Trka receptor modulators

Abstract

There is provided a compound of formula I, or a pharmaceutically acceptable salt thereof, [Formula should be inserted here] wherein R1, R2, R3, R4, R5, R6, A, n, m, X and Y are as defined herein. Such compounds are useful in the treatment of diseases and disorders described herein.

Description

NEW COMPOUNDS AND USESField of the InventionThe present invention relates to novel compounds that are negative allosteric modulators of tropomyosin receptor kinase A (TrkA), compositions comprising such compounds, and the use of such compounds and compositions in medicine. In particular, the present invention relates to the use of such compounds and compositions in methods for the treatment and / or prevention of diseases or disorders in which negative modulation of TrkA is beneficial in human and animal subjects. In particular, the compounds are useful in the treatment of pain and disorders comprising pain and / or inflammation such as arthritis, and particularly osteoarthritis.Background of the InventionThe listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.The family of neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), Neurotrophin (NT)-3 and NT4, act as ligands to the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB and TrkC) (Reichardt, Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences

[2006] , 1545-64). In addition, each neurotrophin also bind to the common p75 neurotrophin receptor (p75NTR), a member of the tumor necrosis factor receptor superfamily (Underwood and Coulson, The International Journal of Biochemistry & Cell Biology

[2008] , 1664-68). NGF binds to TrkA with high affinity, but it can also bind NT3 with lower affinity. The neurotrophins are synthesized as pro-forms which subsequently are cleaved by different proteases to the mature form.Like many other members of the RTK-family, TrkA undergoes homodimerization upon binding of its ligand NGF. Ligand binding and dimerization leads to activation of the intracellular kinase domain of TrkA (Franco et aL, J Bio! Chem

[2020] , 275-86). Activation of the kinase activity of the receptor leads to phosphorylation of the receptor at several site, including tyrosine-residues at position 490, 674 / 675, 751 and 785. This phosphorylation leads to that adaptor binding to site that couples the receptor to SHC adaptor protein 1 (SHC-1), phosphoinositide 3-kinase (PI3K) and phospholipase Cyl (PLCyl) (Sofroniew, Howe, and Mobley, Annual Review of Neuroscience

[2001] , 1217-81). The coupling of adaptor proteins to the receptor initiates several different cellular events including proliferation, differentiation or pain signalling.TrkA-sianalling and painPain is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage. Pain can be broadly grouped into three categories including neuropathic pain, nociceptive pain and nociplastic pain. Neuropathic pain which is caused by a lesion or disease affecting the somatosensory system. Nociceptive pain arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors. Third, nociplastic pain arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors.The pain sensation involving the TrkA receptor can be attributed to both a peripheral mechanism and to a central acting mechanism since TrkA is located on both peripheral sensory neurons, dorsal root ganglia neurons and second order projections neurons (interneurons) (Pezet and McMahon, Annual Review of Neuroscience

[2006] , 507-38)(Barker et aL, J Pain Res

[2020] , 1223-41). In essence, pain is a result of direct or indirect activation of primary afferent sensory neurons leading to the transmission of an action potential via the DRG's to the CNS.Binding of NGF to TrkA is important for formation and survival of sympathetic ganglion neurons and for nociceptive sensory neurons (A delta- and C-fibers) in dorsal root ganglia during development. Patients with mutation in TrkA leading to a loss of function have intellectual disabilities, recurrent episodic fever, an inability to sweat and a lack of pain sensation as well as an inability to distinguish between heat and cold (Houlden et aL, Ann Neurol

[2001] , 521-25)(Indo, Clin Auton Res

[2002] , 120-32). Patients with a mutation in the NGF-gene (R100W) develop a normal CNS function but have a complete loss of pain sensation. Homozygotic carriers of R100W develop Charcot joints at an early age (Einarsdottir et aL, Human Molecular Genetics

[2004] , 799-805). Thus, the involvement of NGF / TrkA-signalling in pain sensation is well documented. The effects of NGF / TrkA signalling on pain can have both an acute / short-term effect and / or a chronic / long-term effect (Barker et aL, J. of Pain Research,

[2020] , 1223-1241).Chronic pain is poorly treated by conventional therapies and so it represents a large unmet medical need. A potential novel analgesic mechanism involves blocking the activity of the pain mediator nerve growth factor or its high affinity receptor TrkA. Anti-NGF antibody therapies in clinical development have shown significant effect in reducing pain in patients with osteoarthritis (OA), albeit with some unwanted side effects such as rapidly progressing OA in some patients (Zhang et al. The EMBO Journal, 2005, 24,4211-4223). Targeting the TrkA receptor may offer a more focussed way of disrupting the NGF signalling, thus avoiding side effects.It is known that NGF not only modulates the function and expression of stimulus transduction proteins such as TR.PV1 (Zhang, Huang, and McNaughton, The EMBO Journal

[2005] , 4211-23)(Bonnington and McNaughton, The Journal of Physiology

[2003] , 433-46) but also the expression and activity of voltage-gated channels. For instance, NGF up-regulates activity of voltage gated sodium channels (Brackenbury and Djamgoz, Journal of Cellular Physiology

[2007] , 602-8) , such as sodium channels Navi.7 (Toledo-Aral et aL, Proc Natl Acad Sci U S A

[1997] , 1527-32) (Diss et aL, Molecular and Cellular Neurosciences

[2008] , 537-47) and Navi.8 (Hameed, Molecular Pain

[2019] , 1744806919858801). In addition, TrkA activation can also indirectly lead to enhanced ion channel activity by release of sensitizing mediators from non-neuronal cells that express TrkA. For instance, NGF produces degranulation of mast cells (Horigome et aL, J Bio! Chem

[1993] , 14881-87) (Marshall et aL, The Journal of Immunology

[1999] , 4271) that will release a variety of sensitizing mediators including histamine, serotonin, bradykinin and NGF. Furthermore, in response to tissue injury and inflammation, NGF is released from other inflammatory cells in peripheral tissue including eosinophils, lymphocytes, macrophages, fibroblasts and keratinocytes (Minnone, Benedetti, and Bracci-Laudiero, Int J Moi Sci

[2017] )(Palazzo et aL, J Cell Physiol

[2012] , 1017-25)(Matsumura et aL, Journal of Dermatological Science

[2015] , 215-23). In experimental models of inflammation, including those induced by carrageenan and complete Freund's adjuvant, NGF is strongly upregulated and NGF lowering therapeutics have a beneficial effect (McMahon et aL, Nat Med

[1995] , 774-80; Woolf et aL, Br J Pharmacol

[1997] , 417-24) (Moller et aL, Eur J Pharmacol

[2015] , 75-84). When NGF is administered locally (Ashraf et aL, Ann Rheum Dis

[2014] , 1710-18) in rodents and humans, spontaneous pain can be observed and the thresholds to thermal and mechanical stimulation are reduced.Thus, NGF / TrkA signalling is associated with a range of biological processes associated with the pain sensation and reducing or inhibiting this signalling by negative modulation of the TrkA receptor is expected to be beneficial in the treatment of pain and pain disorders arising with a wide range of underlying causes.In particular, NGF signalling is known to be involved in pain in diseases affecting the joints, including osteoarthritis and rheumatoid arthritis. Osteoarthritis is a disease involving structures of the entire joint, usually knee or hip joints. Mechanical load and inflammatory process of the osteoarthritic joints leads to less resistance to damage and increased pain. The joints are innervated by both A6 and C-fibers which can mediatepain sensation. Increased NGF concentrations have been observed in both rheumatoid arthritis and osteoarthritis (Halliday et aL, Neurochemical Research

[1998] , 919-22)(Montagnoli et aL, Biol Chem

[2017] , 1045-54). Several animal models of arthritis have shown that anti-NGF treatments are effective in relieving pain symptoms (Ashraf et aL, Arthritis Res Ther

[2016] , 97)(M6ller et aL, European Journal of Pharmacology

[2015] , 75-84) .Other diseases comprising pain symptoms in which negative modulation of NGF / TrkA signalling is likely to be effective include: painful diabetic neuropathy (Dewanjee et aL, Eur J Pharmacol

[2018] , 472-523); migraine / chronic headache (Sarchielli and Gallai, Expert Review of Neurotherapeutics

[2004] , 115-27); peripheral neuropathic pain (Silva et aL, Behavioural Pharmacology

[2018] , 1); chemotherapy-induced peripheral neuropathy (Velasco et aL, Journal of Pain and Symptom Management

[2017] , 815-25); postherpetic neuralgia (Chang et aL, Journal of Pain Research

[2016] , 373-83); sciatic nerve pain (Ro et aL, Pain

[1999] , 265-74); trigeminal neuralgia (Reis et aL, Behav Pharmacol

[2016] , 528-35); abdominal pain (Xu, Liu, and Yao, Journal of Zhejiang University. Science. B

[2016] , 1-9); pain due to interstitial cystitis (painful bladder) (Kawamorita et aL, The Journal of Urology

[2016] , 1920-26)(Liu et aL, Iran. J. Basic Med. Sci.

[2023] , 701-7)(Hsiang, Girard, and Vizzard, Front. Urol.

[2023] , 1089220); complex regional pain syndrome (Sabsovich et aL, Pain

[2008] , 47-60); chronic pelvic pain syndrome (CPPS) including bladder pain syndrome / interstitial cystitis (BPS / IC) and pain associated with irritable bowel syndrome (IBS) (Guerios, Wang, and Bjorling, Neurosci Lett

[2006] , 193-97); chronic musculoskeletal pain (Jayabalan and Schnitzer, Expert Opin Biol Ther

[2017] , 245-54); myofascial pain syndrome (Hayashi et aL, J Pain

[2011] , 1059-68); pancreatitis pain (Friess et aL, Annals of Surgery

[1999] , 615); post-operative pain (Shelton and Vergara, issued 2005) (Zahn et aL, J Pain

[2004] , 157-63)(Majuta et aL, Pain

[2017] , 605-17); fracture pain (Rapp et aL, J Orthop Res

[2015] , 1235-41); bone cancer pain (Sevcik et aL, Pain

[2005] , 128-41); visceral pain

[0047] ; osteoarthritic pain (Schmelz et aL, Pain

[2019] , 2210-20); back pain / lower back pain ; inflammatory pain (McMahon et aL, Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences

[1996] , 431-40); neck pain (Sainoh et aL, Spine (Phila Pa 1976)

[2014] , E757-62); pain due to rheumatoid arthritis (Schmelz et aL, Pain,

[2019] , 160, 2210-2220); cancer pain (Zhu et aL, Journal of Clinical Oncology

[1999] , 2419-2419); pain associated with lumbar degenerative disc disease (Aoki et aL, Arthritis Research & Therapy

[2014] , R159-R159); pain associated with chronic prostatitis (Miller et aL, Urology

[2002] , 603-8); vulvodynia (Hesselink, Kopsky, and Sajben, J Pain Res

[2016] , 757-62); pain in sickle cell disease (Albo et aL, Blood

[2018] , 857-857); fibromyalgia (Favretti,lannuccelli, and Franco, Int. J. Mol. Sci.

[2023] , 10443); soft tissue trauma (strains) (Lee, Nature Communication

[2021] , 12(1), 4939); dysmenorrhea (Lee

[2022] , Journal of human genetics, 67, 449-458) erythromelalgia (Basbaum

[2009] , Cell, 139(2), 267-284) and burns (Summer

[2006] , The Journal of Pain, 12, 884-891).NGF / TrkA signalling is also known to be associated with a range of other diseases and disorders, such as those involving inflammatory components and / or disordered immune function. Some of the most relevant disorders are discussed below.Cardiovascular diseasesExpression of neurotrophins and their receptors are described in vascular smooth muscle cells (VSMCs), vascular endothelial cells and cardiomyocytes. Neurotrophins regulate angiogenesis, vasculogenesis and NGF promotes migration of VSMC's and thus, formation of intimal thickening and atherosclerotic plaque could be a consequence of the action of NGF and other neurotrophins (Ly et aL, Arthritis Research & Therapy

[2014] , 487-487). NGF is also expressed in the vascular inflammatory disease, giant cell arteritis and is suggested to be involved in the pathogenesis of vascular remodeling (Ibid.).Another inflammatory-driven disease is the Kawasaki disease which is characterized by vasculitis with a main complication being coronary artery aneurysm (Galeotti et aL, Autoimmun Rev

[2010] , 441-48). It has been reported that NGF levels in serum of patients with Kawasaki disease had 40-fold higher levels of NGF as compared to healthy aged-matched controls (Falcini et aL, J Rheumatol

[1996] , 1798-1802).Immunological disordersNGF and TrkA are abundantly expressed in different immune cells (Minnone, Benedetti, and Bracci-Laudiero, International Journal of Molecular Sciences,

[2017] , 18(5), 1028) ), airway bronchial cells (Othumpangat et aL, PLoS One

[2009] , e6444), olfactory epithelium (Feron et aL, Brain Res

[2008] , 13-21)(Mackay-Sima and Chuahb, Prog Neurobiol

[2000] , 527-59), and vascular smooth muscle cells (Caporali and Emanueli, Physio! Rev

[2009] , 279-308). Neurotrophin levels increase during allergic airway inflammation, and airway epithelial cells is the major source of NGF [ (Hahn et aL, Journal of Allergy and Clinical Immunology

[2005] , S194). NGF has been shown to affect lymphocyte functions, including inhibition of immunoglobulin production by plasma cells (Kimata et aL, Clin Immuno! Immunopatho!

[1991] , 145-51) but other effects have also been reported (Otten, Ehrhard, and Peck, Proc Natl Acad Sci U S A

[1989] , 10059-63). The function and degranulation of mast cells is also regulated byNGF (Marshall et aL, Journal of Immunology

[1999] , 162(7), 4271-4276), suggesting an immune-modulatory function or crosstalk of NGF in inflammatory responses.Thus, immunological disorders characterized by a dysfunction of the immune system such as autoimmune disorders, including rheumatoid arthritis, multiple sclerosis, hyperimmunoglobulin disorders, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), vasculitis, psoriasis, or other diseases with dysregulated immune response such as asthma, allergic rhinitis and atopic dermatitis, can involve disturbed levels of neurotrophins and could benefit from reduced TrkA signalling.Allergic inflammation, asthma and allergic asthmaThe receptors for NGF, BDNF or NT-3, TrkA, TrkB and TrkC, respectively, has been shown to be expressed in the respiratory tract, including bronchial respiratory epithelium (TrkA), lung macrophages (TrkB) and nasopharynx epithelium (TrkC) (Human Protein Atlas). Neurotrophin levels increase during allergic airway inflammation, and airway epithelial cells is the major source of NGF (Hahn et aL, Journal of Allergy and Clinical Immunology

[2005] , S194)(Hahn et aL, J Allergy Clin Immuno!

[2006] , 787-94). Several studies have identified increased levels of NGF in asthmatic patients (Barrios and Ai, Curr Allergy Asthma Rep

[2018] , 10) and NGF was found to be 35-fold higher in serum from patients with allergic asthma as compared to matched controls (Bonini et aL, Proc Natl Acad Sci U SA

[1996] , 10955-60). The highest NGF levels were found in patients with severe allergic asthma and bronchial hyperreactivity (Ibid.). Also, NGF levels has been shown to be increased in bronchoalveolar lavage fluid from asthmatic patients with the major sites of NGF expression being bronchial epithelium, smooth muscle cells and infiltrating inflammatory cells (Hoglund et aL, Eur RespirJ

[2002] , 1110-16). Interleukin-10 stimulation of bronchial smooth muscle cells leads to increased levels of NGF, independent of treatment with cyclooxygenase inhibitors (Kemi et aL, Respir Res

[2006] , 18). The anti-inflammatory drug dexamethasone reduces NGF expression in human eosinophils (Noga et aL, Regul Pept

[2005] , 74-79), suggesting that parts of the anti-inflammatory effects of dexamethasone could be mediated via reduced expression of NGF. Allergic inflammation in either the respiratory tract or in other tissues is a hallmark for diseases such as asthma and atopic dermatitis. Treatment of allergic inflammation with a selective TrkA inhibitor / NAM could be beneficial in diseases such as asthma, atopic dermatitis and esophagitis (Rochman and Rothenberg, issued 2016) or other diseases where allergic inflammation is a component.Infectious viral diseasesSeveral lines of evidence suggest that levels of neurotrophins are increased during viral infection of the upper respiratory tract (Falcini et al., Journal of Rheumatology

[1996] , 23(10), 1798-1802 (Tortorolo et aL, Am J Respir Crit Care Med

[2005] , 233-37)(Chiaretti et aL, Int J Infect Dis

[2013] , ell86-93). The replication of both influenza A and rhino viruses has been shown to be significantly reduced by inhibitors of receptor tyrosine kinases, including Trk-receptors or by reducing TrkA or NGF expression (Kumar et aL, J Virol

[2011] , 2818-27) (Othumpangat, Regier, and Piedimonte, Am J Physiol Lung Cell Mol Physiol

[2012] , L1057-66)(Mohtasham, Auais, and Piedimonte, Pediatr Pulmonol

[2007] , 496-504). Also, two different receptor tyrosine kinase inhibitors show broad-spectrum antiviral activity against influenza virus, Sendai virus, HSV-1, MHV coronavirus and rotavirus (Kumar et aL, Journal of Virology

[2011] , 85(6), 2818-2827)]. The upregulation of NGF is suggested to have an immuno-modulatory role in H1N1 infection and may contribute to airway inflammation and bronchial hyperreactivity in children (Chiaretti et aL, International Journal of Infectious disease

[2013] , 17(12)). Also, key components of herpes simplex virus type 2 (Cabrera et aL, PLoS Pathogens

[2015] , el004571-el004571) and porcine hemagglutinating encephalomyelitis virus, a highly neuronal virulent coronavirus, has been shown to interact with NGF / TrkA (Li et aL, Journal of Virology

[2018] , e00325-18). In humans infected by respiratory syncytial virus (RSV), NGF is increased in the cellular fraction of bronchoalveolar lavage and TrkA is only expressed in RSV-infected airway cells as compared to non-infected cells. These effects are suggested as major mechanisms behind viral-induced inflammatory response (Tortorolo et aL, "Neurotrophin Overexpression in Lower Airways of Infants with Respiratory Syncytial Virus Infection"). Furthermore, NGF stimulates HIV-1 replication in primary macrophages in a TrkA-dependent manner (Souza et aL, Blood

[2011] , 2944-52).The interference of viruses with NGF / TrkA-signaling could be linked to less apoptosis of host cells and to an immune-modulatory mechanism. Apoptosis limits viral replication and anti-apoptotic effect of NGF may favor viral replication by interfering with the apoptosis of infected cells, thereby allowing the persistence of viral infections. In fact, the genome of several avian pox virus contains genes encoding NGF orthologues (Afonso et aL, J Virol

[2000] , 3815-31), suggesting that NGF is of high importance for certain viruses.Psoriasis, atopic dermatitis, pruritus and skin inflammationNGF and TrkA are expressed by both neuronal and non-neuronal cells in the skin and it has been suggested that NGF / TrkA can play a role in different skin diseases skin (Lopez et aL, Anat Rec

[1998] , 371-83)(Morin and Misery, J Cutan Med Surg

[2019] , 528-36)(Paller, Kabashima, and Bieber, The Journal of Allergy and Clinical Immunology

[2017] , 633-43). UV-irradiation of human skin induces expression of NGF and TrkA, suggesting that the play a role in inflammation or sensitization of inflamed skin (Weinkauf et aL, PLoS ONE

[2012] ). Topical administration of the Trk-inhibitor CT-327 (aka SNA-120, Pegcantratinib) is currently the most advanced Trk inhibitor for the treatment of psoriasis and pruritus, and it has reached phase II clinical trials.OncologyBiological effects of NGF and TrkA-signaling have been reported during cancers of varying origin, related to cancer generation, progression, prognosis, signaling in cancer cells, cancer microenvironment, cancer-associated neuroplasticity, and cancer associated pain (Demiret aL, Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

[2016] , 37-50). This would indicate that inhibition of TrkA signaling could be an efficient way the treat different forms of cancer. The discovery of NTRK gene fusions in cancer has revealed these fusion genes as oncogenic in different solid tumor malignancies, in a manner similar to other oncogenic fusion proteins such as ALK and ROS1 (Cocco, Scaltriti, and Drilon, Nature Reviews. Clinical Oncology

[2018] , 731-47) (Kheder and Hong, Clin Cancer Res

[2018] , 5807-14)(Amatu et aL, Annals of Oncology : Official Journal of the European Society for Medical Oncology

[2019] , viii5— 15)(Bilenker, Naarden, and Nanda, issued 2019) but also in hematological malignancies (Joshi et aL, Leukemia

[2019] , 2563-74) and allowed development of Larotectinib for the treatment of NTRK-fusion driven solid tumors (Federman and McDermott, Expert Rev Clin Pharmacol

[2019] , 931-39).Treatment of malignancies that are driven by a TrkA-fusion protein, with either the wild-type TrkA kinase domain or with different mutated variants thereof fused to different proteins including but not limited to those described previously, could be beneficial with a selective TrkA-inhibitor / NAM either alone or in combination with other treatments such as immuno-based therapies.Existing Trk enzyme and TrkA inhibitorsInhibitors of kinases have been categorized into different types with respect to binding modality: Type I inhibitors bind in the ATP pocket to the active receptor conformation with the Asp-Phe-Gly (DFG) motif in the DFG-IN-conformation. Type II inhibitors bindto the kinase in the inactive conformation (DFG-out) which gives access to a less conserved region. Type III inhibitors bind to an allosteric site not overlapping with the ATP binding pocket or the DFG-motif. Type IV inhibitors binds to an allosteric distant from the ATP-binding site (Wu, Clausen, and Nielsen, Pharmacology & Therapeutics

[2015] , 59-68).Several compounds have been described as ATP competitive non-selective Trk inhibitors (Thress et aL, Mol Cancer Ther

[2009] , 1818-27)(Skerratt et aL, Journal of Medicinal Chemistry, 2016)(Bailey et aL, Expert Opinion on Therapeutic Patents

[2020] , 325-39)(Bagal et aL, Journal of Medicinal Chemistry

[2018] , 6779-6800). ATP-competitive Trk inhibitors (type I) are not selective due to the similarity of the ATP pocket between TrkA, TrkB and TrkC, and also between other RTK's. A very large majority of the inhibitors reported in the literature are likely to be unselective type I binders. However, selectivity for the TrkA receptor over the TrkB and TrkC receptors is highly desirable as negative modulation or inhibition of these receptors is associated with side effects including weight gain and CNS side effects, including impaired cognition.Non-ATP competitive (NAC) inhibitors (Type III or Type IV) or negative allosteric modulators (NAMs) have also been described for kinases (Lesuisse et aL, Bioorg Med Chem Lett

[2011] , 2224-28)(Bhullar et aL, Molecular Cancer

[2018] , 48-48) (Bagal et aL, J Med Chem

[2019] , 247-65). NAC-inhibitors binds to a site distinct from the conserved ATP binding site, thus having the potential to be more selective than the Type I inhibitors.Selective allosteric inhibitors or NAMs have been reported for TrkA including AR786 (Nwosu et aL, Annals of the Rheumatic Diseases

[2016] , 1246-54)(Ashraf et aL, "Selective Inhibition of Tropomyosin-Receptor-Kinase A (TrkA) Reduces Pain and Joint Damage in Two Rat Models of Inflammatory Arthritis" Arthritis Res Ther.

