  • the compound is provided for use in the treatment of bone disorders including Paget's disease, and other diseases in which bone resorption mediates morbidity including prosthesis failure, osteolytic sarcoma, and tumor metastasis to bone; osteolytic disease associated with bone metastasis and other bone diseases in patients.
  • the invention also provides compounds of formula I for use as antiosteolytic agents.
  • the invention therefore further provides the use of a compound of the formula (I), salts or crystalline forms thereof as defined herein, for the manufacture of a medicament for the treatment or prophylaxis of hypercalcemia, osteoarthritis, or sympomatic treatment of bone metastasis.
  • the kinases which the compound of formula I has activity against are implicated in a range of cardiac conditions.
  • the invention therefore provides the compound of formula I for use in the treatment of heart disease and its manifestations, including coronary artery disease, cardiomyopathy (e.g. dilated cardiomyopathy), myocardial contraction, congestive heart failure, cardiac hypertrophy, cardiac remodelling, and heart failure such as congestive heart failure (CHF).
  • cardiomyopathy e.g. dilated cardiomyopathy
  • CHF congestive heart failure
  • Cardiomyopathy which literally means "heart muscle disease", is the deterioration of the function of the myocardium for any reason. Cardiomyopathy is a disease in which the heart muscle becomes inflamed and does not function correctly. There may be multiple causes including viral infections. Patients suffering from cardiomyopathy are often at risk of arrhythmia or sudden cardiac death or both. There are three main types of cardiomyopathy: dilated, hypertrophic and restrictive. Intrinsic cardiomyopathy has a number of causes including drug and alcohol toxicity, certain viral or bacterial infections (including Hepatitis C), and various genetic and idiopathic (i.e., unknown) causes.
  • DCM Dilated cardiomyopathy
  • Hypertrophic cardiomyopathy (HCM or HOCM), is a genetic disorder caused by various mutations in genes encoding sarcomeric proteins. In HCM the heart muscle is thickened, which can obstruct blood flow and prevent the heart from functioning properly.
  • Restrictive cardiomyopathy (RCM) is an uncommon cardiomyopathy. The walls of the ventricles are stiff, but may not be thickened, and resist the normal filling of the heart with blood.
  • cardiomyopathy There are a range of other cardiac conditions under conditions under the term cardiomyopathy include: Coronary artery disease; Congenital heart disease; Ischemic (or ischaemic) cardiomyopathy; Hypertensive cardiomyopathy, Valvular cardiomyopathy; Inflammatory cardiomyopathy; Cardiomyopathy secondary to a systemic metabolic disease and Alcoholic cardiomyopathy.
  • the activity of the compounds in treating a range of heart conditions is considered to arise from their activity as inhibitors of PKCmu, RSK and/or PAK5. Such activity can be measured using the assay set forth in the examples below and the level of activity exhibited by a given compound can be defined in terms of the IC 50 value.
  • Preferred compounds for use in the present invention are compounds having an IC 5 O value of less than 1 micromolar, more preferably less than 0.1 micromolar.
  • pain is used in the broadest sense to describe a spectrum of conditions including nociceptive pain, arising from tissue damage or inflammation, pain related to noxious stimuli, acute pain, chronic pain, and neuropathic pain.
  • treatment refers to both prophylactic or preventative treatment as well as curative or palliative treatment of pain, in particular antinociceptive and anti-allodynic treatment of pain.
  • Examples of types of pain for which the compounds of the present invention will be useful in treating include nociception, somatic pain, visceral pain, acute pain, chronic pain, hyperalgesia, allodynia (e.g. mechanical allodynia), post operative pain, pain due to hypersensivity (e.g. due to alcohol or drug withdrawal), headache, inflammatory pain (rheumatic, dental, dysmenorrhoea or infection), neurological pain, neurogenic pain, skeletal pain (caused by tumor metastasis or osteoarthritis), musculoskeletal pain, cancer related pain or vascular pain.
  • nociception somatic pain, visceral pain, acute pain, chronic pain, hyperalgesia, allodynia (e.g. mechanical allodynia), post operative pain, pain due to hypersensivity (e.g. due to alcohol or drug withdrawal), headache, inflammatory pain (rheumatic, dental, dysmenorrhoea or infection), neurological pain, neurogenic pain, skeletal pain
  • the pain may be other than cancer pain.
  • the pain may be cancer pain.
  • the cancer pain may be cancer pain resulting from structural damage, bone metastasis, periosteal irritation, and nerve entrapment which is the most common complication of both benign and metastatic bone disease, and presents a significant problem in both hospital and community practice (Coleman, 1997, Cancer 80; 1588-1594).
  • the cancer related pain is pain associated with cancer therapy, e. g. postchemotherapy syndromes, chronic postsurgical pain syndromes, post radiation syndromes or bone cancer pain.
  • One subgroup of types of pain includes nociception, somatic pain, visceral pain, acute pain, chronic pain, hyperalgesia, allodynia, post operative pain, pain due to hypersensivity, headache, inflammatory pain (rheumatic, dental, dysmenorrhoea or infection), neurological pain, musculoskeletal pain or vascular pain.
  • the pain includes skeletal pain (e.g caused by tumor metastasis or osteoarthritis), visceral, inflammatory, and neurogenic pain
  • a further aspect of the invention provides the compounds of formula (I) for use in the treatment and/or prophylaxis of allodynia.
  • a further aspect of the invention provides the compounds of formula (I) for use in the treatment and/or prophylaxis of hyperalgesia.
  • allodynia e.g. mechanical allodynia or EtOH or opiate withdrawal-associated allodynia
  • hyperalgesia e.g. thermal hyperalgesia and hyperalgesia during alcohol or opiate withdrawal (also known as alcohol or opiate withdrawal-associated hyperalgesia).
  • the pain may be pain associated with a disease or pathological condition in a mammal.
  • the compound of formula I is used for the direct treatment of pain in diseases and medical conditions.
  • the invention provides the use of the compound of formula I, salts or crystalline forms thereof as defined herein, for the treatment of pain including lessening or reducing pain, management of pain and attenuation of nociception. Pain management includes both a lessening of pain and/or induction of analgesia.
  • the compound is contemplated for treatment of acute pain or chronic pain, as well as for prophylactic treatment of anticipated pain (e.g. palliative treatment).
  • the compound can be administered for use in modulating pain, typically for use in lessening pain, preventing future pain, and/or inhibiting heightened sensitivity to noxious stimuli.
  • Acute pain is that generally short lived with a specific origin e.g. soft tissue damage/trauma (including post surgical pain), inflammation or infection, usually with no persistent psychological reaction.
  • Acute pain can be modulated by analgesics or treatment of the underlying condition e.g. antibiotics to treat infection.
  • Chronic pain is a more complex condition involving persistent pain over long periods with, sometimes with no apparent cause and with no apparent biological purpose. Chronic pain can often have psychological consequences. Common causes of chronic pain include low-back pain, headache, pain associated with cancer, arthritis pain and fibromyalgia or myofascial pain.
  • Neuropathic pain is distinct from "normal” or nociceptive pain, usually results from neurological dysfunction and has a complex and variable etiology. It is often characterised by hyperalgesia (lowered pain threshold and enhanced perception) and allodynia (innocuous thermal or mechanical stimuli causing a perception of pain). Neuropathic pain often fails to respond to the same drugs as nociceptive conditions and is therefore more difficult to treat. Neuropathic pain can arise whenever nerves are damaged by trauma or amputation, disease
  • nucleotide anti-HIV e.g. as a side effect of drug treatment with nucleotide anti-HIV or some antineoplastic drugs.
  • Examples would include monoradiculopathies, trigeminal neuralgia, post herpetic neuralgia, complex regional pain syndromes and peripheral neuropathies.
  • the treatment of pain using the compound of formula I includes the treatment of nociception in particular preventing or protecting against nociception (causing the clinical symptoms not to develop); inhibiting nociception (arresting or suppressing the development of clinical symptoms); and/or relieving nociception (causing the regression of clinical symptoms).
  • Peripheral neuropathy is a neurodegenerative condition affecting peripheral nerves usually manifesting as one or a combination of motor, sensory, sensorimotor, or autonomic dysfunction.
  • Peripheral neuropathies can result from disease e.g. diabetes (diabetic neuropathy), alcoholism, acquired immunodeficiency syndrome (AIDS), drug therapies e.g. treatment with cytostatics or genetic predisposition (e.g. Metachromatic leukodystrophy).
  • Peripheral neuropathies are often accompanied by pain conditions.
  • the compound of formula (I) can be used inter alia in the treatment of pain conditions such as acute and chronic pain (as well as, but not limited to, pain associated with cancer, surgery, arthritis, dental surgery, trauma, musculo-skeletal injury or disease, visceral diseases) and migraine headache.
  • pain conditions such as acute and chronic pain (as well as, but not limited to, pain associated with cancer, surgery, arthritis, dental surgery, trauma, musculo-skeletal injury or disease, visceral diseases) and migraine headache.
  • the painful conditions can be neuropathic; examples of such conditions are post- herpetic neuralgia, diabetic neuropathy, drug- induced neuropathy, HlV- mediated neuropathy, sympathetic reflex dystrophy or causalgia, fibromyalgia, myofacial pain, entrapment neuropathy, phantom limb pain and trigeminal neuralgia.
