WO2016009296A1 - N-acylpiperidine ether tropomyosin-related kinase inhibitors - Google Patents

N-acylpiperidine ether tropomyosin-related kinase inhibitors Download PDF

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Publication number
WO2016009296A1
WO2016009296A1 PCT/IB2015/054968 IB2015054968W WO2016009296A1 WO 2016009296 A1 WO2016009296 A1 WO 2016009296A1 IB 2015054968 W IB2015054968 W IB 2015054968W WO 2016009296 A1 WO2016009296 A1 WO 2016009296A1
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Prior art keywords
compound
oxy
phenyl
trifluoromethoxy
acetyl
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PCT/IB2015/054968
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French (fr)
Inventor
Sharanjeet Kaur Bagal
Kiyoyuki OMOTO
Sarah Elizabeth Skerratt
Nigel Alan Swain
Jingrong Jean Cui
Indrawan James Mcalpine
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Pfizer Inc.
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Publication of WO2016009296A1 publication Critical patent/WO2016009296A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention described herein relates to certain piperidine compounds and the pharmaceutically acceptable salts of such compounds.
  • the invention also relates to the processes for the preparation of the compounds, compositions containing the
  • Trk tropomyosin-related kinase
  • Trks Tropomyosin-related kinases
  • Trks are a family of receptor tyrosine kinases activated by neurotrophins. Trks play important roles in pain sensation as well as tumour cell growth and survival signaling. Thus, inhibitors of Trk receptor kinases might provide targeted treatments for conditions such as pain and cancer.
  • Recent developments in this field have been reviewed by Wang et al in Expert Opin. Ther. Patents (2009) 19(3): 305-319, and McCarthy et al in Expert Opin. Ther. Patents (2014) 24(7): 731-744. An extract from Wang is reproduced below. "1.1 Trk receptors
  • Trk kinases As one of the largest family of proteins encoded by the human genome, protein kinases are the central regulators of signal transduction as well as control of various complex cell processes. Receptor tyrosine kinases (RTKs) are a subfamily of protein kinases (up to 100 members) bound to the cell membrane that specifically act on the tyrosine residues of proteins. One small group within this subfamily is the Trk kinases, with three highly homologous isoforms: TrkA, TrkB, and TrkC.
  • RTKs Receptor tyrosine kinases
  • Trks neurotrophins
  • NGF nerve growth factor
  • BDNF brain-derived neurotrophic factor
  • TrkB NT-4/5
  • TrkB NT-4/5
  • TrkB NT-4/5
  • TrkB NT-4/5
  • TrkB NT-4/5
  • TrkB NT-4/5
  • TrkB NT-4/5
  • TrkB NT-4/5
  • TrkB NT-4/5
  • TrkB NT-4/5
  • TrkB brain-derived neurotrophic factor
  • Trk-3 which activates TrkC.
  • Trks and neurotrophins are well known for their effects on neuronal growth and survival.
  • Trks and cancer Originally isolated from neuronal tissues, Trks were thought to mainly affect the maintenance and survival of neuronal cells.
  • Trks play key roles in malignant transformation, chemotaxis, metastasis, and survival signaling in human tumors.
  • the association between Trks and cancer focused on prostate cancer in earlier years and the topic has been reviewed. For example, it was reported that malignant prostate epithelial cells secrete a series of neurotrophins and at least one Trks. In pancreatic cancer, it was proposed that paracrine and/or autocrine neurotrophin-Trk interactions may influence the invasive behavior of the cancer. TrkB was also reported to be overexpressed in metastatic human pancreatic cancer cells. Recently, there have been a number of new findings in other cancer settings.
  • a translocation leads to expression of a fusion protein derived from the /V-terminus of the ETV6 transcription factor and the C- terminal kinase domain of TrkC.
  • the resulting ETV6-TrkC fusions are oncogenic in vitro and appear causative in secretory breast carcinoma and some acute myelogenous leukemias (AML).
  • Constitutively active TrkA fusions occurred in a subset of papillary thyroid cancers and colon carcinomas.
  • TrkB expression was reported to be a strong predictor of aggressive tumor growth and poor prognosis, and TrkB overexpression was also associated with increased resistance to chemotherapy in neuroblastoma tumor cells in vitro.
  • TrkAIII a novel splice variant of TrkA called TrkAIII signaled in the absence of neurotrophins through the inositol phosphate- AKT pathway in a subset of neuroblastoma.
  • mutational analysis of the tyrosine kinome revealed that Trk mutations occurred in colorectal and lung cancers.
  • Trks have been linked to a variety of human cancers, and discovering a Trk inhibitor and testing it clinically might provide further insight to the biological and medical hypothesis of treating cancer with targeted therapies.
  • Trks are also being recognized as an important mediator of pain sensation.
  • Congenital insensitivity to pain with anhidrosis is a disorder of the peripheral nerves (and normally innervated sweat glands) that prevents the patient from either being able to adequately perceive painful stimuli or to sweat. TrkA defects have been shown to cause CIPA in various ethnic groups.
  • non-steroidal anti-inflammatory drugs NSAIDs
  • opiates have low efficacy and/or side effects (e.g., gastrointestinal/renal and psychotropic side effects, respectively) against neuropathic pain and therefore development of novel pain treatments is highly desired.
  • NGF levels are elevated in response to chronic pain, injury and inflammation and the administration of exogenous NGF increases pain hypersensitivity.
  • inhibition of NGF function with either anti-NGF antibodies or non-selective small molecule Trk inhibitors has been shown to have effects on pain in animal models. It appears that a selective Trk inhibitor (inhibiting at least NGF's target, the TrkA receptor) might provide clinical benefit for the treatment of pain.
  • Excellent earlier reviews have covered targeting NGF/BDNF for the treatment of pain so this review will only focus on small molecule Trk kinase inhibitors claimed against cancer and pain.
  • the NGF antibody tanezumab was very recently reported to show good efficacy in a Phase II trial against osteoarthritic knee pain.”
  • trk-mediated conditions which have been investigated and show promise for treatment with a trk inhibitor include atopic dermatitis, psoriasis, eczema and prurigo nodularis, acute and chronic itch, pruritis, atopic dermatitis, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, pruritis, lower urinary tract disorder, inflammatory lung diseases such as asthma, allergic rhinitis, lung cancer, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel diseases such as ulcerative colitis, Crohn ' s disease, fibrosis, neurodegenerative disease, diseases disorders and conditions related to dysmye!ination or demyelination, certain infectious diseases such as Trypanosoma cruzi infection (Chagas disease), cancer related pain, chronic pain, neuroblastoma, ovarian cancer, colorectal cancer, melanoma, head and neck cancer, gastric
  • Trk inhibitors have a wide variety of potential medical uses. There is a need to provide new Trk inhibitors that are good drug candidates.
  • compounds should preferably bind potently to the Trk receptors in a selective manner compared to other receptors, whilst showing little affinity for other receptors, including other kinase and / or GPC receptors, and show functional activity as Trk receptor antagonists.
  • the ideal drug candidate should be non-toxic and demonstrate few side-effects. Furthermore, the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated. They should preferably be e.g. well absorbed from the gastrointestinal tract, and / or be injectable directly into the bloodstream, muscle, or subcutaneously, and / or be metabolically stable and possess favourable pharmacokinetic properties.
  • WO2009/152083 refer to various fused pyrroles as kinase modulators;
  • International Patent Application publication numbers WO2009/143024 and WO2009/143018 refer to various pyrrolo[2,3-d]pyrimidines substituted as Trk inhibitors;
  • International Patent Application publication numbers WO2004/056830 and WO2005/1 16035 describe various 4-amino-pyrrolo[2,3-d]pyrimidines as Trk inhibitors.
  • International Patent Application publication numbers WO2004/056830 and WO2005/1 16035 describe various 4-amino-pyrrolo[2,3-d]pyrimidines as Trk inhibitors.
  • International Patent Application publication numbers WO2004/056830 and WO2005/1 16035 describe various 4-amino-pyrrolo[2,3-d]pyrimidines as Trk inhibitors.
  • International Patent Application publication numbers WO2004/056830 and WO2005/1 16035 describe various 4-amino-pyrrolo[2,3-d]pyrimidines as Tr
  • Application publication number WO2011/133637 describes various pyrrolo[2,3- d]pyrimidines and pyrrolo[2,3-b]pyridines as inhibitors of various kinases.
  • International Patent Application publication number WO2005/099709 describes bicyclic heterocycles as serine protease inhibitors.
  • International Patent Application publication number WO2007/047207 describes bicyclic heterocycles as FLAP modulators.
  • WO2014/053967, WO2014/053968 and WO2014/053965 describe various heterocyclic compounds as Trk inhibitors.
  • Preferable compounds and salts will show a lack of CYP inhibition/induction, and be CNS-sparing.
  • the present invention provides compounds of Formula I:
  • Q 1 is N or CR 1 ,
  • Q 2 is N or CR 2 ,
  • R 1 , R 2 , R 4 and R 5 are each independently H, F, CN, OH, NH 2 , Ci -3 alkyl optionally substituted by one or more F, or C1-3 alkoxy optionally substituted by one or more F
  • R 3 is H, F, CI, CN, Ci- 4 alkyl optionally substituted by one or more F, Ci- 4 alkoxy optionally substituted by one or more F , or C3-7 cycloalkyloxy optionally substituted by one or more F, or C1-4 alkylthio optionally substituted by one or more F,
  • R 6 and R 7 can be attached at any point on the piperidine ring and are independently H, F, CN, OH, NH 2 , C1 -3 alkyl optionally substituted by one or more F, or C1-3 alkoxy optionally substituted by one or more F,
  • R 6 and R 7 can be taken together, with the atoms to which they are attached, to form a 5- to 7-membered cycloalkane ring,
  • R 8 is CONR 101 R 102 .
  • each of X 1 , X 2 and X 3 is CR 101 or N,
  • R 101 and R 102 are each independently selected from H and C1-3 alkyl
  • Z is CH 2 , CH(CH 3 ), NH or O
  • A is (Ci -4 alkoxy optionally substituted by NH 2 , OH, CONH 2 , S0 2 CH 3 or CN), (Ci -4 alkylamino optionally substituted by NH 2 , OH, CONH 2 , S0 2 CH 3 or CN), or (C 3 - 6 cycloalkyoxy optionally substituted by NH 2 , OH, CONH 2 , S0 2 CH 3 or CN),
  • X 4 is selected from NR 101 , O and S0 2 ,
  • X 5 is H, OH or F
  • R 9 is H or Ci-6 alkyl
  • R 101 and R 102 are each independently selected from H and C1-3 alkyl
  • R 103 and R 104 are each independently selected from H, (C1-6 alkyl optionally substituted by OH, C1-6 alkoxy or by one or more F), and (C3- cycloalkyl optionally substituted by OH, C1-6 alkoxy or by one or more F), and pharmaceutically acceptable salts thereof.
  • the invention also comprises pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention is also directed to a method of treating a disease or condition indicated for treatment with a Trk antagonist, in a subject, by administering to a subject in need thereof a therapeutically effective amount of one or more of the compounds herein, or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention are potent antagonists at Trk receptors, and have a suitable PK profile to enable once daily dosing.
  • the compounds of the present invention are potentially useful in the treatment of a range of disorders where a Trk antagonist is indicated, particularly pain indications.
  • treatment as used herein may include one or more of curative, palliative and prophylactic treatment.
  • a compound of the present invention may be useful to treat any physiological pain such as inflammatory pain, nociceptive pain, neuropathic pain, acute pain, chronic pain, musculo-skeletal pain, on-going pain, central pain, heart and vascular pain, head pain, orofacial pain.
  • Other pain conditions which may be treated include intense acute pain and chronic pain conditions which may involve the same pain pathways driven by pathophysiological processes and as such cease to provide a protective mechanism and instead contribute to debilitating symptoms associated with a wide range of disease states.
  • Pain There are a number of typical pain subtypes: 1) spontaneous pain which may be dull, burning, or stabbing; 2) pain responses to noxious stimuli are exaggerated (hyperalgesia); 3) pain is produced by normally innocuous stimuli (allodynia) (Meyer et al., 1994 Textbook of Pain 13-44). Pain can be divided into a number of different areas because of differing
  • nociceptive nociceptive
  • inflammatory nociceptive
  • neuropathic pain some types of pain have multiple aetiologies and thus can be classified in more than one area, e.g. Back pain, Cancer pain have both nociceptive and neuropathic components.
  • Pain may be either acute or chronic and additionally may be of central and/or peripheral origin. Pain may be of a neuropathic and/or nociceptive and/or inflammatory nature, such as pain affecting either the somatic or visceral systems, as well as dysfunctional pain affecting multiple systems.
  • Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment. The system operates through a specific set of primary sensory neurones and is activated by noxious stimuli via peripheral transducing mechanisms (see Meyer et al., 2006, Wall and Melzack's Textbook of Pain (5 th Ed), Chapter"!).
  • Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organised projection to the spinal cord, the location of the stimulus.
  • the activity generated by nociceptor input is transferred, after complex processing in the dorsal horn, either directly, or via brain stem relay nuclei, to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated.
  • Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually twelve weeks or less). It is usually, although not always, associated with a specific cause such as a defined injury, is often sharp and severe and can result from numerous origins such as surgery, dental work, a strain or a sprain. Acute pain does not generally result in any persistent psychological response. When a substantial injury occurs to body tissue, via disease or trauma, the characteristics of nociceptor activation may be altered such that there is sensitisation in the periphery, locally around the injury and centrally where the nociceptors terminate. These effects lead to a hightened sensation of pain. In acute pain these mechanisms can be useful, in promoting protective behaviours which may better enable repair processes to take place.
  • pain The clinical manifestation of pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain symptoms. Such symptoms can include: 1) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally innocuous stimuli (allodynia) (Meyer et al., 2006, Wall and Melzack's Textbook of Pain (5 th Ed), Chapterl). Although patients suffering from various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and may, therefore, require different treatment strategies. Apart from acute or chronic, pain can also be broadly categorized into: nociceptive pain, affecting either the somatic or visceral systems, which can be inflammatory in nature (associated with tissue damage and the infiltration of immune cells); or neuropathic pain.
  • Nociceptive pain can be defined as the process by which intense thermal, mechanical, or chemical stimuli are detected by a subpopulation of peripheral nerve fibers, called nociceptors, and can be induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 2006, Wall and Melzack's Textbook of Pain (5 tn Ed), Chapter"!).
  • Myelinated A-delta fibres transmit rapidly and are responsible for sharp and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower rate and convey a dull or aching pain.
  • Moderate to severe acute nociceptive pain is a prominent feature of pain from strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, pain associated with gout, cancer pain and back pain.
  • Cancer pain may be chronic pain such as tumour related pain (e.g. bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (e.g. in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy).
  • Back pain may be due to herniated or ruptured intervertabral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Back pain may resolve naturally but in some patients, where it lasts over 12 weeks, it becomes a chronic condition which can be particularly debilitating.
  • Nociceptive pain can also be related to inflammatory states.
  • the inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (McMahon et al., 2006, Wall and Melzack's Textbook of Pain (5 th Ed), Chapter3).
  • a common inflammatory condition assoiciated with pain is arthritis. It has been estimated that almost 27 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease (Lawrence et al., 2008, Arthritis Rheum, 58, 15-35); most patients with osteoarthritis seek medical attention because of the associated pain.
  • OA symptomatic osteoarthritis
  • degenerative joint disease Lawrence et al., 2008, Arthritis Rheum, 58, 15-35
  • Rheumatoid arthritis is an immune-mediated, chronic, inflammatory polyarthritis disease, mainly affecting peripheral synovial joints. It is one of the commonest chronic inflammatory conditions in developed countries and is a major cause of pain.
  • visceral pain results from the activation of nociceptors of the thoracic, pelvic, or abdominal organs (Bielefeldt and Gebhart, 2006, Wall and Melzack's Textbook of Pain (5 th Ed), Chapter48).
  • visceral pain refers to pain associated with conditions of such organs, such as painful bladder syndrome, interstitial cystitis, prostatitis, ulcerative colitis, Crohn's disease, renal colic, irritable bowl syndrome, endometriosis and dysmenorrhea! (Classification of Chronic Pain, available at http://www.iasp-pain.org).
  • Neuropathic pain is currently defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many disorders with diverse aetiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post- stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological as it has no protective role.
  • neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Dworkin, 2009, Am J Med, 122, S1-S2; Geber et al., 2009, Am J Med, 122, S3-S12; Haanpaa et al., 2009, Am J Med, 122, S13-S21).
  • spontaneous pain which can be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).
  • hyperalgesia increased sensitivity to a noxious stimulus
  • allodynia sensitivity to a normally innocuous stimulus
  • fibromyalgia and chronic regional pain syndrome which are often described as dysfunctional pain states e.g. fibromyalgia or complex regional pain syndrome (Woolf, 2010, J Clin Invest, 120, 3742-3744), but which are included in classifications of chronic pain states (Classification of Chronic Pain, available at http://www.iasp-pain.org).
  • Embodiment 1 of the invention is a compound of Formula I:
  • Q 1 is N or CR 1 ,
  • Q 2 is N or CR 2 ,
  • R 1 , R 2 , R 4 and R 5 are each independently H, F, CN, OH, NH 2 , Ci -3 alkyl optionally substituted by one or more F, or C 1 -3 alkoxy optionally substituted by one or more F
  • R 3 is H, F, CI, CN, Ci -4 alkyl optionally substituted by one or more F, Ci -4 alkoxy optionally substituted by one or more F , or C3- cycloalkyloxy optionally substituted by one or more F, or Ci -4 alkylthio optionally substituted by one or more F,
  • R 1 , R 2 , R 3 , R 4 and R 5 are H,
  • R 6 and R 7 can be attached at any point on the piperidine ring and are independently H, F, CN, OH, NH2, C1-3 alkyl optionally substituted by one or more F, or C1-3 alkoxy optionally substituted by one or more F,
  • R 6 and R 7 can be taken together, with the atoms to which they are attached, to form a 5- to 7-membered cycloalkane ring,
  • R 8 is CONR 101 R 102 .