[2016] , 18(1) :97) , several compounds from Pfizer (Bagal et aL, "Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors" J. Med. Chem.

[2018] , 62, 247-265) and compounds from Merck (Su et aL, Proceedings of the National Academy of Sciences

[2017] 114(3), E297-E306). Some of the TrkA-selective compounds has been demonstrated to bind to a site distant from the ATP-binding site but close to the juxtamembrane region (Furuya et aL, Bioorg Med Chem Lett

[2017] , 1233-36).In addition, antibodies that bind to both NGF or TrkA are well described in the literature. An anti-TrkA monoclonal antibody (MNAC-13) with analgesic potential was reported(Ugolini et aL, Proceedings of the National Academy of Sciences

[2007] , 2985). MNAC13 displayed analgesic efficacy in two mouse models of pain (formalin and chronic constriction injury). The humanized anti-NGF antibodies Tanezumab and Fasinumab are two out of several examples of anti-NGF antibodies that has demonstrated analgesic effect in both animals (Enomoto et aL, The Veterinary Record

[2019] , 23-23) and humans (Birbara et aL, Journal of Pain Research

[2018] , 151-64)(Dakin et aL, Arthritis & Rheumatology

[2019] , 1824-34)(Berenbaum et aL, Ann Rheum Dis

[2020] , 800-810).Small molecule allosteric TrkA inhibitors (negative allosteric modulators) have also been described in many patent documents, including WO 2012 / 125667, WO 2012 / 125668, WO 2013 / 009582, WO 2013 / 176970, WO 2015 / 039334, WO 2015 / 042085, WO 2015 / 042088, WO 2015 / 039333, WO 2015 / 143652, WO 2015 / 148350, WO 2015 / 143563, WO 2015 / 148354, WO 2015 / 148344, WO 2015 / 148373, WO 2015 / 143654, WO 2015 / 159175, WO 2015 / 170218, WO 2015 / 175788, WO 2016 / 054807, WO 2016 / 161572 and WO 2016 / 161572.However, despite the large amount of research effort in the field, many existing small molecule TrkA inhibitors and negative allosteric modulators are insufficiently potent and / or insufficiently selective for the TrkA receptor, and, in view of this, although much research has been done in the field, few compounds have progressed into late stage development. Moreover, as mentioned above, anti-NGF antibodies are known to have unwanted side effects.Given this, there is a need for new potent and selective small molecule negative allosteric modulators, or allosteric inhibitors, of the TrkA receptor. Additionally, such small molecules should be peripherally restricted (i.e. have low penetration into the central nervous system) as reducing TrkA signalling in the CNS can lead to side effects including impaired cognition, and preferably have good solubility, which is desirable for oral bioavailability.Detailed Description of the InventionIt has now surprisingly been found that certain compounds of formula I, as described herein, and pharmaceutically acceptable salts thereof, are highly potent and selective negative allosteric modulators of the TrkA receptor, and have been shown to have analgesic and anti-inflammatory effects in a range of animal models, including an osteoarthritis model, and NGF-induced inflammation model and nociceptive andneuropathic pain models. Additionally, the compounds have low penetration into the CNS as a result of their large size (molecular weight above 500 gmol-1) and high polar surface area, and have good aqueous solubility.Thus, the compounds described herein are useful as pharmaceuticals or veterinary medicines in the treatment of diseases or disorders in which negative modulation of the TrkA receptor is beneficial. In particular, the compounds are believed to be useful in the treatment of pain and pain disorders, including particularly degenerative joint disorders, such as arthritis and more particularly osteoarthritis, and the pain and inflammation associated therewith. The compounds are also believed to have beneficial effects in the treatment of certain cardiovascular disorders, immunological disorders, inflammatory disorders, infectious viral diseases and cancers in which negative modulation of the TrkA receptor is beneficial.of the inventionIn a first aspect of the invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof,wherein:R1is selected from hydrogen and a fluoro group;R2is selected from hydrogen and a C1-3 alkyl group, which C1-3 alkyl group is optionally substituted by one or more fluoro group;A is selected from -N- and -C(RA)-; wherein RAis selected from hydrogen and a fluoro group;X and Y are each independently selected from the group consisting of a -CH2- group, a -CHMe- group and a -CMe?- group, which three groups are optionally substituted by one or more fluoro groups;R3is selected from the group consisting of hydrogen, fluoro, chloro, a C1-3 alkyl group and a C1-3 alkoxy group, which C1-3 alkyl and C1-3 alkoxy groups are optionally substituted by one or more fluoro group;R4and R5are each independently selected from the group consisting of fluoro, chloro and a C1-3 alkyl group, which C1-3 alkyl group is optionally substituted by one or more fluoro group;n is selected from 0, 1 and 2;m is selected from 0, 1, 2, 3 and 4;R5is selected from hydrogen, -C(O)R7and a 5-6-membered heteroaryl group, which 5-6-membered heteroaryl group is optionally substituted by one or more groups selected from the group consisting of a fluoro group, a chloro group, a cyano group, a C1-3 alkyl group and a C1-3 alkoxy group, which C1-3 alkyl and C1-3 alkoxy groups are optionally substituted by one or more fluoro group; andR7is selected from a C1-6 alkyl group and a C3-6 cycloalkyl group, which C1-6 alkyl and C3-6 cycloalkyl groups are optionally substituted by one or more fluoro group, which compounds (including pharmaceutically acceptable salts thereof) may be referred to herein as the "compounds of the invention".For the avoidance of doubt, the skilled person will understand that references herein to compounds of particular aspects of the invention (such as the first aspect of the invention, i.e. referring to compounds of formula I as defined in the first aspect of the invention) will include references to all embodiments and particular features thereof, which embodiments and particular features may be taken in combination to form further embodiments and features of the invention.Unless indicated otherwise, all technical and scientific terms used herein will have their common meaning as understood by one of ordinary skill in the art to which this invention pertains.As used herein, pharmaceutically acceptable salts include acid addition salts and base addition salts that are suitable for use in human and / or veterinary medicine. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared using techniques known to those skilled in the art, such as by exchanging a counterion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.Particular acid addition salts that may be mentioned include those formed by reaction with corresponding acids, thus protonating the compound of the invention, to form carboxylate salts (e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, a-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxy-benzoate, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, hippurate, phthalate or terephthalate salts), halide salts (e.g. chloride, bromide or iodide salts), sulphonate salts (e.g. benzenesulphonate, methyl-, bromo- or chloro-benzenesulphonate, xylenesulphonate, methanesulphonate, ethanesulphonate, propanesulphonate, hydroxy-ethanesulphonate, 1- or 2-naphthalene-sulphonate or 1,5-naphthalene-disulphonate salts) or sulphate, pyrosulphate, bisulphate, sulphite, bisulphite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate or nitrate salts, and the like.Particular base addition salts that may be mentioned include salts formed by reaction with corresponding bases, thus removing a proton from compounds of the invention, to form salts with alkali metals (such as Na and K salts), alkaline earth metals (such as Mg and Ca salts), organic bases (such as ethanolamine, diethanolamine, triethanolamine, tromethamine, lysine and arginine) and inorganic bases (such asammonia and aluminium hydroxide). More particularly, base addition salts that may be mentioned include Mg, Ca and, most particularly, K and Na salts.For the avoidance of doubt, compounds of the invention may exist as solids, and thus the scope of the invention includes all amorphous, crystalline and part crystalline forms thereof, and may also exist as oils. Where compounds of the invention exist in crystalline and part crystalline forms, such forms may include solvates, which are included in the scope of the invention.For the avoidance of doubt, compounds of the invention may also exist in solution (i.e. in solution in a suitable solvent). For example, compounds of the invention may exist in aqueous solution, in which case compounds of the invention may exist in the form of hydrates thereof.Compounds of the invention may contain double bonds and, unless otherwise indicated, may thus exist as E entgegen) and Z zusammen) geometric isomers about each individual double bond. Unless otherwise specified, all such isomers and mixtures thereof are included within the scope of the invention.Compounds of the invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention (particularly those of sufficient stability to allow for isolation thereof).Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and / or diastereoisomerism (i.e. existing in enantiomeric or diastereomeric forms). Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers (i.e. enantiomers) may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired enantiomer or diastereoisomer may be obtained from appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a 'chiral pool' method), by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution; for example, with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography), or by reaction with an appropriate chiral reagent or chiral catalyst, all of which methods and processes may be performed under conditions known to the skilled person. Unlessotherwise specified, all stereoisomers and mixtures thereof are included within the scope of the invention.For the avoidance of doubt, the skilled person will understand that where a particular group is depicted herein as being bound to a ring system via a floating bond (i.e. a bond not shown as being bound to a particular atom within the ring), the relevant group may be bound to any suitable atom within the relevant ring system (i.e. the ring within which the floating bond terminates).Unless otherwise specified, or it is clear from context, Ci-Zalkyl groups (where z is an integer specifying the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain, and / or, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic (so forming a C4-z partial cycloalkyl group). Similarly, part cyclic alkyl groups (which may also be referred to as "part cycloalkyl" groups) that may be mentioned include cyclopropylmethyl. When there is a sufficient number of carbon atoms, such groups may also be multicyclic (e.g. bicyclic or tricyclic) and / or spirocyclic. For the avoidance of doubt, particular alkyl groups that may be mentioned include straight chain (i.e. not branched and / or cyclic) alkyl groups.Unless otherwise specified, C2-Z alkenyl groups (where z is an integer specifying the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms, be branched-chain, and / or cyclic (so forming a C4-z cycloalkenyl group). When there is a sufficient number (i.e. a minimum of five) of carbon atoms, such groups may also be part cyclic. For example, part cyclic alkenyl groups (which may also be referred to as "part cycloalkenyl" groups) that may be mentioned include cyclopentenylmethyl and cyclohexenylmethyl. When there is a sufficient number of carbon atoms, such groups may also be multicyclic (e.g. bicyclic or tricyclic) or spirocyclic. For the avoidance of doubt, particular alkenyl groups that may be mentioned include straight chain (i.e. not branched and / or cyclic) alkenyl groups.Unless otherwise specified, C2-Z alkynyl groups (where z is an integer specifying the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, be branched-chain. For the avoidance of doubt, particular alkynyl groups that may be mentioned include straight chain (i.e. not branched and / or cyclic) alkynyl groups.For the avoidance of doubt, unless otherwise specified, groups referred to herein as "alkyl", "alkenyl" and / or "alkynyl" will be taken as referring to the highest degree of unsaturation in a bond present in such groups. For example, such a group having a carbon-carbon double bond and, in the same group, a carbon-carbon triple bond will be referred to as "alkynyl". Alternatively, it may be particularly specified that such groups will comprise only the degree of unsaturation specified (i.e. in one or more bond therein, as appropriate; e.g. in one bond therein).For the avoidance of doubt, C3-Z cycloalkyl groups (wherein z is an integer specifying the upper limit of the range) may be understood to be 'fully cyclic' groups in which all of the carbon atoms within the group are contained within the ring structure. For example, cycloalkyl groups that may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.For the avoidance of doubt, alkyl, alkenyl and alkynyl groups as described herein may also act as linker groups (i.e. groups joining two or more parts of the compound as described), in which case such groups may be referred to as "alkylene", "alkenylene" and / or "alkynylene" groups, respectively.For the avoidance of doubt, as used herein, references to heteroatoms will take their normal meaning as understood by one skilled in the art. Particular heteroatoms that may be mentioned include phosphorus, selenium, tellurium, silicon, boron, oxygen, nitrogen and sulfur (e.g. oxygen, nitrogen and sulfur, such as oxygen and nitrogen).As used herein, the term heterocycloalkyl may refer to non-aromatic monocyclic and (if a sufficient number of atoms may be present) polycyclic (e.g. bicyclic) saturated heterocyclic groups (which groups may, where containing a sufficient number of atoms, also be bridged) in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between three and twelve (e.g. between five and ten, such as between three and eight; for example, forming a 5- or 6-membered heterocycloalkyl group)..As used herein, heterocycloalkyl groups may (if they are are of sufficient size) also contain double or triple bonds, the term heterocycloalkyl therefore may also be understood to include heterocycloalkenyl and heterocycloalkynyl groups.For the avoidance of doubt, the skilled person will understand that heterocycloalkyl groups that may form part of compounds of the invention are those that are chemicallyobtainable, as known to those skilled in the art. Various heterocycloalkyl groups will be well-known to those skilled in the art, such as 7-azabicyclo-[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]-octanyl, 8-azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl, dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, isothiazolidinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]-octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetra hydropyranyl, tetra hydrofuryl, thietanyl, thiiranyl, thiolanyl, tetrahydrothiopyranyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl and the like.Substituents on heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. Further, in the case where the substituent is another cyclic compound, then the cyclic compound may be attached through a single atom on the heterocycloalkyl group, forming a spirocyclic compound. The point of attachment of heterocycloalkyl groups may be via any suitable atom in the ring system, including (where appropriate) a further heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in the / V- or S- oxidised forms, as known to those skilled in the art.At each occurrence when mentioned herein, particular heterocycloalkyl groups that may be mentioned include 3- to 8-membered heterocycloalkyl groups (e.g. a 4- to 6-membered heterocycloalkyl group, such as a 5- or 6- membered heterocycloalkyl group). Most particularly, heterocycloalkyl groups will include oxygen containing heterocloalkyl groups, such as tertrahydropyran.For the avoidance of doubt, references to polycyclic (e.g. bicyclic or tricyclic) groups (for example when employed in the context of heterocycloalkyl or cycloalkyl groups (e.g. heterocycloalkyl)) will refer to ring systems wherein at least two scissions would be required to convert such rings into a non-cyclic (i.e. straight or branched) chain, with the minimum number of such scissions corresponding to the number of rings defined (e.g. the term bicyclic may indicate that a minimum of two scissions would be required to convert the rings into a straight chain). For the avoidance of doubt, the term bicyclic (e.g. when employed in the context of alkyl groups) may refer to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring, to groups in which two non-adjacent atoms are linked by an alkyl(which, when linking two moieties, may be referred to as alkylene) group (optionally containing one or more heteroatoms), which later groups may be referred to as bridged, or to groups in which the second ring is attached to a single atom, which latter groups may be referred to as spiro compounds.As may be used herein, references to heteroaryl (with may also be referred to as heteroaromatic) groups may refer to 5- to 14- (e.g. 5- to 10-) membered heteroaromatic groups containing one or more heteroatoms (such as one or more heteroatoms selected from oxygen, nitrogen and / or sulfur). Such heteroaryl groups may comprise one, two, or three rings, of which at least one is aromatic. Substituents on heteroaryl / heteroaromatic groups may, where appropriate, be located on any suitable atom in the ring system, including a heteroatom (e.g. on a suitable N atom). More particularly, the ring size of the relevant heteroaryl group is specified (e.g. a 5-6-membered heteroaryl group).The point of attachment of heteroaryl / heteroaromatic groups may be via any atom in the ring system including (where appropriate) a heteroatom. Bicyclic heteroaryl / heteroaromatic groups may comprise a benzene ring fused to one or more further aromatic or non-aromatic heterocyclic rings, in which instances, the point of attachment of the polycyclic heteroaryl / heteroaromatic group may be via any ring including the benzene ring or the heteroaryl / heteroaromatic or heterocycloalkyl ring.For the avoidance of doubt, the skilled person will understand that heteroaryl groups that may form part of compounds of the invention are those that are chemically obtainable, as known to those skilled in the art. Various heteroaryl groups will be well-known to those skilled in the art, such as pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, imidazothiazolyl, thienothiophenyl, pyrimidinyl, furopyridinyl, indolyl, azaindolyl, pyrazinyl, pyrazolopyrimidinyl, indazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl and purinyl.For the avoidance of doubt, the oxides of heteroaryl / heteroaromatic groups are also embraced within the scope of the invention (e.g. the N-oxide).As stated above, heteroaryl includes polycyclic (e.g. bicyclic) groups in which one ring is aromatic (and the other may or may not be aromatic). Hence, other heteroaryl groups that may be mentioned include groups such as benzo[l,3]dioxolyl, benzo[l,4]dioxinyl, dihydrobenzo[d]isothiazole, 3,4 dihydrobenz[l,4]oxazinyl, dihydrobenzothiophenyl,indolinyl, 5H,6H,7H-pyrrolo[l,2-b]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, thiochromanyl and the like.Particular heteroaryl groups that may be mentioned include 5-6-membered nitrogencontaining heteroaryl groups, such as pyridinyl groups, pyridazinyl groups, pyramidinyl groups, pyrazinyl groups, pyrrolyl groups, pyrazolyl groups, oxazolyl groups, isoxazolyl groups, thiazolyl groups, isothiazolyl groups, triazinyl groups and tetrazolyl groups.For the avoidance of doubt, where a ring is depicted having circle therein, its presence shall indicate that the relevant ring is aromatic. Alternatively, aromatic groups may be depicted as cyclic groups comprising therein a suitable number of double bonds to allow for aromaticity.The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention. Hence, the compounds of the invention also include deuterated compounds, i.e. compounds of the invention in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of the invention may be the same, the actual identities of the respective substituents are not in any way interdependent.Also for the avoidance of doubt, when a term such as "1 to 6", or similarly, 1-6 is employed herein, this will be understood by the skilled person to mean 1, 2, 3, 4, 5 and 6 inclusively. Unless otherwise stated, the same reasoning will apply to other such terms used herein.Further for the avoidance of doubt, when it is specified that a substituent is itself optionally substituted by one or more substituents (e.g. alkyl, aryl or heteroaryl optionally substituted by one or more groups independently selected from fluoro, chloro and methoxy), these substituents where possible may be positioned on the same or different atoms. Such optional substituents may be present in any suitable numberthereof (e.g. the relevant group may be substituted with one or more such substituents, such as one such substituent).For the avoidance of doubt, where groups are referred to herein as being optionally substituted it is specifically contemplated that such optional substituents may be not present (i.e. references to such optional substituents may be removed), in which case the optionally substituted group may be referred to as being unsubstituted.Where used herein, a dashed or wavy bond (i.e. " - " or"-~w " or the like) may indicate the position of attachment of the relevant substituent to the core molecule (i.e. the compound of the compound of formula I to which the substituent is attached).For the avoidance of doubt, the skilled person will appreciate that compounds of the invention that are the subject of this invention include those that are obtainable, i.e. those that may be prepared in a stable form. That is, compounds of the invention include those that are sufficiently robust to survive isolation, e.g. from a reaction mixture, to a useful degree of purity.In particular embodiments (i.e. particular embodiments of the first aspect of the invention) that may be mentioned, the compound of formula I is such that R1is hydrogen. In other embodiments, the compound of formula I is such that R1is a fluoro group.In particular embodiments that may be mentioned, the compound of formula I is such that R2is selected from hydrogen and a C1-2 alkyl group, which C1-2 alkyl group is optionally substituted by one or more fluoro group. More particularly, R2is selected from hydrogen and a methyl group, which methyl group is optionally substituted by one or more fluoro group (for example, an unsubstituted methyl group). In still more particular embodiments, R2is a methyl group.In particular embodiments that may be mentioned A is -C(RA)-, and RAis hydrogen.In particular embodiments that may be mentioned, the compound of formula I is such that X and Y are each independently selected from -CH2- and -CHMe-, both of which groups are optionally substituted by one or more fluoro groups. More particularly, X and Y are each independently a -CH2- group, which -CH2- group is optionally substituted by one or more fluoro groups. Most particularly, X and Y are each an unsubstituted -CH2- group.In particular embodiments that may be mentioned, the compound of formula I is such that R3is selected from the group consisting of hydrogen, fluoro, chloro, a C1-2 alkyl group and a C1-2 alkoxy group, which C1-2 alkyl and C1-2 alkoxy groups are optionally substituted by one or more fluoro group. More particularly, R3is selected from the group consisting of hydrogen a fluoro group, a methyl group and a methoxy group, which methyl and methoxy groups are optionally substituted by one or more fluoro groups. Yet more particularly, R3is selected from hydrogen, a methyl group and a methoxy group.In further particular embodiments that may be mentioned, R3is a methyl group.In particular embodiments that may be mentioned, R4and R5are independently selected from the group consisting of fluoro group, a chloro group and a C1-2 alkyl group, which C1-2 alkyl group is optionally substituted by one or more fluoro groups. More particularly, R4and R5are each independently selected from the group consisting of a fluoro group and a methyl group, which methyl group is optionally substituted by one or more fluoro groups. Yet more particularly, R4and R5are each a methyl or fluoro group.In other particular embodiments that may be mentioned, the compound of formula I is such that n is selected from 0, 1 and 2 and m is selected from 0, 1 and 2. More particularly, n is selected from 0 or 1 and / or (e.g. and) m is selected from 0 or 1. Yet more particularly, n is 0 and / or (e.g. and) m is 0.Most particularly, in the compound of formula I, n and m both represent 0 and therefore R4and R5are not present.In particular embodiments that may be mentioned, the compound of formula I is such Othat R5is -C(O)R7(which, for the avoidance of doubt, may also be drawn as ).In particular embodiments that may be mentioned, the compound of formula I is such that R7is a C1-6 alkyl group, which C1-6 alkyl group is optionally substituted by one or more fluoro group. More particularly, R7is a C1-4 alkyl group (e.g. a C1-3 alkyl group), which C1-4 alkyl group (or C1-3 alkyl group) is optionally substituted by one or more fluoro group. Yet more particularly, R7is selected from a methyl and an ethyl group.In further particular embodiments that may be mentioned, the compound of formula I is such that R5is a 5-6-membered heteroaryl group, which 5-6 membered heteroaryl group is optionally substituted by one or more groups selected from the group consisting of a fluoro group, a chloro group, a cyano group, a C1-3 alkyl group and a Ci-3 alkoxy group, which C1-3 alkyl and C1-3 alkoxy groups are optionally substituted by one or more fluoro group. More particularly, the (optionally substituted) 5-6-membered heteroaryl group contains at least one nitrogen atom. Yet more particularly, the (optionally substituted) 5-6-membered heteroaryl group contains a nitrogen atom in the 2-position (ortho-position) relative to the point of attachment of the group to the sulfonamide nitrogen atom (in the compound of formula I).Particular (optionally substituted) 5-6-membered heteroaryl groups that may be mentioned include pyridinyl groups, pyridazinyl groups, pyramidinyl groups, pyrazinyl groups, pyrrolyl groups, pyrazolyl groups, imidazolyl groups, oxazolyl groups, isoxazolyl groups, thiazolyl groups, isothiazolyl groups, triazinyl groups and tetrazolyl groups, all of which groups are optionally substituted by one or more groups selected from the group consisting of a fluoro group, a chloro group, a cyano group, a C1-3 alkyl group and a C1-3 alkoxy group, which C1-3 alkyl and C1-3 alkoxy groups are optionally substituted by one or more fluoro group.In embodiments in which R5is a 5-6-membered heteroaryl group, such 5-6-membered heteroaryl groups are preferably attached to the nitrogen atom of the sulfonamide group, such that the nitrogen atom in the heteroaryl group (or one of the nitrogen atoms if more than one nitrogen atom is present in the group) is in the ortho-position relative to the point of attachment of the group to the sulfonamide nitrogen atom (in the compound of formula I).Accordingly, in particular embodiments, the 5-6-membered heteroaryl group in the R5position is selected from the group shown below.wherein represents the point of the attachment to the sulfonamide nitrogen, and each heteroaryl group is optionally substituted by one or more groups selected from the group consisting of a fluoro group, a chloro group, a cyano group a C1-3 alkyl group and a Ci-3 alkoxy group, which C1-3 alkyl and C1-3 alkoxy groups are optionally substituted by one or more fluoro group.In particular embodiments, the 5-6-membered heteroaryl group in the R5position is selected from the group shown below:wherein represents the point of the attachment to the sulfonamide nitrogen, and each heteroaryl group is optionally substituted by one or more groups selected from the group consisting of a fluoro group, a chloro group, a cyano group, a C1-3 alkyl group and a Ci-3 alkoxy group, which C1-3 alkyl and C1-3 alkoxy groups are optionally substituted by one or more fluoro group.In yet more particular embodiments, the 5-6-membered heteroaryl group in the R5position is selected from the group consisting of:wherein represents the point of the attachment to the sulfonamide nitrogen, and each heteroaryl group is optionally substituted by one or more groups selected from the group consisting of a fluoro group, a chloro group, a cyano group, a C1-3 alkyl group and a Ci-3 alkoxy group, which C1-3 alkyl and C1-3 alkoxy groups are optionally substituted by one or more fluoro group.In yet more particular embodiments, the 5-6-membered heteroaryl group in the R5position is selected from the group consisting of:wherein represents the point of the attachment to the sulfonamide nitrogen, and each heteroaryl group is optionally substituted by one or more groups selected from the group consisting of a fluoro group, a chloro group, a cyano group, a C1-3 alkyl group and a Ci-3 alkoxy group, which C1-3 alkyl and C1-3 alkoxy groups are optionally substituted by one or more fluoro group.5-6-membered heteroaryl groups in the R5position of the compounds of the invention are optionally substituted by one or more groups selected from the group consisting of a fluoro group, a chloro group, a cyano group, a C1-3 alkyl group (for example a C1-2 alkyl group, e.g. methyl) and a C1-3 alkoxy group (for example a C1-2 alkoxy group, e.g. methoxy), which C1-3 alkyl (for example a C1-2 alkyl group, e.g. methyl) and C1-3 alkoxy groups (for example a C1-2 alkoxy group, e.g. methoxy), are optionally substituted by one or more fluoro group. More particularly, such heteroaryl groups are optionally substituted by one or more groups selected from a fluoro group, a cyano group, a methyl group, a trifluoromethyl group, a methoxy group and a trifluoromethoxy group. In further particular embodiments, the 5-6-membered heteroaryl group in the R7position of the compounds of the invention is unsubstituted.In particular embodiments that may be mentioned, in the compound of formula I, n and m both represent 0 and therefore R4and R5are not present. In such embodiments, the compound of formula I may be drawn as a compound of formula IAwherein R1, R2, R3, R5, A, X and Y are as defined herein.In further particular embodiments that may be mentioned, the compound of formula I is such that:n and m both represent 0 and therefore R4and R5are not present; andX and X and Y each represent a -CH2- group (i.e. unsubstituted). In such embodiments, the compound of formula I, may be drawn as a compound of formula IBwherein R1, R2, R3, R5and A are as defined herein.In particular embodiments that may be mentioned, there is provided a compound of formula I, IA or IB (as defined herein) wherein:R1is selected from hydrogen and a fluoro group;R2is selected from hydrogen and a methyl group (e.g. a methyl group)A is selected from -N- and -CRA-, wherein RArepresents hydrogen or fluoro R4and R5(if present) are independently selected from a fluoro group and a methyl group;X and Y (if present) are independently a -CH2- group, which -CH2- group is optionally substituted by one or more fluoro groups;R3is selected from the group consisting of hydrogen a fluoro group, a methyl group and a methoxy group, which methyl and methoxy groups are optionally substituted by one or more fluoro groups;R4and R5(if present) are independently selected from a fluoro group and a methyl group;n and m (if present) are each independently selected from 0, 1 and 2;R5is selected from hydrogen and -C(O)R7(e.g. -C(O)R7); andR7is a C1-6 alkyl group (e.g. a C1-4 alkyl group), which C1-6 alkyl group (e.g a C1-4 alkyl group) is optionally substituted by one or more fluoro group.Particular compounds of the invention that may be mentioned include those compounds as described in the examples provided herein, and pharmaceutically acceptable salts thereof. For the avoidance of doubt, where such compounds of the invention include compounds in a particular salt form, compounds of the invention include those compounds in non-salt form and in the form of any pharmaceutically acceptable salt thereof (which may include the salt form present in such examples).Thus, particular compounds of the invention that may be mentioned include:N-{p-[6-({[(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-3-pyridyl]phenylsulfonyl}acetamide;N-{p-[6-({[(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-2-methyl-3-pyridyl]phenylsulfonyl}acetamide;N-{p-[6-({[(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-2-methoxy-3-pyridyl]phenylsulfonyl}acetamide;N-{p-[6-({[(6-fluoro-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl]carbonylamino} methyl)-2-methyl-3-pyridyl]phenylsulfonyl}acetamide;N-{p-[6-({[(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-3-pyridyl] phenylsulfonyl} propionamide;N-{p-[6-({[(3,6-difluoro-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl]carbonylamino} methyl)-2-methyl-3-pyridyl]phenylsulfonyl}acetamide;N-{p-[6-({[(6-fluoro-2-methyl-10-oxa-l,3,9-triaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-2-methyl-3-pyridyl]phenylsulfonyl}acetamide;N-{p-[6-({[(6,7-difluoro-2-methyl-10-oxa-l,3,9-triaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-2-methyl-3-pyridyl]phenylsulfonyl}acetamide;N-{p-[2-fluoro-6-({[(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-3-pyridyl]phenylsulfonyl}acetamide;N-{p-[6-({[(6,7-difluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-2-methyl-3-pyridyl]phenylsulfonyl}acetamide;N-{p-[6-({[(6,7-difluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-3-pyridyl]phenylsulfonyl}acetamide,p-[6-({[(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl]carbonylamino} methyl)-2-methyl-3-pyridy I] benzenesulfonamideN-({6-methyl-5-[p-(3-pyridazinylaminosulfonyl)phenyl]-2-pyridyl}methyl)(6-fluoro- 2-methyl-10-oxa-l,3,9-triaza-9H-anthr-9-yl)acetamide;N-({6-methyl-5-[p-(3-pyridazinylaminosulfonyl)phenyl]-2-pyridyl}methyl)(6-fluoro- 2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)acetamide.and pharmaceutically acceptable salts thereof.More particular compounds of the invention that may be mentioned include:N-{p-[6-({[(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-2-methyl-3-pyridyl]phenylsulfonyl}acetamide;N-{p-[2-fluoro-6-({[(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-3-pyridyl]phenylsulfonyl}acetamide;N-{p-[6-({[(6,7-difluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-2-methyl-3-pyridyl]phenylsulfonyl}acetamide;N-({6-methyl-5-[p-(3-pyridazinylaminosulfonyl)phenyl]-2-pyridyl}methyl)(6-fluoro- 2-methyl-10-oxa-l,3,9-triaza-9H-anthr-9-yl)acetamide;N-({6-methyl-5-[p-(3-pyridazinylaminosulfonyl)phenyl]-2-pyridyl}methyl)(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)acetamide;and pharmaceutically acceptable salts thereof.Medical usesAs indicated herein, the compounds of the invention, and therefore compositions and kits comprising the same, are useful as human and veterinary pharmaceuticals.Thus, according to a further aspect of the invention there is provided a compound of the invention, as hereinbefore defined (i.e. a compound as defined in the first aspect of the invention, including all embodiments and particular features thereof), for use as a pharmaceutical (or for use in human or veterinary medicine).For the avoidance of doubt, references to compounds as defined in the first aspect of the invention will include references to compounds of formula I (including all embodiments thereof) and pharmaceutically acceptable salts thereof.Although compounds of the invention may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. "protected") derivatives of compounds of the invention may exist or be prepared which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to form compounds of the invention. Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the active compounds to which they are metabolised) may therefore be described as "prodrugs" of compounds of the invention.As used herein, references to prodrugs will include compounds that form a compound of the invention, in an experimentally-detectable amount, within a predetermined time, following enteral or parenteral administration (e.g. oral or parenteral administration). All prodrugs of the compounds of the invention are included within the scope of the invention.Furthermore, certain compounds of the invention may possess no or minimal pharmacological activity as such, but may be administered parenterally or orally, and thereafter be metabolised in the body to form compounds of the invention that possess pharmacological activity as such. Such compounds (which also includes compounds that may possess some pharmacological activity, but that activity is appreciably lower than that of the active compounds of the invention to which they are metabolised), may also be described as "prodrugs".For the avoidance of doubt, compounds of the invention are therefore useful because they possess pharmacological activity, and / or are metabolised in the body following administration (e.g. oral or parenteral administration) to form compounds that possess pharmacological activity.As described herein, compounds of the invention are particularly useful in treating and / or preventing diseases or disorders in which negative modulation of tropomyosin receptor kinase A (TrkA) is beneficial.As used herein, negative modulation of TrkA (and similarly negative allosteric modulation) may be understood to indicate reducing the activation of the TrkA receptor induced by its ligands, including nerve growth factor (NGF) and neurotrophin 3 (NT-3). Such a reduction may be partial, or, preferably, complete leading to complete inhibition of the activating effect of ligand binding to TrkA. Accordingly, negative (allosteric) modulation of the TrkA receptor may also be described as allosteric inhibition of the TrkA receptor.Thus, in a further aspect of the invention, there is provided a compound of the invention, as hereinbefore defined, for use in the treatment and / or prevention of a disease or disorder in which negative modulation of tropomyosin receptor kinase A is beneficial in a human or animal subject (e.g. a human subject).In an alternative aspect of the invention, there is provided a method of treating and / or preventing a disease or disorder in which negative modulation of tropomyosin receptor kinase A is beneficial, comprising administering to a human or animal subject in need thereof a therapeutically effective amount of a compound of the invention, as herein before defined.In a further alternative aspect of the invention, there is provided the use of a compound of the invention, as hereinbefore defined, for the manufacture of a medicament for the treatment and / or prevention of a disease or disorder in which negative modulation of tropomyosin receptor kinase A is beneficial in a human or animal subject.The skilled person will understand that references to the treatment of a particular disease or disorder (or, similarly, to treating that disease or disorder) will take their normal meanings in the field of medicine. In particular, the terms may refer to achieving a reduction in the severity and / or frequency of occurrence of one or more clinical symptom associated with the disease or disorder, as adjudged by a physician attending a subject having or being susceptible to such symptoms.As used herein, the term prevention (and, similarly, preventing) will include references to the prophylaxis of the disease or disorder (and vice-versa). As such, references to prevention may also be references to prophylaxis, and vice versa. In particular, suchterms term may refer to achieving a reduction (for example, at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g. at least a 50% reduction) in the likelihood of the patient (or healthy subject) developing the disease or disorder (which may be understood as meaning that the condition of the subject changes such that the subject is diagnosed by a physician as having, e.g. requiring treatment for, the relevant disease or disorder).As used herein, references to a subject (or to subjects) (or, similarly, patients) will refer to a living subject being treated, including mammalian (e.g. human) subjects.The compounds of the invention are expected to have beneficial effects in both human and veterinary medicine. Accordingly, references to subjects (and, similarly, patients) being treated include animal (e.g. mammalian) and human subjects. In particular, animal subjects may be understood to refer to non-human animals, and include mammals such as horses, dogs, cats, sheep, pigs, cattle, poultry and non-human primates (including monkeys, apes and pro-simians).In particular embodiments, the subject to be treated with the compounds of the invention is a human subject.In particular embodiments, the subject to be treated with the compounds of the invention is an animal (e.g. mammalian) subject.For the avoidance of doubt, the skilled person will understand that such treatment or prevention will be performed in a subject (or subjects) in need thereof. The need of a patient (or subject) for such treatment or prevention may be assessed by those skilled the art using routine techniques.As used herein, the term effective amount will refer to an amount of a compound that confers a therapeutic effect in the treated subject. The effect may be observed in a manner that is objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of and / or feels an effect). In particular, the effect may be observed (e.g. measured) in a manner that is objective, using appropriate tests as known to those skilled in the art.For example, in the case of arthritis, and particularly, osteoarthritis in human subjects, the Western Ontario and McMaster Universities Arthritis Index (WOMAC) test may beused to assess the level of pain experienced by the subject and MRI and or X-ray analysis may be used to assess joint degeneration.As described herein, negative modulation of the TrkA receptor is beneficial in the treatment and / or prevention of pain and pain disorders, and the mechanism is thought to be effective in the treatment of nociceptive pain, neuropathic pain and nociplastic pain. The compounds of the invention have also been shown to have beneficial effects in the various pain models, including models of nociceptive pain and neuropathic pain.TrkA is also known to be associated with the inflammation and the inflammatory response, and the compounds of the invention have been shown to reduce inflammation in animal models.Accordingly, in particular embodiments, the disease or disorder in which negative modulation of tropomyosin receptor kinase A (TrkA) is beneficial is selected from pain and inflammation. As pain and inflammation often occur concurrently, the compounds of the invention may also be used for the simultaneous treatment of pain and inflammation.In more particular embodiments, the disease or disorder in which negative modulation of TrkA is beneficial is pain.As used herein, 'pain' includes acute and chronic pain. The term 'pain' also includes nociceptive pain, neuropathic pain and nociplastic pain.In particular embodiments, the pain is chronic pain. In other particular embodiments, the pain is acute pain.In further particular embodiments, the pain is selected from nociceptive pain, neuropathic pain (including central and peripheral neuropathic pain (particularly peripheral neuropathic pain) and nociplastic pain. In particular embodiments, the pain is nociceptive pain. In further particular embodiments, the pain is neuropathic pain. In yet further particular embodiments, the pain is nociplastic pain.In particular embodiments, the pain is peripheral neuropathic pain.In particular embodiments, the pain to be treated and / or prevented with the compounds of the invention is selected from the group consisting of peripheralneuropathic pain, postherpetic neuralgia, sciatic nerve pain, trigeminal neuralgia, abdominal pain, musculoskeletal pain (including chronic musculoskeletal pain), postoperative pain, fracture pain, cancer pain, bone cancer pain, visceral pain, osteoarthritic pain, back pain (including lower back pain), inflammatory pain, neck pain, pain associated with (or due to) rheumatoid arthritis, and pain associated with (or due to) psoriatic arthritis .In other particular embodiments, the pain to be treated and / or prevented with the compounds of the invention is associated with a disease or disorder selected from the group consisting of painful diabetic neuropathy, migraine, chronic headache, chemotherapy induced peripheral neuropathy, interstitial cystitis (painful bladder), complex regional pain syndrome, chronic pelvic pain syndrome (including bladder pain syndrome / interstitial cystitis), irritable bowel syndrome, myofascial pain syndrome, pancreatitis, lumbar degenerative disk diseases, chronic prostatitis, vulvodynia, sickle cell disease, fibromyalgia, soft tissue trauma (including sprains, strains and contusion of any tissue that is not bone, such as tendon, ligament and muscle injuries), dysmenorrhea, erythromelalgia and burns.As used herein, references to pain (or, similarly, inflammation) being associated with a relevant disease or disorder, particularly include that the pain (and / or inflammation) occurs as a result of the relevant disease or disorder, and therefore include pain (and / or inflammation) 'caused