  • Neuropathic conditions include central pain related to stroke, multiple sclerosis, spinal cord injury, arachnoiditis, neoplasms, syringomyelia, Parkinson's disease and epilepsy.
  • Another sub-group of pain conditions includes all of the pain conditions listed in the preceding paragraph other than cancer pain, i.e. pain associated with cancer.
  • the present invention is particularly applicable to the palliative treatment of pain, i.e. the direct relief of pain in addition to the relief of pain as the result of amelioration of the underlying disease or medical condition, which is the cause of the pain.
  • the invention provides methods and uses for the direct analgesic or acute treatment of pain.
  • the potential activity of the compounds in treating pain conditions may be tested using a variety of well known techniques.
  • Such techniques include observations of spontaneous pain (ie gait analysis/spontaneous foot lifting/weight bearing), evoked elements (e.g. heat (Hargreaves test and hot plate test), cold (application of acetone), paw pressure test (Randal Siletoe test) or mechanical (von Frey hairs) stimuli or rat tail clip test) or similar/equivalent assays, in test species exposed to the test compound in comparison to appropriate controls.
  • Pain levels can be calibrated on a subjective scale, or by measuring the subject's response to the pain by, for example, release of stress related factors or the activity of pain-transducing nerves in the peripheral nervous system or the central nervous system. Pain levels can also be calibrated by measuring the amount of an analgesic required for the subject to report that no pain is present or for a subject to stop exhibiting symptoms of pain).
  • the activity of the compounds in treating pain is considered to arise from their activity as inhibitors of PKC-gamma and/or FMS, in particular PKC-gamma. Such activity can be measured using the assay set forth in the examples below and the level of activity exhibited by a given compound can be defined in terms of the IC 5 Q value.
  • Preferred compounds for use in the present invention are compounds having an IC 5 O value of less than 1 micromolar, more preferably less than 0.1 micromolar.
  • Protein kinases play widespread essential roles in transducing extracellular signals that regulate cell proliferation, differentiation, and survival, and consequently, might contribute to tumorigenesis through a variety of mechanisms. Excessive or inappropriate signaling via these kinases can be achieved through structural changes that relieve the requirement for activation by ligands or other upstream signals or by virtue of being overexpressed, inappropriately stabilised or mutationally activated.
  • Mutations can arise naturally in a population and be translated through the germline which might have little impact on the physiological function of the kinase but might change the sensitivity of the mutated kinase to one or more inhibitors. Such germline mutations can be more frequent in certain racial and cultural groups. Mutations arising in tumours as a consequence of disease or drug treatment (somatic mutations) are non-heritable.
  • Chromosome translocations that produce fusions between tyrosine kinases and other cellular proteins can also result in dysregulated kinase activity owing to either subcellularly mislocalized kinase activity, inappropriate kinase expression, loss of a regulatory domain or deregulated kinase activity due to conformational changes.
  • Mutations that directly impact kinase catalytic domains can affect the interaction with protein substrates, potentially resulting in an altered profile of downstream signaling.
  • kinase mutations can result in qualitative as well as quantitative changes in signaling, and so there might be multiple mechanisms by which activating kinase mutations contribute to oncogenesis.
  • Mutations can also activate kinases by effective stabilization of a specific state of the enzyme e.g. an intermediate state of the enzyme.
  • the kinase can also be stabilised by post translational modification.
  • kinase inhibitors In addition, for certain drugs acquired drug resistance will substantially limit the clinical benefit of kinase inhibitors as single agent therapies.
  • Acquired resistance to drugs is often associated with primary or secondary mutations within the kinase domain that impair drug binding while retaining oncogenic kinase activity.
  • Acquired drug resistant kinase mutations that arise in patient populations treated with kinase inhibitors can occur, in part, in the regions of the protein that bind to or interact with the particular inhibitor used in therapy. Such mutations reduce the capacity of the inhibitor to bind to and inhibit the kinase in question. This can occur at any of the amino acid residues which interact with the inhibitor or are important for supporting the binding of said inhibitor to the target.
  • Another inhibitor that binds to a target kinase without requiring the interaction with the mutated amino acid residue will likely be unaffected by the mutation and will remain an effective inhibitor of the enzyme (Carter et al, PNAS, 2005, 102, 31, 11011-110116).
  • Other potential resistance mechanisms include amplification of the kinase gene, activation of additional kinases, and reduced bioavailability of the drug.
  • gate keeper residue One common site at which drug resistant mutations occur is the so-called gate keeper residue. This particular residue forms a key site of interaction for several kinase inhibitors and their respective targets.
  • imatinib (Gleevec) binds in part to threonine 315 the gate keeper residue in the abl kinase domain.
  • T315I mutations are one of the major forms of drug resistance arising in imatinib treated CML patients and may also be seen in patients with acute lymphoblastic leukemia.
  • mutated kinases or “mutated form of a kinase” includes mutations to the kinase that occur (i) as mutations transmitted through the germline or (ii) those occurring locally and are non-heritable (somatic mutations). In both cases the mutations could be due to genetic or chromosomal aberration. Somatic mutations can often arise as a point mutation or deletion due to treatment with clinical compounds.
  • the treatment is related to or directed at a mutated form of a kinase, such as discussed herein.
  • Diagnosis of tumours with such mutations or driven by mutated kinases could be performed using techniques known to a person skilled in the art and as described herein such as RTPCR and FISH.
  • Compound I might be particularly effective in cases where the targeted kinase has undergone mutational activation.
  • the mutated kinse is selected from PKC e.g. PKC gamma, FMS, RSK e.g. RSK2 or PAK5.
  • the compound is used to treat a disease characterized by excessive activity of a kinase described herein (in particular RSK).
  • a kinase described herein in particular RSK.
  • the present invention encompasses a method for treating a disease characterized by excessive kinase activity, comprising the step of administering to a subject in need thereof, a pharmaceutical composition comprising an effective amount of compound I.
  • the excessive activity is due to a mutation.
  • Antibacterial activity against various human and animal pathogens is important as a means of treating or preventing conditions caused by, or contributed to, by Gram-positive or Gram- negative bacteria.
  • Antibiotic compounds with activity against both Gram-positive and Gram- negative pathogens are generally regarded as having a broad spectrum of activity.
  • the compound of the present invention is regarded as effective against both Gram-positive and Gram-negative pathogens in particular Gram-negative.
  • the lactate or citrate salts of the compound of the formula (I) have activity against Gram- positive and Gram-negative bacteria.
  • the invention provides the use of the compound of the formula (I) as defined herein as an antibacterial agent.
  • the compound of the formula (I) as defined herein may be used in animal medicine (for example in the treatment of mammals such as humans), or in the treatment of plants (e.g. in agriculture and horticulture), or as general antibacterial agents, for example as preservatives and disinfectants.
  • the invention provides a compound of the formula (I) as defined herein for use in the prophylaxis or treatment of a bacterial infection in a mammal such as a human.
  • a compound of the formula (I) thereof as defined herein for the manufacture of a medicament for use in the prophylaxis or treatment of a bacterial infection in a mammal such as a human.
  • a person or animal being treated according to the methods herein is infected with Gram-positive bacterium such as a Staphylococcus bacterium in particular S. aureus, including against drug resistant strains thereof.
  • Gram-positive bacterium such as a Staphylococcus bacterium in particular S. aureus, including against drug resistant strains thereof.
  • the compounds of the invention can be administered to humans or animals to inhibit the growth of bacteria, such as Staphylococcus, including MRSA.
  • a person or animal being treated according to the methods herein is infected with a Gram-negative bacterium such as a Pseudomonas bacterium, in particular Pseudomonas aeruginosa, including against drug resistant strains thereof.
  • a Gram-negative bacterium such as a Pseudomonas bacterium, in particular Pseudomonas aeruginosa, including against drug resistant strains thereof.
  • Compounds with anti-bacterial activity can be used in the treatment of a range of conditions caused by bacteria.
  • the compounds of the invention can also be administered for the treatment or prophylaxis of systemic bacterial infections.
  • the compounds of the invention may be administered to human patients suffering from, or at risk of infection by topical bacterial infections.