  • each of X 1 , X 2 and X 3 is independently CR 101 or N,
  • R 101 and R 102 are each independently selected from H and C1-3 alkyl
  • Z is CH 2 , CH(CH 3 ), NH or O
  • A is (C1-4 alkoxy optionally substituted by NH 2 , OH, CONH 2 , S0 2 CH 3 or CN), (C1-4 alkylamino optionally substituted by NH 2 , OH, CONH 2 , S0 2 CH 3 or CN), or (C 3 - 6 cycloalkyoxy optionally substituted by NH 2 , OH, CONH 2 , S0 2 CH 3 or CN),
  • A is a phenyl or a 5- or 6-membered saturated or unsaturated heterocyclic ring containing 1 , 2 or 3 hetero-atoms selected from S, N and O,
  • X 4 is selected from NR 101 , O and S0 2 ,
  • X 5 is H, OH or F
  • R 9 is H or Ci-6 alkyl
  • R 101 and R 102 are each independently selected from H and C1-3 alkyl
  • R 103 and R 104 are each independently selected from H, (C1-6 alkyl optionally substituted by OH, C1-6 alkoxy or by one or more F), and (C3- cycloalkyl optionally substituted by OH, C1-6 alkoxy or by one or more F), Or a pharmaceutically acceptable salt thereof.
  • Embodiment 2 A compound or salt according to embodiment 1 wherein one of X 1 , X 2 and X 3 is CR 101 or N, and the others are CR 101 .
  • Embodiment 3 A compound or salt according to embodiment 1 or 2 wherein X 1 is CH or N.
  • Embodiment 4 A compound or salt according to embodiment 1 , 2 or 3 wherein X 2 and X 3 are CH.
  • Embodiment 5 A compound or salt according to embodiment 1 , 2, 3 or 4 wherein X 1 is CH.
  • Embodiment 6 A compound or salt according to embodiment 1 , 2, 3, 4 or 5 wherein Z is CH 2 , CH(CH 3 ) or NH.
  • Embodiment 7 A compound or salt according to embodiment 1 , 2, 3, 4, 5 or 7 wherein Z is CH 2 .
  • Embodiment 8 A compound or salt according to embodiment 1 , 2, 3, 4, 5, 6 or 7 wherein R 8 is CONH 2 .
  • Embodiment 9 A compound or salt according to embodiment 1 , 2, 3, 4, 5, 6, 7 or 8 wherein R 6 is H, F or CH 3 .
  • Embodiment 10 A compound or salt according to embodiment 1 , 2, 3, 4, 5, 6, 7, 8 or 9 wherein Q 1 is CH or N.
  • Embodiment 11 A compound or salt according to embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 wherein Q 2 is CH or N.
  • Embodiment 12 A compound or salt according to embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 wherein R 7 is F, H or CH 3 .
  • Embodiment 13 a compound or salt according to embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9 , 10, 11 or 12 which has the substructure
  • Embodiment 14 A compound or salt according to embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 or 13 wherein R 3 is OCF 3 , CF 3 , C(CH 3 ) 3 , SCF 3 , CH(CH 3 ) 2 or cyclopropyloxy
  • Embodiment 15 A compound or salt according to embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 wherein A is an imidazolyl, morpholinyl, pyrrolidinyl, thiazolyl, pyridyl, phenyl, or pyrazolyl group optionally substituted by 1 or 2 substituents independently selected from CO 2 R 9 and Co-6 alkyl optionally substituted by 1 or 2 substituents independently selected from OH, NH 2 , SC> 2 CH 3 , Ci -4 alkoxy,
  • Embodiment 16 a compound or salt according to embodiment 15 where A is an imidazolyl, morpholinyl, pyrrolidinyl, thiazolyl, pyridyl, phenyl, or pyrazolyl group
  • Embodiment 17 a compound or salt according to embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 wherein A is (Ci- 4 alkoxy optionally substituted by NH2, OH, CONH2, SO2CH3 or CN), (C1-4 alkylamino optionally substituted by NH 2 , OH, CONH 2 , SO2CH3 or CN), or (C 3 - 6 cycloalkyoxy optionally substituted by NH 2 , OH, CONH 2 , S0 2 CH 3 or CN).
  • A is (Ci- 4 alkoxy optionally substituted by NH2, OH, CONH2, SO2CH3 or CN), (C1-4 alkylamino optionally substituted by NH 2 , OH, CONH 2 , SO2CH3 or CN), or (C 3 - 6 cycloalkyoxy optionally substituted by NH 2 , OH, CONH 2 , S0 2 CH 3 or CN).
  • Embodiment 18 a compound or salt according to embodiment 13, 14 or 15 as appropriate wherein A is morpholin-1-yl, methoxy, OCH2CN, OCH2C(0)NH2,
  • Embodiment 19 a compound or salt according to embodiment 18 wherein A is morpholin-1-yl, methoxy, OCH 2 CN, OCH 2 C(0)NH 2 , OCH 2 S0 2 CH 3 , (C 2 - 4 alkoxy optionally substituted by NH 2 or OH), (C 2 - 4 alkylamino optionally substituted by NH 2 or OH), or (C 3 -6 cycloalkyoxy optionally substituted by NH 2 or OH).
  • Embodiment 20 A compound or salt according to Embodiment 1 which has the formula IB
  • R 3 is OCF 3 or cyclopropyloxy
  • X 1 is CH or N.
  • Embodiment 21 A compound selected from any of the Examples below, or a pharmaceutically acceptable salt thereof.
  • Embodiment 22 A pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of the preceding embodiments 1 to 21 , and a pharmaceutically acceptable carrier.
  • Embodiment 23 A compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 21 , for use as a medicament.
  • Embodiment 24 A compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 21 for use in the treatment of a disease for which a Trk receptor antagonist is indicated.
  • Embodiment 25 A compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 21 for use in the treatment of pain or cancer.
  • Embodiment 26 The use of a compound of the formula (I) or a pharmaceutically acceptable salt or composition thereof, as defined in any one of embodiments 1 to 21 , for the manufacture of a medicament to treat a disease for which a Trk receptor antagonist is indicated
  • Embodiment 27 The use of a compound of the formula (I) or a pharmaceutically acceptable salt or composition thereof, as defined in any one of embodiments 1 to 21 , for the manufacture of a medicament to treat pain or cancer.
  • Embodiment 28 A method of treatment of a mammal, to treat a disease for which a Trk receptor antagonist is indicated, comprising treating said mammal with an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 21.
  • Embodiment 29 A method of treatment of pain or cancer in a mammal, comprising treating said mammal with an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 21.
  • Embodiment 30 A compound or salt according to any one of embodiments 1 to 21 for use in a medical treatment in combination with a further drug substance.
  • Halogen means a fluoro, chloro, bromo or iodo group.
  • Alkyl groups containing the requisite number of carbon atoms, can be unbranched or branched. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl.
  • “Pharmaceutically acceptable salts” of the compounds of formula I include the acid addition and base addition salts (including disalts, hemisalts, etc.) thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate
  • Suitable base addition salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • the compounds of the invention may be administered as prodrugs.
  • prodrugs certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic or enzymatic cleavage.
  • Such derivatives are referred to as 'prodrugs'.
  • Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).
  • Prodrugs can, for example, be produced by replacing appropriate functionalities present in a compound of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985).
  • Examples of prodrugs include phosphate prodrugs, such as dihydrogen or dialkyl (e.g. di-tert-butyl) phosphate prodrugs.
  • amino acid such as histidine, alanine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, ornithine, proline, selenocysteine
  • the compounds of the invention include compounds of formula I and salts thereof as hereinbefore defined, polymorphs, and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labelled compounds of formula I.
  • compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers.
  • a compound of formula (I) contains for example, a keto or guanidine group or an aromatic moiety
  • tautomeric isomerism ('tautomerism') can occur. It follows that a single compound may exhibit more than one type of isomerism.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
  • racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on a resin with an asymmetric stationary phase and with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture. Mixtures of stereoisomers may be separated by conventional techniques known to those skilled in the art.
  • the present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and 125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labelled reagents in place of the non-labelled reagent previously employed.
  • the compounds of the invention may be prepared by any method known in the art for the preparation of compounds of analogous structure.
  • the compounds of the invention can be prepared by the procedures described by reference to the Schemes that follow, or by the specific methods described in the Examples, or by similar processes to either.
  • the skilled person will appreciate that the experimental conditions set forth in the schemes that follow are illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or desirable to vary the precise conditions employed for the preparation of compounds of formula (I). It will be further appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.
  • the skilled person will appreciate that it may be necessary or desirable at any stage in the synthesis of compounds of the invention to protect one or more sensitive groups, so as to prevent undesirable side reactions.
  • it may be necessary or desirable to protect amino or carboxylic acid groups.
  • the protecting groups used in the preparation of the compounds of the invention may be used in conventional manner. See, for example, those described in 'Greene's Protective Groups in Organic Synthesis' by Theodora W Greene and Peter G M Wuts, third edition, (John Wiley and Sons, 1999), in particular chapters 7 ("Protection for the Amino Group") and 5 (“Protection for the Carboxyl Group”), incorporated herein by reference, which also describes methods for the removal of such groups.
  • A is O-linked and R 8 is CONH 2 ;
  • Hal is fluoro or chloro
  • LG is a leaving group such as iodide, bromide, chloride, mesylate, carbonate or epoxide
  • Compounds of formula (I) may be prepared from compounds of formula (II) according to process step (v), an alkylation step with compounds of formula (IX).
  • Typical conditions include an inorganic base with an organic solvent such as DMF at a range of elevated temperatures.
  • Preferred conditions comprise potassium or cesium carbonate in DMF at from 50-1 10°C.
  • a contains a protecting group a deprotection step may be employed to afford compounds of formula (I).
  • trityl is present, an acid mediated deprotection step may be employed.
  • Preferred conditions comprise TFA in DCM at room temperature.
  • benzyl is present, deprotection may occur in the presence of a metal catalyst and hydrogen donor.
  • Preferred conditions comprise palladium on carbon either i) in methanol under a balloon of hydrogen or ii) in acetic acid with formic acid at room temperature.
  • an oxidation step may be employed to afford compounds of formula (I) that include a sulfone.
  • Preferred conditions comprise oxone in MeOH at room temperature.
  • A contains a carboxylic ester
  • the ester may be reduced to an alcohol through a number of functional group interconversions; namely a hydrolysis reaction followed by mixed anhydride formation followed by a reduction reaction.
  • Preferred conditions comprise lithium hydroxide in THF and water, followed by isobutylchloroformate with triethylamine in THF, followed by sodium borohydride in water, all at room temperature.
  • Compounds of formula (II) may be prepared from compounds of formula (III) according to process step (iv) a deprotection step under hydrogenation conditions.
  • Preferred conditions comprise palladium on carbon in an alcoholic solvent such as ethanol under a balloon of hydrogen at room temperature.
  • Compounds of formula (III) may be prepared from compounds of formula (V) according to process step (iii), an amide bond formation reaction with activation of the carboxylic acid (IV), using a suitable organic base and suitable coupling agents such as EDCI/HOBt, HATU or HBTU.
  • Preferred conditions comprise EDCI with HOBt or HATU with triethylamine in DCM or THF at room temperature.
  • Compounds of formula (V) may be prepared from compounds of formula (VI) according to process steps (ii) and (iia), a base mediated hydrolysis reaction followed by an acid mediated deprotection step.
  • Preferred conditions comprise potassium hydroxide in tBuOH at 80°C followed by 4M HCI in dioxane at room temperature.
  • Compounds of formula (VI) may be prepared from compounds of formulae (VII) and (VIII) according to process step (i) a nucleophilic substitution reaction.
  • Typical conditions include an inorganic base in a polar organic solvent at from room to elevated temperatures.
  • Preferred conditions comprise potassium hydroxide, potassium tert- butoxide or cesium carbonate in tert-butanol, dioxane or DMF at from room temperature to 100°C.
  • compounds of formula (III) may be prepared from compounds of formulae (IV), (XIII) and (IX) as illustrated by Scheme 2,
  • A is O-linked.
  • Compounds of formula (III) may be prepared from compounds of formula (X) according to process steps (viii) and (iii), a base mediated hydrolysis reaction followed by an amide bond forming reaction as described in Scheme 1 with amines of formula (XXV).
  • Preferred conditions comprise sodium hydroxide in methanol at from room temperature to reflux followed by HBTU and DIPEA in DMF with 7M ammonia in MeOH at room temperature.
  • Compounds of formula (X) may be prepared from compounds of formula (XI) and (IX) according to process step (vii), a nucleophilic substitution reaction.
  • Typical conditions comprise an inorganic base in a polar organic solvent at from room temperature to 100°C.
  • Preferred conditions comprise cesium carbonate in DMSO at 100°C.
  • Compounds of formula (XI) may be prepared from compounds of formula (XII) according to process step (vi), a mesylation reaction. Preferred conditions comprise methanesulfonyl chloride in DCM with triethylamine at from 0°C to room temperature.
  • Compounds of formula (XII) may be prepared from compounds of formula (IV) and (XIII) according to process step (iii) as described in Scheme 1.
  • compounds of formula (I) may be prepared from compounds of formulae (XVI), (XVII) and (IV) as illustrated by Scheme 3,
  • Compounds of formula (XIV) may be prepared from compounds of formula (XV) according to process step (ii), an acid mediated deprotection step as described in Scheme 1.
  • Compounds of formula (XV) may be prepared according from compounds of formula (XVII) and (XVI) according to process step (vii), a nucleophilic substitution reaction as described in Scheme 2.
  • compounds of formula (I) may be prepared from compounds of formula (XXI), (VII) and (IV) as illustrated by Scheme 4,
  • Hal is fluoro or chloro
  • Compounds of formula (I) may be prepared from compounds of formula (XVIII) according to process step (viii), a nucleophilic aromatic substitution reaction with compounds of formula (XXII).
  • Typical conditions employ an inorganic base in a polar organic solvent at elevated temperatures.
  • Preferred conditions comprise cesium carbonate in DMF at 80°C.
  • compounds of formula (IA) (I; where A is a hyroxy-alkyl ether group of formula OCH2CR x CR y OH) may be prepared from compounds of formula (II) and (XXIV) as illustrated by Scheme 5,
  • A can be a OCH 2 CR x R y OH group.
  • Compounds of formula (IA) may be prepared from compounds of formula (II) according to process step (v) as described in Scheme 1 , an alkylation step with epoxides of formula (XXIV).
  • the present invention provides novel intermediate compounds described herein.
  • Pharmaceutically acceptable salts of a compound of formula (I) may be readily prepared by mixing together solutions of the compound of formula (I) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the salt may vary from completely ionised to almost non-ionised.
  • a trk antagonist may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of pain.
  • Another pharmacologically active compound or with two or more other pharmacologically active compounds, particularly in the treatment of pain.
  • the skilled person will appreciate that such combinations offer the possibility of significant advantages, including patient compliance, ease of dosing and synergistic activity.
  • the compound of the invention may be administered simultaneously, sequentially or separately in combination with the other therapeutic agent or agents.
  • a trk antagonist compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, may be administered in combination with one or more agents selected from:
  • a selective Nav1.3 channel modulator such as a compound disclosed in WO2008/118758;
  • a selective Nav1.7 channel modulator such as a compound disclosed in WO2010/079443, e.g. 4-[2-(5-amino-1 H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2- fluoro-N-1 ,3-thiazol-4-ylbenzenesulfonamide or 4-[2-(3-amino-1 H-pyrazol-4-yl)-4- (trifluoromethyl)phenoxy]-5-chloro-2-fluoro-N-1 ,3-thiazol-4-ylbenzenesulfonamide, or a pharmaceutically acceptable salt of either;
  • ⁇ a compound which modulates activity at more than one Nav channel, including a non-selective modulator such as bupivacaine, carbamazepine, lamotrigine, lidocaine, mexiletine or phenytoin; • any inhibitor of nerve growth factor (NGF) signaling, such as: an agent that binds to NGF and inhibits NGF biological activity and/or downstream pathway(s) mediated by NGF signaling (e.g. tanezumab), a TrkA antagonist or a p75 antagoinsist, or an agent that inhibits downstream signaling in regard to NGF stimulated TrkA or P75 signalling;
  • NGF nerve growth factor
  • a compound which increases the levels of endocannabinoid such as a compound with fatty acid amid hydrolase inhibitory (FAAH) or monoacylglycerol lipase (MAGL) activity;
  • FAAH fatty acid amid hydrolase inhibitory
  • AML monoacylglycerol lipase
  • an analgesic in particular paracetamol
  • an opioid analgesic such as: buprenorphine, butorphanol, ***e, codeine, dihydrocodeine, fentanyl, heroin, hydrocodone, hydromorphone, levallorphan levorphanol, meperidine, methadone, morphine, nalmefene, nalorphine, naloxone, naltrexone, nalbuphine, oxycodone, oxymorphone, propoxyphene or pentazocine;
  • an opioid analgesic which preferentially stimulates a specific intracellular pathway, for example G-protein as opposed to beta arrestin recruitment, such as TRV130; an opioid analgesic with additional pharmacology, such as: noradrenaline (norepinephrine) reuptake inhibitory (NRI) activity, e.g. tapentadol; serotonin and norepinephrine reuptake inhibitory (SNRI) activity, e.g. tramadol; or nociceptin receptor (NOP) agonist activity, such as GRT6005;
  • NRI noradrenaline
  • SNRI serotonin and norepinephrine reuptake inhibitory
  • NOP nociceptin receptor
  • NSAID nonsteroidal antiinflammatory drug
  • COX non-selective cyclooxygenase
  • a non-selective cyclooxygenase (COX) inhibitor e.g. aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac; or a COX-2 selective inhibitor, e.g. celecoxib,
  • microsomal prostaglandin E synthase type 1 (mPGES-1) inhibitor • a microsomal prostaglandin E synthase type 1 (mPGES-1) inhibitor
  • a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone
  • a GABA A modulator with broad subtype modulatory effects mediated via the benzodiazepine binding site such as chlordiazepoxide, alprazolam, diazepam, lorazepam, oxazepam, temazepam, triazolam, clonazepam or clobazam;
  • a GABAA modulator with subtype-selective modulatory effects mediated via the benzodiazepine binding site with reduced adverse effects, for example sedation, such as TPA023, TPA023B, L-838,417, CTP354 or NSD72;
  • a GABAA modulator acting via alternative binding sites on the receptor such as barbiturates, e.g. amobarbital, aprobarbital, butabital, mephobarbital, methohexital, pentobarbital, phenobartital, secobarbital, or thiopental; neurosteroids such as alphaxalone, alphadolone or ganaxolone; ⁇ -subunit ligands, such as etifoxine; or ⁇ - preferring ligands, such as gaboxadol;
  • barbiturates e.g. amobarbital, aprobarbital, butabital, mephobarbital, methohexital, pentobarbital, phenobartital, secobarbital, or thiopental
  • neurosteroids such as alphaxalone, alphadolone or ganaxolone
  • ⁇ -subunit ligands such as
  • a skeletal muscle relaxant e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, metaxolone, methocarbamol or orphrenadine;
  • a glutamate receptor antagonist or negative allosteric modulator such as an NMDA receptor antagonist, e.g. dextromethorphan, dextrorphan, ketamine or, memantine; or an mGluR antagonist or modulator;
  • an alpha-adrenergic such as clonidine, guanfacine or dexmetatomidine
  • a beta-adrenergic such as propranolol
  • a tricyclic antidepressant e.g. desipramine, imipramine, amitriptyline or nortriptyline;
  • a tachykinin (NK) antagonist such as aprepitant or maropitant
  • a muscarinic antagonist e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium
  • a tachykinin (NK) antagonist such as aprepitant or maropitant
  • a muscarinic antagonist e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium
  • TRPV1 Transient Receptor Potential V1 (TRPV1) receptor agonist (e.g. resinferatoxin or capsaicin) or antagonist (e.g. capsazepine or mavatrap);
  • TRPV1 receptor agonist e.g. resinferatoxin or capsaicin
  • antagonist e.g. capsazepine or mavatrap
  • TRPA1 receptor agonist e.g. cinnamaldehyde or mustard oil
  • antagonist e.g. GRC17536 or CB-625
  • TRPM8 Transient Receptor Potential M8 (TRPM8) receptor agonist (e.g. menthol or icilin) or antagonist;
  • TRPV3 Transient Receptor Potential V3 receptor agonist or antagonist
  • a corticosteroid such as dexamethasone
  • a 5-HT receptor agonist or antagonist particularly a 5-HT 1 B /I D agonist, such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan
  • eletriptan a corticosteroid
  • naratriptan a 5-HT 1 B /I D agonist
  • rizatriptan such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan
  • a cholinergic (nicotinic) analgesic such as ispronicline (TC-1734), vareniclineor nicotine;
  • a PDEV inhibitor such sildenafil, tadalafilor vardenafil
  • an alpha-2-delta ligand such as gabapentin, gabapentin enacarbil or pregabalin, ;
  • SRI serotonin reuptake inhibitor
  • sertraline demethylsertraline
  • fluoxetine norfluoxetine
  • fluvoxamine paroxetine
  • citalopram desmethylcitalopram
  • escitalopram d,l-fenfluramine
  • femoxetine ifoxetine
  • cyanodothiepin litoxetine
  • nefazodone cericlamine and trazodone
  • anNRI such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine, especially a selective noradrenaline reuptake inhibitor such as reboxetine;
  • an SNRI such as venlafaxine, O-desmethylvenlafaxine, clomipramine, desmethylclomipramine, duloxetine, milnacipran and imipramine;
  • iNOS inducible nitric oxide synthase
  • ⁇ a 5-lipoxygenase inhibitor, such as zileuton;
  • a potassium channel opener or positive modulator such as an opener or positive modulator of KCNQ/Kv7 (e.g. retigabine or flupirtine), a G protein-coupled inwardly- rectifying potassium channel (GIRK), a calcium-activated potassium channel (Kca) or a potassium voltage-gated channel such as a member of subfamily A (e.g. Kv1.1), subfamily B (e.g. Kv2.2) or subfamily K (e.g. TASK, TREK or TRESK);
  • a P2X 3 receptor antagonist e.g. AF219 or an antagonist of a receptor which contains as one of its subunits the P2X 3 subunit, such as a P2X 2 /3 heteromeric receptor;
  • compositions suitable for the delivery of compounds and salts of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995).