by' 'due to' or 'experienced as a result of' the relevant disease or disorder.In particular embodiments that may be mentioned, the pain to be treated and / or prevented with the compounds of the invention is pain associated with arthritis, and more particularly the pain is osteoarthritic pain.The skilled person will understand that inflammation includes acute, chronic and subacute inflammation. Acute inflammation is part of the body's response to harmful stimuli, such as pathogens, damaged cells and other irritants, involving the production of inflammatory mediators, by the innate and acquired immune system. Acute inflammation is a generally beneficial response, but excessive inflammation can be harmful, and require treatment. Chronic inflammation includes inflammation occurring over several months or years. In some instances, chronic inflammation has an identifiable cause, such as harmful stimuli, but the cause of long-term inflammation can also be difficult to determine. Chronic inflammation is involved in many chronic disorders, such as autoimmune diseases, neurodegenerative diseases, musculoskeletaldiseases, metabolic disorders and gastrointestinal diseases. Sub-acute inflammation is inflammation occurring for an intermediate period of time, such as from 2 to 6 weeks.Accordingly, in particular embodiments that may be mentioned, the inflammation to be treated and / or prevented with the compounds of the invention is acute, chronic or subacute inflammation. Acute inflammation includes particularly harmful or excessive acute inflammation.More particularly, the inflammation is chronic inflammation.In particular embodiments, the disease or disorder to be treated and / or prevented with the compounds of the invention is Still's disease, such as juvenile Still's disease (e.g., systemic juvenile idiopathic arthritis) and / or adult-onset Still's disease.The beneficial effects of the compounds of the invention in the treatment and / or prevention of pain and / or inflammation make them suitable for a range of disorders that pain and / or inflammation are associated with (such as arthritis and osteoarthritis). In addition, as discussed herein, such as in the background to the invention, NGF-TrkA increased levels of NGF and / or activation of the TrkA receptor (leading to excessive TrkA signalling) has been specifically linked with a range of disorders, including cardiovascular diseases, immunological disorders, asthma, allergic inflammation, infectious diseases, inflammatory skin diseases and cancer, suggesting that the compounds, would also be useful in the treatment of these disorders.Accordingly, in further embodiments that may be mentioned, the disease or disorder in which negative modulation of tropomyosin receptor kinase A is beneficial is selected from the group consisting of a cardiovascular disease, an immunological disorder, arthritis, asthma, allergic inflammation, allergic asthma, esophagitis, an infectious disease, psoriasis, atopic dermatitis, pruritus, skin inflammation and cancer.Cardiovascular diseases in which negative modulation of tropomyosin receptor kinase A is likely to be beneficial include cardiovascular diseases with an inflammatory component. Particular, cardiovascular diseases that may be mentioned in this context include arteriosclerosis, atherosclerosis, myocardial infarction, vascular inflammatory disease, giant cell arteritis and Kawasaki disease.Thus, in particular embodiments, the disease or disorder to be treated and / or prevented with the compounds of the invention is a cardiovascular disease. More particularly, thecardiovascular disease is selected from arteriosclerosis, atherosclerosis, myocardial infarction, vascular inflammatory disease, giant cell arteritis and Kawasaki disease.In further particular embodiments, the disease or disorder to be treated and / or prevented with the compounds of the invention is an immunological disorder.Immunological disorders in which negative modulation of tropomyosin receptor kinase A is likely to be beneficial include autoimmune disorders, such as rheumatoid arthritis, multiple sclerosis, hyperimmunoglobulin disorders, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), vasculitis and psoriasis; and other diseases involving dysregulated immune response, such as asthma, allergic rhinitis and atopic dermatitis.In further particular embodiments, the immunological disorder to be treated with the compounds of the invention is an autoimmune disorder, optionally selected from multiple sclerosis, a hyperimmunoglobulin disorder, inflammatory bowel disease (including Crohn's disease and ulcerative colitis) and vasculitis. In further particular embodiments, the immunological disorder is allergic rhinitis.In further particular embodiments, the disease or disorder to be treated with the compounds of the invention is arthritis. More particularly, the arthritis is selected from rheumatoid arthritis, osteoarthritis and psoriatic arthritis. Most particularly, the arthritis is osteoarthritis.In further particular embodiments, the disease or disorder to be treated with the compounds of the invention is selected from the group consisting of asthma, allergic inflammation, allergic asthma, esophagitis, psoriasis, atopic dermatitis, pruritus and skin inflammation.Infectious diseases in which negative modulation of the TrkA receptor is beneficial include infectious viral diseases. Thus, in particular embodiments, the infectious disease to be treated and / or prevented with the compounds of the invention is an infectious viral disease.In particular embodiments, the infectious viral disease is caused by infection with a virus selected from an influenza virus (e.g. H1N1) Sendai virus, a herpes simplex virus, mouse hepatitis virus, a coronavirus (e.g. severe acute respiratory syndrome coronavirus 2 (COVID-19), porcine hemagglutinating encephalomyelitis virus), arotavirus, a respiratory syncytial virus and human immunodeficiency virus (e.g. HIV-1).Accordingly, in particular embodiments, the disease or disorder to be treated with the compounds of the invention is an infectious disease. More particularly, the disease or disorder is a viral infectious disease. Yet more particularly, the infectious viral disease is caused by a virus selected from an influenza virus (e.g. H1N1), Sendai virus, a herpes simplex virus, mouse hepatitis virus, a coronavirus (e.g. severe acute respiratory syndrome coronavirus 2 (COVID-19), porcine hemagglutinating encephalomyelitis virus), a rotavirus, a respiratory syncytial virus and human immunodeficiency virus (e.g. HIV-1).In further particular embodiments that may be mentioned, the disease or disorder to be treated with the compounds of the invention is cancer.The compounds of the invention have been found to be highly effective in the treatment of both inflammation and pain associated with osteoarthritis in animal models.Therefore, in particularly preferred embodiments, the disease or disorder to be treated with the compounds of the invention is osteoarthritis.In further particularly preferred embodiments, the disease or disorder to be treated with the compounds of the invention is chemotherapy-induced peripheral neuropathy.In further particularly preferred embodiments, the disease or disorder to be treated with the compounds of the invention is post-operative pain.Pharmaceutical and veterinary compositionsAs described herein, compounds of the invention are useful as pharmaceuticals and veterinary medicines. Such compounds may be administered alone or may be administered by way of known pharmaceutical compositions / formulations.In a further aspect of the invention, there is provided a pharmaceutical or veterinary composition comprising a compound of the invention as defined herein, and optionally one or more pharmaceutically-acceptable excipient.As used herein, the term pharmaceutically-acceptable excipients includes excipients suitable for use in veterinary medicines and include vehicles, adjuvants, carriers, diluents, pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like. In particular, such excipients may include adjuvants, diluents or carriers.In a particular embodiment of this aspect of the invention, the pharmaceutical or veterinary composition comprises at least one pharmaceutically-acceptable excipient.For the avoidance of doubt, references herein to compounds of invention being for particular uses (and, similarly, to uses and methods of use relating to compounds of the invention) may also apply to pharmaceutical and veterinary compositions comprising compounds of the invention, as described herein.Thus, in a further aspect of the invention, there is provided a pharmaceutical or veterinary composition as defined above of the invention for use in the treatment and / or prevention of a disease or disorder in which negative modulation of tropomyosin receptor kinase A is beneficial (as defined herein).The skilled person will understand that compounds of the invention may act systemically and / or locally (i.e. at a particular site), and may therefore be administered accordingly using suitable techniques known to those skilled in the art.The skilled person will understand that compounds and compositions as described herein will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, intranasally, topically, intrathecally, intraarticularly, intramuscularly, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.Pharmaceutical and veterinary compositions as described herein will include compositions in the form of tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like. Alternatively, particularly where such compounds of the invention act locally, pharmaceutical and veterinary compositions may be formulated for topical administration.Thus, in particular embodiments, the pharmaceutical or veterinary formulation is provided in a pharmaceutically or veterinarily acceptable dosage form, including tabletsor capsules, liquid forms to be taken orally or by injection, suppositories, creams, gels, foams, inhalants (e.g. to be applied intranasally), or forms suitable for topical administration. For the avoidance of doubt, in such embodiments, compounds of the invention may be present as a solid (e.g. a solid dispersion), liquid (e.g. in solution) or in other forms, such as in the form of micelles.For example, in particular embodiments for topical administration, the pharmaceutical or veterinary formulation is provided in a pharmaceutically or veterinarily acceptable dosage form selected from the list consisting of a cream, a (topical) (e.g. liquid) spray, a (topical) patch, a gel, an ointment, a lotion and a paste.In the preparation of pharmaceutical and veterinary formulations for oral administration, the compound may be mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture may then be processed into granules or compressed into tablets.Soft gelatin capsules may be prepared with capsules containing one or more active compounds (e.g. compounds of the first and, therefore, second and third aspects of the invention, and optionally additional therapeutic agents), together with, for example, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules. Similarly, hard gelatine capsules may contain such compound(s) in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the compound(s) mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions, containing the compound(s) and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, suchliquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.Solutions for parenteral administration may be prepared as a solution of the compound(s) in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and / or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.Depending on e.g. potency and physical characteristics of the compound of the invention (i.e. active ingredient), pharmaceutical formulations that may be mentioned include those in which the active ingredient is present in an amount that is at least 1% (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1:99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.The skilled person will understand that compounds of the invention may be administered (for example, as formulations as described hereinabove) at varying doses, with suitable doses being readily determined by one of skill in the art. For example, when administered orally, treatment with such compounds may comprise administration of a formulations typically containing between about 0.01 pg to about 2000 mg, for example between about 0.1 pg to about 500 mg, or between 1 pg to about 100 mg (e.g. about 20 pg to about 80 mg), of the active ingredient(s). When administered intravenously, the most preferred doses will range from about 0.001 to about 10 pg / kg / hour during constant rate infusion. Advantageously, treatment may comprise administration of such compounds and compositions in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily (e.g. twice daily with reference to the doses described herein, such as a dose of 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 400 mg twice daily).When used herein in relation to a specific value (such as an amount), the term "about" (or similar terms, such as "approximately") will be understood as indicating that such values may vary by up to 10% (particularly, up to 5%, such as up to 1%) of the value defined. It is contemplated that, at each instance, such terms may be replaced withthe notation "±10%", or the like (or by indicating a variance of a specific amount calculated based on the relevant value). It is also contemplated that, at each instance, such terms may be deleted.For the avoidance of doubt, the skilled person (e.g. the physician) will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the route of administration, the type and severity of the condition that is to be treated, as well as the species, age, weight, sex, renal function, hepatic function and response of the particular patient to be treated. Although the above-mentioned dosages are exemplary of the average case, there can, of course, be individual instances where higher or lower dosage ranges are merited, and such doses are within the scope of the invention.Combinations and kits-of-partsThe skilled person will understand that treatment with compounds of the invention may further comprise (i.e. be combined with) further treatment(s) and / or preventative methods for the same condition. In particular, treatment with compounds of the invention may be combined with other means for the treatment of a disease or disorder in which negative modulation of tropomyosin receptor kinase A is beneficial (such as pain and / or inflammation and / or diseases or disorders comprising the same as described herein, e.g. osteoarthritis), such as treatment with one or more other therapeutic agent that is useful in the in the treatment and / or prevention of a disease or disorder in which negative modulation of tropomyosin receptor kinase A is beneficial and / or one or more physical method used in the treatment and / or prevention of a disease or disorder in which negative modulation of tropomyosin receptor kinase A is beneficial (such as treatment through surgery), as known to those skilled in the art.As described herein, compounds of the invention may also be combined with one or more other (i.e. different) therapeutic agents (i.e. agents that are not compounds of the invention) that are useful in the treatment and / or prevention of a disease or disorder in which negative modulation of tropomyosin receptor kinase A is beneficial. Such combination products that provide for the administration of a compound of the invention in conjunction with one or more other therapeutic agent may be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as asingle formulation including a compound of the invention and the one or more other therapeutic agent).Thus, according to a further aspect of the invention, there is provided a combination product comprising:(I) a compound of the invention, as hereinbefore defined (i.e. in the first aspect of the invention, including all embodiments and particular features thereof); and (II) one or more other therapeutic agent that is useful in the treatment and / or prevention of a disease or disorder in which negative modulation of tropomyosin receptor kinase A is beneficial in a human or animal subject (such as a pain and / or inflammation and / or diseases or disorders comprising the same, as described herein),wherein each of components (I) and (II) is formulated in admixture, optionally with one or more a pharmaceutically-acceptable excipient.In a further aspect of the invention, there is provided a kit-of-parts comprising:(a) a pharmaceutical or veterinary composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, as hereinbefore defined; and(b) one or more other therapeutic agent that is useful in the treatment and / or prevention of a disease or disorder in which negative modulation of tropomyosin receptor kinase A is beneficial in a human or animal subject (such as a pain and / or inflammation and / or diseases or disorders comprising the same, as described herein), optionally in admixture with one or more pharmaceutically-acceptable excipient,which components (a) and (b) are each provided in a form that is suitable for administration in conjunction (i.e. concomitantly or sequentially) with the other.With respect to the kits-of-parts as described herein, by "administration in conjunction with" (and similarly "administered in conjunction with") we include that respective formulations are administered, sequentially, separately or simultaneously, as part of a medical intervention directed towards treatment of the relevant condition.Thus, in relation to the present invention, the term "administration in conjunction with" (and similarly "administered in conjunction with") includes that the two active ingredients) are administered (optionally repeatedly) either together, or sufficiently closely in time, to enable a beneficial effect for the patient, that is greater, over the course of the treatment and / or prevention of the relevant condition, than if either agent is administered (optionally repeatedly) alone, in the absence of the other component,over the same course of treatment and / or prevention. Determination of whether a combination provides a greater beneficial effect in respect of, and over the course of, treatment and / or prevention of a particular condition will depend upon the condition to be treated and / or prevented, but may be achieved routinely by the skilled person.Further, in the context of the present invention, the term "in conjunction with" includes that one or other of the two formulations may be administered (optionally repeatedly) prior to, after, and / or at the same time as, administration of the other component. When used in this context, the terms "administered simultaneously" and "administered at the same time as" includes instances where the individual doses of the compound of the invention and the additional compound for the treatment of a disease or disorder in which negative modulation of tropomyosin receptor kinase A is beneficial, or pharmaceutically acceptable salts thereof, are administered within 48 hours (e.g. within 24 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes or 10 minutes) of each other.As used herein, references to other therapeutic agents that are "useful" in a certain manner (e.g. in the treatment of a certain disease or disorder) will refer to agents that are known to be suitable for use in that manner (e.g. agents commonly used for that purpose). Such references may therefore be replaced with references to agents "suitable for" the relevant purpose.Other therapeutic agents useful in the treatment and / or prevention of a disease or disorder in which negative modulation of tropomyosin receptor kinase A is beneficial in human or animal subjects (such as a pain and / or inflammation and / or diseases or disorders comprising the same, as described herein) will be well-known to those skilled in the art. For example, such other therapeutic agents may include: paracetamol, nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, opioids, gabapentin, pregabalin, antidepressants, antiepileptic drugs, serotonin and norepinephrine reuptake inhibitors (SNRIs), TRPV1 antagonists, sodium channel blockers (such as selective Navi.8 and Navi.7 sodium channel blockers and unselective sodium channel blockers, such as xylocaine and bupivacaine) and CGRP inhibitors.Preparation of compounds / compositionsPharmaceutical compositions / formulations, combination products and kits as described herein may be prepared in accordance with standard and / or accepted pharmaceutical practice.Thus, in a further aspect of the invention there is provided a process for the preparation of a pharmaceutical composition / formulation, as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, with one or more pharmaceutically-acceptable excipient.In further aspects of the invention, there is provided a process for the preparation of a combination product or kit-of-parts as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, with the other therapeutic agent that is useful in the treatment of the relevant disease or disorder, and at least one pharmaceutically-acceptable excipient.As used herein, references to bringing into association will mean that the two components are rendered suitable for administration in conjunction with each other.Thus, in relation to the process for the preparation of a kit-of-parts as hereinbefore defined, by bringing the two components "into association with" each other, we include that the two components of the kit-of-parts may be:(i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or(ii) packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy.Compounds of the invention as described herein may be prepared, either as the neutral compound (free acid or base) or as a pharmaceutically acceptable salt, in accordance with techniques that are well known to those skilled in the art, such as those described in the examples provided hereinafter.According to a further aspect of the invention there is provided a process for the preparation of a compound of formula I of the invention, which comprises the step of reacting a compound of formula II,wherein R1, R2, A and X are as hereinbefore defined, with a compound of formula IIIwherein R3, R4, R5, R5, m, n and Y are as hereinbefore defined, in the presence of a suitable peptide coupling agent (such as HATU), a suitable base (such as diisopropylethylamine) and a suitable solvent (such as DMF or acetonitrile) at a suitable reaction temperature (e.g. between 0° C and reflux temperature).Alternatively compounds of formula I of the invention can be prepared by reacting a compound of formula IVwherein R1, R2, R3, R4, n, A, X and Y are as hereinbefore defined, with a compound of formula Vwherein R5, R5and m are as hereinbefore