  • Bacterial infections that can be treated or prevented include infections caused by Gram-positive bacteria, such as Staphylococcus spp., Streptococcus spp., Enterococcus spp., Clostridium spp., Bacillus spp., Mycobacteria spp.
  • Gram-negative bacteria such as Escherichia spp., Salmonella spp., Pseudomonas spp., Helicobacter app., Legionella spp., Moraxella spp., Neisseria spp., Hemophilus spp., Klebsiella spp., Actinobacteria spp., Proteus, Shigella and Enterobacter spp..
  • These bacterial genera include species such as Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus diogenes, Streptococcus pneumoniae, Streptococcus mutans, Streptococcus gordonii, S.
  • Gram-positive bacteria are involved in a range of diseases, for example C. botulinum causes botulism, C. difficile causes pseudomembranous colitis, C perfringens causes food poisoning , gas gangrene and enterotoxemia ("overeating disease” or "pulpy kidney disease” in sheep and goats), C. tetani is the causative organism of tetanus, B. anthracis causes anthrax and Listeria are responsible for listeriosis.
  • Streptococcal infections include strep throat, impetigo, cellulitis, erysipelas, tonsillitis, and scarlet fever, and certain Streptococcus species are responsible for many cases of meningitis, bacterial pneumonia, endocarditis, and necrotizing fasciitis (the 'flesh- eating' bacterial infections).
  • Important clinical infections caused by Enterococcus include urinary tract infections, bacteremia, bacterial endocarditis, diverticulitis, and meningitis.
  • Mycobacteria cause a number of serious diseases in mammals, including tuberculosis and leprosy.
  • Respiratory tract infections can be caused by certain Gram-negative strains including Haemophilus influenzae and Moraxella catarrhalis.
  • Respiratory tract-associated infections include bronchitis e.g. tracheobronchitis, sinusitis, laryngitis and otitis media, and pneumonia in particular, bronchopneumonia, as well as exacerbations of existing chronic obstructive pulmonary disease (COPD).
  • bronchitis e.g. tracheobronchitis, sinusitis, laryngitis and otitis media
  • pneumonia in particular, bronchopneumonia
  • COPD chronic obstructive pulmonary disease
  • Other Moraxella species are involved in eye infection in mammals such as M. lacunata in blepharoconjunctivitis and M. bovis is involved in bovine eye infections, resulting in a progressive, non-self-limiting keratitis, ulceration and - ultimately - rupture of the cornea.
  • N. gonorrhoeae also called the gonococcus
  • N. meningitidis also called the meningococcus
  • Salmonella causes typhoid fever, paratyphoid fever, and foodborne illness, and while many Escherichia are harmless commensals, some species are human pathogens and the cause of urinary tract infections and gastrointestinal diseases ranging from simple diarrhoea to dysentery-like conditions.
  • coli is responsible for the vast majority of Escherichia-related pathogenesis, other members of the genus have also been implicated in human disease.
  • Klebsiella organisms can lead to a wide range of disease states, notably pneumonia, urinary tract infections, septicemia, Ankylosing spondylitis, and soft tissue infections.
  • H. pylori is strongly associated with peptic ulcers, chronic gastritis, duodenitis, and stomach cancer.
  • L. pneumophila causes legionellosis (Legionnaires' disease), a potentially fatal form of pneumonia which can affect anybody, but which principally affects those who are susceptible because of age, illness, immunosuppression, smoking etc.
  • the Haemophilis genus includes commensal organisms along with some significant pathogenic strains such as H. influenzae a cause of bacteremia, sepsis and bacterial meningitis and can cause ear (otitis media) and eye (conjunctivitis) infections, cellulitis, osteomyelitis, epiglottitis, joint infections, lower respiratory tract infections, sinusitis, and is associated with pneumonia.
  • H. ducreyi is the causative agent of chancroid.
  • Enterobacteriaceae family cause opportunistic infections in immunocompromised (usually hospitalized) hosts with urinary and respiratory tract are the most common sites of infection such as in venous catheter insertions, and/or surgical procedures.
  • Proteus genus includes pathogens responsible for many human urinary tract infections and Shigella is the causative agent of human shigellosis and dysentery.
  • Corynebacter spp. Micrococcus spp., Streptomyces spp., Nocardia spp., Actinomyces spp., Yersinia spp., Chlamydia spp., Mycoplasma spp., Rickettsiae spp., Pasteurella spp., Campylobacter spp., Bacteroides spp., Clostridia spp. and Spirillum spp. Further bacteria are described in Paster et al. J. Bac. 2001, 183, 12, 3770-3783. Yersinia pestis in particular causes plague.
  • Further conditions caused by, or contributed to by bacteria include community acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, hospital acquired lung infections or bone and joint infections, and other bacterial infections, for example, mastitis, catheter infection, foreign body, prosthesis infections or peptic ulcer disease. Therefore these compounds are useful in the treatment of community acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, hospital acquired lung infections, bone and joint infections, and other bacterial infections, for example, mastitis, catheter infection, foreign body, prosthesis infections or peptic ulcer disease.
  • S. aureus is implicated in skin infections, such as pimples, impetigo, boils, cellulitis, folliculitis, furuncles, carbuncles, endocarditis, osteomyelitis, septic arthritis, pneumonia and meningitis, toxic shock syndrome (TSS), food poisoning, and scalded skin syndrome (Staphylococcal scalded skin syndrome or SSSS). It is a major cause of nosocomial infections, causing infection of surgical wounds and sites of indwelling medical devices (e.g. prosthetic joints), which may lead to sepsis for example septicemia.
  • indwelling medical devices e.g. prosthetic joints
  • the compound of the invention are useful in the treatment of skin infections (in particular pimples, impetigo, boils, cellulitis, folliculitis, furuncles, carbuncles), endocarditis, osteomyelitis, septic arthritis, pneumonia, meningitis, toxic shock syndrome (TSS), food poisoning and scalded skin syndrome (Staphylococcal scalded skin syndrome or SSSS).
  • skin infections in particular pimples, impetigo, boils, cellulitis, folliculitis, furuncles, carbuncles
  • endocarditis osteomyelitis
  • septic arthritis pneumonia
  • meningitis toxic shock syndrome
  • TSS toxic shock syndrome
  • SSSSSS food poisoning and scalded skin syndrome
  • the compound of the invention is useful in the treatment of nosocomial infections for example sepsis and septicemia.
  • the skin infection is a complicated skin and soft tissue infection (eSSTI ⁇ . In one embodiment the skin infection is a diabetic foot infection.
  • P. aeruginosa infects the pulmonary tract, urinary tract, external ear, burns, wounds, causes blood infections and is the most frequent colonizer of medical devices (e.g.catheters).
  • Pseudomonas can cause community acquired pneumonias, as well as ventilator-associated pneumonias, is responsible for a considerable proportion of intensive care infections and is also a common cause of post-operative infection in radial keratotomy surgery patients. Cystic fibrosis patients are predisposed to P. aeruginosa infection of the lungs. P. aeruginosa may also be a common cause of "hot-tub rash" (dermatitis).
  • the compound of the invention are useful in the treatment of infections the pulmonary tract, urinary tract, external ear, burns, wounds, blood; intensive care infections; infection of the lungs in cystic fibrosis patients; post-operative infection in radial keratotomy surgery patients; pneumonias such as community acquired pneumonias and ventilator-associated pneumonias; and dermatitis.
  • Antibacterial agents can be used against infections of the type hereinbefore defined, or opportunistic infections that commonly occur in debilitated and immunosuppressed patients such as patients with leukemias and lymphomas, people who are receiving immunosuppressive therapy, and patients with predisposing conditions such as diabetes mellitus or AIDS, as well as for non-immunosuppressed patients.
  • One embodiment of the invention provides the compound of the formula (I) or salts, solvates or tautomers thereof, for use in the treatment or prophylaxis of a disease state or condition caused by a Gram-negative bacteria such as H. pylori; and wherein the disease state or condition is stomach cancer.
  • the compound of the invention can also be useful for treatment of bacterial infections in, and diseases resulting from bacteria, in plants and animals.
  • the compound of the invention can also be useful for treatment of M. bovis infections in cattle, mastitis in dairy cows, bumblefoot in chickens and soft rot. Therefore the compound of the invention is useful in treatment of vegetal and animal infections.
  • the invention provides an antibacterial composition for agricultural (including horticultural) use, comprising a compound of the formula (I) as defined herein together with an agriculturally acceptable diluent or carrier.
  • the invention further provides a method of treating an animal (including a mammal such as a human), plant or seed having a bacterial infection, which comprises treating said animal, plant or seed, or the locus of said plant or seed, with an effective amount of a compound of the formula (I) as defined herein.
  • the invention also provides a method of treating a bacterial infection in a plant or seed which comprises treating the plant or seed with an antibacterially effective amount of an antibacterial composition containing a compound of the formula (I) as defined herein.
  • the disease state or condition is an infection.
  • the antibacterial spectrum and potency of a particular compound may be determined in a range of standard test systems. Assays described in the art can be used to screen for agents which may be useful for inhibiting at least Gram-negative and Gram-positive bacteria. The screening assays can be used to identify anti-bacterial agents which may have therapeutic value in the treatment of human, mammal and plant bacterial infections.