  • Compounds and salts of the invention intended for pharmaceutical use may be prepared and administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • Oral Administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations, such as tablets, capsules containing particulates, liquids, or powders; lozenges (including liquid-filled), chews; multi- and nano-particulates; gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.
  • Liquid formulations include suspensions, solutions, syrups and elixirs.
  • Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents.
  • Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, V ⁇ _ (6), 981-986 by Liang and Chen (2001).
  • the drug may make up from 1 weight% to 80 weight% of the dosage form, more typically from 5 weight% to 60 weight% of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from 1 weight% to 25 weight%, preferably from 5 weight% to 20 weight% of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents may comprise from 0.2 weight % to 5 weight% of the tablet, and glidants may comprise from 0.2 weight% to 1 weight% of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25 weight% to 10 weight%, preferably from 0.5 weight% to 3 weight% of the tablet.
  • Other possible ingredients include anti-oxidants, colourants, flavoring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80% drug, from about 10 weight% to about 90 weight% binder, from about 0 weight% to about 85 weight% diluent, from about 2 weight% to about 10 weight% disintegrant, and from about 0.25 weight% to about 10 weight% lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6, 106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.
  • the compounds and salts of the invention may be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile nonaqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of formula (I) and salts used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • compounds and salts of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound.
  • An example of such formulations include drug- coated stents.
  • the compounds and salts of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated [see, for example, Finnin and Morgan, J Pharm Sci, 88 (10), 955-958 (October 1999).] Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection.
  • the compounds and salts of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 , 1 , 1 ,2-tetrafluoroethane or 1 , 1 , 1 ,2,3,3,3- heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • a pressurised container, pump, spray, atomizer, or nebuliser may contain a solution or suspension of the compound(s) or salt(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules made, for example, from gelatin or HPMC
  • blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound or salt of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 pg to 20mg of the compound or salt of the invention per actuation and the actuation volume may vary from 1 ⁇ to 10 ⁇ .
  • a typical formulation may comprise a compound of formula (I) or salt thereof, propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavours such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA).
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the dosage unit is determined by a prefilled capsule, blister or pocket or by a system that utilises a gravimetrically fed dosing chamber .
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from 1 to 5000 ⁇ 9 of the compound or salt.
  • the overall daily dose will typically be in the range 1 ⁇ g to 20 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
  • Rectal/lntravaginal Administration The compounds and salts of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various well known alternatives may be used as appropriate.
  • the compounds and salts of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid; a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose; or a heteropolysaccharide polymer, for
  • gelan gum may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • the compounds and salts of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11 172, WO 94/02518 and WO 98/55148.
  • the total daily dose of the compounds and salts of the invention is typically in the range 0.1 mg to 200 mg depending, of course, on the mode of administration, preferred in the range 1 mg to 100 mg and more preferred in the range 1 mg to 50 mg.
  • the total daily dose may be administered in single or divided doses. These dosages are based on an average human subject having a weight of about 65kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • the dosage administered will, of course, vary with the compound or salt employed, the mode of administration, the treatment desired and the disorder indicated.
  • (l)/salt/solvate (active ingredient) will, generally, be in the range from 1 mg to 1 gram, preferably 1 mg to 250 mg, more preferably 10 mg to 100 mg.
  • the total daily dose may be administered in single or divided doses.
  • the present invention also encompasses sustained release compositions.
  • the pharmaceutical composition may, for example, be in a form suitable for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
  • the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
  • Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
  • Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents.
  • the pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • excipients such as citric acid
  • disintegrants such as starch, alginic acid and certain complex silicates
  • binding agents such as sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes.
  • Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules.
  • Preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of
  • the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patient in practicing the present invention.
  • dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person
  • administering or supervising the administration of the compositions and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values.
  • the present invention encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regiments for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.
  • a pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses.
  • a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • parenteral dosages this may conveniently be prepared as a solution or as a dry powder requiring dissolution by a pharmacist, medical practitioner or the patient. It may be provided in a bottle or sterile syringe. For example it may be provided as a powder in a multicompartment syringe which allows the dry powder and solvent to be mixed just prior to administration (to aid long-term stability and storage). Syringes could be used which allow multiple doses to be administered from a single device.
  • compositions of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1 % and 100% (w/w) active ingredient.
  • composition of the invention may further comprise one or more additional pharmaceutically active agents.
  • Controlled- or sustained-release formulations of a pharmaceutical composition of the invention may be made using conventional technology.
  • parenteral administration of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue.
  • Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like.
  • parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like.
  • administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrasternal injection, and kidney dialytic infusion techniques.
  • Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi-dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained- release or biodegradable formulations as discussed below.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents.
  • the active ingredient is provided in dry (i.e. powder or granular) form for reconstitution with a suitable vehicle (e.g. sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.
  • a composition of the present invention can be administered by a variety of methods known in the art.
  • the route and/or mode of administration vary depending upon the desired results.
  • the active compounds can be prepared with carriers that protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are described by e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, (1978). Pharmaceutical compositions are preferably manufactured under GMP conditions.
  • the pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution.
  • This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein.
  • Such sterile injectable formulations may be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water or 1 ,3-butane diol, for example.
  • Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides.
  • Other parentally-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer system.
  • compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.
  • each active ingredient will vary depending upon any number of factors, including but not limited to, the type of animal and type of disease state being treated, the age of the animal, and the route(s) of administration.
  • t-Bu 3 PHBF 4 is tri-terf-butylphosphinetetrafluoroborate salt;
  • t-BuOH is terf-butanol;
  • °C is degrees centigrade
  • COM U ® is (1-cyano-2-ethoxy-2- oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate
  • CS2CO3 is cesium carbonate
  • CuS0 4 .5H 2 0 is copper sulphate pentahydrate
  • HATU is 1-[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; HCI is hydrochloric acid; HOBt is hydroxybenzotriazole;
  • HPLC high-performance liquid chromatography
  • IPA isopropanol
  • KOH is potassium hydroxide
  • KOAc is potassium acetate
  • LCMS liquid chromatography mass
  • Pd(dppf) 2 CI 2 is [1 , 1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane;
  • SEM is 2-[(trimethylsilyl)ethoxy]methyl;
  • TFA is trifluoroacetate;
  • THF is tetrahydrofuran;
  • THP is tetrahydropyran and TLC is thin layer chromatography;
  • Boc is tert-butyloxycarbonyl
  • Bn is benzyl
  • °C is degrees celcius
  • CDCI 3 is deutero-chloroform
  • CS2CO3 is cesium carbonate
  • DCM is dichloromethane; methylene chloride;
  • DIAD is diisopropylazodicarboxylate
  • DIPEA is N-ethyldiisopropylamine, N,N-diisopropylethylamine;
  • DMF is N,N-dimethylformamide
  • DMSO dimethyl sulphoxide
  • EDCI.HCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; EtOAc is ethyl acetate;
  • g is gram
  • HATU is 1-[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate;
  • HBTU is N,N,N',N'-Tetramethyl-0-(1 H-benzotriazol-1-yl)uronium hexafluorophosphate
  • HCI is hydrochloric acid
  • HOBt is N-hydroxybenzotriazole hydrate
  • HPLC high pressure liquid chromatography
  • IPA is isopropyl alcohol
  • KOH potassium hydroxide
  • KOtBu potassium tert-butoxide
  • m is multiplet
  • M is molar
  • MeCN is acetonitrile
  • MeOH is methanol
  • MHz is mega Hertz
  • ml_ is milli litre
  • Ms is mesylate
  • MS m/z is mass spectrum peak
  • NaHCC sodium hydrogencarbonate
  • NaOH sodium hydroxide
  • NMR nuclear magnetic resonance
  • Pd/C is palladium on carbon
  • pH is power of hydrogen
  • Rt is retention time
  • t is triplet
  • TBME is tert-butyl dimethyl ether
  • TFA is trifluoroacetic acid
  • THF is tetrahydrofuran
  • TLC is thin layer chromatography
  • ⁇ _ is microlitre
  • UV Waters 2487 detector at 225 and 255 nm
  • Mass spectrometer Waters ZQ using electrospray ionisation
  • UV Waters 2487 detector at 225 and 255 nm
  • Mass spectrometer Waters ZQ using electrospray ionisation
  • Detectors ELSD Polymer labs PL-ELS 2100
  • UV Waters 2487 detector at 225 and 255 nm
  • Mass spectrometer Waters ZQ using electrospray ionisation Basic analytical conditions:
  • the residue was purified using silica gel column chromatography eluting with 2% MeOH in DCM.
  • the residue was dissolved in MeOH (2.8 mL) and water (0.7 mL) and treated with oxone (25 mg, 0.16 mmol).
  • the reaction was stirred at room temperature for 2 hours.
  • the reaction was diluted with water and extracted into EtOAc.
  • the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo.
  • the residue was purified using preparative TLC eluting with 3% MeOH in DCM to afford the title compound as a white solid (15 mg, 10% over 2 steps).
  • the title compound was prepared according to the method described for Example 14 using 2-(((3S,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4- hydroxybenzamide (Preparation 2) and trans-3-(benzyloxy)cyclobutyl- methanesulfonate (Preparation 33).
  • the residue was purified using preparative TLC eluting with 5% I PA in DCM.
  • the title compound was prepared according to the method described by Example 17 using 1-amino-2-methyl-propan-2-ol. The residue was purified using silica gel column chromatography eluting with 2-3% MeOH in DCM followed by preparative TLC eluting with 5% MeOH in EtOAc.
  • the reaction was cooled, diluted with EtOAc and washed with water, brine, dried over sodium sulphate and concentrated in vacuo.
  • the residue was purified using silica gel column chromatography eluting with 3% MeOH in DCM. Part of the residue (125 mg, 0.177 mmol) was dissolved in AcOH (10 ml_) and formic acid (3 ml_) and degassed with argon. Pd/C (40 mg) was added and the reaction stirred at room temperature for 16 hours. The reaction was filtered through Celite and the filtrate concentrated in vacuo. The residue was basified with saturated aqueous sodium carbonate solution and extracted into EtOAc twice.
  • the residue was purified using silica gel column chromatography eluting with 6% EtOAc in hexanes.
  • the residue was dissolved in THF (5 mL) and treated with NaOH (147 mg, 3.67 mmol). The reaction was stirred at room temperature for 2 hours before extracting into DCM. The organic layer was collected, dried over sodium sulphate and concentrated in vacuo.
  • the residue was purified using silica gel column chromatography eluting with 15% EtOAc in hexanes to afford the title compound as a yellow gum (300 mg, 92%).
  • Isolated TRK Enzyme assays use the HTRF KinEASE-TK kit (Cisbio Cat# 62TK0PEJ) with recombinant His-tagged cytoplasmic domains of TRKA receptor sourced from Invitrogen (see table below).
  • This activity-assay measures the phosphorylation of tyrosine residues within a substrate from the HTRF kit which has been validated by Cisbio for a variety of tyrosine kinases including the TRK receptors.
  • 0.5mM stock solutions of test compounds are prepared and serially diluted in 100% DMSO.
  • a standard curve using the compound of Example 135 disclosed in WO2005/116035 of 150uM is also prepared on each test plate.
  • High percentage effect (HPE) is defined by 150uM (using the compound of Example 135 as disclosed in WO2005/116035) and 0% effect (ZPE) is defined by 100% DMSO.
  • Greiner low volume black plates containing 0.2ul of serially diluted compound, standard and HPE/ZPE are created using the Bravo nanolitre dispenser.
  • 1X enzyme buffer is prepared from 5X Enzymatic Buffer from the Cisbio KinEASE TK kit using MilliQ water. The buffer is then supplemented with 10mM MgCI and 2mM DTT (both from Sigma). In the case of TRKB, the buffer is also supplemented with 125nM Supplement Enzymatic Buffer (SEB) from the Cisbio kit.
  • SEB Supplement Enzymatic Buffer
  • 2X FAC of enzyme and 2X FAC ATP diluted in 1X complete enzyme buffer is incubated at room temperature for 20minutes to preactivate the enzyme. Following this preactivation step, 5ul/well of enzyme + ATP mix is added using a Multidrop Micro to the assay plate, spotted with 0.2ul 100% DMSO compound. This is left for 20mins at room temperature before adding 5ul of 2uM TK-substrate-Biotin (from the Cisbio kit) diluted in 1X enzyme buffer (1 uM FAC) using the Multidrop Micro. The reaction is incubated at room temperature for the optimized assay reaction time (see table). The reaction is stopped by adding 10ul/well HTRF Detection Buffer containing 0.25uM Streptavidin- XL665 (0.125uM FAC) and 1 :200 TK Antibody-Cryptate using a Multidrop.
  • HTRF signal is read using an Envision reader, measured as a ratio of emissions at two different wavelengths, 620nm and 665nm. Any compound that inhibits the action of the TRK kinase will have a lower fluorescence ratio value 665/620nM than compounds which do not inhibit theTRK kinase.
  • Test compound data are expressed as percentage inhibition defined by HPE and ZPE values for each plate. Percentage inhibition in the presence of test compound is plotted against compound concentration on a log scale to determine an IC50 from the resultant sigmoid curve.
  • Cell Based Assays were carried out using Cell lines from DiscoveRx utilising their PathHunter technology and reagents in an antagonist assay:
  • the assays are based upon DiscoveRx's proprietary Enzyme Fragment Complementation (EFC) technology.
  • EFC Enzyme Fragment Complementation
  • the enzyme acceptor (EA) protein is fused to a SH2 protein and the TRK receptor of interest has been tagged with a Prolink tag.
  • the TRKA receptor becomes phosphorylated, and the tagged SH2 protein binds. This results in functional complementation and restored ⁇ - Galactosidase activity which is can be measured using the luminescent Galacton Star substrate within the PathHunter reagent kits.
  • small molecule inhibitors bind to the kinase domain so are not competing with the neurotrophin (agonist) which binds to an extracellular site. This means that the IC 50 is a good measure of affinity and should be unaffected by concentration neurotrophin stimulant.
  • Cryopreserved PathHunter cells are used from either in-house produced batches or bulk batches bought directly from DiscoveRx. Cryopreserved cells are resuscitated, spun l OOOrpm for 4min to remove freezing media, and resuspended in MEM + 0.5% horse serum (both Invitrogen) to 5e 5 cells/ml. The cells are then plated using a Multidrop into Greiner white tissue culture treated plates at 20ul/well and incubated for 24h at 37°C, 5% CO 2 , high humidity. On the day of the assay, the cell plates are allowed to cool to room temperature for 30min prior to the assay.
  • HPE High percentage effect
  • ZPE 0% effect
  • Plates containing 1 ul of serially diluted compound, standard and HPE/ZPE are diluted 1/66 in assay buffer (PBS minus Ca 2+ , minus Mg 2+ with 0.05% pluronic F127) using a Wellmate.
  • test compounds 5ul of 1/66 diluted test compounds is then transferred to the cell plate and allowed to reach equilibrium by incubating for 30min at room temperature before addition of agonist stimulus: 10ul/well of 2nM (0.571 nM FAC) of the cognate neurotrophin (Peprotech) diluted in agonist buffer (HBSS with 0.25% BSA). Final assay concentration of the test compounds is 8.66 ⁇ , (the compound of Example 135, WO2005/116035 FAC is 0.325uM).
  • the plates are left at room temperature for a further 2hours before addition of 10ul of the DiscoveRx PathHunter detection reagent (made up by adding 1 part Galacton Star, 5 parts Emerald II and 19 parts Cell Assay Buffer as per the manufacturer's instructions).