defined, and M1is selected from -B(OH)2 andin the presence of a suitable base (such as CS2CO3), a suitable catalyst (such as Pd (dppf) CI2.DCM) and a suitable solvent (such as a mixture of dioxane and water (8:2)) at an elevated temperature (such as above 50 °C (e.g. 100 °C)) for a suitable time such as 1 to 24 hours (e.g. 2 h).Compounds of formula III can be prepared from a compound of formula VIBocwherein R3, R4' R5, R5, n, m and Y are as hereinbefore defined, and Boc represents a tert-butoxycarbonyl protecting group, by reacting the compound of formula VI under suitable conditions to remove the Boc-group (such as HCI in Dioxane at room temperature).Compounds of formula VI can be prepared by reacting a compound of formula VII,wherein R3, R4, n and Y are as hereinbefore defined and M2is selected from-B(OH)2 andwith a compound of formula VIIIwherein R5- R5and m are as hereinbefore defined, in the presence of a suitable base (such as CS2CO3), a suitable catalyst (such as Pd(dppf)Cl2.DCM) and a suitable solvent (such as a mixture of dioxane and water (8:2)) at an elevated temperature (such as above 50 °C (e.g. 100 °C)) for a suitable time such as 1 to 24 hours (e.g. 2 h).Compounds of formula VI can also be prepared by reacting compounds of formula IX Bocwherein R3, R4, n and Y are as hereinbefore defined,with compounds of formula V in the presence of a suitable base (such as CS2CO3) and a suitable catalyst (such as Pd(dppf)Cl2.DCM) with a suitable solvent (such as a mixture of dioxane and water (8:2)) at an elevated temperature such as 100° C for a suitable time such as 2 h.Compounds of formula V in which M1iscan be prepared by reacting a compound of formula VIII in the presence of a suitable borylating agent (for example Bis pinacol diborane), a suitable solvent (such as dioxane), a suitable base (such as containing KOAc) and a suitable catalyst (such as X-Phos Pd G4) at an elevated temperature (such as above 50 °C (e.g. 100 °C)) for a suitable time such as 1 to 24 hours (e.g. 2 h).Compounds of formula II may be prepared by hydrolysing of an ester (such as methyl or ethyl ester) of formula Xwherein R1, R2, A and Y are as hereinbefore defined, and R8represents a C1-3 alkyl group (e.g. methyl) for example by reacting the compound of formula XI in the presence of a suitable strong base such as (LiOH), water and a suitable solvent such as THF.Compounds of formula X may be prepared from compounds of formula XI,wherein R1, R2and A are as hereinbefore defined, in the presence of a suitable alkylating agent, such as a halo acetate ester, preferably bromo or chloro acetate esters, such as ethyl bromoacetate in the presence of a suitable base such as NaH, in a suitable solvent such as DMF.Compounds of formula XI may be prepared from the condensation of compounds of formula XIIwherein R1is as hereinbefore defined, with di-halogen or halogen and nitro substituted pyrimidines or pyridines (and N-oxides thereof), such compounds of formula XIII, XIV or XVIwherein R2and A are as hereinbefore defined,in the presence of a suitable solvent (such as DMAc) together with a suitable base (such CS2CO3) and heating at elevated temperatures, such as 80-180° C for an appropriate time, such as 1-6 h.Compounds of formulae V, VII, VIII, IX, XII, XIII, XIV, XV, XVI are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. In this respect, the skilled person may refer to inter alia "Comprehensive Organic Synthesis" edited by Paul Knochel and Gary A. Molander, Elsevier, 2014. Further references that may be employed include "Heterocyclic Chemistry" by J. A. Joule and K. Mills, 5thedition, published by Wiley-Blackwell, 2010, "Comprehensive Heterocyclic Chemistry IV" edited by D. StC. Black, J. Cossy and C. V. Stevens, Elsevier, 2022, "Science of Synthesis", Volumes 9-17 (Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006 and March's Advanced Organic Chemistry by Michael B. Smith, Wiley, 2020.The skilled person will understand that the substituents as defined herein, and substituents thereon, may be modified one or more times, after or during the processes described above for the preparation of compounds of the invention by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, dehydrogenations, alkylations, dealkylations, acylations, hydrolyses, esterifications, etherifications, halogenations and nitrations. The precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence. The skilled person may also refer to "Comprehensive Organic Functional Group Transformations" by A. R. Katritzky, O. Meth-Cohn and C. W. Rees, Pergamon Press, 1995 and / or "Comprehensive Organic Transformations" by R. C. Larock, Wiley-VCH, 1999.Compounds of the invention may be isolated from their reaction mixtures and, if necessary, purified using conventional techniques as known to those skilled in the art. Thus, processes for preparation of compounds of the invention as described herein may include, as a final step, isolation and optionally purification of the compound of the invention.It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to beprotected by protecting groups. The protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.Protecting groups may be applied and removed in accordance with techniques that are well-known to those skilled in the art and as described hereinafter. For example, protected compounds / intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques. The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis. The use of protecting groups is fully described in "Greene's Protective Groups in Organic Synthesis", 5th edition, P.G.M. Wutz, Wiley (2014), the contents of which are incorporated herein by reference.Without wishing to be bound by theory, it is believed that compounds of the invention surprisingly provide highly potent and selective negative modulators (allosteric inhibitors) of tropomyosin receptor kinase A, and are therefore useful in the treatment of diseases and disorders in which negative modulation of Trk A is beneficial, such as pain and / or inflammation and the diseases and disorders described herein. The compounds are also peripherally restricted (having low CNS penetration), which reduces the risk of CNS side effects, and have high oral bioavailability.Compounds of the invention may further have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and / or have a better pharmacokinetic profile (e.g. higher oral bioavailability and / or lower clearance) than, and / or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise. In particular, compounds of the invention may have the advantage that they are more efficacious and / or exhibit advantageous properties in vivo.Brief description of the FiguresFigure 1 shows the effect of Example compound 2 on the knee diameter in a rat monoiodoacetate (MIA) induced osteoarthritis model (described in Biological Example 2). Twice daily dosing of Example 2 at 3, 10 and 30 mg / kg led to a reduction in the knee diameter at day 20 at all doses (Figure 1). Thus, compound 2 reduced the monoiodoacetate induced inflammation.Figure 2 shows the effect of Example compound 2 on weight-bearing on the affected limb in a rat mono-iodoacetate (MIA) induced osteoarthritis model (described in Biological Example 2). Twice daily dosing of Example 2 at 3, 10 and 30 mg / kg led to a significant improvement in weight bearing on the affected limb at day 20 at all doses (as indicated by the increased % weight distribution to the affected limb in the treatment groups).Figure 3 shows the effect of Example compound 2 on mechanical allodynia in a rat mono-iodoacetate (MIA) induced osteoarthritis model (described in Biological Example 2). Twice daily dosing of Example 2 at 3, 10 and 30 mg / kg led to a significant reduction in mechanical allodynia.Figure 4 shows the effect of twice daily dosing of Example compound 2 at 3, 10 or 30 mg / kg on the knee joint histopathology score of rats in a mono-iodoacetate (MIA) induced osteoarthritis model (described in Biological Example 2). A significant reduction in knee joint histopathology score was observed at all dosages.Figure 5 shows the effect of two daily doses of Example compound 2 in the Brennan model of post-incisional pain (post-operative pain), described in Biological Example 3. Twice daily dosing at 3, 10 or 30 mg / kg by per oral administration led to a significant reduction of mechanical allodynia (as shown by the increased 50% paw withdrawal threshold for all dosages).Figure 6 shows the effect of a single dose of Example compound 2 on paclitaxel-induced neuropathic pain in the rat model described in Biological Example 4. On single per oral dose of 3, 10 or 30 mg / kg led to a significant reduction in mechanical allodynia (as shown by the increased 50% paw withdrawal threshold for all dosages).Figure 7 shows the effects of 1 and 3 mg / kg doses of Example compound 2 on NGF-induced paw inflammation and thermal hypersensitivity, as measured in the rat plantar test described in Biological Example 5. A single 3 mg / kg per oral dose of Example compound 2 led to a significant reduction in heat hypersensitivity (as shown by the increased paw withdrawal latency in the treatment group). Treatment with 1 mg / kg of Example compound 2 did not cause a statistically significant reduction in heat hypersensitivity.Figure 8 shows the effects of a single 10 mg / kg dose of Example compound 2 on NGF-induced paw inflammation and thermal hypersensitivity, as measured in the rat plantartest described in Biological Example 5. A single 10 mg / kg per oral dose of Example compound 2 led to a significant reduction in paw volume, a measurement of NGF-induced inflammation.Figure 9 shows the effects of a single dose 10 mg / kg dose of Example compound 2 on CGRP levels in plasma (a measurement of NGF-induced inflammation), as measured in the rat plantar test (Hargreaves test) described in Biological Example 6. A single 10 mg / kg dose caused a statistically significant decrease in CGRP levels in plasma, suggesting a reduction in NGF-induced inflammation.For the avoidance of doubt, the numbering used in figure legends refers to the numbering of compounds of the examples as provided herein.ExamplesAbbreviationsACN - AcetonitrileAmphos - di-tert-butyl(4-dimethylaminophenyl)phosphineDCM - dichloromethaneDMAc -N, / V-DimethylacetamideDMSO - DimethylsulfoxideDppf - l,l'-Bis(diphenylphosphino)ferroceneES - Electrospray ionisationRBF - Round bottom flaskRP - Reverse phaseTFA - trifluoroacetic acidTHF - tetra hydro furanX-Phos Pd G4 - dicyclohexyl-[2-[2,4,6-tri(propan-2-yl) phenyl] phenyl] phosphanium;methanesulfonic acid; / V-methyl-2-phenylaniline; palladiumExperimental proceduresStarting materials and intermediates used in the synthesis of compounds described herein are commercially available or can be prepared by the methods described herein or by methods known in the art.Experiments were generally carried out under inert atmosphere (nitrogen or argon), particularly in cases where oxygen- or moisture-sensitive reagents or intermediates were used.Mass spectrometry data are reported from liquid chromatography-mass spectrometry (LC-MS) using electrospray ionization. Chemical shifts for NMR data are expressed in parts per million (ppm, 6) referenced to residual peaks from the deuterated solvent used.For syntheses referencing general procedures, reaction conditions (such as length of reaction or temperature) may vary. In general, reactions were followed by thin layer chromatography or LC-MS, and subjected to work-up when appropriate. Purifications may vary between experiments: in general, solvents and the solvent ratios used for eluents / gradients were chosen to provide an appropriate Rf and / or retention time.General methodsAll solvents were of analytical grade and commercially available anhydrous solvents were routinely used for reactions. Starting materials used were available from commercial sources or prepared according to literature procedures, Room temperature refers to 20-25°C. Solvent mixture compositions are given as volume percentages or volume ratios.Microwave (MW) heating was performed in a standard MW reactor producing continuous irradiation at 2450 MHz. It is understood that MWs can be used for the heating of reaction mixtures. Typically, an Anton Paar microwave synthesizer 300 was used as a microwave synthesizer.Thin layer chromatography (TLC) was performed on Merck TLC-plates (Silica gel 60 F254) and spots were UV visualized. TLC was generally used to monitor reaction progression and solvents used were for example: ethyl acetate or acetonitrile or DCM with 1-10% of MeOH, ethyl acetate with 0-95% hexane. Straight phase flash column chromatography ("flash chromatography" / "column chromatography") was manually performed on Merck Silica gel 60 (0.040-0.063mm) or basic aluminium oxide or neutral aluminium oxide, or automatically using ISCO Combiflash® Companion™ system using RediSep™ normal-phase flash columns ("Combiflash") using the solvent system indicated.Nuclear Magnetic Resonance (NMR) spectra was recorded on a 400 MHz NMR spectrometer (Bruker 400 MHz Avance-III) fitted with a probe of suitable configuration. Spectra were recorded at ambient temperature unless otherwise stated. Chemical fields are given in ppm down- and upfield from TMS (0.00 ppm). The following reference signals were used in ^-NMR: TMS d 0.00, or residual solvent signal of DMSO-d6 6 2.49, CDCH 6 7.25 (unless otherwise indicated). Resonance multiplicities are denoted s, d, t, q, m, dd, tt, dt br and app for singlet, doublet, triplet, quartet, doublet of doublet, triplet of triplet, doublet of triplet, multiplet, broad and apparent, respectively. In some cases only diagnostic signals are reported.Mass spectrometry (MS) analysis were performed in positive and / or negative ion mode using electrospray ionization (ESI+ / -).Preparative HPLC chromatography was run on a Shimadzu LC-20AP and UV detector. The column used was Sunfire cl8 (250*19) mm, 5 p, sunfire cl8 (150*19) mm, 5p or XSELECT Phenyl Hexyl C18 (250*19) mm, 5 p using a column flow was between 10-20 ml / min with a suitable mobile phase used as an isocratic or gradient system as defined below. The UV spectra were typically recorded at 202nm & between 214 and 260 nm Lambda max.High pressure liquid chromatography (HPLC) was performed on a straight phase column. A linear gradient or isocratic flow was applied using for example phase A (Hexane) and B (Ethylacetate)Compounds have been named using CDD vault from Collaborative Drug Discovery Inc. Burlingame CA, USA.In the event that there is a discrepancy between nomenclature and any compounds depicted graphically, then it is the latter that presides (unless contradicted by any experimental details that may be given or unless it is clear from the context).Experimental ProceduresIntermediate 1Method A6-fluoro-2-methyl-10-oxa-l,3,9-triaza-9H -anthraceneIn a 250 ml RBF previously equipped with a magnetic stirrer was taken 2-amino-5-fluorophenol (3.7 g, 0.0291 mol) in DMAc (55.5 ml). 5-bromo-4-chloro-2-methylpyrimidine (6.04 g, 0.0291 mol) and CS2CO3 (28.45 g, 0.0873 mol) were added at room temperature. The reaction mixture was heated to 180 °C and stirred at same temperature for 16 h. The reaction mixture was filtered through a celite bed and the solvent was removed under reduced pressure to obtain the crude product which was purified by column chromatography using 10-15% EtOAc in Hexane as the mobile phase to obtain the title compound (3 g, 47.45%).XH NMR (400 MHz, DMSO-cfe): 6 2.25 (s, 3H), 6.57-6.61 (m, 1H), 6.65-6.72 (m, 2H), 7.61 (s, 1H), 9.74 (s, 1H). MS (ES+) m / z 218.1 [M + H]+.Intermediate 2Method BEthyl (6-fluoro-2-methyl-10-oxa-l,3,9-triaza-9H-anthr-9-yl)acetateIn a 100 ml RBF previously equipped with a magnetic stirrer and argon balloon was taken Intermediate 1 (3.0 g, 0.0138 mol) in DMF (30 ml) and the mixture was cooled to 0 °C. To the mixture, NaH (0.93 g, 0.0276 mol) was added portion wise manner and the reaction mixture was stirred for 30 minutes at 0 °C. Ethyl bromoacetate (3.46 g, 0.0207 mol) was added drop wise manner at 0 °C and the reaction mixture was allowed to reach room temperature. The reaction mixture was stirred for 2h at room temperature. The reaction mixture was poured into ice cold water (60 ml) and stirred for 5 minutes at 0°C. The obtained solid was filtered, dried under reduced pressure to obtain the crude product (3.8 g, 91%).XH NMR (400 MHz, DMSO-cfe): 6 1.21 (t, J = 6.8Hz, 3H), 2.30 (s, 3H), 4.14-4.20 (m, 2H), 4.67 (s, 2H), 6.78-6.85 (m, 3H), 7.77 (s, 1H). MS (ES+) m / z 304.2 [M + H]+.Intermediate 3Method C(6-fluoro-2-methyl-10-oxa-l,3,9-triaza-9H-anthr-9-yl)acetic acidIn a 250 ml RBF previously equipped with a magnetic stirrer was taken Intermediate 2 (3.8 g, 0.0125 mol) in THF (38 ml) and the mixture was cooled to 0 °C. A LiOH Solution (2.6 g, 0.0626 mol) [dissolved in H2O (38 ml)] was added and the reaction mixture was stirred for 16 hrs at room temperature. Solvent was removed under reduced pressure and the residue was acidified with 2N HCI and stirred for 5 minutes at 0°C. The obtained solid was filtered, dried under reduced pressure to obtain the crude product (2.8 g, 81%).XH NMR (400 MHz, DMSO-de): 62.32 (s, 3H), 4.60 (s, 2H), 6.78-6.84 (m, 3H), 7.76 (s, 1H), 13.08 (s, 1H). MS (ES+) m / z 276.1 [M + H]+.Intermediate 46-fluoro-2-methyl-10-oxa-l,9-diaza-9H -anthraceneWe have prepared Intermediate 4 using 140 g of 2-amino-5-fluorophenol and 190 g 2-chloro-6-methyl-3-nitropyridine by following the method described in Method A to produce 8.5 g (3.6%) of the title compound.XH NMR (400 MHz, DMSO-cfe): 6 2.09 (s, 3H), 6.41 (d, J = 7.6 Hz, 1H), 6.50-6.54 (m, 1H), 6.61 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 7.6 Hz, 1H), 8.99(s, 1H). MS (ES+) m / z 217.4 [M + H]+.Intermediate 5Ethyl (6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)acetateIntermediate 5 was prepared according to Method B using 8.5 g Intermediate 4 and Ethyl bromoacetate (9.8 g) to produce 5.5g (46%) of the title compound.XH NMR (400 MHz, DMSO-cfe): 6 1.18-1.26 (m, 3H), 2.19 (s, 3H), 4.41-4.17 (m, 2H), 4.63 (s, 2H), 6.54 (d, J = 7.6 Hz, 1H), 6.69-6.74 (m, 3H), 6.94 (d, J = 8.0 Hz, 1H). MS (ES+) m / z 303.2 [M + H]+.Intermediate 6(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)acetic acidIntermediate 6 was prepared according to Method C using 5.5 g Intermediate 5 to produce 4.2 g (86%) of the title compound.XH NMR (400 MHz, DMSO-cfe): 6 2.2 (s, 3H), 4.50 (s, 2H), 6.52 (d, J = 7.6 Hz, 1H), 6.64 (d, J = 4.8 Hz, 1H), 6.63-6.68 (m, 2H), 6.91 (d, 8.0 Hz, 1H). MS (ES+) m / z 276.3 [M + H]+.Intermediate 76-fluoro-10-oxa-l,9-diaza-9H-anthraceneIntermediate 7 was prepared according to Method A using 15 g 2-amino-5-fluorophenol and 2-chloro-3-nitropyridine (18.7 g) to produce 7.0 g (29%) of the title compound.XH NMR (400 MHz, DMSO-de): 6 6.57 - 6.67 (m, 4H), 6.93 (d, J= 7.6 Hz, 1H), 7.57 (d, J= 4.4 Hz, 1H), 9.04 (s, 1H). MS (ES+) m / z 203.1 [M + H]+.Intermediate 8Ethyl (6-fluoro-10-oxa-l,9-diaza-9H-anthr-9-yl)acetateIntermediate 8 was prepared according to Method B using 7.0 g of Intermediate 7 and Ethyl bromoacetate (8.7 g) to produce 5.2 g (52%) of the title compound. MS (ES+) m / z 289.4 [M + H]+.Intermediate 9(6-fluoro-10-oxa-l,9-diaza-9H-anthr-9-yl)acetic acidIntermediate 9 was prepared according to Method C using 5.2 g Intermediate 8 to produce 4.0 g (85%) of the title compound.XH NMR (400 MHz, DMSO-cfe): 6 4.45 (s, 2H), 6.59-6.73 (m, 4H), 6.99 (d, J= 7.6 Hz, 1H), 7.65 (d, J= 4.4 Hz, 1H).(Acid proton is not visible, due to presence of moisture in NMR solvent.)MS (ES+) m / z 261.2 [M + H]+.Intermediate 103,6-difluoro-10-oxa-l,9-diaza-9H-anthraceneIntermediate 10 was prepared using 5 g 2-amino-5-fluorophenol and 2-chloro-5-fluoro-3-nitropyridine (6.9 g) according to Method A. The obtained crude was purified by combi-flash chromatography and pure product was eluted using 40 % Ethyl acetate in Hexane to obtain 1.5 g (17%) of the title compound.XH NMR (400 MHz, DMSO-cfe): 6 6.54-6.57 (m, 1H), 6.65-6.68 (m, 2H), 7.09 (dd, J = 8.8, 2.0 Hz, 1H), 7.57 (d, J = 2.4 Hz, 1H), 9.11 (s, 1H). MS (ES+) m / z 221.1 [M + H]+.Intermediate 11Ethyl (3,6-difluoro-10-oxa-l,9-diaza-9H-anthr-9-yl)acetateIntermediate llwas prepared according to Method B using 1.5 g Intermediate 10 and Ethyl bromoacetate (1.7 g) to produce 1.0 g (48%) of the title compound. MS (ES+) m / z 306.9 [M + H]+.Intermediate 12(3,6-difluoro-10-oxa-l,9-diaza-9H-anthr-9-yl)acetic acidIntermediate 12 was prepared according to Method C using 1.0 g Intermediate 11 to produce 0.7 g (77%) of the title compound. MS (ES-) m / z 277.0 [M-H]-.Intermediate 136,7-difluoro-2-methyl-10-oxa-l,3,9-triaza-9H-anthraceneIntermediate 13 was prepared according to Method A using 3 g 2-amino-4,5-difluorophenol and 5-bromo-4-chloro-2-methylpyrimidine (4.3 g) to produce 1.8 g (37%) of the title compound.XH NMR (400 MHz, DMSO-cfc): 6 9.81 (s, 1H), 7.65 (s, 1H), 7.00 (dd, J = 7.20, 11.00 Hz, 1H), 6.58 (dd, J = 8.00, 10.80 Hz, 1H), 2.26 (s, 3H). MS (ES+) m / z 236.1 [M + H]+.Intermediate 14Ethyl (6,7-difluoro-2-methyl-10-oxa-l,3,9-triaza-9H-anthr-9-yl)acetateIntermediate 14 was prepared according to Method B using 1.8 g Intermediate 13 and Ethyl bromoacetate (1.9 g) to produce 2.1 g (85%) of the title compound.XH NMR (400 MHz, DMSO-cfe): 6 7.80 (s, 1H), 7.10-7.20 (m, 2H), 4.64 (s, 2H), 4.17 (dd, J = 7.20, 14.20 Hz, 2H), 2.32 (d, J = 8.80 Hz, 3H), 1.22 (t, J = 7.20 Hz, 3H). MS (ES+) m / z 321.6 [M + H]+.Intermediate 15(6,7-difluoro-2-methyl-10-oxa-l,3,9-triaza-9H-anthr-9-yl)acetic acidIntermediate 15 was prepared according to Method C using 2.1 g Intermediate 14 to produce 1.7 g (89%) of the title compoundXH NMR (400 MHz, DMSO-cfe): 6 13.13 (s, 1H), 7.77 (s, 1H), 7.08-7.15 (m, 2H), 4.57 (s, 2H), 2.31 (s, 3H). MS (ES+) m / z 294.1 [M + H]+.Intermediate 163-bromo-2-chloro-6-methyl-l-pyridinium-l-olateIn a RB flask previously equipped with a magnetic stirrer was taken 3-bromo-2-chloro-6-methylpyridine (20 g, 0.09686 mol) in CHCh (200 ml). To this 70 % mCPBA (47.58 g, 0.1937 mol) were added at room temperature. The reaction mixture was then heatedto 50 °C and stirred at same temperature for 16 hours. The solvent was removed under reduced pressure to obtain the crude product that was purified by column chromatography using 15-25% Ethyl acetate in Hexanes to obtain 18 g (83%) of the title compound. MS (ES+) m / z 224.01 [M + H]+.Intermediate 176,7-difluoro-2-methyl-10-oxa-l,9-diaza-9H-anthraceneIntermediate 17 was prepared according to Method A using 5 g of 2-amino-4,5-difluorophenol and Intermediate 16 (7.7 g) to produce 1.6 g of title compound.XH NMR (400 MHz, DMSO-cfe): 6 9.07 (s, 1H), 6.81-6.89 (m, 2H), 6.43-6.52 (m, 2H), 2.16 (s, 3H). MS (ES+) m / z 235.12 [M + H]+.Intermediate 18Ethyl (6,7-difluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)acetateIntermediate 18 was prepared according to Method B using 1.6 g of Intermediate 17 and Ethyl bromoacetate (1.7 g) to produce 1.9 g of the title