  • the antibacterial properties of the compounds of the invention may be demonstrated and assessed using in vivo conventional tests, for example by oral and/or intravenous dosing of a compound to a warm-blooded mammal with an appropriate bacterial infection using standard techniques.
  • the in vivo evaluation of the compound can be carried out at a series of dose levels by intraperitoneal or intravenous injection or by oral administration, to mice that have been inoculated with a bacterium.
  • the activity of the compounds can be assessed by monitoring the growth of the bacterial infection in groups of treated and untreated mice. The activity may be measured in terms of the dose level at which the compound provides 50% protection against the lethal effect of the infection (PD 50 ).
  • the efficacy of the antimicrobial activity may be demonstrated by the Preservative Efficacy Test (PET) described in European Pharmacopeia 5th Edition, Chpt 5.1.3. 'Efficacy Of Antimicrobial Preservation'.
  • PET Preservative Efficacy Test
  • the Preservative Efficacy Test (PET) gives an indication of the antimicrobial activity of a preparation.
  • the Preservative Efficacy Test investigates the antimicrobial efficacy of a preparation against two bacterial strains, one Gram-negative and one Gram-positive, and two fungal strains.
  • the antimicrobial activity of the preparation as such or, if necessary, with the addition of a suitable preservative or preservatives provides adequate protection from adverse effects that may arise from microbial contamination or proliferation during storage and use of the preparation.
  • the preparation tested herein comprised the compound of formula I in lactate salt form in citrate buffer, therefore the PET described herein in Example 17 and Example 18 can be used to determine if the pharmaceutical preparation itself has antimicrobial activity.
  • the test consists of challenging the preparation with a prescribed inoculum of suitable micro- organisms, storing the inoculated preparation at a prescribed temperature, withdrawing samples from the container at specified intervals of time a and counting the organisms in the samples so removed.
  • the antimicrobial activity of the preparation is investigated over the period of validity to ensure that such activity has not been impaired by storage.
  • the preservative properties of the preparation are considered adequate if, in the conditions of the test, there was a significant fall or no increase, as appropriate, in the number of micro-organisms at the conditions tested.
  • the criteria of acceptance for preservative efficacy in terms of decrease in the number of micro-organisms with time vary for different types of preparations according to the degree of protection intended. In addition the results can be used to demonstrate that the compound has antibacterial activity.
  • the antibacterial properties can be tested using standard in- vitro test systems.
  • the in vitro Minimum Inhibitory Concentration (MIC: El/fl) has been an indicator of in vitro antibacterial activity widely used in the art.
  • the MIC of test compounds can be determined by a standard agar dilution method, (Chemotherapy, 1981, 29 (1), 76), or for example as laid out below in the Example 19.
  • MIC can also be determined using the microtitre broth dilution method (National Committee for Clinical Laboratory Standards (1997), Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 4th ed. Approved standard M7-A4, Wayne, Pa.; Amsterdam, D. 1996. Susceptibility testing of antimicrobials in liquid media, p.52-111. In Loman, V., ed. Antibiotics in laboratory medicine, 4th ed. Williams and Wilkins, Baltimore, MD).
  • in vitro evaluation of the antibacterial activity of the compounds can be performed by determining the minimum inhibitory concentration (M.I.C.) which is the concentration of the test compounds, in a suitable medium, at which growth of the particular microorganism fails to occur.
  • M.I.C. minimum inhibitory concentration
  • a series of agar plates, each having the test compound incorporated at a particular concentration is inoculated with a standard culture and each plate is then incubated for an appropriate period at 37 0 C. The plates are then examined for the presence or absence of growth of the bacteria and the appropriate M.I.C. value is noted.
  • the antibacterial activity of a compound can be tested by Minimum Bactericidal Dilution and a protocol outlining an example of this assay can be found in Example 21.
  • bioactivity of these compounds can be tested by Kirby-Bauer diffusion assay against methicillin resistant S. aureus (MRSA).
  • MRSA methicillin resistant S. aureus
  • the activity of the compounds in treating bacterial infections is considered to arise from their activity as inhibitors of Gram-positive (e.g. S. aureus) and Gram-negative (e.g. P. aeruginosa) bacterium as demonstrated in the PET. Such activity can be measured using the assay set forth in the examples below.
  • Gram-positive e.g. S. aureus
  • Gram-negative e.g. P. aeruginosa
  • resistance of Gram-negative and Gram-positive bacteria to certain drugs can be inherent to the organism or acquired due to mutation or transfer of genes from other microorganisms.
  • Resistance to antibiotics can arise due to a number of different mechanisms including blocking the antibiotic's accumulation (e.g. efflux pumps), modification of the antibiotic (e.g. beta-lactamases) or changes in the antibacterial target itself (e.g. ribosomal modification (erm) strains).
  • drug resistant bacteria or “drug resistant strains thereof includes bacteria that are resistant to drugs (i) due to inherent or (ii) aquired resistance to the drug.
  • the treatment is related to or directed at a drug resistant strain of a bacteria, such as discussed herein.
  • Diagnosis of drug resistant bacterial infections can be performed using techniques known to a person skilled in the art and as described herein.
  • the drug resistant strain of bacteria is MRSA.
  • the compound could therefore be useful in the treatment of the following infections: nosocomial pneumonia caused by S. aureus (methicillin- susceptible and -resistant strains) or Streptococcus pneumoniae (including multidrug-resistant strains (MDRSP) where MDRSP refers to isolates resistant to two or more of the following antibiotics: penicillins, second- generation cephalosporins, macro lides, tetracyclines, and tnmethopnm /sulfamethoxazole); complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by S.
  • MDRSP multidrug-resistant strains
  • the compound of the invention are useful in the treatment of conditions such as nosocomial pneumoniae, community acquired pneumoniae, caused by methicillin-resistant S. aureus (MRSA) , including concurrent bacteremia, penicillin resistance and sensitive streptococcus pneumoniae, diabetic foot infections and skin and skin structure infections, and all other infections caused by bacteria sensitive to the compounds described in the invention.
  • MRSA methicillin-resistant S. aureus
  • the compounds of the present invention may be effective against a number of human or animal pathogens, clinical isolates, including vancomycin-resistant organisms and methicillin- resistant organisms.
  • the compound of the invention is anti-MRSA.
  • the compound of the formula (I) has a number of advantages over prior art compounds.
  • the compound of formula (I) is potent in its activities against different kinases including kinases implicated in cancer development and maintenance such as Mer, MSK2, DRAKl, SIK, FMS, RSKl -4 (in particular RSK2, RSK3, RSK4, PKC-mu (PKC ⁇ ), PKC- gamma (PKC ⁇ ), PAK5, BrSK2 and TLK2 kinases (see Table A).
  • Many of the kinases targeted by the compound lie in oncogenic signalling pathways and have the potential to contribute in a positive way to the anti-tumour action of the compound (Rsk, Mer, PKC).
  • the potency against a number of kinases could be of potential interest in the treatment of pain, heart conditions (e.g. CHF), and bone disorders.
  • kinases targeted by the compound could be of interest in particular in preventing or inhibiting further members of the PKC family (PKC ⁇ , PKC ⁇ , PKC ⁇ l, PKC ⁇ ll, PKC ⁇ , PKC ⁇ ,PKC ⁇ , PKC ⁇ , PKCi) Mskl, and BrSKl. (Table B).
  • the compound of formula (I) is also advantageous over prior art compounds in that it has different susceptibilities to P450 enzymes (Table A).
  • Table C Inhibition of expressed cytochrome P450 isoforms in vitro.
  • compounds of the invention are also advantageous over prior art compounds in that they exhibit improvements with regard to drug metabolism and pharmacokinetic properties.
  • the compounds of the invention have reduced plasma protein binding.
  • the binding of the compound to plasma proteins was comparably moderate across all species tested, ranging from 61% in rat to 82% in mouse plasma. This could confer the advantage of having more free drug available in the systemic circulation to reach the appropriate site of action to exert its therapeutic effect. Increased free fraction to exert pharmacological action in tumours potentially leads to improved efficacy which thereby allows reduced dosages to be administered.
  • the compound of formula (I) has a reduced toxicity and therefore a greater therapeutic window. Furthermore, salt forms of the compound of formula (I) demonstrate improved solubility in aqueous solution and better physicochemical properties, e.g. a lower logD.
  • the compound of the formula (I) can be prepared in accordance with synthetic methods well known to the skilled person.
  • the invention contemplates methods for preparing the compound of the invention for use in the treatments described herein which comprises the provision of 4-amino-lH-pyrazole-3- carboxylic acid (2-amino-4-morpholin-4-ylmethyl-phenyl)-amide or 4-amino-lH-pyrazole-3- carboxylic acid (2-amino-5-morpholin-4-ylmethyl-phenyl)-amide and protected forms thereof as chemical intermediates.