  • test compound data are expressed as percentage inhibition defined by HPE and ZPE values for each plate. Percentage inhibition in the presence of test compound is plotted against compound concentration on a log scale to determine an IC50 from the resultant sigmoid curve.
  • TrkA IC50 data generated using the PV3144 TrkA enzyme assay where more than one reading was taken, the arithmetic mean is presented.

Abstract

The present invention relates to compounds of Formula (I) described herein and their pharmaceutically acceptable salts, and their use in medicine, in particular as Trkantagonists.

Description

N-ACYLPI PERI DINE ETHER TROPOMYOSIN-RELATED KINASE INHIBITORS
The invention described herein relates to certain piperidine compounds and the pharmaceutically acceptable salts of such compounds. The invention also relates to the processes for the preparation of the compounds, compositions containing the
compounds, and the uses of such compounds and salts in treating diseases or conditions associated with tropomyosin-related kinase (Trk), activity. More specifically the invention relates to the compounds and their salts useful as inhibitors of Trk . BACKGROUND
Tropomyosin-related kinases (Trks) are a family of receptor tyrosine kinases activated by neurotrophins. Trks play important roles in pain sensation as well as tumour cell growth and survival signaling. Thus, inhibitors of Trk receptor kinases might provide targeted treatments for conditions such as pain and cancer. Recent developments in this field have been reviewed by Wang et al in Expert Opin. Ther. Patents (2009) 19(3): 305-319, and McCarthy et al in Expert Opin. Ther. Patents (2014) 24(7): 731-744. An extract from Wang is reproduced below. "1.1 Trk receptors
As one of the largest family of proteins encoded by the human genome, protein kinases are the central regulators of signal transduction as well as control of various complex cell processes. Receptor tyrosine kinases (RTKs) are a subfamily of protein kinases (up to 100 members) bound to the cell membrane that specifically act on the tyrosine residues of proteins. One small group within this subfamily is the Trk kinases, with three highly homologous isoforms: TrkA, TrkB, and TrkC. All three isoforms are activated by high affinity growth factors named neurotrophins (NT): i) nerve growth factor (NGF), which activates TrkA; ii) brain-derived neurotrophic factor (BDNF) and NT-4/5, which activate TrkB; and iii) NT-3, which activates TrkC. The binding of neurotrophins to the extracellular domain of Trks causes the Trk kinase to autophosphorylate at several intracellular tyrosine sites and triggers downstream signal transduction pathways. Trks and neurotrophins are well known for their effects on neuronal growth and survival. 1.2 Trks and cancer Originally isolated from neuronal tissues, Trks were thought to mainly affect the maintenance and survival of neuronal cells. However, in the past 20 years, increasing evidence has suggested that Trks play key roles in malignant transformation, chemotaxis, metastasis, and survival signaling in human tumors. The association between Trks and cancer focused on prostate cancer in earlier years and the topic has been reviewed. For example, it was reported that malignant prostate epithelial cells secrete a series of neurotrophins and at least one Trks. In pancreatic cancer, it was proposed that paracrine and/or autocrine neurotrophin-Trk interactions may influence the invasive behavior of the cancer. TrkB was also reported to be overexpressed in metastatic human pancreatic cancer cells. Recently, there have been a number of new findings in other cancer settings. For example, a translocation leads to expression of a fusion protein derived from the /V-terminus of the ETV6 transcription factor and the C- terminal kinase domain of TrkC. The resulting ETV6-TrkC fusions are oncogenic in vitro and appear causative in secretory breast carcinoma and some acute myelogenous leukemias (AML). Constitutively active TrkA fusions occurred in a subset of papillary thyroid cancers and colon carcinomas. In neuroblastoma, TrkB expression was reported to be a strong predictor of aggressive tumor growth and poor prognosis, and TrkB overexpression was also associated with increased resistance to chemotherapy in neuroblastoma tumor cells in vitro. One report showed that a novel splice variant of TrkA called TrkAIII signaled in the absence of neurotrophins through the inositol phosphate- AKT pathway in a subset of neuroblastoma. Also, mutational analysis of the tyrosine kinome revealed that Trk mutations occurred in colorectal and lung cancers. In summary, Trks have been linked to a variety of human cancers, and discovering a Trk inhibitor and testing it clinically might provide further insight to the biological and medical hypothesis of treating cancer with targeted therapies.
1.3 Trks and pain
Besides the newly developed association with cancer, Trks are also being recognized as an important mediator of pain sensation. Congenital insensitivity to pain with anhidrosis (CIPA) is a disorder of the peripheral nerves (and normally innervated sweat glands) that prevents the patient from either being able to adequately perceive painful stimuli or to sweat. TrkA defects have been shown to cause CIPA in various ethnic groups. Currently, non-steroidal anti-inflammatory drugs (NSAIDs) and opiates have low efficacy and/or side effects (e.g., gastrointestinal/renal and psychotropic side effects, respectively) against neuropathic pain and therefore development of novel pain treatments is highly desired. It has been recognized that NGF levels are elevated in response to chronic pain, injury and inflammation and the administration of exogenous NGF increases pain hypersensitivity. In addition, inhibition of NGF function with either anti-NGF antibodies or non-selective small molecule Trk inhibitors has been shown to have effects on pain in animal models. It appears that a selective Trk inhibitor (inhibiting at least NGF's target, the TrkA receptor) might provide clinical benefit for the treatment of pain. Excellent earlier reviews have covered targeting NGF/BDNF for the treatment of pain so this review will only focus on small molecule Trk kinase inhibitors claimed against cancer and pain. However, it is notable that the NGF antibody tanezumab was very recently reported to show good efficacy in a Phase II trial against osteoarthritic knee pain."
Further trk-mediated conditions which have been investigated and show promise for treatment with a trk inhibitor include atopic dermatitis, psoriasis, eczema and prurigo nodularis, acute and chronic itch, pruritis, atopic dermatitis, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, pruritis, lower urinary tract disorder, inflammatory lung diseases such as asthma, allergic rhinitis, lung cancer, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel diseases such as ulcerative colitis, Crohn's disease, fibrosis, neurodegenerative disease, diseases disorders and conditions related to dysmye!ination or demyelination, certain infectious diseases such as Trypanosoma cruzi infection (Chagas disease), cancer related pain, chronic pain, neuroblastoma, ovarian cancer, colorectal cancer, melanoma, head and neck cancer, gastric carcimoma, lung carcinoma, breast cancer, glioblastoma, medu!iob!astoma, secratory breast cancer, salivary gland cancer, papillary thyroid carcinoma, adult myeloid leukaemia, tumour growth and metastasis, interstitial cystitis and Alzheimer's disease (McCarthy et al in Expert Opin. Ther. Patents (2014) 24(7): 731-744; C.
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2002;293:614-619; Grewe M, Vogelsang K, Ruzicka T, Stege H, Krutmann J., J Invest Dermatol. 2000; 114:1 108-11 12; Urashima R, Mihara M.. Virchows Arch. 1998;432:363- 370; Kinkelin I, Motzing S, Koltenzenburg M, Brocker EB., Cell Tissue Res.
2000;302:31-37; Tong Liu & Ru-Rong Ji, Pflugers Arch - Eur J Physiol, DO!
10.1Q07/sQ0424-013- 1284-2, published online 1 May 2013.); International Patent Application publication numbers WO2012/158413, WO20 3/088256, WO2013/088257 and WO2013/161919, (Brodeur, G. M. , Nat. Rev. Cancer 2003, 3, 203-216),
(Davidson. B. , et al. , Clin. Cancer Res. 2003, 9, 2248-2259), (Bardelli, A. , Science 2003, 300, 949), (Truzzi, F. , et al. , Dermato-Endocrinology 2008, 3 (I), pp. 32-36), Yilmaz.T. , et al. , Cancer Biology and Therapy 2010, 10 (6), pp. 644-653), (Du, J. et al. .World Journal of Gastroenterology 2003, 9 (7), pp. 1431-1434), (Ricci A. , et al. , American Journal of Respiratory Cell and Molecular Biology 25 (4), pp. 439-446), (Jin, W. , et al. , Carcinogenesis 2010, 31 (11), pp. 1939-1947), (Wadhwa, S. , et al. .Journal of Biosciences 2003, 28 (2), pp. 181-188), (Gruber-Olipitz, M. , et al. , Journal of Proteome Research 2008, 7 (5), pp. 1932-1944), (Euthus, D. M. et al. , Cancer Cell 2002, 2 (5), pp. 347-348), (Li, Y. -G. , et al. , Chinese Journal of Cancer Prevention and Treatment 2009, 16 (6), pp. 428-430), (Greco, A. , et al. , Molecular and Cellular Endocrinology 2010, 321 (I), pp. 44-49), (Eguchi, M. , et al. , Blood 1999, 93 (4), pp. 1355-1363), (Nakagawara, A. (2001) Cancer Letters 169: 107-1 14; Meyer, J. et al.
(2007) Leukemia, 1—10; Pierottia, M. A. and Greco A. , (2006) Cancer Letters 232:90 — 98; Eric Adriaenssens, E. , et al. Cancer Res (2008) 68:(2) 346-351), (Freund- Michel, V; Frossard, N. , Pharmacology ck Therapeutics (2008) 1 17(1), 52-76), (Hu Vivian Y; et. al. The Journal of Urology (2005), 173(3), 1016-21), (Di Mola, F. F, et. al. Gut (2000) 46(5), 670-678) (Dou, Y. -C. ,et. al. Archives of Dermatological Research (2006) 298(1), 31-37), (Raychaudhuri, S. P. , et al. , J. Investigative Dermatology (2004) 122(3), 812-819) and (de Melo-Jorge, M. et al. , Cell Host ck Microbe (2007) 1 (4), 251- 261). Thus Trk inhibitors have a wide variety of potential medical uses. There is a need to provide new Trk inhibitors that are good drug candidates. In particular, compounds should preferably bind potently to the Trk receptors in a selective manner compared to other receptors, whilst showing little affinity for other receptors, including other kinase and / or GPC receptors, and show functional activity as Trk receptor antagonists. They should be non-toxic and demonstrate few side-effects. Furthermore, the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated. They should preferably be e.g. well absorbed from the gastrointestinal tract, and / or be injectable directly into the bloodstream, muscle, or subcutaneously, and / or be metabolically stable and possess favourable pharmacokinetic properties.
International Patent Application publication number WO2009/012283 refers to various fluorophenyl compounds as Trk inhibitors; International Patent Application publication numbers WO2009/152087, WO2008/080015 and WO2008/08001 and
WO2009/152083 refer to various fused pyrroles as kinase modulators; International Patent Application publication numbers WO2009/143024 and WO2009/143018 refer to various pyrrolo[2,3-d]pyrimidines substituted as Trk inhibitors; International Patent Application publication numbers WO2004/056830 and WO2005/1 16035 describe various 4-amino-pyrrolo[2,3-d]pyrimidines as Trk inhibitors. International Patent
Application publication number WO2011/133637 describes various pyrrolo[2,3- d]pyrimidines and pyrrolo[2,3-b]pyridines as inhibitors of various kinases. International Patent Application publication number WO2005/099709 describes bicyclic heterocycles as serine protease inhibitors. International Patent Application publication number WO2007/047207 describes bicyclic heterocycles as FLAP modulators.
International Patent Application publication numbers WO2012/137089,
WO2014/053967, WO2014/053968 and WO2014/053965 describe various heterocyclic compounds as Trk inhibitors.
United States Patent Application Serial No. 61/918,783, filed December 20, 2013, having Pfizer Docket No. PC72019 is included herein by reference in its entirety and provides compounds of Formula I:
Figure imgf000007_0001
Especially of interest re US 61/918,783 are the substituents "A" and relevant intermediates incorporating the "A" moiety. Among the aims of this invention are to provide orally-active, efficacious, compounds and salts which can be used as active drug substances, particularly Trk antagonists, i.e. that block the intracellular kinase activity of the Trk, e.g. TrkA (NGF) receptor. Other desirable features include good HLM/hepatocyte stability, oral bioavailability, metabolic stability, absorption, selectivity over other types of kinase, dofetilide selectivity.
Preferable compounds and salts will show a lack of CYP inhibition/induction, and be CNS-sparing.
SUMMARY
The present invention provides compounds of Formula I:
Figure imgf000007_0002
I Wherein
Q1 is N or CR1 ,
Q2 is N or CR2,
R1 , R2, R4 and R5 are each independently H, F, CN, OH, NH2, Ci-3 alkyl optionally substituted by one or more F, or C1-3 alkoxy optionally substituted by one or more F, R3 is H, F, CI, CN, Ci-4 alkyl optionally substituted by one or more F, Ci-4 alkoxy optionally substituted by one or more F , or C3-7 cycloalkyloxy optionally substituted by one or more F, or C1-4 alkylthio optionally substituted by one or more F,
With the proviso that at least 2 of R1, R2, R3, R4 and R5 are H,
R6 and R7 can be attached at any point on the piperidine ring and are independently H, F, CN, OH, NH2, C1 -3 alkyl optionally substituted by one or more F, or C1-3 alkoxy optionally substituted by one or more F,
or R6 and R7 can be taken together, with the atoms to which they are attached, to form a 5- to 7-membered cycloalkane ring,
R8 is CONR101 R102,
each of X1, X2 and X3 is CR101 or N,
R101 and R102 are each independently selected from H and C1-3 alkyl,
Z is CH2, CH(CH3), NH or O,
A is (Ci -4 alkoxy optionally substituted by NH2, OH, CONH2, S02CH3 or CN), (Ci-4 alkylamino optionally substituted by NH2, OH, CONH2, S02CH3 or CN), or (C3-6 cycloalkyoxy optionally substituted by NH2, OH, CONH2, S02CH3 or CN),
Or
A is a phenyl or a 5- or 6-membered saturated or unsaturated heterocyclic ring containing 1 , 2 or 3 hetero-atoms selected from S, N and O, each of which is optionally fused to a further 5- or 6-membered saturated or unsaturated heterocyclic ring containing 1 , 2 or 3 hetero-atoms selected from S, N and O, and which phenyl or heterocyclic ring or fused ring system is optionally substituted by 1 , 2 or 3 substituents independently selected from =0, CO2 9, CN and Co-6 alkyl optionally substituted by 1 or 2 substituents independently selected from OH, NH2, SO2CH3, Ci-4 alkoxy, CON(R103)(R104) and a group selected from
Figure imgf000009_0001
where X4 is selected from NR101 , O and S02,
X5 is H, OH or F,
R9 is H or Ci-6 alkyl,
R101 and R102 are each independently selected from H and C1-3 alkyl,
R103 and R104 are each independently selected from H, (C1-6 alkyl optionally substituted by OH, C1-6 alkoxy or by one or more F), and (C3- cycloalkyl optionally substituted by OH, C1-6 alkoxy or by one or more F), and pharmaceutically acceptable salts thereof. The invention also comprises pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The invention is also directed to a method of treating a disease or condition indicated for treatment with a Trk antagonist, in a subject, by administering to a subject in need thereof a therapeutically effective amount of one or more of the compounds herein, or a pharmaceutically acceptable salt thereof.
Other aspects of the invention will be apparent from the remaining description and claims. Preferably, the compounds of the present invention are potent antagonists at Trk receptors, and have a suitable PK profile to enable once daily dosing. The compounds of the present invention are potentially useful in the treatment of a range of disorders where a Trk antagonist is indicated, particularly pain indications. Depending on the disease and condition of the patient, the term "treatment" as used herein may include one or more of curative, palliative and prophylactic treatment. According to the invention a compound of the present invention may be useful to treat any physiological pain such as inflammatory pain, nociceptive pain, neuropathic pain, acute pain, chronic pain, musculo-skeletal pain, on-going pain, central pain, heart and vascular pain, head pain, orofacial pain. Other pain conditions which may be treated include intense acute pain and chronic pain conditions which may involve the same pain pathways driven by pathophysiological processes and as such cease to provide a protective mechanism and instead contribute to debilitating symptoms associated with a wide range of disease states.
Pain is a feature of many trauma and disease states. When a substantial injury, via disease or trauma, to body tissue occurs the characteristics of nociceptor activation are altered, this leads to hypersensitivity at the site of damage and in nearby normal tissue. In acute pain the sensitivity returns to normal once the injury has healed. However, in many chronic pain states, the hypersensitivity far outlasts the healing process and is normally due to nervous system injury due to maladaptation of the afferent fibres (Woolf & Salter 2000 Science 288: 1765-1768). Clinical pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. There are a number of typical pain subtypes: 1) spontaneous pain which may be dull, burning, or stabbing; 2) pain responses to noxious stimuli are exaggerated (hyperalgesia); 3) pain is produced by normally innocuous stimuli (allodynia) (Meyer et al., 1994 Textbook of Pain 13-44). Pain can be divided into a number of different areas because of differing
pathophysiology, these include nociceptive, inflammatory, neuropathic pain among others. It should be noted that some types of pain have multiple aetiologies and thus can be classified in more than one area, e.g. Back pain, Cancer pain have both nociceptive and neuropathic components.
Disorders for which a trk inhibitor may be indicated include pain. Pain may be either acute or chronic and additionally may be of central and/or peripheral origin. Pain may be of a neuropathic and/or nociceptive and/or inflammatory nature, such as pain affecting either the somatic or visceral systems, as well as dysfunctional pain affecting multiple systems. Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment. The system operates through a specific set of primary sensory neurones and is activated by noxious stimuli via peripheral transducing mechanisms (see Meyer et al., 2006, Wall and Melzack's Textbook of Pain (5th Ed), Chapter"!). These sensory fibres are known as nociceptors, and are characteristically small diameter axons with slow conduction velocities, of which there are two main types, A-delta fibres (myelinated) and C fibres (non-myelinated). Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organised projection to the spinal cord, the location of the stimulus. The activity generated by nociceptor input is transferred, after complex processing in the dorsal horn, either directly, or via brain stem relay nuclei, to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated.
Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually twelve weeks or less). It is usually, although not always, associated with a specific cause such as a defined injury, is often sharp and severe and can result from numerous origins such as surgery, dental work, a strain or a sprain. Acute pain does not generally result in any persistent psychological response. When a substantial injury occurs to body tissue, via disease or trauma, the characteristics of nociceptor activation may be altered such that there is sensitisation in the periphery, locally around the injury and centrally where the nociceptors terminate. These effects lead to a hightened sensation of pain. In acute pain these mechanisms can be useful, in promoting protective behaviours which may better enable repair processes to take place. The normal expectation would be that sensitivity returns to normal once the injury has healed. However, in many chronic pain states, the hypersensitivity far outlasts the healing process and is often due to nervous system injury or alteration which can be associated with maladaptation and aberrant activity (Woolf & Salter, 2000, Science, 288, 1765-1768). As such, chronic pain is long-term pain, typically persisting for more than three months and leading to significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy or postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post-surgical pain, but may include any chronic painful condition affecting any system, such as those described by the International Association for the Study of Pain (Classification of Chronic Pain, a publication freely available for download at http://www.iasp-pain.org).