compound.XH NMR (400 MHz, DMSO-de): 6 6.93-7.01 (m, 3 H), 6.57 (d, J = 7.6 Hz, 1H), 4.59 (s, 2H), 4.12-4.17 (m, 2H), 2.08 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H). MS (ES+) m / z 321.8 [M + H]+.Intermediate 19(6,7-difluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)acetic acidIntermediate 19 was prepared according to Method C using 1.9 g Intermediate 18 to produce 1.0 g of the title compound.XH NMR (400 MHz, DMSO-cfe): 6 12.85 (s, 1H), 6.90-7.00 (m, 3H), 6.57 (d, J = 7.2 Hz, 1H), 4.59 (s, 2H), 2.09 (s, 3H). MS (ES+) m / z 293.9 [M + H]+.Intermediate 20N-[(5-bromo-2-pyridyl)methyl](6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)acetamideMethod DIn a seal tube previously equipped with a magnetic stirrer and nitrogen balloon was taken Intermediate 6 (0.13 g, 0.000474 mol, 1.0 eq.) in DMF (1.3 ml, 10 vol) at 0 °C. To the reaction mixture, HATU (0.45 g, 0.001185 mol, 2.5 eq.) was added and reaction mixture was stirred for 1 h at 0 °C. After 1 h, the [(5-bromo-2-pyridyl)methyl]amine hydrochloride (0.12 g, 0.000521 mol, 1.1 eq.) and DIPEA (0.33 ml, 0.00237 mol, 5 eq.) were added and reaction mixture was stirred for 1 h at room temperature. The reaction mixture was poured into water (3 mL) and aqueous Layer was extracted with ethyl acetate (3 x 5 mL). Combined organic layer was dried over sodium sulphate and solvent was removed under reduced pressure to obtain crude product which was purified by combi flash chromatography using 30 % Ethyl acetate in Hexane as a mobile phase to produce 0.150 g (71%) of the title compound.XH NMR (400 MHz, DMSO-d6): 6 2.22 (s, 3H), 4.34 (d, J = 4.00 Hz, 2H), 4.51 (s, 2H), 6.51-6.59 (m, 2H), 6.71 (t, J = 8.2 Hz, 2H), 6.90 (d, J= 8.0 Hz, 1H), 7.23 (d, J = 8 Hz, 1H), 7.98-8.01(dd, J = 2.1, 2.0 Hz, 1H), 8.62 (s, 1H), 8.84 (t, J = 5.6 Hz 1H). MS (ES-) m / z 441.3 [M-H]’.Intermediate 21tert-butyl [(5-bromo-6-methyl-2-pyridyl)methyl]carbamateMethod EIn a 25 mL R.BF previously equipped with a magnetic stirrer and nitrogen balloon was taken 5-bromo-6-methyl-2-pyridinecarbonitrile (0.5 g, 0.00253 mol.) in Methanol (5 ml). To the reaction mixture, NiCl2.6H2O (0.07 g, 0.00025 mol) and Boc anhydride (0.69 ml, 0.00304 mol) was added at 0°C and the reaction mixture was stirred for 15 min at same temperature. NaBH4 (0.58 g, 0.01522 mol) were added slowly at 0°C and the reaction mixture was stirred for 2 h at room temperature. The solvent was remove from the reaction mixture under reduced pressure to get the crude product which was purified by combi flash chromatography using 50 % Ethyl acetate and Hexane as a mobile phase to produce 0.55 g (72%) of the title compound. MS (ES+) m / z 301.18 [M + H]+.Intermediate 22[(5-bromo-6-methyl-2-pyridyl)methyl]amine hydrochlorideMethod FIn a 25 ml R.BF previously equipped with a magnetic stirrer was taken Intermediate 21 (0.5 g, 0.00166 mol.) in DCM (5.0 ml) and the mixture was cooled to 0°C. To the mixture, 4M HCI in dioxane (2.5 ml) was added drop wise and the reaction mixture was stirred for 6 h at room temperature. The solvents were removed under reduced pressurea and the residue obtained was washed with 70% EtOAc / Hexane to get 0.35 g (89%) of the title crude product. MS (ES-) m / z 200.9 [M-H]-.Intermediate 23N-[(5-bromo-6-methyl-2-pyridyl)methyl](6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)acetamideIntermediate 23 was prepared according to Method D using 0.10 g Intermediate 6 and Intermediate 22 (0.095 g) to produce 0.09 g (54%) of the title compound. MS (ES+) m / z 457.09 [M + H]+.Intermediate 24tert-butyl [(5-bromo-6-methoxy-2-pyridyl)methyl]carbamateIntermediate 24 was prepared using 1.0 g of 5-bromo-6-methoxy-2-pyridinecarbonitrile using Method E. The obtained crude was purified by combi-flash chromatography using 20 % Ethyl acetate in Hexane as the mobile 0.600 g (40%) of the title compound. MS (ES+) m / z 316.9 [M + H]+.Intermediate 25[(5-bromo-6-methoxy-2-pyridyl)methyl]amine hydrochlorideIntermediate 25 was prepared using 0.6 g of Intermediate 24 using Method F to obtain 0.450 g (93%) of the title compound. MS (ES+) m / z 216.9 [M + H]+.Intermediate 26N-[(5-bromo-6-methoxy-2-pyridyl)methyl](6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)acetamideIntermediate 26 was prepared using 0.3 g Intermediate 6 and Intermediate 25 (0.3 g) using Method D. The obtained crude was purified by Combi flash chromatography using DCM containing 1% MeOH as mobile phase to obtain 0.150 g (28%) of the title compound. MS (ES+) m / z 473.1 [M + H]+.Intermediate 27N-[(5-bromo-6-methyl-2-pyridyl)methyl](6-fluoro-10-oxa-l,9-diaza-9H-anthr-9-yl)acetamideIntermediate 27 was prepared using 0.2 g Intermediate 9 and Intermediate 22 (0.20 g) using Method D. The crude product was purified by combi flash chromatography using 60 % Ethyl acetate and Hexane as a mobile phase to obtain 0.150 g (44%) of the title compound. MS (ES+) m / z 358.3 [M + H]+.Intermediate 28N-p-bromophenylsulfonylpropionamideIn a 50 mL RBF previously equipped with a magnetic stirrer and nitrogen balloon, propionamide (0.157 g, 0.0215 mol) were taken in THF (10 ml) and reaction mixture was cooled to 0 °C. NaH (60% dispersion in mineral oil) (0.235 g, 0.00586 mol) was added at same temperature and the reaction mixture was stirred at RT for 30 min, p-bromo(chlorosulfonyl)benzene (0.5 g, 0.00195 mol) was added at same temperature and the reaction mixture was stirred at RT for 16 h. The reaction mixture was filtered through a celite bed and the filtrate was concentrated under reduced pressure to obtain the crude product which was purified by column chromatography with 20% EtOAc in Hexane as the mobile phase to obtain 0.4 g (70%) of the title compound.MS (ES+) m / z 290.0 [M + H]+.Intermediate 29{5-[p-(propionylaminosulfonyl)phenyl]--methyl-2-propanecarbamateIntermediate 29 was prepared using 0.4 g of Intermediate 28 and tert-butyl {[5-(dihydroxyboryl)-2-pyridyl]methyl}carbamate (0.38 g) according to Method G (see Example 1). The obtained crude was purified by column chromatography using 30% EtOAc in Hexane as solvent to obtain 0.3 g (52%) of the title compound. MS (ES+) m / z 420.2 [M + H]+.Intermediate 30N-{p-[6-(aminomethyl)-3-pyridyl] phenylsulfonyl} propionamide hydrochlorideIntermediate 30 was prepared using 0.3 g of Intermediate 29 using Method F.After completion of the reaction, the reaction mixture was distilled under reduced pressure to obtain crude product and triturated with Et?O to 0.2 g (78%) of the title compound. MS (ES+) m / z 320.0 [M + H]+.Intermediate 31N-[(5-bromo-6-methyl-2-pyridyl)methyl](3,6-difluoro-10-oxa-l,9-diaza-9H-anthr-9-yl)acetamideIntermediate 31 was prepared using 0.08 g Intermediate 12 and Intermediate 22 (0.075 g) according to Method D. The crude product was purified by normal phase column chromatography using 40 - 45% EtOAc in hexane as an eluent to obtained 0.090 g (67%) of the title compound. MS (ES+) m / z 461.2 [M + H]+.Intermediate 32tert-butyl [(5-chloro-6-fluoro-2-pyridyl)methyl]carbamateIn a 30 ml seal tube previously equipped with a magnetic stirrer and nitrogen balloon was taken 6-bromo-3-chloro-2-fluoropyridine (0.5 g, 0.00237 mol) and tert-butyl [(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methyl]carbamate (0.73 g, 0.00285 mol) in mixture of 1,4-Dioxane, Acetonitrile and water (4.0 ml: 4.0 ml: 2.0 ml). The reaction mixture was purged with argon gas for 15 min. K3PO4 (1.55 g, 0.00712 mol) and Pd(amphos)Cl2 (1.55 g, 0.00712 mol) was added and the mixture was again purged with argon gas for 10 min. To the reaction mixture Pd(dppf)Cl2.DCM (0.17 g, 0.00023 mol) was added and again purged for 10 min. The reaction mixture was heated to 80 °C for 16 h. The solvent was removed from the reaction mixture under reduced pressure to obtain crude product which was purified by combi flash chromatography using 15 % Ethyl acetate and Hexane as a mobile phase to obtain 0.35 g of the crude titlecompound used in the next step without further purification. MS (ES+) m / z 160.8 [M + H]+.Intermediate 33[(5-chloro-6-fluoro-2-pyridyl)methyl]amine hydrochlorideIntermediate 33 was prepared using 0.35 g of Intermediate 32 according to Method F to produce 0.2 g of the the crude title compound. MS (ES+) m / z 161.0 [M + H]+.Intermediate 34N-[(5-chloro-6-fluoro-2-pyridyl)methyl](6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)acetamideIntermediate 34 was prepared using 0.18 g of Intermediate 6 and Intermediate 33 (0.142 g) according to Method D. The crude product was purified by combi flash chromatography using 90 % Ethyl acetate in Hexane as a mobile phase to obtain 0.12 g (43%) of the title compound. MS (ES+) m / z 417.2 [M + H]+.Intermediate 35N-[(5-bromo-6-methyl-2-pyridyl)methyl](6,7-difluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)acetamideIntermediate 35 was prepared according to Method D using 0.300 g Intermediate 19 and Intermediate 22 (0.268 g) to produce 0.5 g of the crude title compound that was used as such in the next step. MS (ES+) m / z 477.26 [M + H]+.Intermediate 36N-[(5-bromo-2-pyridyl)methyl](6,7-difluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)acetamideIntermediate 36 was prepared from 0.150 g Intermediate 19 and [(5-bromo-2-pyridyl)methyl]amine hydrochloride (0.126 g) according to Method D to obtain 0.200 g of the title compound. MS (ES+) m / z 463.3 [M+H]+.Intermediate 37N-((4-bromophenyl)sulfonyl)acetamideIn a 3-litre assembly with overhead stirrer and nitrogen balloon, 4-bromobenzenesulfonyl chloride (200 g, 1.87 mol) and acetamide (115 g, 1.94 mol) were taken in dry THF (2000 ml) and reaction mixture was cooled to 0 °C. NaH (60% dispersion in mineral oil) (77.96 g, 1.94 mol) was added (portion wise) at 0 °C and reaction mixture was stirred at RT for 2 hours. The completion of reaction was confirmed by the TLC using 30% Ethyl acetate in Hexane as a mobile phase. After completion of the reaction, reaction mixture was quenched by ice cold water (1000 ml) and acidified by IN HCI (pH= 6) then extracted by Ethyl acetate (2 x 1500 ml), the combine organic layers were dried over sodium sulphate and evaporated under reduced pressure to obtain crude product as off-white solid. The crude product was washed by hexane (1000 ml) and filter it to obtained 175 g (Yield 80%) of N-((4-bromophenyl) sulfonyl) acetamide as off-white solid. 1H NMR (400 MHz, DMSO): 6 1.94 (S, 3H), 7.80-7.90(m, 4H), 12.20 (s, 1H). MS (ES+) m / z 280.0 [M + H]+.Intermediate 38N-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)acetamideIn a 3-liter assembly with overhead stirrer and nitrogen balloon was taken N-((4-bromophenyl) sulfonyl) acetamide (100 g, 0.359 mol) and Bis pinacol diborane (108.6 g, 0.427 mol) in Dioxane (2000 ml). The reaction mixture was purged with argon gas for 10 minutes. After that KOAc (105.4 g, 1.075 mol) was added and again purged for 10 minutes. To reaction mixture X-Phos Pd G4 (2.78 g, 0.00323 mol) was added and again purged for 10 minutes. The reaction mixture was heated at 100 °C and maintained at same temperature for 2 hours. The reaction mixture was distilled out under reduced pressure to obtain crude. The crude was dissolved in water (1000 ml) and extracted by ethyl acetate (2 x 1500). The combined organic layer was washed with Brine water (1000 ml) and the organic layer were dried over sodium sulphate and the solvent was removed under reduced pressure to obtain the crude product as a brown solid. The solid was stirred with n-Pentane (1000 ml) for 20 min and filtered. The filter cake was washed with n-Pentane (2 x 200 ml) to obtained 70 g (Yield 60%) of the title compound as off white solid.XH NMR (400 MHz, DMSO): 6 1.31 (S, 12H), 1.91 (s, 3H), 7.87-7.92(m, 4H), 12.14 (s, 1H). MS (ES+) m / z 244.18 [M + H]+.Intermediate 39{5-[p-(acetylaminosulfonyl)phenyl]-6-methyl-2-pyridyl}methyl 2-methyl-2-propanecarbamateIn a 2 L four neck R.BF previously equipped with an overhead stirrer and under nitrogen atmosphere was taken Intermediate 21 (50 g, 0.166 mol) and Intermediate 38 (59.35 g, 0.182 mol) in a mixture of Dioxane (500 ml) and water (100 ml). CS2CO3 (162.27 g,0.498 mol) was added and the mixture purged with argon gas for 10 minutes. Pd(dppf)Cl2.DCM (13.55 g, 0.016 mol) was added and the mixture was again purged with argon gas for 10 minutes. The reaction mixture was heated at 110 °C and maintained at same temperature for 2 hours. The reaction mixture solvent was removed under reduced pressure to obtain the crude product which was purified by Column Chromatography using 5-10% MeOH in DCM to obtained 60 g (86%) of the title compound.XH NMR (400 MHz, DMSO-cfc): 6 1.42 (s, 9H), 1.94 (s, 3H), 2.42 (s, 3H), 4.24 (d, J = 6.0 Hz, 2H), 7.20 (d, J= 7.6 Hz, 1H), 7.46-7.49 (m, 1H), 7.62-7.69 (m, 3H), 7.97 (d, 8.4 Hz, 1H), 12.18 (s, 1H). MS (ES+) m / z 420.24 [M + H]+.Intermediate 40N-{p-[6-(aminomethyl)-2-methyl-3-pyridyl]phenylsulfonyl}acetamide TFA saltIn a RBF previously equipped with an overhead stirrer was taken Intermediate 39 (50 g, 0.119 mol) in DCM (500 ml) and the mixture was cooled to 0 °C. TFA (250 ml; 5 vol) was added drop wise to the reaction mixture and it was stirred at same temperature for 2 hours. Toluene (500 ml) was added and solvents were removed under reduced pressure to get crude product which was triturated by 20% ethyl acetate: Hexane (3 x 500 mL). The solvent was decanted and the solid obtained was dried under reduce pressure to obtain 47 g (Yield 91%) of title compound TFA saltTH NMR (400 MHz, DMSO-de): 6 1.96 (s, 3H), 2.49 (s, 3H), 4.22 (d, J = 5.6 Hz, 2H), 7.46 (d, J= 7.6 Hz, 1H), 7.67-7.69 (m, 2H), 7.79 (d, J= 7.6 Hz, 1H), 8.01 (d, 8.4 Hz, 2H), 8.30 (s, 2H), 12.22 (s, 1H). MS (ES+) m / z 320.2 [M + H]+.Intermediate 41p-(6-{[tert-butyl(oxycarbonylamino)]methyl}-2-methyl-3-pyridyl)benzenesulfonamideIn a seal tube previously equipped with a magnetic stirrer and nitrogen balloon were taken Intermediate 21 (1 g, 0.0033 mol) and (4-sulfamoylphenyl) boronic acid (0.734 g, 0.003652 mol) was treated according to Method G. The crude product was purified by Column Chromatography using silica gel to obtain 0.85 g (68% yield) of the title compound.XH NMR (400 MHz, DMSO-d6): 6 1.42 (s, 9H), 2.42 (s, 3H), 4.24 (d, J = 6.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 1H), 7.43 (s, 2H), 7.46-7.49 (m, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.4 Hz, 2H). MS (ES+) m / z 378.2 [M + H]+.Intermediate 42p-[6-(aminomethyl)-2-methyl-3-pyridy I] benzenesulfonamide TFA saltIn a RBF previously equipped with a magnetic stirrer was taken Intermediate XX (0.900 g, 0.0023843 mol) in DCM (9 ml) and cooled to 0 °C. To the reaction mixture, TFA (4.5 ml; 5 vol) was added drop wise and it was stirred at same temperature for 2 h. The solvent were removed under reduced pressure to get the crude product which was triturated by hexane (3 x 50 mL). The solvent was decanted and the solid dried under reduce pressure to obtain 0.65 g (Yield 72%) of the title compound TFA salt.XH NMR (400 MHz, DMSO-d6): 6 2.50 (s, 3H), 4.24 (d, J = 6.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.47 (s, 2H), 7.53-7.57 (m, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 2H), 8.30 (s, 2H). MS (ES+) m / z 278.2 [M + H]+.Intermediate 43tert-butyl {[5-(dihydroxyboryl)-6-methyl-2-pyridyl]methyl}carbamateIn a RBF previously equipped with a condenser and magnetic stirrer, Intermediate 21 (0.5 g, 0.0017 mol) and Bis(pinacolato) diboron (0.84 g, 0.0033 mol) were taken in 1,4-Dioxane (5.0 ml) and reaction mixture was purged with argon gas for 5 minutes. Pd(dppf)Cl2.DCM (0.14 g, 0.00017 mol) and KOAc (0.49 g, 0.0050 mol) were addedto the reaction mixture and it was again purged with argon gas for 5 minutes. The reaction mixture was heated at 100°C for 2 h. The reaction mixture was filtered and the filtrate were evaporated under reduced pressure to obtain 0.4 g of the crude title compound which was used in the next step as such. MS (ES+) m / z\ 267.3 [(M + H) + ] .Intermediate 44tert-butyl({6-methyl-5-[p-(3-pyridazinylaminosulfonyl)phenyl]-2-pyridyl}methyl) carbamatep-bromophenylsulfonyl)-3-pyridazinylamine (0.5 g) and Intermediate 43 (0.4 g) was treated according to Method E to produce 0.34 g of the title compound. MS (ES+) m / z\ 456.3 E(M + H) + ].Intermediate 453-{p-[6-(aminomethyl)-2-methyl-3-pyridyl]phenylsulfonylamino}pyridazine hydrochlorideIntermediate 44 (0.33 g) was treated according to Method F to produce 0.18 g of the title compound as hydrochloride salt. MS (ES+) m / z\ 356.0 [(M + H) + ] .EXAMPLESExample 1N-{p-[6-({[(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-3-pyridyl]phenylsulfonyl}acetamideMethod GIn a 30 ml seal tube previously equipped with a magnetic stirrer and nitrogen balloon was taken Intermediate 20 (0.09 g, 0.000203 mol, 1.0 eq.) and Intermediate 38 (0.043 g, 0.00025 mol, 1.1 eq) in mixture of Dioxane and water (0.8 ml: 0.2 ml). The reaction mixture was purged with argon gas for 15 minutes. After that CS2CO3 (0.20 g, 0.000609 mol, 3 eq.) was added and again purged for 10 minutes. To the reaction mixture Pd (dppf) CI2.DCM (0.02 g, 0.00002 mol, 0.1 eq.) was added and again purged for 10 minutes. After that reaction mixture was heated at 100 °C and maintained at same temperature for 2 h. The reaction mixture was poured into water (2.5 mL) and aq. layer was extracted with ethyl acetate (3 x 3.0 mL). Combined organic layer was dried over sodium sulphate and solvent was removed under reduced pressure to obtain crude product that was purified by RP-Column Chromatography using a mixture of water (containing 0.1% formic acid) (45%) and ACN (55%) as the mobile phase to produce 0.023 g (27%) of the title compound.XH NMR (400 MHz, DMSO-d6): 6 1.94 (s, 3H), 2.25 (s, 3H), 4.45 (d, J = 4.80 Hz, 2H), 4.55 (s, 2H), 6.53 (d, J = 7.60 Hz, 1H), 6.62 (d, J = 4.80 Hz, 1H), 6.72 (d, J = 8.00 Hz, 2H), 6.91 (d, J = 8.00 Hz, 1H), 7.39 (d, J = 8.00 Hz, 1H), 7.99 (s, 4H), 8.12 (d, J = 8.00 Hz, 1H), 8.89 (s, 2H), 12.19 (s, 1H). MS (ES+) m / z 562.25 [M + H]+.Example 2N-{p-[6-({[(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-2-methyl-3-pyridyl]phenylsulfonyl}acetamideExample 2 was prepared using 0.10 g of Intermediate 23 and Intermediate 38 (0.78 g) according to Method G. The crude product was purified by RP-Column Chromatography on a C18 Column using 45% water (containing 0.1% formic acid) and 55% Acetonitrile as the mobile phase to produce 0.027 g (21%) of the title compound.XH NMR (400 MHz, DMSO-d6): 6 1.96 (s, 3H), 2.23 (s, 3H), 2.41 (s, 3H), 4.40 (d, J = 4.8 Hz, 2H), 4.54 (s, 2H), 6.52 (d, J = 7.6 Hz, 1H), 6.61 (d, J = 4.8 Hz, 1H), 6.71 (d, J = 6.4 Hz, 2H), 6.90 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 7.21 Hz, 1H), 7.62-7.66 (m, 3H), 7.99 (d, J = 6.8 Hz, 2H), 8.85 (s, 1H), 12.19 (s, 1H). MS (ES+) m / z 576.06 [M + H]+.Example 3N-{p-[6-({[(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-2-methoxy-3-pyridyl]phenylsulfonyl}acetamideExample 3 was prepared using 0.15 g Intermediate 26 and Intermediate 38 (0.11 g) using Method G. The obtained crude was purified by Combi flash chromatography was eluted using DCM containing 1.5% MeOH to obtain 0.012 g (6.4%) of the titlecompound.XH NMR (400 MHz, DMSO-c / e): 6 1.87 (s, 3H). 2.24 (s, 3H), 3.88 (s, 3H), 4.36 (d, J = 5.6 Hz, 2H), 4.55 (s, 2H), 6.53 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 5.6 Hz, 1H), 6.71 (s, 2H), 6.91 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 7.71-7.80 (m, 3H), 7.90 (d, J = 8.0 Hz, 2H), 8.81 (s, 1H), 12.16 (s, 1H). MS (ES+) m / z 592.5 [M + H]+.Example 4N-{p-[6-({[(6-fluoro-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl]carbonylamino} methyl)-2-methyl-3-pyridyl]phenylsulfonyl}acetamideExample 4 was prepared using 0.08 g Intermediate 27 and Intermediate 38 (0.065 g) using Method G. The compound was purified by RP-HPLC chromatography on gradient system using a mobile phase containing 0.1% Formic acid in water (90-0%)and (B) Acetonitrile (10-100%) to obtain 0.028 g (27%) of the title compound.XH NMR (400 MHz, DMSO-d6): 6 1.95 (s, 3H), 2.42 (s, 3H), 4.39 (d, J = 5.20 Hz, 2H), 4.55 (s, 2H), 6.64-6.75 (m, 4H), 7.00 (d, J = 7.60 Hz, 1H), 7.24 (d, J = 7.60 Hz, 1H), 7.64-7.70 (m, 4H), 7.98 (d, J = 8.00 Hz, 2H), 8.85 (s, 1H), 12.20 (s, 1H). MS (ES+) m / z 562.0 [M + H]+.Example 5N-{p-[6-({[(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-3-pyridyl] phenylsulfonyl} propionamideExample 5 was prepared using 0.15 g of Intermediate 6 and Intermediate 30 (0.21 g) according to Method D. The crude product was purified by prep HPLC with a gradient mobile phase containing (A) 0.1% Trifluoroacetic acid in water (75 - 0%) and (B) Acetonitrile (25 -100%) to produce 0.031 g (9.8%) of the title compound.XH NMR (400 MHz, DMSO-de): 6 12.13 (s, 1H), 8.91 (s, 2H), 8.16 (d, J = 5.60 Hz, 1H), 8.00 (d, J = 3.20 Hz, 4H), 7.42 (d, J = 7.60 Hz, 1H), 6.91 (d, J = 7.20 Hz, 1H), 6.72 (s, 2H), 6.62 (d, J = 5.20 Hz, 1H), 6.53 (d, J = 7.60 Hz, 1H), 4.55 (s, 2H), 4.47 (d, J = 4.40 Hz, 2H), 2.45 (s, 2H), 2.25 (s, 3H), 0.90 (t, J = 5.60 Hz, 3H). MS (ES+) m / z 576.2 [M + H]+.Example 6N-{p-[6-({[(3,6-difluoro-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl]carbonylamino} methyl)-2-methyl-3-pyridyl]phenylsulfonyl}acetamideExample 6 was prepared using 0.08 g Intermediate 31 and Intermediate 38 (0.062 g) according to Method G. The crude product was purified by reverse phase column chromatography using 20-25 % ACN in water (containing 0.1% Ammonia) as an eluent to obtained 0.044 g (43%) of the title compound.XH NMR (400 MHz, DMSO-cfe): 6 1.98 (s, 3H), 2.46 (s, 3H), 4.44 (d, J = 5.2 Hz, 2H), 4.54 (s, 2H), 6.69 (d, J = 4.8 Hz, 1H), 6.79 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.68-7.78 (m, 3H), 7.81 (d, J = 7.6 Hz, 1H), 8.02 (d, J = 7.2 Hz, 2H), 8.89 (s, 1H), 12.21 (s, 1H). MS (ES+) m / z 580.3 [M + H]+.Example 7N-{p-[6-({[(6-fluoro-2-methyl-10-oxa-l,3,9-triaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-2-methyl-3-pyridyl]phenylsulfonyl}acetamideExample 7 was prepared using Intermediate 3 (0.150 g, 0.000544 mol) and Intermediate 40 (0.191 g, 0.0005993 mol) according to Method D. The crude product was purified by RP-Column Chromatography with a mobile phase containing 30% water (with 0.1% formic acid) and 70% ACN to obtain 0.024 g (9%) of the title compound.XH NMR (400 MHz, DMSO-d6): 6 12.16 (s, 1H), 8.90 (s, 1H), 7.95 (d, J = 8 Hz, 2H), 7.70 (s, 1H), 7.62 (d, J = 8 Hz, 3H), 7.17 (d, J = 7.6 Hz, 1H) 6.79-6.71 (m,3H), 4.54 (s, 2H), 4.38 (d, J = 5.2 Hz, 2H), 2.41 (d, J = 10.8 Hz, 3H), 2.31 (s, 3H), 1.92 (s, 3H). MS (ES+) m / z 577.0 [M + H]+.Example 8N-{p-[6-({[(6,7-difluoro-2-methyl-10-oxa-l,3,9-triaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-2-methyl-3-pyridyl]phenylsulfonyl}acetamideExample 8 was prepared from Intermediate 15 (0.150 g, 0.000511 mol) and Intermediate 40 (0.179 g, 0.0005626 mol) according to Method D.The crude product was purified by RP-Column Chromatography with 30% water (containing 0.1% formic acid) and and 70% ACN as the mobile phase to produce 0.017 g (6%) of the title compound.XH NMR (400 MHz, DMSO-d6): 6 12.6 (s, 1H), 9.54 (s, 1H), 8.53 (d, J = 7.2 Hz, 1H), 8.35 (s, 1H), 8.23-8.17 (m, 3H), 7.83 (d, J = 7.6 Hz, 1H), 7.60-7.65 (m, 3H), 5.17 (s, 2H), 5.01 (s, 2H), 3.02 (s, 3H), 2.94 (s, 3H) 2.52 (s, 3H). MS (ES+) m / z 577.0 [M + H]+.Example 9N-{p-[2-fluoro-6-({[(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-3-pyridyl]phenylsulfonyl}acetamideMethod HIn a 30 ml seal tube previously equipped with a magnetic stirrer and nitrogen balloon was taken Intermediate 34 (0.10 g, 0.00023 mol) and Intermediate 38 (0.312 g, 0.00095 mol) in mixture of Dioxane and water (1.0 ml: 0.1 ml). The reaction mixture was purged with argon gas for 15 min. After that CS2CO3 (0.20 g, 0.00059 mol) was added and again purged for 10 min. To the reaction mixture XPhos Pd G4 (0.02 g, 0.00002 mol) and KI (0.02 g, 0.00011 mol) was added and the mixture was again purged for 10 min. After that reaction mixture was heated at 110 °C for 16 h. The solvent was removed under reduced pressure to obtain crude product that was purified by RP-HPLC using a gradient system with a mobile phase containing (A ) water (containing 0.1% formic acid (60 - 0%) and (B) Acetonitrile (40 -100 %) to produce 0.04 g (28%) of the title compound.XH NMR (400 MHz, DMSO-d6): 6 12.23 (s, 1H), 8.93 (s, 1H), 8.17 (t, J = 9.60 Hz, 1H), 8.03 (d, J = 8.40 Hz, 2H), 7.87 (d, J = 8.00 Hz, 2H), 7.38 (d, J = 7.20 Hz, 1H), 6.93 (d, J = 7.60 Hz, 1H), 6.73 (d, J = 8.40 Hz, 2H), 6.65 (d, J = 5.20 Hz, 1H), 6.55 (d, J = 7.60 Hz, 1H), 4.57 (s, 2H), 4.41 (d, J = 6.00 Hz, 2H), 2.26 (s, 3H), 1.97 (s, 3H). MS (ES+) m / z 580.4 [M + H]+.Example 10N-{p-[6-({[(6,7-difluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-2-methyl-3-pyridyl]phenylsulfonyl}acetamideExample 10 was prepared using 0.140 g Intermediate 35 and N-p-(dihydroxyboryl)phenylsulfonylacetamide (0.286 g) according to Method H. The compound was purified by RP-Column Chromatography using 50% water (containing 0.1% Formic acid) and 50% Acetonitrile to produce 0.016 g (9%) of the title compound.XH NMR (400 MHz, DMSO-d6): 6 12.18 (s, 1H), 8.88-8.89 (m, 1H), 7.98 (d, J = 7.20 Hz, 2H), 7.59-7.62 (m, 3H), 7.22 (d, J = 7.60 Hz, 1H), 6.90-6.95 (m, 2H), 6.76-6.79 (m, 1H), 6.55 (d, J = 6.80 Hz, 1H), 4.54 (s, 2H), 4.40 (d, J = 2.8 Hz, 2H), 2.40(s, 3H), 2.23 (s, 3H), 1.95 (s, 3H). MS (ES+) m / z 594.42 [M + H]+.Example 11N-{p-[6-({[(6,7-difluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-3-pyridyl]phenylsulfonyl}acetamideExample 11 was prepared prepared from 0.150 g Intermediate 36 and N-p-(dihydroxyboryl)phenylsulfonylacetamide (0.316 g) according to Method H. The compound was purified by Column Chromatography using 2-4% Methanol in DCM as the mobile phase to obtain 0.043 g (22%) of the title compound.XH NMR (400 MHz, DMSO-d6): 6 12.19 (s, 1H), 8.88 (s, 2H), 7.98-8.12 (m, 5H), 7.43 (d, J = 8.40 Hz, 1H), 6.92-6.97 (m, 2H), 6.80-6.85 (m, 1H), 6.58 (d, J = 7.60 Hz, 1H), 4.57 (s, 2H), 4.47 (d, J = 4.80 Hz, 2H), 2.26 (s, 3H), 1.95 (s, 3H). MS (ES+) m / z 580.45 [M + H]+.Example 12p-[6-({[(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl]carbonylamino} methyl)-2-methyl-3-pyridy I] benzenesulfonamideExample 8 was prepared from Intermediate 6 (0.250g, 0.0009115 mol) and Intermediate 42 (0.410 g, 0.0010938 mol) according to Method D. The compound was purified by RP-HPLC using a gradient system with a mobile phase containing (A) water (containing 5 mM ammonium bicarbonate +0.1% NH3 (65 - 0%) and (B) Acetonitrile:MeOH (50:50) (35 -100 %) to produce 0.110 g (23 %) of the title compound.XH NMR (400 MHz, DMSO-d6): 6 2.22 (s, 3H), 2.40 (s, 3H), 4.39 (d, J = 5.6 Hz, 2H), 4.53 (s, 2H), 6.51 (d, J = 7.6 Hz, 1H), 6.56-6.60 (m, 1H), 6.68-6.71 (m, 2H), 6.88-6.91 (m, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.44 (s, 2H), 7.58-7.60 (m, 3H), 7.88-7.90 (m, 2H), 8.81-8.83 (m, 1H). MS (ES+) m / z 534.4 [M + H]+.Example 13N-({6-methyl-5-[p-(3-pyridazinylaminosulfonyl)phenyl]-2-pyridyl}methyl)(6-fluoro- 2-methyl-10-oxa-l,3,9-triaza-9H-anthr-9-yl)acetamideExample 12 was prepared form Intermediate 3 (0.05 g) and Intermediate 45 (0.078 g) according to method D. The compound was purified by RP-HPLC using gradient system with (A) water containing 0.1% Formic acid (90-0%) and (B) Acetonitrile (10-100%) as the mobile phase to produce 0.015 g (13% yield) of the title compound.XH NMR(400 MHz, DMSO-d6): 6 8.92 (s, 1H), 8.81 (d, J = 4.80 Hz, 1H), 8.18 (d, J = 8.40 Hz, 2H), 7.94 (d, J = 4.80 Hz, 1H), 7.72-7.68 (m, 3H), 7.64 (d, J = 8.00 Hz, 1H), 7.23 (s, 2H), 7.18 (d, J = 8.00 Hz, 1H), 6.80 (d, J = 8.80 Hz, 1H), 6.76-6.72 (m, 2H), 4.56 (s, 2H), 4.40 (d, J = 5.60 Hz, 2H), 2.39 (s, 3H), 2.32 (s, 3H). MS (ES+) m / z 613.5 [(M + H) + ],Example 14N-({6-methyl-5-[p-(3-pyridazinylaminosulfonyl)phenyl]-2-pyridyl}methyl)(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)acetamideExample 13 was prepared using Intermediate 6 (0.05 g) and Intermediate 45 (0.79 g) according to method D. The compound was purified by RP-HPLC with a gradient system using (A) water containing 0.1% Formic acid (90-0%) and (B) Acetonitrile (10-100%) as the mobile phase to obtain 0.02 g (18% yield) of the title compound.XH NMR (400 MHz, DMSO-d6): 6 8.86-8.82 (m, 2H), 8.53 (s, 2H), 8.20 (d, J = 8.40 Hz, 2H), 7.95 (d, J = 4.80 Hz, 1H), 7.70 (d, J = 8.40 Hz, 1H), 7.64 (d, J = 8.00 Hz, 1H), 7.25-7.19 (m, 2H), 6.91 (d, J = 7.60 Hz, 1H), 6.72 (d, J = 9.20 Hz, 2H), 6.60 (s, 1H), 6.53 (d, J = 7.60 Hz, 1H), 4.55 (s, 2H), 4.40 (d, J = 6.00 Hz, 2H), 2.40 (s, 3H), 2.24 (s, 3H). MS (ES+) m / z 612.5 [(M + H) + ].Table 1. Example compounds"><>Biological AssaysBiological Example 1 - In vitro assay using U2OS-cells overexpressing recombinant receptor tyrosine kinasesThe purpose of the assay was to identify compounds that modulate neurotrophin signalling.The assay uses Enzyme Fragment Complementation (EFC) technique, which is a proximity-based assay. The cells used in this assay over-express two fusion proteins, i.e. the TrkA, TrkB orTrkC receptor, fused to a small peptide of b-galactosidase and an adaptor protein, i.e. SHC1 fused to the major part of b-galactosidase. Binding of ligand (NGF, BDNF, NT-3) to the receptor induces phosphorylation of the intracellular domain and hence, recruitment of the adaptor protein to the receptor. The proximity between the small activating peptide on the receptor and the major part of b-galactosidase on the adaptor protein leads to an active b-galactosidase enzyme. The activation of the receptor is quantified by measuring the amount of active b-galactosidase by its conversion of a non-luminescent substrate into a luminescent product.U2OS-cells, over-expressing Trk-receptors were plated in 384-well plates and incubated overnight. On the following day, test compound was pre-mixed with ligand and the ligand-compound mixture was then added to the cells to yield a final ligand concentration of 10 ng / mL. After 3 hours of incubation at room temperature, the incubation was stopped by the addition of a b-galactosidase substrate mixture containing detergents. The substrate mixture was incubated for 60 minutes at ambient temperature. The luminescence was thereafter read by the use of a suitable plate reader.ResultsData from the assay for the Example compounds are shown in the Table below. The potency is expressed as IC50 (nM) for the human TrkA receptor stimulated by 10 ng / ml NGF, human TrkB receptor stimulated by 10 ng / mL BDNF and human TrkC receptor stimulated by 10 ng / mL NT-3. The absence of an IC50 value indicates that this has not been determined for the relevant Example compound.All Example compounds reduced NGF-induced activation of the TrkA receptor to the same level as in unstimulated cells, indicating complete inhibition of NGF-TrkA signalling.The data indicate that the compounds of the invention are highly potent and effective negative modulators the TrkA receptor and have very high selectivity for the TrkA receptor over the TrkB and TrkC receptors. Therefore, the compounds are expected topossess useful therapeutic properties, such as in the treatment of pain, inflammation and the other diseases and disorders described herein.>*Partial inhibition, approximately 40% reduction in stimulationBiological Example 2 - Effects of Example compound 2 in a mono-iodoacetate (MIA)-induced osteoarthritis modelProcedureMale Sprague Dawley rats were quarantined for 7 days and acclimatized for one day prior to experiment initiation. During this period, rats were observed daily for clinical signs.On day -1, all the animals were assessed for basal mechanical allodynia (threshold in g). On day 0 osteoarthritis was induced by intraarticular injection of 2 mg / mL MIA at a dose volume of 50pL per rat under isoflurane anesthesia to left hind limb. On day 3 of post MIA injection, mechanical allodynia was measured and the animals which showed 50% reduction in the basal paw withdrawal threshold were considered for the study and randomized into groups. From day 3 to day 20 animals were administered with either vehicle or a test compound (Example compound 2) by oral gavage.On day 7, 14 and 20, non-evoked pain was measured using weight bearing. Mechanical allodynia were assessed at lh, 3h and 6h post dose on day 11 and 21. Weight bearing, and knee diameter were assessed on day 3, single time point (baseline), and on day 7, day 14 and day 20 at 3-3.5 h post dose. Mechanical allodynia was assessed by using Dynamic Planter Aesthesiometer (Ugo Basile) at maximum time force 50 g and ramping time 20sec. Paw withdrawal thresholds were recorded on ipsilateral paw for three times at interval of ~2 min. Weight bearing was analyzed using an In capacitance meter (IITC Life Science, CA, USA). In this assay, the weight distribution between the hind legs of the animal is measured, and a 50% weight distribution would indicate no pain in either limb, if the animal experiences pain in one limb, the % weight distribution to that limb is reduced. Knee diameter was measured using a digital Vernier caliper (Mitutoyo) in ipsilateral limb joints and expressed in mm units.On day 11 post 6 h assessment of mechanical allodynia the blood (~ 500pl in EDTA containing tubes) was collected for all the animals under isoflurane anaesthesia. The plasma was separated by centrifugation at 4°C, 5000 RPM for 10 minutes. Plasma samples were stored at -80° C and all the animals were humanely sacrificed by carbon dioxide anaphylaxis then knee joint was isolated and preserved in neutral buffered saline for H&E staining.ResultsKnee diameterRepeated twice daily dosing of Example compound 2 at 3, 10 or 30 mg / kg by per oral administration starting at day 3 through day 20 in the in mono-iodoacetate (MIA) induced osteoarthritis model led to significant reduction of knee diameter as a measurement of clinical symptom of inflammation. The reduction in inflammation was evident at all doses (3, 10 and 30 mg / kg) at day 20 (Figure 1). This suggests that the compounds of the invention are likely to have utility in the treatment of inflammation mediated by TrkA and in inflammatory disorders involving inflammation caused by NGF and / or its interactions with the TrkA receptor, especially for inflammation associated with degenerative joint diseases.Weight bearingRepeated twice daily dosing of Example 2 at 3, 10 or 30 mg / kg by per oral administration starting at day 3 through day 20 in the in mono-iodoacetate (MIA)induced osteoarthritis model led to a significant improvement in weight bearing on the affected limb, a measurement of non-evoked pain (as indicated by the increase in percentage weight distribution on the affected limb in the treatment groups). The analgesic effect was evident at day 20 for 3, 10 and 30 mg / kg group (Figure 2). This suggests that the compounds of invention are likely to have utility in the treatment of pain mediated by TrkA and in pain disorders involving inflammation caused by NGF and / or its interactions with the TrkA receptor, especially for pain associated with arthritis.Mechanical allodyniaRepeated twice daily dosing of example 2 at 3, 10 or 30 mg / kg by per oral administration starting at day 3 through day 20 in the in mono-iodoacetate (MIA) induced osteoarthritis model led to significant reduction of mechanical allodynia, a measurement of evoked pain. The analgesic effect was evident at day 20 for 3, 10 and 30 mg / kg group (Figure 3). This suggests that the compounds of the invention are likely to have utility in the treatment of pain mediated by TrkA and in pain disorders involving inflammation caused by NGF and / or its interactions with the TrkA receptor, especially for pain associated with arthritis.Knee joint histopathologyRepeated twice daily dosing of example 2 at 3, 10 or 30 mg / kg by per oral administration starting at day 3 through day 20 in the in mono-iodoacetate (MIA) induced osteoarthritis model led to significant reduction of knee joint histopathology score, a measurement of knee joint pathology. The effect was evident at day 20 for 3, 10 and 30 mg / kg group (Figure 4). This suggests that the compounds of the invention are likely to have utility in the treatment of degenerative joint disorders mediated by TrkA and degenerative joint disorders involving inflammation caused by NGF and / or its interactions with the TrkA receptor, especially for degenerative joints disorders.Biological Example 3 - Biological Example 3 - Effects of Example compound 2 in Brennan model of post-incisional pain in male Sprague Dawley ratsProcedureA paw incision procedure waw performed on the rats, following the method outlined by Brennan et al. Pain, 1996, 493-502. The rats were anesthetized using isoflurane, with3% for induction and 2-3% for maintenance. Afterwards, a 1 cm incision was made along the plantar aspect of the right hind paw, starting 0.5 cm from the edge of the heel and extending toward the toe. This incision involved a longitudinal cut of the plantaris muscle. Finally, the wound was closed using 6.0 nylon sutures (Monofilament Polyamide Black, ETHILON® Nylon Suture by J&J). The male SD rats were familiarized with the experimental environment for 60 minutes before the behavioural study begins. To prepare for the pain assessment, the rats were individually placed in a transparent testing chamber with a mesh floor for two consecutive days. The baseline paw withdrawal threshold was assessed around 30 minutes before the surgical procedure and then again between 20 to 22 hours following the surgery. On the day of pain assessment, post-surgery, animals were randomly assigned to treatment groups consisting of 12 animals per group. Individual rats were placed in separate enclosures with mesh flooring and allowed to adapt to their surroundings for one hour. The withdrawal threshold was measured using calibrated von Frey filaments with forces of 0.41, 0.60, 1.00, 2.00, 3.63, 5.50, 8.50, and 15.10 grams (provided by Bioseb In Vivo Research Instruments). The tactile stimulus that results in a 50% withdrawal response was determined using the up-down method. On the day of testing post-surgery, each group of rats received the respective treatments via per oral (p.o.,) and the tactile allodynia was evaluated at a specific post-treatment time at 1,3 and 6 h.ResultsTwo daily doses of example 2 at 3, 10 or 30 mg / kg by per oral administration in the Brennan model of post-incisional pain (post-operative pain) model led to a significant reduction of mechanical allodynia, a measurement of evoked pain. The effect was evident for 3, 10 and 30 mg / kg group (Figure 5). This suggests that the compounds of the invention are likely to have utility in the treatment of nociceptive pain, in particular nociceptive pain mediated by TrkA or caused by NGF and / or its interactions with the TrkA receptor, especially for pain associated with recovery after surgical / operative procedures.Biological Example 4 - - Effects of Example compound 2 in paclitaxel-induced peripheral neuropathic pain in male Sprague Dawley ratsProcedureNeuropathic pain in rats was induced by injecting paclitaxel (lOOmg, from Hetero Healthcare Ltd) at a dosage of 2 mg / kg into the intraperitoneal cavity on days 0, 2, 4,and 6, resulting in a cumulative dose of 8 mg / kg for Groups 2-9. Group 1 served as the control group and received saline with a vehicle. On the 13th day following paclitaxel administration, baseline tactile allodynia (sensitivity to calibrated manual von Frey filaments) was assessed using Dixon's up-and-down method on both paws. Rats were randomized into the groups based on a 50% paw withdrawal threshold (<5g, as the selection criteria). Subsequently, at specific time points, rats were administered the test compound (Example compound 2) or vehicle.The rats were allowed to acclimate to the experimental environment for 60 minutes before the behavioral study. Prior to pain assessment, individual rats were familiarized with the transparent testing chamber with a mesh floor for two consecutive days. On day 15 post paclitaxel administration, each group of rats received the respective treatments (test compound or vehicle) via a per oral (p.o.,) administration and the tactile allodynia was evaluated at Oh and at specific post-treatment time at 1, 3 and 6h. Withdrawal threshold was determined using calibrated von Frey filaments (Bioseb, France). Since paclitaxel induces bilateral allodynia with no differences between the left and right hind paws, the PWT values of both paws was averaged.ResultsOne single dose of example 2 at 3, 10 or 30 mg / kg by per oral administration in the chemotherapy-induced peripheral neuropathy (CIPN) model of neuropathic pain model led to a significant reduction of mechanical allodynia, a measurement of evoked pain. The effect was evident for 3, 10 and 30 mg / kg group (Figure 6). This suggests that the compounds of the invention are likely to have utility in the treatment of neuropathic pain, in particular neuropathic pain mediated by TrkA or caused by NGF and it / or its interactions with the TrkA receptor, especially for neuropathic pain associated with chemotherapy-induced peripheral neuropathy.Biological Example 5 - Evaluation of the analgesic and anti-inflammatory effects of Example compound 2 using NGF-induced paw inflammation and thermal hypersensitivity as measured in the rat plantar testProcedureTo induce thermal sensitivity, nerve growth factor (NGF) or vehicle (PBS), was given as an intra plantar injection into the animal's left hind paw (ILP), once per animal with a maximum volume of 30pL. This was carried out 3 hours before the Plantar test. Example compound 2 (1 mg / kg or 3 mg / kg dose) was administered 60 minutes afterNGF injection. Thermal sensitivity was determined in the Plantar test using a thermal paw stimulator (Hargreave's apparatus). After 1 hour of habituation to the test room, the rats were placed into individual modular enclosures mounted on a glass surface and allowed a 15-20 min acclimation period.A thermal stimulus (infrared (IR.) beam) was applied to the sensitized plantar surface of the hind paw. The stimulus current (35%) was held constant, and a cut-off time of exposure was set at 30s to limit possible tissue damage. A trial was initiated by pressing start from the emitter buttons or from the touch screen. When the animal felt pain and withdrew its paw, the I.R. source switched off and the reaction time counter stopped. The withdrawal latency to the nearest 0.1 s was automatically detected and stored. Paw withdrawal latency (PWL) was assessed in both the ipsilateral (ILP) and contralateral (CLP) hind paw of each rat. Each rat / hind paw was tested in three sequential trials with 5 min. Hind paw edema / volume (both in ILP and CLP) was measured using a Plethysmometer (electronic volume meter) in connection with sacrifice. After the test the animals were anesthetized with isoflurane. After blood sampling, skin biopsies were collected, and the animal was sacrificed by decapitation.ResultsOne single dose of Example compound 2 at 1 or 3 mg / kg by per oral administration in the NGF-induced paw thermal hypersensitivity model as measured in the rat plantar test (Hargreaves test) led to a significant reduction of heat hypersensitivity, a measurement of heat evoked pain. The effect was evident for the 3 mg / kg group (Figure 7).In a separate experiment, one single dose of Example compound 2 at 10 mg / kg by per oral administration in the NGF-induced paw thermal hypersensitivity model as measured in the rat plantar test (Hargreaves test) led to a significant reduction in paw volume, a measurement of NGF-induced inflammation. The effect was evident for the 10 mg / kg group (Figure 8).These results suggest that the compounds of the invention are likely to have utility in the treatment of inflammation mediated by TrkA or caused by NGF and it / or its interactions with the TrkA receptor, especially for inflammatory disorders associated with increased NGF levels or increased TrkA signalling.Biological Example 6 - Effect of Example compound 2 on levels of Calcitonin gene-related peptide (CGRP) in rat paw biopsiesProcedure36 male Sprague Dawley rats were obtained from Charles River, Italy, 5-6 weeks of age at arrival. The animals were housed in groups of 2 rats in standard cages (Tecniplast Green Line IVC Sealsafe PLUS rat (900cm2-395x346x213 mm or Allentown Type IV-S (1350 cm2)-387x503x250mm in a temperature- and humidity-controlled room with a 12-hr light / dark cycle (lights on at 6.00 am), with free access to standard lab chow and tap water. The animals were allowed to habituate to the maintenance facilities. The rats were marked with a pen on the tail during the study. To induce thermal sensitivity, nerve growth factor (NGF; 5pg) or vehicle (PBS), were given as an intra plantar injection into the animal's left hind paw, once per animal and the maximum volume was 30pL. Compound or vehicle, was administered orally 2h prior to Plantar test.Directly after the test, the rats were anesthetized by inhalation of Isoflurane. In connection with sacrifice, organs, tissue, and blood were collected. Blood was centrifuged and plasma was separated and stored at -80°C. Skin biopsies were snap frozen, stored at -80°C and later homogenized and centrifuged. The resulting supernatants were stored at -80°C before CGRP were determined by ELISA according to the manufacturer's instructions. Absorbance was measured with an iD5 plate reader from Molecular Devices.ResultsOne single dose of example 2 at 10 mg / kg by per oral administration in the NGF-induced paw thermal hypersensitivity model as measured in the rat plantar test (Hargreaves test) led to a significant decrease in CGRP levels in plasma, a measurement of NGF-induced inflammation. The effect was evident for the 10 mg / kg group (Figure 9). This suggests that the compounds of the invention are likely to have utility in the treatment of inflammation mediated by TrkA or caused by NGF and it / or its interactions with the TrkA receptor, especially for disorders associated with increased CGRP levels.