  • One particular preferred chemical intermediate of formula ((XXVII) of WO 2006/070195 is [3-(2-amino-4-morpholin-4-ylmethyl-phenylcarbamoyl)-lH- pyrazol-4-yl]-carbamic acid tert-butyl ester.
  • One particularly preferred chemical intermediate of Formula (XXVIII) of WO 2006/070195 is [3-(2-amino-5-morpholin-4-ylmethylphenyl- carbamoyl)-lH-pyrazol-4-yl]-carbamic acid tert-butyl ester.
  • the compound of formula ((XXVIIa) of WO 2006/070195 in the process for preparing 3-(5- morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-ylamine or a salt thereof or process for preparing l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)- lH-pyrazol-4-yl]-urea or a salt thereof above, can be prepared by a process which comprises:
  • the processes described herein have the further step of recrystallising the salt to give a crystalline form, e.g. a crystalline form as defined herein.
  • WO 2006/070195 Techniques for recrystallisation of Compound (I) are as described in WO 2006/070195, the contents of which are incorporated herein by reference.
  • the contents of WO 2006/070195 which relate to recrystallisation at pages 110 to 111 are hereby incorporated herein by reference. Therefore, in a further embodiment the lactate salt of the compound prepared herein is optionally recrystallised to give a crystalline form, e.g. a crystalline form as defined herein.
  • a compound e.g. a compound of the formula (I) or l-cyclopropyl-3-[3- (5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea or all salts thereof such as the lactate or citrate salt
  • a pharmaceutical composition e.g.
  • formulation comprising at least one active compound of the invention together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents; for example agents that reduce or alleviate some of the side effects associated with chemotherapy.
  • agents include anti-emetic agents and agents that prevent or decrease the duration of chemotherapy-associated neutropenia and prevent complications that arise from reduced levels of red blood cells or white blood cells, for example erythropoietin (EPO), granulocyte macrophage-colony stimulating factor (GM-CSF), and granulocyte-colony stimulating factor (G-CSF).
  • EPO erythropoietin
  • GM-CSF granulocyte macrophage-colony stimulating factor
  • G-CSF granulocyte-colony stimulating factor
  • the present invention further provides, for the novel uses of the invention as defined herein, pharmaceutical compositions, as defined herein, and pharmaceutical compositions made by a method comprising admixing a compound of the formula (I) or (I ) or l-cyclopropyl-3-[3- (5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea or all salts thereof such as the lactate or citrate salt, as defined above, together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilizers, or other materials, as described herein.
  • pharmaceutically acceptable refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a subject e.g. human
  • Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • the invention provides, for the novel uses of the invention as defined herein, the lactate or citrate salt or mixtures thereof of l-cyclopropyl-3-[3-(5- morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea as defined herein in the form of pharmaceutical compositions.
  • the pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, ophthalmic, otic, rectal, intra- vaginal, or transdermal administration.
  • compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery.
  • the delivery can be by bolus injection, short term infusion or longer term infusion and can be via passive delivery or through the utilisation of a suitable infusion pump.
  • tablets and capsules typically contain 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids and/or 0-99% (w/w) fillers/ or bulking agents (depending on drug dose). They may also contain 0-10% (w/w) polymer binders, 0-5% (w/w) antioxidants, 0-5% (w/w) Pigments. Slow release tablets would in addition contain 0-99% (w/w) polymers (depending on dose).
  • the film coats of the tablet or capsule typically contain 0-10% (w/w) polymers, 0-3% (w/w) pigments, and/or 0-2% (w/w) plasticizers.
  • Parenteral formulations typically contain 0-20% (w/w) buffers, 0-50% (w/w) cosolvents, and/or 0-99% (w/w) Water for Injection (WFI) (depending on dose and if freeze dried).
  • WFI Water for Injection
  • Formulations for intramuscular depots may also contain 0-99% (w/w) oils.
  • One particular pharmaceutical composition is a form suitable for administration via topical routes.
  • the compound is provided as an antibacterial composition adapted for direct application to skin (for example human skin).
  • skin for example human skin.
  • the activity of the present compositions can be affected through the selection of excipients to provide varying degree of skin penetration or to control release. Activity of the present formulations can be increased by occlusion of the skin after application with a suitable bandage or wrap.
  • persistent action can be increased by use of controlled release technologies which delay release of active over time.
  • a topical treatment an effective amount of a compound of Formula I is admixed in a pharmaceutically acceptable gel or cream vehicle that can be applied to the patient's skin at the area of treatment. Preparation of such creams and gels is well known in the art and can include penetration enhancers.
  • the invention further encompasses methods for inhibiting the growth of bacteria by contacting the bacteria with an effective amount of the compound of the invention in vitro or in vivo, or by applying the compound to a substrate (surface) likely to come in contact with the bacteria, such as a work surface, table, surgical instrument, implant or other device to be placed in or on the body (i.e., foreign object to be inserted into a subject, such as a stent, catheter, access port, intravenous delivery tube (Hickman), heart valve, dental implant, electro-mechanical device, prosthetic device, glucose sensor, or stabilizing device such as orthopedic nails and pins), eating or cooking utensil, etc.
  • the subject invention also concerns substrates which have a compound of the invention attached or applied thereto.
  • formulations contemplated herein can also be coated or otherwise incorporated into medical devices such as wipes, sponges, bandages, surgical drapes, hospital gowns, surgical gowns.
  • Formulations can be developed that are suitable for in disinfecting medical devices. Such formulations could be in the form of a liquid which could be used for spraying onto surfaces, soaking of devices, pumping through devices or incorporated into wipes for decontaminating a surface.
  • compositions adapted for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Examples of these are described in R. G. Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, VoI 21(2) 2004, p 201-230.
  • compositions may contain co-solvents, organic solvent mixtures, cyclodextrin complexation agents, emulsifying agents (for forming and stabilizing emulsion formulations), liposome components for forming liposomes, gellable polymers for forming polymeric gels, lyophilisation protectants and combinations of agents for, inter alia, stabilising the active ingredient in a soluble form and rendering the formulation isotonic with the blood of the intended recipient.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • a drug molecule that is ionizable can be solubilized to the desired concentration by pH adjustment if the drug's pKa is sufficiently away from the formulation pH value.
  • the acceptable range is pH 2-12 for intravenous and intramuscular administration, but subcutaneously the range is pH 2.7-9.0.
  • the solution pH is controlled by either the salt form of the drug, strong acids/bases such as hydrochloric acid or sodium hydroxide, or by solutions of buffers which include but are not limited to buffering solutions formed from glycine, citrate, acetate, maleate, succinate, histidine, phosphate, tris(hydroxymethyl)aminomethane (TRIS), or carbonate.
  • the combination of an aqueous solution and a water-soluble organic solvent/surfactant is often used in injectable formulations.
  • the water-soluble organic solvents and surfactants used in injectable formulations include but are not limited to propylene glycol, ethanol, polyethylene glycol 300, polyethylene glycol 400, glycerin, dimethylacetamide (DMA), N-methyl-2- pyrrolidone (NMP; Pharmasolve), dimethylsulphoxide (DMSO), Solutol HS 15, Cremophor EL, Cremophor RH 60, and polysorbate 80.
  • Such formulations can usually be, but are not always, diluted prior to injection.
  • Propylene glycol, PEG 300, ethanol, Cremophor EL, Cremophor RH 60, and polysorbate 80 are the entirely organic water-miscible solvents and surfactants used in commercially available injectable formulations and can be used in combinations with each other.
  • the resulting organic formulations are usually diluted at least 2-fold prior to IV bolus or IV infusion.
  • Liposomes are closed spherical vesicles composed of outer lipid bilayer membranes and an inner aqueous core and with an overall diameter of ⁇ 100 ⁇ m.
  • moderately hydrophobic drugs can be solubilized by liposomes if the drug becomes encapsulated or intercalated within the liposome.
  • Hydrophobic drugs can also be solubilized by liposomes if the drug molecule becomes an integral part of the lipid bilayer membrane, and in this case, the hydrophobic drug is dissolved in the lipid portion of the lipid bilayer.
  • a typical liposome formulation contains water with phospholipid at 5-20 mg/ml, an isotonicif ⁇ er, a pH 5-8 buffer, and optionally cholesterol.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • sterile liquid carrier for example water for injections
  • the pharmaceutical formulation can be prepared by lyophilising a compound of the formula (I ) or l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]- urea or all salts thereof such as the lactate or citrate salt thereof as defined herein.
  • Lyophilisation refers to the procedure of freeze- drying a composition. Freeze- drying and lyophilisation are therefore used herein as synonyms.