The clinical manifestation of pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain symptoms. Such symptoms can include: 1) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally innocuous stimuli (allodynia) (Meyer et al., 2006, Wall and Melzack's Textbook of Pain (5th Ed), Chapterl). Although patients suffering from various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and may, therefore, require different treatment strategies. Apart from acute or chronic, pain can also be broadly categorized into: nociceptive pain, affecting either the somatic or visceral systems, which can be inflammatory in nature (associated with tissue damage and the infiltration of immune cells); or neuropathic pain.
Nociceptive pain can be defined as the process by which intense thermal, mechanical, or chemical stimuli are detected by a subpopulation of peripheral nerve fibers, called nociceptors, and can be induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 2006, Wall and Melzack's Textbook of Pain (5tn Ed), Chapter"!). Myelinated A-delta fibres transmit rapidly and are responsible for sharp and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower rate and convey a dull or aching pain. Moderate to severe acute nociceptive pain is a prominent feature of pain from strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, pain associated with gout, cancer pain and back pain. Cancer pain may be chronic pain such as tumour related pain (e.g. bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (e.g. in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy). Back pain may be due to herniated or ruptured intervertabral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Back pain may resolve naturally but in some patients, where it lasts over 12 weeks, it becomes a chronic condition which can be particularly debilitating.
Nociceptive pain can also be related to inflammatory states. The inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (McMahon et al., 2006, Wall and Melzack's Textbook of Pain (5th Ed), Chapter3). A common inflammatory condition assoiciated with pain is arthritis. It has been estimated that almost 27 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease (Lawrence et al., 2008, Arthritis Rheum, 58, 15-35); most patients with osteoarthritis seek medical attention because of the associated pain. Arthritis has a significant impact on psychosocial and physical function and is known to be the leading cause of disability in later life. Rheumatoid arthritis is an immune-mediated, chronic, inflammatory polyarthritis disease, mainly affecting peripheral synovial joints. It is one of the commonest chronic inflammatory conditions in developed countries and is a major cause of pain. In regard to nociceptive pain of visceral origin, visceral pain results from the activation of nociceptors of the thoracic, pelvic, or abdominal organs (Bielefeldt and Gebhart, 2006, Wall and Melzack's Textbook of Pain (5th Ed), Chapter48). This includes the reproductive organs, spleen, liver, gastrointestinal and urinary tracts, airway structures, cardiovascular system and other organs contained within the abdominal cavity. As such visceral pain refers to pain associated with conditions of such organs, such as painful bladder syndrome, interstitial cystitis, prostatitis, ulcerative colitis, Crohn's disease, renal colic, irritable bowl syndrome, endometriosis and dysmenorrhea! (Classification of Chronic Pain, available at http://www.iasp-pain.org). Currently the potential for a neuropathic contribution (either through central changes or nerve injury/damage) to visceral pain states is poorly understood but may play a role in certain conditions (Aziz et al., 2009, Dig Dis 27, Suppl 1 , 31-41)
Neuropathic pain is currently defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many disorders with diverse aetiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post- stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological as it has no protective role. It is often present well after the original cause has dissipated, commonly lasting for years, significantly decreasing a patient's quality of life (Dworkin, 2009, Am J Med, 122, S1-S2; Geber et al., 2009, Am J Med, 122, S3-S12; Haanpaa et al., 2009, Am J Med, 122, S13- S21). The symptoms of neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Dworkin, 2009, Am J Med, 122, S1-S2; Geber et al., 2009, Am J Med, 122, S3-S12; Haanpaa et al., 2009, Am J Med, 122, S13-S21). They include spontaneous pain, which can be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus). It should be noted that some types of pain have multiple aetiologies and thus can be classified in more than one area, e.g. back pain, cancer pain and even migaine headaches may include both nociceptive and neuropathic components. Similarly other types of chronic pain, perhaps less well understood, are not easily defined by the simplistic definitions of nociceptive or neuropathic. Such conditions include in particular fibromyalgia and chronic regional pain syndrome, which are often described as dysfunctional pain states e.g. fibromyalgia or complex regional pain syndrome (Woolf, 2010, J Clin Invest, 120, 3742-3744), but which are included in classifications of chronic pain states (Classification of Chronic Pain, available at http://www.iasp-pain.org).
DETAILED DESCRIPTION
Embodiment 1 of the invention is a compound of Formula I:
Figure imgf000015_0001
Wherein
Q1 is N or CR1 ,
Q2 is N or CR2,
R1 , R2, R4 and R5 are each independently H, F, CN, OH, NH2, Ci-3 alkyl optionally substituted by one or more F, or C1-3 alkoxy optionally substituted by one or more F, R3 is H, F, CI, CN, Ci-4 alkyl optionally substituted by one or more F, Ci-4 alkoxy optionally substituted by one or more F , or C3- cycloalkyloxy optionally substituted by one or more F, or Ci-4 alkylthio optionally substituted by one or more F, With the proviso that at least 2 of R1, R2, R3, R4 and R5 are H,
R6 and R7 can be attached at any point on the piperidine ring and are independently H, F, CN, OH, NH2, C1-3 alkyl optionally substituted by one or more F, or C1-3 alkoxy optionally substituted by one or more F,
or R6 and R7 can be taken together, with the atoms to which they are attached, to form a 5- to 7-membered cycloalkane ring,
R8 is CONR101 R102,
each of X1, X2 and X3 is independently CR101 or N,
R101 and R102 are each independently selected from H and C1-3 alkyl,
Z is CH2, CH(CH3), NH or O,
A is (C1-4 alkoxy optionally substituted by NH2, OH, CONH2, S02CH3 or CN), (C1-4 alkylamino optionally substituted by NH2, OH, CONH2, S02CH3 or CN), or (C3-6 cycloalkyoxy optionally substituted by NH2, OH, CONH2, S02CH3 or CN),
Or
A is a phenyl or a 5- or 6-membered saturated or unsaturated heterocyclic ring containing 1 , 2 or 3 hetero-atoms selected from S, N and O,
each of which is optionally fused to a further 5- or 6-membered saturated or unsaturated heterocyclic ring containing 1 , 2 or 3 hetero-atoms selected from S, N and O, and which phenyl or heterocyclic ring or fused ring system is optionally substituted by 1 , 2 or 3 substituents independently selected from =0, C02R9, CN and Co-6 alkyl optionally substituted by 1 or 2 substituents independently selected from OH, NH2, S02CH3, Ci-4 alkoxy, CON(R103)(R104) and a group selected from
Figure imgf000016_0001
where X4 is selected from NR101 , O and S02,
X5 is H, OH or F,
R9 is H or Ci-6 alkyl,
R101 and R102 are each independently selected from H and C1-3 alkyl,
R103 and R104 are each independently selected from H, (C1-6 alkyl optionally substituted by OH, C1-6 alkoxy or by one or more F), and (C3- cycloalkyl optionally substituted by OH, C1-6 alkoxy or by one or more F), Or a pharmaceutically acceptable salt thereof.
Embodiment 2: A compound or salt according to embodiment 1 wherein one of X1 , X2 and X3 is CR101 or N, and the others are CR101. Embodiment 3: A compound or salt according to embodiment 1 or 2 wherein X1 is CH or N.
Embodiment 4: A compound or salt according to embodiment 1 , 2 or 3 wherein X2 and X3 are CH.
Embodiment 5: A compound or salt according to embodiment 1 , 2, 3 or 4 wherein X1 is CH.
Embodiment 6: A compound or salt according to embodiment 1 , 2, 3, 4 or 5 wherein Z is CH2, CH(CH3) or NH.
Embodiment 7: A compound or salt according to embodiment 1 , 2, 3, 4, 5 or 7 wherein Z is CH2. Embodiment 8: A compound or salt according to embodiment 1 , 2, 3, 4, 5, 6 or 7 wherein R8 is CONH2. Embodiment 9: A compound or salt according to embodiment 1 , 2, 3, 4, 5, 6, 7 or 8 wherein R6 is H, F or CH3.
Embodiment 10: A compound or salt according to embodiment 1 , 2, 3, 4, 5, 6, 7, 8 or 9 wherein Q1 is CH or N.
Embodiment 11 : A compound or salt according to embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 wherein Q2 is CH or N. Embodiment 12: A compound or salt according to embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 wherein R7 is F, H or CH3.
Embodiment 13: a compound or salt according to embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9 , 10, 11 or 12 which has the substructure
Figure imgf000018_0001
la
Embodiment 14: A compound or salt according to embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 or 13 wherein R3 is OCF3, CF3, C(CH3)3, SCF3, CH(CH3)2 or cyclopropyloxy
Embodiment 15: A compound or salt according to embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 wherein A is an imidazolyl, morpholinyl, pyrrolidinyl, thiazolyl, pyridyl, phenyl, or pyrazolyl group optionally substituted by 1 or 2 substituents independently selected from CO2R9 and Co-6 alkyl optionally substituted by 1 or 2 substituents independently selected from OH, NH2, SC>2CH3, Ci-4 alkoxy,
CON(R103)(R104) and a group selected from
Figure imgf000019_0001
Embodiment 16: a compound or salt according to embodiment 15 where A is an imidazolyl, morpholinyl, pyrrolidinyl, thiazolyl, pyridyl, phenyl, or pyrazolyl group
bstituted by CH3, CH2SO2CH3 or by
Figure imgf000019_0002
Embodiment 17: a compound or salt according to embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 wherein A is (Ci-4 alkoxy optionally substituted by NH2, OH, CONH2, SO2CH3 or CN), (C1-4 alkylamino optionally substituted by NH2, OH, CONH2, SO2CH3 or CN), or (C3-6 cycloalkyoxy optionally substituted by NH2, OH, CONH2, S02CH3 or CN).
Embodiment 18: a compound or salt according to embodiment 13, 14 or 15 as appropriate wherein A is morpholin-1-yl, methoxy, OCH2CN, OCH2C(0)NH2,
OCH2SO2CH3, (C2-4 alkoxy optionally substituted by NH2, OH, CONH2, S02CH3 or CN), (C2-4 alkylamino optionally substituted by NH2, OH, CONH2, S02CH3 or CN), or (C3-6 cycloalkyoxy optionally substituted by NH2, OH, CONH2, S02CH3 or CN). Embodiment 19: a compound or salt according to embodiment 18 wherein A is morpholin-1-yl, methoxy, OCH2CN, OCH2C(0)NH2, OCH2S02CH3, (C2-4 alkoxy optionally substituted by NH2 or OH), (C2-4 alkylamino optionally substituted by NH2 or OH), or (C3-6 cycloalkyoxy optionally substituted by NH2 or OH). Embodiment 20: A compound or salt according to Embodiment 1 which has the formula IB
Figure imgf000020_0001
IB wherein
R3 is OCF3 or cyclopropyloxy,
And X1 is CH or N.
Embodiment 21 : A compound selected from any of the Examples below, or a pharmaceutically acceptable salt thereof. Embodiment 22: A pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of the preceding embodiments 1 to 21 , and a pharmaceutically acceptable carrier.
Embodiment 23: A compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 21 , for use as a medicament.
Embodiment 24: A compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 21 for use in the treatment of a disease for which a Trk receptor antagonist is indicated.
Embodiment 25: A compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 21 for use in the treatment of pain or cancer. Embodiment 26: The use of a compound of the formula (I) or a pharmaceutically acceptable salt or composition thereof, as defined in any one of embodiments 1 to 21 , for the manufacture of a medicament to treat a disease for which a Trk receptor antagonist is indicated
Embodiment 27: The use of a compound of the formula (I) or a pharmaceutically acceptable salt or composition thereof, as defined in any one of embodiments 1 to 21 , for the manufacture of a medicament to treat pain or cancer. Embodiment 28: A method of treatment of a mammal, to treat a disease for which a Trk receptor antagonist is indicated, comprising treating said mammal with an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 21. Embodiment 29: A method of treatment of pain or cancer in a mammal, comprising treating said mammal with an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 21.
Embodiment 30: A compound or salt according to any one of embodiments 1 to 21 for use in a medical treatment in combination with a further drug substance.
Further embodiments include:
A compound or salt according to any one of embodiments 1 -21 wherein Q1 has the value of Q1 in any of the Examples;
A compound or salt according to any one of embodiments 1-21 wherein Q2 has the value of Q2 in any of the Examples;
A compound or salt according to any one of embodiments 1-21 wherein R3 has the value of R3 in any of the Examples;
A compound or salt according to any one of embodiments 1-21 wherein R4 has the value of R4 in any of the Examples;
A compound or salt according to any one of embodiments 1-21 wherein R5 has the value of R5 in any of the Examples; A compound or salt according to any one of embodiments 1-21 wherein R has the value of R6 in any of the Examples;
A compound or salt according to any one of embodiments 1-21 wherein R7 has the value of R7 in any of the Examples;
A compound or salt according to any one of embodiments 1-21 wherein R8 has the value of R8 in any of the Examples;
A compound or salt according to any one of embodiments 1-21 wherein Z has the value of Z in any of the Examples;
A compound or salt according to any one of embodiments 1-21 wherein X1 has the value of X1 in any of the Examples;
A compound or salt according to any one of embodiments 1-21 wherein X2 has the value of X2 in any of the Examples;
A compound or salt according to any one of embodiments 1-21 wherein X3 has the value of X3 in any of the Examples;
A compound or salt according to any one of embodiments 1-21 wherein X3 has the value of X4 in any of the Examples;
A compound or salt according to any one of embodiments 1-21 wherein X3 has the value of X5 in any of the Examples;
A compound or salt according to any one of embodiments 1-21 wherein A has the value of A in any of the Examples;
A prodrug of a compound according to any previous embodiment;
Any novel genus of intermediates described in the Schemes below;
Any novel specific intermediate described in the Preparations below;
Any novel process described herein.
"Halogen" means a fluoro, chloro, bromo or iodo group.
"Alkyl" groups, containing the requisite number of carbon atoms, can be unbranched or branched. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl.
"Pharmaceutically acceptable salts" of the compounds of formula I include the acid addition and base addition salts (including disalts, hemisalts, etc.) thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.
Suitable base addition salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
The compounds of the invention may be administered as prodrugs. Thus certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic or enzymatic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).
Prodrugs can, for example, be produced by replacing appropriate functionalities present in a compound of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985). Examples of prodrugs include phosphate prodrugs, such as dihydrogen or dialkyl (e.g. di-tert-butyl) phosphate prodrugs.
Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references. Specific prodrug groups envisaged for, and included in the definition of, the invention include: phosphate esters of alcohols "ROH", e.g. RO-P(=0)(OH)2 or salts thereof; and amino acid esters of alcohols "ROH", e.g. RO-C(=0)-C*-NH2 wherein NH2-C*-C02H is an amino acid such as histidine, alanine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, ornithine, proline, selenocysteine, tyrosine; Or derivative thereof such as dimethylglycine, and the like.
The compounds of the invention include compounds of formula I and salts thereof as hereinbefore defined, polymorphs, and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labelled compounds of formula I.
Unless otherwise specified, compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula (I) contains for example, a keto or guanidine group or an aromatic moiety, tautomeric isomerism ('tautomerism') can occur. It follows that a single compound may exhibit more than one type of isomerism.
Included within the scope of the claimed compounds of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base addition salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine. Examples of types of potential tautomerisms shown by the compounds of the invention include hydroxypyridine pyridone; amide hydroxyl-imine and keto o enol tautomersims:
Figure imgf000025_0001
Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or other derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on a resin with an asymmetric stationary phase and with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture. Mixtures of stereoisomers may be separated by conventional techniques known to those skilled in the art. [see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994).] The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123l and 125l, nitrogen, such as 13N and 15N, oxygen, such as 150, 170 and 180, phosphorus, such as 32P, and sulphur, such as 35S.
Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
Substitution with positron emitting isotopes, such as 11C, 18F, 150 and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labelled reagents in place of the non-labelled reagent previously employed.
The routes below, including those mentioned in the Examples and Preparations, illustrate methods of synthesising compounds of formula (I). The skilled person will appreciate that the compounds of the invention, and intermediates thereto, could be made by methods other than those specifically described herein, for example by adaptation of the methods described herein, for example by methods known in the art. Suitable guides to synthesis, functional group interconversions, use of protecting groups, etc., are for example:"Comprehensive Organic Transformations" by RC Larock, VCH Publishers Inc. (1989); Advanced Organic Chemistry" by J. March, Wiley Interscience (1985); "Designing Organic Synthesis" by S Warren, Wley Interscience (1978); Organic Synthesis - The Disconnection Approach" by S Warren, Wiley Interscience (1982); "Guidebook to Organic Synthesis" by RK Mackie and DM Smith, Longman (1982); "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley and Sons, Inc. (1999); and "Protecting Groups" by PJ, Kocienski, Georg Thieme Verlag (1994); and any updated versions of said standard works.
In addition, the skilled person will appreciate that it may be necessary or desirable at any stage in the synthesis of compounds of the invention to protect one or more sensitive groups, so as to prevent undesirable side reactions. In particular, it may be necessary or desirable to protect amino or carboxylic acid groups. The protecting groups used in the preparation of the compounds of the invention may be used in conventional manner. See, for example, those described in 'Greene's Protective Groups in Organic Synthesis' by Theodora W Greene and Peter G M Wuts, third edition, (John Wley and Sons, 1999), in particular chapters 7 ("Protection for the Amino Group") and 5 ("Protection for the Carboxyl Group"), incorporated herein by reference, which also describes methods for the removal of such groups. In the general synthetic methods below, unless otherwise specified, the substituents are as defined above with reference to the compounds of formula (I) above. Where ratios of solvents are given, the ratios are by volume. General Schemes
The compounds of the invention may be prepared by any method known in the art for the preparation of compounds of analogous structure. In particular, the compounds of the invention can be prepared by the procedures described by reference to the Schemes that follow, or by the specific methods described in the Examples, or by similar processes to either. The skilled person will appreciate that the experimental conditions set forth in the schemes that follow are illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or desirable to vary the precise conditions employed for the preparation of compounds of formula (I). It will be further appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.