Claims

Claims1. A compound of formula I, or a pharmaceutically acceptable salt thereof,wherein:R1is selected from hydrogen and a fluoro group;R2is selected from hydrogen and a C1-3 alkyl group, which C1-3 alkyl group is optionally substituted by one or more fluoro group;A is selected from -N- and -C(RA)-; wherein RAis selected from hydrogen and a fluoro group;X and Y are each independently selected from the group consisting of a -CH2- group, a -CHMe- group and a -CMe?- group, which three groups are optionally substituted by one or more fluoro groups;R3is selected from the group consisting of hydrogen, fluoro, chloro, a C1-3 alkyl group and a C1-3 alkoxy group, which C1-3 alkyl and C1-3 alkoxy groups are optionally substituted by one or more fluoro group;R4and R5are each independently selected from the group consisting of fluoro, chloro and a C1-3 alkyl group, which C1-3 alkyl group is optionally substituted by one or more fluoro group;97n is selected from 0, 1 and 2;m is selected from 0, 1, 2, 3 and 4;R5is selected from hydrogen, -C(O)R7and a 5-6-membered heteroaryl group, which 5-6 membered heteroaryl group is optionally substituted by one or more groups selected from the group consisting of a fluoro group, a chloro group, a cyano group, a C1-3 alkyl group and a C1-3 alkoxy group, which C1-3 alkyl and C1-3 alkoxy groups are optionally substituted by one or more fluoro group; andR7is selected from a C1-6 alkyl group and a C3-6 cycloalkyl group, which C1-6 alkyl and C3-6 cycloalkyl groups are optionally substituted by one or more fluoro group.

2. A compound, or a pharmaceutically acceptable salt thereof, as claimed in Claim 1, wherein R2is selected from hydrogen and a methyl group, which methyl group is optionally substituted by one or more fluoro groups.

3. A compound, or a pharmaceutically acceptable salt thereof, as claimed in Claim 1 or Claim 2, wherein R3is selected from the group consisting of hydrogen, a fluoro group, a methyl group and a methoxy group, which methyl and methoxy groups are optionally substituted by one or more fluoro groups.

4. A compound, or a pharmaceutically acceptable salt thereof, as claimed in any one of Claims 1 to 3 wherein R4and R5are each independently selected from the group consisting of a fluoro group and a methyl group, which methyl group is optionally substituted by one or more fluoro groups.

5. A compound, or a pharmaceutically acceptable salt thereof, as claimed in any one of Claims 1 to 4, wherein n is selected from 0 or 1 and / or m is selected from 0 or 1.

6. A compound, or a pharmaceutically acceptable salt thereof, as claimed in Claim 5, wherein n is 0 and / or m is 0.

7. A compound, or a pharmaceutical salt thereof, as claimed in any one of Claims 1 to 6, wherein R5is -C(O)R7.

988. A compound, or a pharmaceutically acceptable salt thereof, as claimed in any one of Claims 1 to 7, wherein R7is a Ci-6 alkyl group, which Ci-6 alkyl group is optionally substituted by one or more fluoro group.

9. A compound, or a pharmaceutically acceptable salt thereof, as claimed in Claim 8, wherein R7is selected from the group consisting of a methyl group and an ethyl group.

10. A compound, or a pharmaceutically acceptable salt thereof, as claimed in any one of Claims 1 to 7, wherein R5is a 5-6-membered heteroaryl group, which 5-6 membered heteroaryl group is optionally substituted by one or more groups selected from the group consisting of a fluoro group, a chloro group, a cyano group, a C1-3 alkyl group and a C1-3 alkoxy group, which C1-3 alkyl and C1-3 alkoxy groups are optionally substituted by one or more fluoro group.

11. A compound, or a pharmaceutically acceptable salt thereof, as claimed in Claim 10, wherein R5is a 5-6-membered heteroaryl group selected from the group consisting of a pyridinyl group, a pyridazinyl group, a pyramidinyl group, a pyrazinyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a triazinyl group and a tetrazolyl group, all of which groups are optionally substituted by one or more groups selected from a fluoro group, a chloro group, a cyano group, a C1-3 alkyl group and a C1-3 alkoxy group, which C1-3 alkyl and C1-3 alkoxy groups are optionally substituted by one or more fluoro group.

12. A compound, or a pharmaceutically acceptable salt thereof, as claimed in Claim 11, wherein R5is selected from the group consisting of:wherein -^ represents the point of the attachment to the sulfonamide nitrogen, and each heteroaryl group is optionally substituted by one or more groups selected from the group consisting of a fluoro group, a chloro group, a cyano group, a C1-3 alkyl group and a C1-3 alkoxy group, which C1-3 alkyl and C1-3 alkoxy groups are optionally substituted by one or more fluoro group.

13. A compound, or a pharmaceutically acceptable salt thereof, as claimed in any one of Claims 1 to 12, wherein, when R5is a 5-6-membered heteroaryl group, the 5-6-membered heteroaryl group is optionally substituted by one or more groups selected from the group consisting of a fluoro group, a cyano group, a methyl group, a trifluoromethyl group, a methoxy group and a trifluoromethoxy group.

14. A compound, or a pharmaceutically acceptable salt thereof, as claimed in any one of Claims 1 to 13, wherein X and Y each represent -CH2-.

15. A compound, or a pharmaceutically acceptable salt thereof, as claimed in Claim 1, wherein the compound is selected from the group consisting of:N-{p-[6-({[(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-3-pyridyl]phenylsulfonyl}acetamide;N-{p-[6-({[(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-2-methyl-3-pyridyl]phenylsulfonyl}acetamide;100N-{p-[6-({[(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-2-methoxy-3-pyridyl]phenylsulfonyl}acetamide;N-{p-[6-({[(6-fluoro-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl]carbonylamino} methyl)-2-methyl-3-pyridyl]phenylsulfonyl}acetamide;N-{p-[6-({[(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-3-pyridy I] phenylsulfonyl} propionamide;101N-{p-[6-({[(3,6-difluoro-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl]carbonylamino} methyl)-2-methyl-3-pyridyl]phenylsulfonyl}acetamide;N-{p-[6-({[(6-fluoro-2-methyl-10-oxa-l,3,9-triaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-2-methyl-3-pyridyl]phenylsulfonyl}acetamide;N-{p-[6-({[(6,7-difluoro-2-methyl-10-oxa-l,3,9-triaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-2-methyl-3-pyridyl]phenylsulfonyl}acetamide;102N-{p-[2-fluoro-6-({[(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-3-pyridyl]phenylsulfonyl}acetamide;N-{p-[6-({[(6,7-difluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-2-methyl-3-pyridyl]phenylsulfonyl}acetamide;N-{p-[6-({[(6,7-difluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl] carbonylamino}methyl)-3-pyridyl]phenylsulfonyl}acetamide;103p-[6-({[(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)methyl]carbonylamino} methyl)-2-methyl-3-pyridy I] benzenesulfonamide;N-({6-methyl-5-[p-(3-pyridazinylaminosulfonyl)phenyl]-2-pyridyl}methyl)(6-fluoro- 2-methyl-10-oxa-l,3,9-triaza-9H-anthr-9-yl)acetamide; andN-({6-methyl-5-[p-(3-pyridazinylaminosulfonyl)phenyl]-2-pyridyl}methyl)(6-fluoro-2-methyl-10-oxa-l,9-diaza-9H-anthr-9-yl)acetamide.

16. A pharmaceutical or veterinary composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined in any one of Claims 1 to 15, and, optionally, one or more pharmaceutically acceptable excipient.10417. A compound of formula I, or a pharmaceutically acceptable salt thereof, as defined in any one of Claims 1 to 15, or a pharmaceutical or veterinary composition as defined in Claim 16, for use in medicine.

18. A compound of formula I, or a pharmaceutically acceptable salt thereof, as defined in any one of Claims 1 to 15, or a pharmaceutical or veterinary composition as defined in Claim 16, for use in the treatment and / or prevention of a disease or disorder in which negative modulation of tropomyosin receptor kinase A is beneficial in a human or animal subject.

19. A method of treating and / or preventing a disease or disorder in which negative modulation of tropomyosin receptor kinase A is beneficial, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined in any one of Claims 1 to 15 or a pharmaceutical or veterinary composition as defined in Claim 16 to a human or animal subject in need thereof.

20. The use of a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined in any one of Claims 1 to 15, or a pharmaceutical or veterinary composition, as defined in Claim 16, for the manufacture of a medicament for the treatment and / or prevention of disease or disorder in which negative modulation of tropomyosin receptor kinase A is beneficial in a human or animal subject.

21. The compound or composition for use, method or use as claimed in any one of Claims 18 to 20, wherein the disease or disorder in which negative modulation of tropomyosin receptor kinase A is beneficial is selected from pain and inflammation.

22. The compound or composition for use, method or use as claimed in Claim 21, wherein the disease or disorder in which negative modulation of tropomyosin receptor kinase A is beneficial is pain.

23. The compound or composition for use, method or use as claimed in Claim 22, wherein the pain is selected from the group consisting of peripheral neuropathic pain, postherpetic neuralgia, sciatic nerve pain, trigeminal neuralgia, abdominal pain, musculoskeletal pain, post-operative pain, fracture pain, cancer pain, bone cancer pain, visceral pain, osteoarthritic pain, back pain / lower back pain, inflammatory pain, neck pain, pain associated with rheumatoid arthritis and pain associated with psoriatic arthritis.10524. The compound or composition for use, method or use as claimed Claim 22, wherein the pain is associated with a disease or disorder selected from the group consisting of painful diabetic neuropathy, migraine, chronic headache, chemotherapy induced peripheral neuropathy, interstitial cystitis, complex regional pain syndrome, chronic pelvic pain syndrome, irritable bowel syndrome, myofascial pain syndrome, pancreatitis, lumbar degenerative disk diseases, chronic prostatitis, vulvodynia, sickle cell disease, fibromyalgia, soft tissue trauma, dysmenorrhea, erythromelalgia and burns.

25. The compound or composition for use, method or use as claimed in Claim 22, wherein the pain is associated with arthritis.

26. The compound or composition for use method or use as claimed in Claim 25, wherein the arthritis is osteoarthritis.

27. The compound or composition for use, method or use, as claimed in any one of Claims 18 to 20, wherein the disease or disorder in which negative modulation of tropomyosin receptor kinase A is beneficial is selected from the group consisting of a cardiovascular disease, an immunological disorder, arthritis, asthma, allergic inflammation, allergic asthma, esophagitis, an infectious disease, psoriasis, atopic dermatitis, pruritus, skin inflammation and cancer.

28. The compound or composition for use, method or use, as claimed in Claim 27, wherein:(i) the cardiovascular disease is selected from the group consisting of arteriosclerosis, atherosclerosis, myocardial infarction, vascular inflammatory disease, giant cell arteritis and Kawasaki disease; and / or(ii) the infectious disease is an infectious viral infectious disease, optionally wherein the virus is selected from an influenza virus, Sendai virus, a herpes simplex virus, mouse hepatitis virus, a coronavirus, a rotavirus, a respiratory syncytial virus and human immunodeficiency virus; and / or(iii) the immunological disorder is selected from an autoimmune disorder, optionally selected from multiple sclerosis, a hyperimmunoglobulin disorder, inflammatory bowel disease and vasculitis; or the immunological disorder is allergic rhinitis.

29. The compound or composition for use, method or use as claimed in Claim 27, wherein the disease or disorder in which negative modulation or tropomyosin receptor A is beneficial is arthritis, optionally wherein the arthritis is osteoarthritis.

30. A combination product comprising:(I) a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined in any one of Claims 1 to 15 and(II) one or more other therapeutic agent that is useful in the treatment and / or prevention of a disease or disorder in which negative modulation of tropomyosin receptor kinase A is beneficial in a human or animal subject,wherein each of components (I) and (II) is formulated in admixture, optionally with one or more a pharmaceutically-acceptable excipient.

31. A kit-of-parts comprising :(a) a pharmaceutical or veterinary composition as defined in Claim 16; and (b) one or more other therapeutic agent that is useful in the treatment and / or prevention of a disease or disorder in which negative modulation of tropomyosin receptor kinase A is beneficial in a human or animal subject, optionally in admixture with one or more pharmaceutically-acceptable excipient,which components (a) and (b) are each provided in a form that is suitable for administration in conjunction (i.e. concomitantly or sequentially) with the other.

32. A process for the preparation of a compound of formula I, as defined in any one of Claims 1 to 15, which process comprises the step of reacting a compound of formula IIwherein R1, R2, A and X are as defined in any one of Claims 1 to 15, with a compound of formula IIIwherein R3, R4, R5, R5, m, n and Y are as defined in any one of Claims 1 to 15, in the presence of a suitable peptide coupling agent, a suitable base and a suitable solvent.

33. A process for the preparation of a compound of formula I, as defined in any one of Claims 1 to 15, which process comprises reacting a compound of formula IVwherein R1, R2, R3, R4, n, A, X and Y are as defined in any one of Claims 1 to 15, with a compound of formula V or VIwherein R5- R5and m are as defined in any one of Claims 1 to 15, and M1is selectedfromthe presence of a suitable base, a suitable catalyst, and a suitable solvent.108

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