  • a typical process is to solubilise the compound and the resulting formulation is clarified, sterile filtered and aseptically transferred to containers appropriate for lyophilisation (e.g. vials).
  • vials they are partially stoppered with lyo-stoppers.
  • the formulation can be cooled to freezing and subjected to lyophilisation under standard conditions and then hermetically capped forming a stable, dry lyophile formulation.
  • the composition will typically have a low residual water content, e.g. less than 5% e.g. less than 1% by weight based on weight of the lyophile.
  • the lyophilisation formulation may contain other excipients for example, thickening agents, dispersing agents, buffers, antioxidants, preservatives, and tonicity adjusters.
  • Typical buffers include phosphate, acetate, citrate and glycine.
  • antioxidants include ascorbic acid, sodium bisulphite, sodium metabisulphite, monothioglycerol, thiourea, butylated hydroxytoluene, butylated hydroxyl anisole, and ethylenediamietetraacetic acid salts.
  • Preservatives may include benzoic acid and its salts, sorbic acid and its salts, alkyl esters of /> ⁇ r ⁇ -hydroxybenzoic acid, phenol, chlorobutanol, benzyl alcohol, thimerosal, benzalkonium chloride and cetylpyridinium chloride.
  • the buffers mentioned previously, as well as dextrose and sodium chloride, can be used for tonicity adjustment if necessary.
  • Bulking agents are generally used in lyophilisation technology for facilitating the process and/or providing bulk and/or mechanical integrity to the lyophilized cake.
  • Bulking agent means a freely water soluble, solid particulate diluent that when co-lyophilised with the compound or salt thereof, provides a physically stable lyophilized cake, a more optimal freeze- drying process and rapid and complete reconstitution.
  • the bulking agent may also be utilised to make the solution isotonic.
  • the water-soluble bulking agent can be any of the pharmaceutically acceptable inert solid materials typically used for lyophilisation.
  • Such bulking agents include, for example, sugars such as glucose, maltose, sucrose, and lactose; polyalcohols such as sorbitol or mannitol; amino acids such as glycine; polymers such as polyvinylpyrrolidine; and polysaccharides such as dextran.
  • the ratio of the weight of the bulking agent to the weight of active compound is typically within the range from about 1 to about 5, for example of about 1 to about 3, e.g. in the range of about 1 to 2.
  • dosage forms may be via filtration or by autoclaving of the vials and their contents at appropriate stages of the formulation process.
  • the supplied formulation may require further dilution or preparation before delivery for example dilution into suitable sterile infusion packs.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • Pharmaceutical compositions of the present invention for parenteral injection can also comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • aqueous and nonaqueous carriers, diluents, solvents or vehicles examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • carboxymethylcellulose and suitable mixtures thereof such as vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • a compound not stable in aqueous media or has low solubility in aqueous media it can be formulated as a concentrate in organic solvents.
  • the concentrate can then be diluted to a lower concentration in an aqueous system, and can be sufficiently stable for the short period of time during dosing. Therefore in another aspect, there is provided a pharmaceutical composition comprising a non aqueous solution composed entirely of one or more organic solvents, which can be dosed as is or more commonly diluted with a suitable IV excipient (saline, dextrose; buffered or not buffered) before administration (Solubilizing excipients in oral and injectable formulations, Pharmaceutical Research, 21(2), 2004, p201-230).
  • a suitable IV excipient saline, dextrose; buffered or not buffered
  • solvents and surfactants are propylene glycol, PEG300, PEG400, ethanol, dimethylacetamide (DMA), N- methyl-2-pyrrolidone (NMP, Pharmasolve), Glycerin, Cremophor EL, Cremophor RH 60 and polysorbate.
  • Particular non aqueous solutions are composed of 70-80% propylene glycol, and 20-30% ethanol.
  • One particular non aqueous solution is composed of 70% propylene glycol, and 30% ethanol.
  • the typical amounts for bolus IV formulations are -50% for Glycerin, propylene glycol, PEG300, PEG400, and -20% for ethanol.
  • the typical amounts for IV infusion formulations are -15% for Glycerin, 3% for DMA, and -10% for propylene glycol, PEG300, PEG400 and ethanol.
  • the pharmaceutical composition is in a form suitable for i.v. administration, for example by injection or infusion.
  • the solution can be dosed as is, or can be injected into an infusion bag (containing a pharmaceutically acceptable excipient, such as 0.9% saline or 5% dextrose), before administration.
  • the pharmaceutical composition is in a form suitable for subcutaneous (s.c.) administration.
  • Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches and buccal patches.
  • compositions containing a compound of the formula (I) or l-cyclopropyl-3-[3- (5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea or all salts thereof such as the lactate or citrate salt can be formulated in accordance with known techniques, see for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.
  • tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g.
  • swellable crosslinked polymers such as crosslinked carboxymethylcellulose
  • lubricating agents e.g. stearates
  • preservatives e.g. parabens
  • antioxidants e.g. BHT
  • buffering agents for example phosphate or citrate buffers
  • effervescent agents such as citrate/bicarbonate mixtures.
  • Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form.
  • Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof.
  • the solid dosage forms can be coated or un-coated, but typically have a coating, for example a protective film coating (e.g. a wax or varnish) or a release controlling coating.
  • a protective film coating e.g. a wax or varnish
  • the coating e.g. a Eudragit TM type polymer
  • the coating can be designed to release the active component at a desired location within the gastro-intestinal tract.
  • the coating can be selected so as to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively release the compound in the stomach or in the ileum or duodenum.
  • the drug can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract.
  • a release controlling agent for example a release delaying agent which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract.
  • the matrix material or release retarding coating can take the form of an erodible polymer (e.g. a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract.
  • the active compound can be formulated in a delivery system that provides osmotic control of the release of the compound. Osmotic release and other delayed release or sustained release formulations may be prepared in accordance with methods well known to those skilled in the art.
  • compositions comprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient.
  • Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, dragees, tablets or capsules.
  • compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture, and processing the mixture, if desired or necessary, after the addition of appropriate excipients, into tablets, dragee cores or capsules. It is also possible for them to be incorporated into plastics carriers that allow the active ingredients to diffuse or be released in measured amounts.
  • compositions for topical use include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods.
  • compositions for parenteral administration are typically presented as sterile aqueous or oily solutions or fine suspensions, or may be provided in finely divided sterile powder form for making up extemporaneously with sterile water for injection.
  • formulations for rectal or intra- vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped moldable or waxy material containing the active compound.
  • Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known.
  • the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.
  • the antibacterial compounds can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin; or they can be incorporated, at a concentration between 1 and 10%, into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required.
  • the pharmaceutical formulations may be presented to a patient in "patient packs" containing an entire course of treatment in a single package, usually a blister pack.
  • Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient's supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in patient prescriptions.
  • the inclusion of a package insert has been shown to improve patient compliance with the physician's instructions.
  • a compound of the formula (I) or l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea or all salts thereof such as the lactate or citrate salt will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity.
  • a formulation intended for oral administration may contain from 0.1 milligrams to 2 grams of active ingredient, or 1 nanogram to 2 milligrams of active ingredient.
  • particular sub-ranges of compound are 0.1 milligrams to 2 grams of active ingredient (more usually from 10 milligrams to 1 gram, for example, 50 milligrams to 500 milligrams or 1 microgram to 20 milligrams (for example 1 microgram to 10 milligrams, e.g. 0.1 milligrams to 2 milligrams of active ingredient).
  • a unit dosage form may contain from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, e.g. 100 milligrams to 1 gram, of active compound.
  • the active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.
  • a patient in need thereof for example a human or animal patient
  • the compound and pharmaceutically acceptable compositions thereof can be administered to the person or animal via any suitable route.
  • the compound of the invention can also be formulated for livestock and the use thereof is contemplated by the present invention.