In addition, the skilled person will appreciate that it may be necessary or desirable at any stage in the synthesis of compounds of the invention to protect one or more sensitive groups, so as to prevent undesirable side reactions. In particular, it may be necessary or desirable to protect amino or carboxylic acid groups. The protecting groups used in the preparation of the compounds of the invention may be used in conventional manner. See, for example, those described in 'Greene's Protective Groups in Organic Synthesis' by Theodora W Greene and Peter G M Wuts, third edition, (John Wiley and Sons, 1999), in particular chapters 7 ("Protection for the Amino Group") and 5 ("Protection for the Carboxyl Group"), incorporated herein by reference, which also describes methods for the removal of such groups.
All of the derivatives of the formula (I) can be prepared by the procedures described in the general methods presented below or by routine modifications thereof. The present invention also encompasses any one or more of these processes for preparing the derivatives of formula (I), in addition to any novel intermediates used therein. According to a first process, compounds of formula (I) may be prepared from compounds of formula (VIII), (VII) and (IV) as illustrated by Scheme 1 ,
Figure imgf000029_0001
(ll) (I)
Scheme 1
wherein A is O-linked and R8 is CONH2;
wherein Hal is fluoro or chloro; LG is a leaving group such as iodide, bromide, chloride, mesylate, carbonate or epoxide;
Compounds of formulae (VIII), (VII), (IV) and (IX) are commercially available or may be synthesized by those skilled in the art according to the literature or preparations described herein.
Compounds of formula (I) may be prepared from compounds of formula (II) according to process step (v), an alkylation step with compounds of formula (IX). Typical conditions include an inorganic base with an organic solvent such as DMF at a range of elevated temperatures. Preferred conditions comprise potassium or cesium carbonate in DMF at from 50-1 10°C. Wherein A contains a protecting group, a deprotection step may be employed to afford compounds of formula (I). Wherein trityl is present, an acid mediated deprotection step may be employed. Preferred conditions comprise TFA in DCM at room temperature. Wherein benzyl is present, deprotection may occur in the presence of a metal catalyst and hydrogen donor. Preferred conditions comprise palladium on carbon either i) in methanol under a balloon of hydrogen or ii) in acetic acid with formic acid at room temperature.
Wherein A contains a sulfane, an oxidation step may be employed to afford compounds of formula (I) that include a sulfone. Preferred conditions comprise oxone in MeOH at room temperature.
Wherein A contains a carboxylic ester, the ester may be reduced to an alcohol through a number of functional group interconversions; namely a hydrolysis reaction followed by mixed anhydride formation followed by a reduction reaction. Preferred conditions comprise lithium hydroxide in THF and water, followed by isobutylchloroformate with triethylamine in THF, followed by sodium borohydride in water, all at room temperature. Compounds of formula (II) may be prepared from compounds of formula (III) according to process step (iv) a deprotection step under hydrogenation conditions. Preferred conditions comprise palladium on carbon in an alcoholic solvent such as ethanol under a balloon of hydrogen at room temperature.
Compounds of formula (III) may be prepared from compounds of formula (V) according to process step (iii), an amide bond formation reaction with activation of the carboxylic acid (IV), using a suitable organic base and suitable coupling agents such as EDCI/HOBt, HATU or HBTU. Preferred conditions comprise EDCI with HOBt or HATU with triethylamine in DCM or THF at room temperature.
Compounds of formula (V) may be prepared from compounds of formula (VI) according to process steps (ii) and (iia), a base mediated hydrolysis reaction followed by an acid mediated deprotection step. Preferred conditions comprise potassium hydroxide in tBuOH at 80°C followed by 4M HCI in dioxane at room temperature.
Compounds of formula (VI) may be prepared from compounds of formulae (VII) and (VIII) according to process step (i) a nucleophilic substitution reaction. Typical conditions include an inorganic base in a polar organic solvent at from room to elevated temperatures. Preferred conditions comprise potassium hydroxide, potassium tert- butoxide or cesium carbonate in tert-butanol, dioxane or DMF at from room temperature to 100°C.
According to a second process, compounds of formula (III) may be prepared from compounds of formulae (IV), (XIII) and (IX) as illustrated by Scheme 2,
Figure imgf000031_0001
Scheme 2
wherein A is O-linked.
Compounds of formula (IV), (XIII) and (IX) are commercially available or may be synthesized by those skilled in the art according to the literature or preparations described herein.
Compounds of formula (III) may be prepared from compounds of formula (X) according to process steps (viii) and (iii), a base mediated hydrolysis reaction followed by an amide bond forming reaction as described in Scheme 1 with amines of formula (XXV). Preferred conditions comprise sodium hydroxide in methanol at from room temperature to reflux followed by HBTU and DIPEA in DMF with 7M ammonia in MeOH at room temperature.
Compounds of formula (X) may be prepared from compounds of formula (XI) and (IX) according to process step (vii), a nucleophilic substitution reaction. Typical conditions comprise an inorganic base in a polar organic solvent at from room temperature to 100°C. Preferred conditions comprise cesium carbonate in DMSO at 100°C.
Compounds of formula (XI) may be prepared from compounds of formula (XII) according to process step (vi), a mesylation reaction. Preferred conditions comprise methanesulfonyl chloride in DCM with triethylamine at from 0°C to room temperature. Compounds of formula (XII) may be prepared from compounds of formula (IV) and (XIII) according to process step (iii) as described in Scheme 1.
According to a third process, compounds of formula (I) may be prepared from compounds of formulae (XVI), (XVII) and (IV) as illustrated by Scheme 3,
Figure imgf000032_0001
(XIV) (IV) (I)
Scheme 3
Compounds of formula (XVI), (XVII) and (IV) are commercially available or may be synthesized by those skilled in the art according to the literature or preparations described herein.
Compounds of formula (I) may be prepared from compounds of formula (XIV) and (IV) according to process step (iii), an amide bond forming reaction as described in Scheme 1.
Compounds of formula (XIV) may be prepared from compounds of formula (XV) according to process step (ii), an acid mediated deprotection step as described in Scheme 1. Compounds of formula (XV) may be prepared according from compounds of formula (XVII) and (XVI) according to process step (vii), a nucleophilic substitution reaction as described in Scheme 2. According to a fourth process, compounds of formula (I) may be prepared from compounds of formula (XXI), (VII) and (IV) as illustrated by Scheme 4,
Figure imgf000033_0001
(I)
Scheme 4
wherein Hal is fluoro or chloro;
Compounds of formulae (XXI), (VII), (IV) and (XXII) are commercially available or may be synthesized by those skilled in the art according to the literature or preparations described herein.
Compounds of formula (I) may be prepared from compounds of formula (XVIII) according to process step (viii), a nucleophilic aromatic substitution reaction with compounds of formula (XXII). Typical conditions employ an inorganic base in a polar organic solvent at elevated temperatures. Preferred conditions comprise cesium carbonate in DMF at 80°C.
Compounds of formula (XVII) may be prepared from compounds of formula (IV) and (XIX) according to process step (iii) an amide bond forming reaction as described in Scheme 1.
Compounds of formula (XIX) may be prepared from compounds of formula (XX) according to process step (ii), an acid mediated deprotection step as described in Scheme 1.
Compounds of formula (XX) may be prepared from compounds of formula (XXI) and (VII) according to process step (i) as described in Scheme 1.
According to a fifth process, compounds of formula (IA) (I; where A is a hyroxy-alkyl ether group of formula OCH2CRxCRyOH) may be prepared from compounds of formula (II) and (XXIV) as illustrated by Scheme 5,
Figure imgf000034_0001
(ID (IA)
Scheme 5
Wherein A can be a OCH2CRxRyOH group.
Compounds of formula (XXIV) are commercially available or may be synthesized by those skilled in the art according to the literature or preparations described herein.
Compounds of formula (IA) may be prepared from compounds of formula (II) according to process step (v) as described in Scheme 1 , an alkylation step with epoxides of formula (XXIV). According to a further embodiment the present invention provides novel intermediate compounds described herein. Pharmaceutically acceptable salts of a compound of formula (I) may be readily prepared by mixing together solutions of the compound of formula (I) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the salt may vary from completely ionised to almost non-ionised.
A trk antagonist may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of pain. The skilled person will appreciate that such combinations offer the possibility of significant advantages, including patient compliance, ease of dosing and synergistic activity.
In the combinations that follow the compound of the invention may be administered simultaneously, sequentially or separately in combination with the other therapeutic agent or agents.
A trk antagonist compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, may be administered in combination with one or more agents selected from:
• a selective Nav1.3 channel modulator, such as a compound disclosed in WO2008/118758;
• a selective Nav1.7 channel modulator, such as a compound disclosed in WO2010/079443, e.g. 4-[2-(5-amino-1 H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2- fluoro-N-1 ,3-thiazol-4-ylbenzenesulfonamide or 4-[2-(3-amino-1 H-pyrazol-4-yl)-4- (trifluoromethyl)phenoxy]-5-chloro-2-fluoro-N-1 ,3-thiazol-4-ylbenzenesulfonamide, or a pharmaceutically acceptable salt of either;
• a selective Nav1.8 channel modulator;
• a selective Nav1.9 channel modulator;
· a compound which modulates activity at more than one Nav channel, including a non-selective modulator such as bupivacaine, carbamazepine, lamotrigine, lidocaine, mexiletine or phenytoin; • any inhibitor of nerve growth factor (NGF) signaling, such as: an agent that binds to NGF and inhibits NGF biological activity and/or downstream pathway(s) mediated by NGF signaling (e.g. tanezumab), a TrkA antagonist or a p75 antagoinsist, or an agent that inhibits downstream signaling in regard to NGF stimulated TrkA or P75 signalling;
• a compound which increases the levels of endocannabinoid, such as a compound with fatty acid amid hydrolase inhibitory (FAAH) or monoacylglycerol lipase (MAGL) activity;
• an analgesic, in particular paracetamol;
· an opioid analgesic, such as: buprenorphine, butorphanol, ***e, codeine, dihydrocodeine, fentanyl, heroin, hydrocodone, hydromorphone, levallorphan levorphanol, meperidine, methadone, morphine, nalmefene, nalorphine, naloxone, naltrexone, nalbuphine, oxycodone, oxymorphone, propoxyphene or pentazocine;
• an opioid analgesic which preferentially stimulates a specific intracellular pathway, for example G-protein as opposed to beta arrestin recruitment, such as TRV130;an opioid analgesic with additional pharmacology, such as: noradrenaline (norepinephrine) reuptake inhibitory (NRI) activity, e.g. tapentadol; serotonin and norepinephrine reuptake inhibitory (SNRI) activity, e.g. tramadol; or nociceptin receptor (NOP) agonist activity, such as GRT6005;
· a nonsteroidal antiinflammatory drug (NSAID), such as a non-selective cyclooxygenase (COX) inhibitor, e.g. aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac; or a COX-2 selective inhibitor, e.g. celecoxib, deracoxib, etoricoxib, mavacoxib or parecoxib;
• a prostaglandin E2 subtype 4 (EP4) antagonist;
• a microsomal prostaglandin E synthase type 1 (mPGES-1) inhibitor;
• a sedative, such as glutethimide, meprobamate, methaqualone or dichloralphenazone; • a GABAA modulator with broad subtype modulatory effects mediated via the benzodiazepine binding site, such as chlordiazepoxide, alprazolam, diazepam, lorazepam, oxazepam, temazepam, triazolam, clonazepam or clobazam;
• a GABAA modulator with subtype-selective modulatory effects mediated via the benzodiazepine binding site with reduced adverse effects, for example sedation, such as TPA023, TPA023B, L-838,417, CTP354 or NSD72;
• a GABAA modulator acting via alternative binding sites on the receptor, such as barbiturates, e.g. amobarbital, aprobarbital, butabital, mephobarbital, methohexital, pentobarbital, phenobartital, secobarbital, or thiopental; neurosteroids such as alphaxalone, alphadolone or ganaxolone; β-subunit ligands, such as etifoxine; or δ- preferring ligands, such as gaboxadol;
• a GlyR3 agonist or positive allosteric modulator;
• a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, metaxolone, methocarbamol or orphrenadine;
· a glutamate receptor antagonist or negative allosteric modulator, such as an NMDA receptor antagonist, e.g. dextromethorphan, dextrorphan, ketamine or, memantine; or an mGluR antagonist or modulator;
• an alpha-adrenergic, such as clonidine, guanfacine or dexmetatomidine;
• a beta-adrenergic such as propranolol;
· a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline;
• a tachykinin (NK) antagonist, such as aprepitant or maropitant; a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;
• a Transient Receptor Potential V1 (TRPV1) receptor agonist (e.g. resinferatoxin or capsaicin) or antagonist (e.g. capsazepine or mavatrap);
• a Transient Receptor Potential A1 (TRPA1) receptor agonist (e.g. cinnamaldehyde or mustard oil) or antagonist (e.g. GRC17536 or CB-625);
• a Transient Receptor Potential M8 (TRPM8) receptor agonist (e.g. menthol or icilin) or antagonist;
· a Transient Receptor Potential V3 (TRPV3) receptor agonist or antagonist (e.g.
GRC- 15300);
• a corticosteroid such as dexamethasone; • a 5-HT receptor agonist or antagonist, particularly a 5-HT1 B/I D agonist, such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;
• a 5-HT2A receptor antagonist;
• a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1734), vareniclineor nicotine;
• a PDEV inhibitor, such sildenafil, tadalafilor vardenafil;
• an alpha-2-delta ligand such as gabapentin, gabapentin enacarbil or pregabalin, ;
• a serotonin reuptake inhibitor (SRI) such as sertraline, demethylsertraline, fluoxetine, norfluoxetine, fluvoxamine, paroxetine, citalopram, desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;
• anNRI, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine, especially a selective noradrenaline reuptake inhibitor such as reboxetine;
• an SNRI, such as venlafaxine, O-desmethylvenlafaxine, clomipramine, desmethylclomipramine, duloxetine, milnacipran and imipramine;
• an inducible nitric oxide synthase (iNOS) inhibitor;
• a leukotriene B4 antagonist;
· a 5-lipoxygenase inhibitor, such as zileuton;
• a potassium channel opener or positive modulator, such as an opener or positive modulator of KCNQ/Kv7 (e.g. retigabine or flupirtine), a G protein-coupled inwardly- rectifying potassium channel (GIRK), a calcium-activated potassium channel (Kca) or a potassium voltage-gated channel such as a member of subfamily A (e.g. Kv1.1), subfamily B (e.g. Kv2.2) or subfamily K (e.g. TASK, TREK or TRESK);
• a P2X3 receptor antagonist (e.g. AF219) or an antagonist of a receptor which contains as one of its subunits the P2X3 subunit, such as a P2X2/3 heteromeric receptor;
• a Cav2.2 calcium channel blocker (N-type), such as ziconotide; and
· a Cav3.2 calcium channel blocker (T-type), such as ethosuximide. Pharmaceutical compositions suitable for the delivery of compounds and salts of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995).
Compounds and salts of the invention intended for pharmaceutical use may be prepared and administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
Oral Administration The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations, such as tablets, capsules containing particulates, liquids, or powders; lozenges (including liquid-filled), chews; multi- and nano-particulates; gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, V\_ (6), 981-986 by Liang and Chen (2001). For tablet dosage forms, depending on dose, the drug may make up from 1 weight% to 80 weight% of the dosage form, more typically from 5 weight% to 60 weight% of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight% to 25 weight%, preferably from 5 weight% to 20 weight% of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 weight % to 5 weight% of the tablet, and glidants may comprise from 0.2 weight% to 1 weight% of the tablet.
Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight% to 10 weight%, preferably from 0.5 weight% to 3 weight% of the tablet. Other possible ingredients include anti-oxidants, colourants, flavoring agents, preservatives and taste-masking agents.
Exemplary tablets contain up to about 80% drug, from about 10 weight% to about 90 weight% binder, from about 0 weight% to about 85 weight% diluent, from about 2 weight% to about 10 weight% disintegrant, and from about 0.25 weight% to about 10 weight% lubricant.
Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247- 6918-X).
The foregoing formulations for the various types of administration discussed above may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6, 106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.
Parenteral Administration The compounds and salts of the invention may be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile nonaqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of compounds of formula (I) and salts used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
Formulations for parenteral administration may be formulated to be immediate and/or modified release. Thus, compounds and salts of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. An example of such formulations include drug- coated stents. Topical Administration
The compounds and salts of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated [see, for example, Finnin and Morgan, J Pharm Sci, 88 (10), 955-958 (October 1999).] Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.
Inhaled/lntranasal Administration
The compounds and salts of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 , 1 , 1 ,2-tetrafluoroethane or 1 , 1 , 1 ,2,3,3,3- heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
A pressurised container, pump, spray, atomizer, or nebuliser may contain a solution or suspension of the compound(s) or salt(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
Capsules (made, for example, from gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound or salt of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 pg to 20mg of the compound or salt of the invention per actuation and the actuation volume may vary from 1 μΙ to 10ΟμΙ. A typical formulation may comprise a compound of formula (I) or salt thereof, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA). Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
In the case of dry powder inhalers and aerosols, the dosage unit is determined by a prefilled capsule, blister or pocket or by a system that utilises a gravimetrically fed dosing chamber . Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from 1 to 5000 μ9 of the compound or salt. The overall daily dose will typically be in the range 1 μg to 20 mg which may be administered in a single dose or, more usually, as divided doses throughout the day. Rectal/lntravaginal Administration The compounds and salts of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various well known alternatives may be used as appropriate. Ocular and Aural Administration
The compounds and salts of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid; a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose; or a heteropolysaccharide polymer, for
example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.
Other Technologies
The compounds and salts of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11 172, WO 94/02518 and WO 98/55148.
For administration to human patients, the total daily dose of the compounds and salts of the invention is typically in the range 0.1 mg to 200 mg depending, of course, on the mode of administration, preferred in the range 1 mg to 100 mg and more preferred in the range 1 mg to 50 mg. The total daily dose may be administered in single or divided doses. These dosages are based on an average human subject having a weight of about 65kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
For the above-mentioned therapeutic uses, the dosage administered will, of course, vary with the compound or salt employed, the mode of administration, the treatment desired and the disorder indicated. The total daily dosage of the compound of formula
(l)/salt/solvate (active ingredient) will, generally, be in the range from 1 mg to 1 gram, preferably 1 mg to 250 mg, more preferably 10 mg to 100 mg. The total daily dose may be administered in single or divided doses. The present invention also encompasses sustained release compositions.
The pharmaceutical composition may, for example, be in a form suitable for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc. Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired. Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials, therefor, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of
compounding such an active compound for the treatment of sensitivity in individuals.
Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patient in practicing the present invention.
It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person
administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the present invention encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regiments for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.
A pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses. As used herein, a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
For parenteral dosages, this may conveniently be prepared as a solution or as a dry powder requiring dissolution by a pharmacist, medical practitioner or the patient. It may be provided in a bottle or sterile syringe. For example it may be provided as a powder in a multicompartment syringe which allows the dry powder and solvent to be mixed just prior to administration (to aid long-term stability and storage). Syringes could be used which allow multiple doses to be administered from a single device.
The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1 % and 100% (w/w) active ingredient.
In addition to the active ingredient, a pharmaceutical composition of the invention may further comprise one or more additional pharmaceutically active agents.
Controlled- or sustained-release formulations of a pharmaceutical composition of the invention may be made using conventional technology.
As used herein, "parenteral administration" of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral
administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrasternal injection, and kidney dialytic infusion techniques.
Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi-dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained- release or biodegradable formulations as discussed below. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in dry (i.e. powder or granular) form for reconstitution with a suitable vehicle (e.g. sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.
A composition of the present invention can be administered by a variety of methods known in the art. The route and/or mode of administration vary depending upon the desired results. The active compounds can be prepared with carriers that protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are described by e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, (1978). Pharmaceutical compositions are preferably manufactured under GMP conditions.
The pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations may be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water or 1 ,3-butane diol, for example. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides. Other parentally-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer system.
Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.
The precise dosage administered of each active ingredient will vary depending upon any number of factors, including but not limited to, the type of animal and type of disease state being treated, the age of the animal, and the route(s) of administration.
The following non-limiting Preparations and Examples illustrate the preparation of compounds and salts of the present invention.
In the non-limiting Examples and Preparations that are set out later in the description, and in the aforementioned Schemes, the following the abbreviations, definitions and analytical procedures may be referred to:
t-Bu3PHBF4 is tri-terf-butylphosphinetetrafluoroborate salt; t-BuOH is terf-butanol;
°C is degrees centigrade; COM U® is (1-cyano-2-ethoxy-2- oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate; CS2CO3 is cesium carbonate; CuS04.5H20 is copper sulphate pentahydrate;
DCM is dichloromethane; methylene chloride; DEA is diethylamine; DIPEA is N- ethyldiisopropylamine, Ν,Ν-diisopropylethylamine; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; EDCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; EtOAc is ethyl acetate; EtOH is ethanol; H2S04 is sulphuric acid;
HATU is 1-[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; HCI is hydrochloric acid; HOBt is hydroxybenzotriazole;
HPLC is high-performance liquid chromatography; IPA is isopropanol; KOH is potassium hydroxide; KOAc is potassium acetate; LCMS is liquid chromatography mass
spectrometry (Rt = retention time); Me is methyl; MeCN is acetonitrile; MeOH is methanol; MgS04 is magnesium sulphate; MS is mass spectrometry; NaHC03 is sodium hydrogen carbonate; NaOH is sodium hydroxide; Na2S04 is sodium sulphate; NH3 is ammonia; Pd/C is palladium on carbon; Pd(PP i3)4 is palladium tetrakis; PdCl2(PPh3)2 is bis(triphenylphosphine)palladium (II) dichloride; Pd2(dba)3 is
tris(dibenzylideneacetone)dipalladium (0); Pd(dppf)2CI2 is [1 , 1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane; SEM is 2-[(trimethylsilyl)ethoxy]methyl; TFA is trifluoroacetate; THF is tetrahydrofuran; THP is tetrahydropyran and TLC is thin layer chromatography;
1 H and 19F Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million downfield from tetramethylsilane (for 1H-NMR) and upfield from trichloro-fluoro-methane (for 19F NMR) using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations have been used for common solvents: CDCI3, deuterochloroform; d6- DMSO, deuterodimethylsulphoxide; and CD3OD, deuteromethanol.
Mass spectra, MS (m/z), were recorded using either electrospray ionisation (ESI) or atmospheric pressure chemical ionisation (APCI).
Where relevant and unless otherwise stated the m/z data provided are for isotopes 19F, 35CI, 79Br and 127l.
Preparative HPLC:
Where singleton compounds are purified by preparative HPLC, there are two methods used, shown below:
Method 1 acidic conditions
Column Gemini NX C18, 5um 21.2 x 100mm
Temperature Ambient
Detection ELSD-MS
Mobile Phase A 0.1 % formic acid in water
Mobile Phase B 0.1 % formic acid in acetonitrile
Gradient initial 0%B, 1 mins- 5%B; 7 mins - 98% B; 9 mins - 98% B; 9.1 mins - 5% B; 10 mins -5% B
Flow rate 18 mL/min
Injection volume 1000uL Method 2 basic conditions
Column Gemini NX C18, 5um 21.2 x 100mm
Temperature Ambient
Detection ELSD-MS
Mobile Phase A 0.1 % diethylamine in water
Mobile Phase B 0.1 % diethylamine in acetonitrile
Gradient initial 0%B, 1 mins- 5%B; 7 mins - 98% B; 9 mins - 98% B; 9.1 mins - 5% B; 10 mins -5% B
Flow rate 18 ml_/min
Injection volume 1000uL
In the non-limiting Examples and Preparations that are set out later in the description, and in the aforementioned Schemes, the following the abbreviations, definitions and analytical procedures may be referred to:
AcOH is acetic acid;
aq is aqueous;
Boc is tert-butyloxycarbonyl;
Bn is benzyl;
br is broad;
°C is degrees celcius;
CDCI3 is deutero-chloroform;
CS2CO3 is cesium carbonate;
δ is chemical shift;
d is doublet;
DCM is dichloromethane; methylene chloride;
DIAD is diisopropylazodicarboxylate;
DIPEA is N-ethyldiisopropylamine, N,N-diisopropylethylamine;
DMF is N,N-dimethylformamide;
DMSO is dimethyl sulphoxide;
EDCI.HCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; EtOAc is ethyl acetate;
EtOH is ethanol;
g is gram;
HATU is 1-[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate;
HBTU is N,N,N',N'-Tetramethyl-0-(1 H-benzotriazol-1-yl)uronium hexafluorophosphate; HCI is hydrochloric acid;
HOBt is N-hydroxybenzotriazole hydrate;
HPLC is high pressure liquid chromatography;
IPA is isopropyl alcohol;
KOH is potassium hydroxide;
KOtBu is potassium tert-butoxide;
L is litre;
LCMS is liquid chromatography mass spectrometry (Rt = retention time);
m is multiplet;
M is molar;
MeCN is acetonitrile;
MeOH is methanol;
mg is milligram;
MHz is mega Hertz;
min is minutes;
ml_ is milli litre;
mmol is millimole;
mol is mole;
Ms is mesylate;
MS m/z is mass spectrum peak;
NaHCC is sodium hydrogencarbonate;
NaOH is sodium hydroxide;
NMR is nuclear magnetic resonance;
Pd/C is palladium on carbon;
pH is power of hydrogen;
ppm is parts per million; q is quartet;
Rt is retention time;
s is singlet;
t is triplet;
TBME is tert-butyl dimethyl ether;
TFA is trifluoroacetic acid;
THF is tetrahydrofuran;
TLC is thin layer chromatography;
μΙ_ is microlitre; and
μηιοΙ is micromol
1 H and 19F Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million downfield from tetramethylsilane (for 1H-NMR) and upfield from trichloro-fluoro-methane (for 19F NMR) using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations have been used for common solvents: CDCI3, deuterochloroform; d6- DMSO, deuterodimethylsulphoxide; and CD3OD, deuteromethanol. Exchangeable protons may not be observed in the data provided.
Mass spectra, MS (m/z), were recorded using either electrospray ionisation (ESI) or atmospheric pressure chemical ionisation (APCI).
Where relevant and unless otherwise stated the m/z data provided are for isotopes 19F, 35CI, 79Br and 127l.
Preparative HPLC:
Where singleton compounds are purified by preparative HPLC, there are two methods used, shown below: Preparative HPLC using acid:
Column: Gemini 5u C18 1 10A 100*21.2mm 5 micron
Mobile phase A: Water Mobile phase B: Acetonitrile
Modifier: 0.1 % formic acid
Room temperature; 10 minute run time; Initial: 95%A, 5%B to 5% A and 95% B at 7 minutes, hold time 2 minutes, then back to 95% A, 5% B at 9.1 minutes. Flow rate 18 mL/min.
Detectors
ELSD = Polymer labs PL-ELS 2100
UV= Waters 2487 detector at 225 and 255 nm
Mass spectrometer= Waters ZQ using electrospray ionisation
Preparative H PLC using base:
Column: Gemini 5u C18 1 1 OA 100*21.2mm 5 micron
Mobile phase A: Water
Mobile phase B: Acetonitrile
Modifier: 0.1 % diethylamine
Room temperature; 10 minute run time; Initial: 95%A, 5%B to 5% A and 95% B at 7 minutes, hold time 2 minutes, then back to 95% A, 5% B at 9.1 minutes. Flow rate 18 mL/min.
Detectors
ELSD = Polymer labs PL-ELS 2100
UV= Waters 2487 detector at 225 and 255 nm
Mass spectrometer= Waters ZQ using electrospray ionisation
Following Preparative HPLC the following analytical conditions were employed:
Acidic analytical conditions:
Column: Gemini 3u C18 1 10A 50*4.6mm 3 micron
Mobile phase A: Water
Mobile phase B: Acetonitrile
Modifier: 0.1 % formic acid
Room temperature; 5 minute run time; Initial: 95%A, 5%B to 5% A and 95% B at 3 minutes, hold time 1 minutes, then back to 95% A, 5% B at 4.1 minutes. Flow rate 1.5 mL/min.
Detectors ELSD = Polymer labs PL-ELS 2100
UV= Waters 2487 detector at 225 and 255 nm
Mass spectrometer= Waters ZQ using electrospray ionisation Basic analytical conditions:
Column: Gemini 3u C18 1 1 OA 50*4.6mm 3 micron
Mobile phase A: Water
Mobile phase B: Acetonitrile
Modifier: 0.1 % ammonia
Room temperature; 5 minute run time; Initial: 95%A, 5%B to 5% A and 95% B at 3 minutes, hold time 1 minutes, then back to 95% A, 5% B at 4.1 minutes. Flow rate 1.5 mL/min.
Detectors
ELSD = Polymer labs PL-ELS 2100
U V= Waters 2487 detector at 225 and 255 nm
Example 1
2-(((3R,4S)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4-(2- hydroxy-2-methylpropoxy)benzamide
Figure imgf000057_0001
To a solution of 2-(((3R,4S)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4- yl)oxy)-4- hydroxy benzamide (Preparation 1 , 500 mg, 1.1 mmol) in DMF (8 mL) was added potassium carbonate (302 mg, 2.2 mmol) followed by isobutylene oxide (0.49 mL, 5.48 mmol). The reaction was heated to 100°C in a sealed tube for 16 hours. The reaction was cooled and diluted with EtOAc. The solution was washed with water, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 5-7% MeOH in DCM to afford the title compound (150 mg, 26%).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .21 -1.26 (m, 6H), 1.66-1.74 (m, 1 H), 1.93-1.99 (m, 1 H), 2.85-3.12 (m, 1 H), 3.23-3.26 (m, 0.5H), 3.43-3.55 (m, 0.5H), 3.67-4.02 (m, 4H), 4.35-4.38 (m, 1 H), 4.65-4.69 (m, 1 H), 4.99-5.12 (m, 2H), 6.66-6.68 (m, 1 H), 6.81 (s, 1 H), 7.28-7.45 (m, 6H), 7.87-7.88 (m, 1 H).
LCMS (Zorbax SB C18 4.6x40mm, 1.8 micron, mobile phase A: 0.05% TFA in water; mobile phase B: MeCN). Rt = 5.55 minutes MS m/z 529 [M+H]+ Examples 2-9 were prepared according to the method described for Example 1 above using the appropriate phenol and the appropriate alkyl halide, alkyl carbonate or isobutylene oxide as described below. Any alternative reaction or purification conditions are described.
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Example 10
2-a(3S.4RV3-fluoro-1-(2-(4-(trifluorom
hvdroxypropan-2-yl)oxy)benzamide
Figure imgf000060_0002
To a solution of 2-(((3S,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4- yl)oxy)-4-hydroxybenzamide (Preparation 2, 130 mg, 0.329 mmol) in DMF (5 mL) was added potassium carbonate (45 mg, 0.329 mmol) followed by (S)-1-(trityloxy)propan-2-yl methanesulfonate (J.O.C. (1987), 52 (7), 1309-15, 100 mg, 0.219 mmol). The reaction was stirred at 80°C for 16 hours. The reaction was cooled, poured onto ice-water and extracted with EtOAc. The organic layer was washed with water, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 3-4% MeOH in DCM. The residue was dissolved in DCM (5 ml_), treated with TFA (0.037 ml_, 0.476 mmol) and stirred at room temperature for 16 hours. The reaction was concentrated in vacuo and diluted with EtOAc. The solution was washed with water, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using preparative TLC eluting with 5% MeOH in DCM to afford the title compound as a light brown solid (5 mg, 5.6%).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .17-1.33 (m, 3H), 1.60-1.80 (m, 1 H), 1.90-2.05 (m, 1 H), 2.80-3.15 (m, 2H), 3.45-4.10 (m, 6H), 4.30-4.70 (m, 2H), 4.85-5.20 (m, 2H), 6.67-6.69 (m, 1 H), 6.79 (s, 1 H), 7.30-7.42 (m, 6H), 7.85-7.87 (m, 1 H).
MS m/z 515 [M+H]+
Example 11
2-(((3S,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4-(((S)-1 - hvdroxypropan-2-yl)oxy)benzamide
Figure imgf000061_0001
The title compound was prepared according to the method described for Example 10 using (R)-1-(trityloxy)propan-2-yl methanesulfonate (J.O.C. (1987), 52 (7), 1309-15). 1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .17-1.33 (m, 3H), 1.60-1.70 (m, 1 H), 1.95-2.00 (m, 1 H), 2.85-3.20 (m, 2H), 3.40-3.60 (m, 2H), 3.67-3.84 (m, 2H), 3.95-4.05 (m, 1 H), 4.30-4.40 (m, 1 H), 4.50-4.70 (m, 1.5H), 4.88-4.89 (m, 0.5H), 4.90-5.15 (m, 2H), 6.67- 6.69 (m, 1 H), 6.79 (s, 1 H), 7.28-7.42 (m, 4H), 7.85-7.87 (m, 1 H).
MS m/z 515 [M+H]+ Example 12
2-(((3S,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4-
((methylsulfonyl)methoxy)benzamide
Figure imgf000062_0001
To a solution of 2-(((3S,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4- yl)oxy)-4-hydroxybenzamide (Preparation 2, 100 mg, 0.219 mmol) in DMF (2.5 mL) was added (chloromethyl)(methyl)sulfane (0.092 mL, 1.1 mmol) and potassium carbonate (60 mg, 0.44 mmol). The reaction was stirred at room temperature for 6 hours before partitioning between EtOAc and water. The organic layer was collected, washed with water, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 2% MeOH in DCM. The residue was dissolved in MeOH (2.8 mL) and water (0.7 mL) and treated with oxone (25 mg, 0.16 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was diluted with water and extracted into EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified using preparative TLC eluting with 3% MeOH in DCM to afford the title compound as a white solid (15 mg, 10% over 2 steps).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .67-1.74 (m, 1 H), 1.96-2.02 (m, 1 H), 2.84-2.90 (m, 0.5H), 3.00-3.13 (m, 3H), 3.22-3.30 (m, 0.5H), 3.42-3.54 (m, 1 H), 3.68-3.88 (m, 2H), 4.00-4.03 (m, 0.5H), 4.35-4.38 (m, 1 H), 4.62-4.67 (m, 0.5H), 4.96-5.14 (m, 2H), 5.37- 5.43 (m, 2H), 6.85-6.87 (m, 1 H), 7.04 (s, 1 H), 7.28-7.35 (m, 4H), 7.40 (br s, 1 H), 7.55 (br s, 1 H), 7.87-7.89 (m, 1 H).
MS m/z 549 [M+H]+
Example 13
2-(((3S,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4-((1- hvdroxy-2-methylpropan-2-yl)oxy)benzamide
Figure imgf000063_0001
To a solution of 2-(((3S,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4- yl)oxy)-4-hydroxybenzamide (100 mg, 0.219 mmol) in DMF (5 ml_) was added 2-bromo- 2-methylpropionic acid methyl ester (0.043 ml_, 0.329 mmol) and cesium carbonate (142 mg, 0.439 mmol). The reaction was heated to 100-1 10°C for 16 hours before cooling and partitioning between EtOAc and water. The organic layer was collected, washed with brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 2% MeOH in DCM. Part of the residue (50 mg, 0.09 mmol) was dissolved in THF (5 ml_) and water (1 ml_) and treated with LiOH (15 mg, 0.36 mmol). The reaction was stirred at room temperature for 4 hours before acidifying with 1 N HCI to pH=3-4 and extracting into EtOAc. The organic layer was collected, dried over sodium sulphate and concentrated in vacuo. To a solution of the residue (40 mg, 0.074 mmol) in THF (5 ml_) was added triethylamine (0.021 ml_, 0.148 mmol) followed by isobutylchloroformate (0.015 ml_, 0.11 mmol) at 0°C. The reaction was stirred at room temperature for 2 hours before filtering through Celite. To the filtrate was added a solution of sodium borohydride (5.6 mg) in water (2 ml_) and the reaction stirred at room temperature for 1 hour. The reaction was diluted with EtOAc and washed with water, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using preparative TLC eluting with 3% MeOH in DCM to afford the title compound as a white solid (20 mg, 41 % over 4 steps).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1.26 (s, 6H), 1 .60-1.70 (m, 1 H), 1.85-1.95 (m, 1 H), 2.85-3.15 (m, 2H), 3.30-3.60 (m, 2H), 3.70-4.00 (m, 1 H), 4.40-4.50 (m, 1 H), 4.60-4.70 (m, 1 H), 4.85-5.00 (m, 2.5H), 5.10-5.15 (m, 0.5H), 6.75-6.77 (m, 1 H), 6.85 (s, 1 H), 7.28- 7.42 (m, 6H), 7.81 -7.83 (m, 1 H).