Abstract

L'invention porte sur un composé de formule (I) : ou sur des sels, solvates ou tautomères de celui-ci, pour une utilisation : a) dans la prophylaxie ou le traitement d'un état de maladie ou d'un état facilité par une kinase, ou une forme mutée de ceux-ci, qui est un membre de la famille AXL, ou de la famille PKC, ou de la sous-famille des récepteurs CSF-1/PDGF, ou de la famille des kinases activées par mitogène et contrainte, ou de la famille des protéines kinases induisant l'apoptose apparentées à la DAP kinase; ou est une kinase inductible par sel; ou est un membre de la famille des kinases S6 ribosomiques de 90 Da, ou de la famille des kinases activées par p21 (PAK), ou de la famille des kinases spécifiques du cerveau, ou de la famille des kinases de type Tousled (TLK); ou b) en tant qu'agent antibactérien; ou c) en tant qu'agent neuroprotecteur, agent immunosuppresseur ou agent anti-ostéolytique; ou d) dans la prophylaxie ou le traitement d'une maladie ou d'un état choisi parmi ce qui suit : la douleur; une maladie artérienne coronaire, une contraction myocardiale, une cardiomyopathie, un remodelage cardiaque et une insuffisance cardiaque, une hypertension, des maladies vasculaires systémiques et un ensemble d'états de poumon, de lésions de poumon; des états de maladie ou des conditions conduisant à une formation osseuse excessive; des maladies osseuses; et des maladies dans lesquelles une résorption osseuse facilite la morbidité; une vitréorétinopathie proliférative, une fibrose du foie, une insuffisance rénale, un syndrome de côlon irritable, des troubles neurodégénératifs liés à un stress oxydant et une nephro- et neuropathie diabétique; une ischémie cérébrale, le syndrome de Coffin-Lowry, la maladie de Borna, l'ataxie spinocerebelleuse de type 14, la schizophrénie, le rejet de greffe, la transplantation d'organe, la résistance à une transplantation, la réaction du greffon contre l'hôte, la pancréatite et un empoisonnement par du métal; un adénocarcinome pancréatique, des adénocarcinomes gastriques; un cancer du sein invasif et/ou métastatique; une métastase provenant de divers cancers; une adénopathie, une hépatosplénomégalie, et des lymphoblastes circulants; une andallodynie et une hyperalgésie.
PCT/GB2009/050520 2008-05-14 2009-05-14 Utilisation thérapeutique de la 1-cyclopropyl-3-[3-(5-morpholin-4-ylméthyl-1h-benzoimidazol-2-yl)-lh-pyrazol-4-yl]-urée WO2009138799A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0808731.4 2008-05-14
GB0808731A GB0808731D0 (en) 2008-05-14 2008-05-14 New uses
GB0809774A GB0809774D0 (en) 2008-05-30 2008-05-30 New use
GB0809774.3 2008-05-30

Publications (1)

Publication Number Publication Date
WO2009138799A1 true WO2009138799A1 (fr) 2009-11-19

Family

ID=40996817

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2009/050520 WO2009138799A1 (fr) 2008-05-14 2009-05-14 Utilisation thérapeutique de la 1-cyclopropyl-3-[3-(5-morpholin-4-ylméthyl-1h-benzoimidazol-2-yl)-lh-pyrazol-4-yl]-urée

Country Status (1)

Country Link
WO (1) WO2009138799A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013115280A1 (fr) 2012-01-31 2013-08-08 第一三共株式会社 Dérivé de pyridone
KR20170029495A (ko) 2014-07-07 2017-03-15 다이이찌 산쿄 가부시키가이샤 테트라하이드로피라닐메틸기를 갖는 피리돈 유도체
CN113262230A (zh) * 2021-04-30 2021-08-17 华中农业大学 一种靶向猪链球菌丝氨酸、苏氨酸蛋白激酶抑制剂及应用
CN113827622A (zh) * 2021-08-31 2021-12-24 南方医科大学 奇异变形杆菌外膜囊泡在制备预防或治疗骨溶解性疾病药物中的应用
CN114767864A (zh) * 2022-05-10 2022-07-22 天津医科大学总医院 Pak3抑制剂在治疗瑞芬太尼诱发的切口痛觉过敏中的应用
WO2023083330A1 (fr) * 2021-11-12 2023-05-19 百极优棠(广东)医药科技有限公司 Inhibiteur de drak2, son procédé de préparation et son utilisation

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003035065A1 (fr) * 2001-10-26 2003-05-01 Aventis Pharmaceuticals Inc Benzimidazoles et analogues et leur utilisation comme inhibiteurs de proteines kinases
WO2006070195A1 (fr) * 2004-12-30 2006-07-06 Astex Therapeutics Limited Composes de pyrazole regulant l’activite de kinases cdk, gsk et aurora
WO2007077435A1 (fr) * 2005-12-30 2007-07-12 Astex Therapeutics Limited Composes pharmaceutiques
WO2008001115A2 (fr) * 2006-06-29 2008-01-03 Astex Therapeutics Limited Combinaisons pharmaceutiques
WO2008001101A2 (fr) * 2006-06-29 2008-01-03 Astex Therapeutics Limited Combinaisons pharmaceutiques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003035065A1 (fr) * 2001-10-26 2003-05-01 Aventis Pharmaceuticals Inc Benzimidazoles et analogues et leur utilisation comme inhibiteurs de proteines kinases
WO2006070195A1 (fr) * 2004-12-30 2006-07-06 Astex Therapeutics Limited Composes de pyrazole regulant l’activite de kinases cdk, gsk et aurora
WO2007077435A1 (fr) * 2005-12-30 2007-07-12 Astex Therapeutics Limited Composes pharmaceutiques
WO2008001115A2 (fr) * 2006-06-29 2008-01-03 Astex Therapeutics Limited Combinaisons pharmaceutiques
WO2008001101A2 (fr) * 2006-06-29 2008-01-03 Astex Therapeutics Limited Combinaisons pharmaceutiques

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013115280A1 (fr) 2012-01-31 2013-08-08 第一三共株式会社 Dérivé de pyridone
KR20140117439A (ko) 2012-01-31 2014-10-07 다이이찌 산쿄 가부시키가이샤 피리돈 유도체들
US8933103B2 (en) 2012-01-31 2015-01-13 Daiichi Sankyo Company, Limited Pyridone derivatives
EP3868757A1 (fr) 2014-07-07 2021-08-25 Daiichi Sankyo Company, Limited Dérivés de la pyridone ayant le groupe tétrahydropyranylmethyl
US10442797B2 (en) 2014-07-07 2019-10-15 Daiichi Sankyo Company, Limited Pyridone derivatives having tetrahydropyranylmethyl groups
KR20170029495A (ko) 2014-07-07 2017-03-15 다이이찌 산쿄 가부시키가이샤 테트라하이드로피라닐메틸기를 갖는 피리돈 유도체
US11208403B2 (en) 2014-07-07 2021-12-28 Daiichi Sankyo Company, Limited Pyridone derivatives having tetrahydropyranylmethyl groups
CN113262230A (zh) * 2021-04-30 2021-08-17 华中农业大学 一种靶向猪链球菌丝氨酸、苏氨酸蛋白激酶抑制剂及应用
CN113262230B (zh) * 2021-04-30 2022-06-17 华中农业大学 一种靶向猪链球菌丝氨酸、苏氨酸蛋白激酶抑制剂及应用
CN113827622A (zh) * 2021-08-31 2021-12-24 南方医科大学 奇异变形杆菌外膜囊泡在制备预防或治疗骨溶解性疾病药物中的应用
CN113827622B (zh) * 2021-08-31 2023-11-07 南方医科大学 奇异变形杆菌外膜囊泡在制备预防或治疗骨溶解性疾病药物中的应用
WO2023083330A1 (fr) * 2021-11-12 2023-05-19 百极优棠(广东)医药科技有限公司 Inhibiteur de drak2, son procédé de préparation et son utilisation
CN114767864A (zh) * 2022-05-10 2022-07-22 天津医科大学总医院 Pak3抑制剂在治疗瑞芬太尼诱发的切口痛觉过敏中的应用
CN114767864B (zh) * 2022-05-10 2023-05-12 天津医科大学总医院 Pak3抑制剂在治疗瑞芬太尼诱发的切口痛觉过敏中的应用

Similar Documents

Publication Publication Date Title
JP5507049B2 (ja) 医薬品
KR101344691B1 (ko) 키나제 억제제로서의4-(2,6-디클로로-벤조일아미노)-1ｈ-피라졸-3-카르복실산피페리딘-4-일아미드 산 부가염
WO2009138799A1 (fr) Utilisation thérapeutique de la 1-cyclopropyl-3-[3-(5-morpholin-4-ylméthyl-1h-benzoimidazol-2-yl)-lh-pyrazol-4-yl]-urée
US9040542B2 (en) Solid forms of gyrase inhibitor (R)-1-ethyl-3-[6-fluoro-5-[2-(1-hydroxy-1-methyl-ethyl)pryimidin-5-yl]-7-(tetrahydrofuran-2-yl)-1H-benzimidazol-2-yl]urea
AU2012205416B2 (en) Solid forms of gyrase inhibitor (R)-1-ethyl-3-(5-(2-{1-hydroxy-1-methyl-ethyl}pyrimidin-5-yl)-7-(tetrahydrofuran-2-yl}-1H-benzimidazol-2-yl)urea
KR20150074186A (ko) 헤테로아릴기 알킨 화합물 및 그 응용
US20190375745A1 (en) (hetero)arylamide compound for inhibiting protein kinase activity
WO2012051708A1 (fr) Composés antibactériens modulateurs de la pyruvate kinase, compositions, utilisations et méthodes associées
WO2019199496A1 (fr) Agents antibactériens à base de benzamide
US20200377473A9 (en) (hetero)arylamide compound for inhibiting protein kinase activity
US20230036867A1 (en) N-(3-(5-(pyrimidin-4-yl)thiazol-4-yl)phenyl)sulfonamide compounds and their uses as braf inhibitors
JP2014503578A (ja) Ｍｄｒポンプ阻害活性を有する新規なアザクマリン誘導体
NZ612912B2 (en) Solid forms of gyrase inhibitor (r)-1-ethyl-3-[5-[2-{1-hydroxy-1-methyl-ethyl}pyrimidin-5-yl]-7-(tetrahydrofuran-2-yl}-1h-benzimidazol-2-yl]urea

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09746116

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09746116

Country of ref document: EP

Kind code of ref document: A1