MS m/z 529 [M+H]+ Example 14
Trans-2-(((3S^R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4- - h yd roxycycl o butoxy) benzamide
Figure imgf000064_0001
To a solution of 2-(((3S,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4- yl)oxy)-4-hydroxybenzamide (Preparation 2, 85 mg, 0.33 mmol) in DMF (3 mL) was added cis-3-(benzyloxy)cyclobutyl-methanesulfonate (Preparation 32, 100 mg, 0.219 mmol and cesium carbonate (213 mg, 0.66 mmol) and the reaction was heated to 100°C for 16 hours. The reaction was cooled and diluted with EtOAc, washed with water, brine, dried over sodium sulphate and concentrated in vacuo. The residue was dissolved in MeOH (5 mL) and degassed with argon. 10% Pd/C (50 mg) was added and the reaction was hydrogenated under a balloon of hydrogen at room temperature for 16 hours. The reaction was filtered through Celite and the filtrate concentrated in vacuo. The residue was purified using preparative TLC eluting with 4% MeOH in DCM to afford the title compound as a white solid (15 mg, 13% over 2 steps).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .65-1.72 (m, 1 H), 1.92-1.98 (m, 1 H), 2.29-2.32 (m, 4H), 2.80-2.90 (m, 1 H), 3.00-3.15 (m, 1 H), 3.40-3.55 (m, 1 H), 3.65-3.90 (m, 2H), 3.95-4.05 (m, 1 H), 4.30-4.40 (m, 2H), 4.60-4.70 (m, 0.5H), 4.88-5.25 (m, 2.5H), 6.50- 6.52 (m, 1 H), 6.71 (s, 1 H), 7.28-7.44 (m, 6H), 7.85-7.87 (m, 1 H).
MS m/z 527 [M+H]+
Example 15
(((3S,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)
h yd roxycvcl ob utoxy) benzamide
Figure imgf000065_0001
The title compound was prepared according to the method described for Example 14 using 2-(((3S,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4- hydroxybenzamide (Preparation 2) and trans-3-(benzyloxy)cyclobutyl- methanesulfonate (Preparation 33). The residue was purified using preparative TLC eluting with 5% I PA in DCM.
1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .89-1.98 (m, 4H), 2.83-2.85 (m, 2H), 3.71-4.05 (m, 4H), 4.32-4.40 (m, 2H), 4.60-4.70 (m, 1 H), 4.90-5.20 (m, 4H), 6.55-6.57 (m, 1 H), 6.72 (s, 1 H), 7.28-7.43 (m, 6H), 7.84-7.86 (m, 1 H).
MS m/z 527 [M+H]+
Example 16
2-(((3S,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenvnacetvnpiperidin-4-vnoxy)-4- morpholinobenzamide
Figure imgf000065_0002
To a solution of 2-(((3S,4R)-3-fluoropiperidin-4-yl)oxy)-4-morpholinobenzamide hydrochloride (Preparation 18, 84 mg, 0.23 mmol) in THF (10 ml_) was added 4- trifluoromethoxyphenylacetic acid (51 mg, 0.23 mmol), HATU (133 mg, 0.35 mmol) and triethylamine (118 mg, 1.16 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was diluted with water and extracted into EtOAc. The organic layer was collected, washed with water, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 5% MeOH in DCM followed by trituration with ether to afford the title compound as a white solid (25 mg, 20%).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .65-1.71 (m, 1 H), 1.90-1.98 (m, 1 H), 2.84-3.09 (m, 2H), 3.24-3.31 (m, 4H), 3.39-3.56 (m, 1 H), 3.67-3.90 (m, 4H), 3.98-4.02 (m, 1 H), 4.30-4.40 (m, 1 H), 4.60-4.75 (m, 1 H), 4.90-5.10 (m, 2H), 6.54-6.65 (m, 2H), 7.28-7.38 (m, 6H), 7.79-7.82 (m, 1 H).
MS m/z 526 [M+H]+
Example 17
2-(((3S.4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-6- morpholinonicotinamide
Figure imgf000066_0001
To a solution of 6-chloro-2-(((3S,4R)-3-fluoro-1 -(2-(4-
(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)nicotinamide (Preparation 13, 100 mg, 0.21 mmol) in DMF (3 ml_) was added cesium carbonate (136 mg, 0.42 mmol) followed by morpholine (36 mg, 0.42 mmol). The reaction was heated to 80°C in a sealed tube for 16 hours. The reaction was poured onto ice-water and extracted into EtOAc. The organic layer was collected, washed with water, brine, dried over sodium sulphate and concentrated in vacuo. The residue was concentrated in vacuo and purified using preparative TLC eluting with 10% MeOH in EtOAc to afford the title compound as a white solid (35 mg, 34%).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .70-1.85 (m, 1 H), 1.95-2.05 (m, 1 H), 2.90-3.30 (m, 2H), 3.50-3.55 (m, 4H), 3.60-3.70 (m, 4H), 3.85-4.02 (m, 2H), 4.25-4.40 (m, 1 H), 4.60-4.70 (m, 1 H), 5.00-5.15 (m, 1 H), 5.35-5.50 (m, 1 H), 6.50-6.52 (m, 1 H), 7.17 (br s, 1 H), 7.31-7.39 (m, 5H), 8.06-8.08 (m, 1 H).
MS m/z 527 [M+H]+ Example 18
2-(((3S,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-6-((2- hvdroxy-2-methylpropyl)amino)nicotinamide
Figure imgf000067_0001
The title compound was prepared according to the method described by Example 17 using 1-amino-2-methyl-propan-2-ol. The residue was purified using silica gel column chromatography eluting with 2-3% MeOH in DCM followed by preparative TLC eluting with 5% MeOH in EtOAc.
1 H NMR (400 MHz, DMSO-d6):5 ppm 1.08 (s, 6H), 1 .75-1.80 (m, 1 H), 1.98-2.03 (m, 1 H), 2.85-3.31 (m, 2H), 3.49-3.72 (m, 2H), 3.88-3.90 (m, 1 H), 4.00-4.10 (m, 1 H), 4.30-4.50 (m, 3H), 4.60-4.70 (m, 1 H), 5.00-5.20 (m, 1 H), 5.35-5.50 (m, 1 H), 6.26-6.28 (m, 1 H), 7.1 1 (br s, 1 H), 7.22 (br s, 1 H), 7.28-7.36 (m, 4H), 7.88-7.90 (m, 1 H).
MS m/z 529 [M+H]+
Example 19
4-(2-amino-2-methylpropoxy)-2-(((3S.4R)-3-fluoro-1-(2-(4-
(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)benzamide
Figure imgf000068_0001
To a solution of 2-(((3S,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenl)acetyl)piperidin-4- yl)oxy)-4-hydroxybenzamide (Preparation 2, 200 mg, 0.438 mmol) in DMF (5 ml_) was added cesium carbonate (427 mg, 1.31 mmol) followed by 2-(dibenzylamino)-2- methylpropyl methanesulfonate (Preparation 36, 228 mg, 0.657 mmol). The reaction was heated to 1 10°C for 16 hours in a sealed tube. The reaction was cooled, diluted with EtOAc and washed with water, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 3% MeOH in DCM. Part of the residue (125 mg, 0.177 mmol) was dissolved in AcOH (10 ml_) and formic acid (3 ml_) and degassed with argon. Pd/C (40 mg) was added and the reaction stirred at room temperature for 16 hours. The reaction was filtered through Celite and the filtrate concentrated in vacuo. The residue was basified with saturated aqueous sodium carbonate solution and extracted into EtOAc twice. The combined organic layers were washed with brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 5- 6% MeOH in DCM. The residue was dissolved in 20% IPA in DCM and washed with 1 M aqueous potassium carbonate solution twice, brine, dried over sodium sulphate and concentrated in vacuo to afford the title compound as a light brown solid (55 mg, 48% over 2 steps).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1.27 (s, 6H), 1 .60-1.80 (m, 2H), 1.90-2.00 (m, 1 H), 2.89-3.15 (m, 1 H), 3.20-3.45 (m, 1 H), 3.80-3.90 (m, 2H), 4.00-4.05 (m, 1 H), 4.30-4.40 (m, 1 H), 4.60-4.70 (m, 1 H), 4.90-5.15 (m, 2H), 6.74-6.76 (m, 1 H), 6.84 (s, 1 H), 7.28-7.35 (m, 4H), 7.42 (br s, 1 H), 7.49 (br s, 1 H), 7.81-7.83 (m, 1 H).
MS m/z 528 [M+H]+
Preparation 1 2-(((3R,4S)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4- hydroxybenzamide
Figure imgf000069_0001
To a solution of 4-(benzyloxy)-2-(((3R,4S)-3-fluoro-1 -(2-(4- (trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)benzamide (Preparation 9, 900 mg, 1.65 mmol) in EtOH (25 ml_) was degassed with argon before the addition of palladium on carbon (400 mg). The reaction was hydrogenated under a balloon of hydrogen for 2 hours at room temperature. The reaction was filtered through Celite and concentrated in vacuo to afford the title compound as a white solid (700 mg, 93%).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .66-1.74 (m, 1 H), 1.93-1.98 (m, 1 H), 2.83-2.89 (m, 0.5H), 3.04-3.32 (m, 1 H), 3.42-3.55 (m, 1 H), 3.67-3.71 (m, 0.5H), 3.78-3.87 (m, 1 H), 3.99-4.09 (m, 0.5H), 4.33-4.38 (m, 1 H), 4.61-4.67 (m, 0.5H), 6.48-6.49 (m, 1 H), 6.62 (s, 1 H), 7.28-7.38 (m, 6H), 7.78-7.80 (m, 1 H), 10.1 1 (s, 1 H).
MS m/z 457 [M+H]+
Preparation 2
2-(((3S,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenl)acetyl)piperidin-4-yl)oxy)-4- hydroxybenzamide
Figure imgf000069_0002
The title compound was prepared according to the method described for Preparation 1 using 4-(benzyloxy)-2-(((3S,4R)-3-fluoro-1 -(2-(4-
(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)benzamide (Preparation 10). 1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .65-1.73 (m, 1 H), 1.93-1.98 (m, 1 H), 2.86-3.13 (m, 1 H), 3.25-3.52 (m, 1.5H), 3.67-4.03 (m, 2H), 4.34-4.40 (m, 1 H), 4.64-4.70 (m, 0.5H), 4.80-4.90 (m, 1 H), 4.99-5.1 1 (m, 1 H), 6.48-6.50 (m, 1 H), 6.61 (s, 1 H), 7.28-7.35 (m, 6H), 7.77-7.80 (m, 1 H), 10.14 (br s, 1 H).
MS m/z 457 [M+H]+
Preparation 3
2-(((3R,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4- hydroxybenzamide
Figure imgf000070_0001
The title compound was prepared according to the method described for Preparation 1 using 4-(benzyloxy)-2-(((3R,4R)-3-fluoro-1 -(2-(4-
(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)benzamide (Preparation 11).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .65-1.75 (m, 1 H), 2.00-2.10 (m, 1 H), 3.24-3.41 (m, 2H), 3.54-3.90 (m, 4H), 4.10-4.25 (m, 1 H), 4.70-4.95 (m, 2H), 6.45-6.48 (m, 1 H), 6.60 (s, 1 H), 7.28-7.36 (m, 6H), 7.68-7.71 (m, 1 H).
MS m/z 457 [M+H]+
Preparation 4
2-(((3S,4S)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4- hydroxybenzamide
Figure imgf000070_0002
The title compound was prepared according to the method described for Preparation 1 using 4-(benzyloxy)-2-(((3S,4S)-3-fluoro-1-(2-(4- (trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)benzamide (Preparation 12).
MS m/z 457 [M+H]+
Preparation 5
4-hvdroxy-2-((1-( -(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)benzamide
Figure imgf000071_0001
The title compound was prepared according to the method described for Preparation 1 using 4-(benzyloxy)-2-((1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4- yl)oxy)benzamide (Preparation 6) with palladium hydroxide at 50°C. The residue was purified using silica gel column chromatography eluting with EtOAc followed by THF. 1 H NMR (400 MHz, MeOH-d4):5 ppm 1 .70-1.80 (m, 2H), 2.00-2.10 (m, 2H), 3.45-3.50 (m, 2H), 3.80-4.00 (m, 3H), 4.75-4.80 (m, 2H), 6.50-6.52 (m, 1 H), 6.58 (s, 1 H), 7.10-7.12 (m, 2H), 7.18-7.20 (m, 2H), 7.80-7.82 (m, 1 H).
Preparation 6
4-(benzyloxy)-2- -(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)benzamide
Figure imgf000071_0002
To a solution of 4-(benzyloxy)-2-((1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4- yl)oxy)benzoic acid (Preparation 7, 490 mg, 0.93 mmol) in DMF (6 mL) was added HBTU (701 mg, 1.85 mmol) followed by a 7M ammonia in MeOH (0.66 mL, 4.65 mmol) and DIPEA (0.75 mL, 4.30 mmol). The reaction was stirred at room temperature for 1 hour and concentrated in vacuo. The residue was dissolved in EtOAc (10 mL) and washed with 2M HCI (10 mL), saturated aqueous NaHCC solution (10 mL), water (10 mL), dried over sodium sulphate and concentrated in vacuo to afford the title compound as a colourless oil (371 mg, 76%).
1 H NMR (400 MHz, CDCI3):5 ppm 1 .60-2.00 (m, 4H), 3.35-3.50 (m, 2H), 3.65-3.80 (m, 3H), 3.90-4.00 (m, 1 H), 4.45-4.50 (m, 1 H), 5.10 (s, 2H), 5.80 (br s, 1 H), 6.50 (s, 1 H), 6.70-6.75 (m, 1 H), 7.20-7.40 (m, 9H), 7.50 (br s, 1 H), 8.10-8.15 (m, 1 H).
MS m/z 529 [M+H]+
Preparation 7
4-(benzyloxy)-2-((1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)benzoic acid
Figure imgf000072_0001
To a solution of methyl 4-(benzyloxy)-2-((1-(2-(4-
(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)benzoate (Preparation 8, 1.34 g, 2.47 mmol) in MeOH (5 mL) was added water (5 mL) followed by sodium hydroxide (99 mg, 2.47 mmol). The reaction was stirred at room temperature for 90 minutes, then heated to reflux for 90 minutes. The reaction was concentrated to low volume in vacuo and partitioned between water (10 mL) and EtOAc (10 mL). The aqueous layer was collected and acidified to pH=4 with 2M HCI and extracted into EtOAc (3 x 10 mL). The combined organic extracts were dried over sodium sulphate and concentrated in vacuo to afford the title compound as a colourless gum (438 mg, 38%).
1 H NMR (400 MHz, CDCI3):5 ppm 1 .70-2.00 (m, 5H), 3.40-3.90 (m, 5H), 4.60-4.70 (m, 1 H), 5.10 (s, 2H), 6.55 (s, 1 H), 6.70-6.80 (m, 1 H), 7.20-7.40 (m, 9H), 8.05-8.10 (m, 1 H). MS m/z 530 [M+H]+ Preparation 8
Methyl 4-(benzyloxy)-2-((1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4- yl)oxy)benzoate
Figure imgf000073_0001
To a solution of methyl 4-(benzyloxy)-2-hydroxybenzoate (J.Med.Chem. (2012), 55 (16), 7114-7140, 135 mg, 0.5 mmol) in DMSO (3 mL) was added cesium carbonate (342 mg, 1.05 mmol) and the reaction was stirred at room temperature for 10 minutes. 1-(2- (4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl methanesulfonate (Preparation 30, 270 mg, 1.05 mmol) was added and the reaction heated to 100°C for 2 hours. The reaction was cooled and partitioned between EtOAc (12 mL) and water (12 mL). The organic layer was washed with brine (12 mL), dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 50- 75% EtOAc in heptanes to afford the title compound as a colourless gum (61 mg, 24%). 1 H NMR (400 MHz, CDCI3):5 ppm 1 .52-1.60 (m, 1 H), 1.70-1.95 (m, 3H), 3.45-3.55 (m, 2H), 3.60-3.75 (m, 3H), 3.80 (s, 3H), 3.98-4.00 (m, 1 H), 4.58-4.60 (m, 1 H), 5.08 (s, 2H), 6.50 (s, 1 H), 6.58-6.60 (m, 1 H), 7.16-7.40 (m, 9H), 7.84-7.86 (m, 1 H).
MS m/z 544 [M+H]+ Preparation 9
4-(benzyloxy)-2-(((3R,4S)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4- yl)oxy)benzamide
Figure imgf000074_0001
To a solution of 4-(benzyloxy)-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzamide hydrochloride (Preparation 14, 695 mg, 2.02 mmol) in DCM (10 mL) was added triethylamine (1.95 mL, 14.10 mmol) followed by EDCI (577 mg, 3.022 mmol) and HOBt (407 mg, 3.02 mmol). To the reaction was added 4-trifluoromethoxyphenylacetic acid (443 mg, 2.01 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction was diluted with DCM and washed with saturated aqueous NaHC03 solution, water, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 2-3% MeOH in DCM to afford the title compound as a white solid (900 mg, 82%).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .63-1.71 ( m, 1 H), 1.88-1.95 (m,1 H), 2.81-3.10 (m, 1 H), 3.20-3.53 (m, 1 H), 3.62-3.75 (m, 1 H), 3.84-3.90 (m, 2H), 4.30-4.40 (m, 1 H), 4.60-4.70 (m, 0.5H), 4.95-5.05 (m, 1.5H), 5.08-5.20 (m, 2H), 6.70-6.72 (m, 1 H), 6.90 (s, 1 H), 7.25-7.50 (m, 1 1 H), 7.87-7.89 (m, 1 H).
MS m/z 547 [M+H]+
Preparation 10
4-(benzyloxy)-2-(((3S,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4- yl)oxy)benzamide
Figure imgf000074_0002
The title compound was prepared according to the method described for Preparation 9 using 4-(benzyloxy)-2-(((3S,4R)-3-fluoropiperidin-4-yl)oxy)benzamide hydrochloride (Preparation 15).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .62-1.70 (m, 1 H), 1.88-1.91 (m, 1 H), 2.81-2.87 (m, 0.5H), 2.96-3.09 (m, 1 H), 3.19-3.25 (m, 0.5H), 3.40-3.53 (m, 1 H), 3.67-3.70 (m, 0.5H), 3.84-3.88 (m, 1 H), 3.98-4.03 (m, 0.5H), 4.34-4.37 (m, 1 H), 4.63-4.69 (m, 0.5H), 4.93-5.05 (m, 1 H), 5.10-5.12 (m, 0.5H), 5.17 (s, 2H), 6.75-6.77 (m, 1 H), 6.89 (s, 1 H), 7.31-7.47 (m, 11 H), 7.87-7.89 (m, 1 H).
MS m/z 547 [M+H]+
Preparation 11
4-(benzyloxy)-2-(((3R,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4- yl)oxy)benzamide
Figure imgf000075_0001
The title compound was prepared according to the method described for Preparation 9 using 4-(benzyloxy)-2-(((3R,4R)-3-fluoropiperidin-4-yl)oxy)benzamide hydrochloride (Preparation 16).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .60-1.75 (m, 1 H), 1.95-2.10 (m, 1 H), 3.36-3.60 (m, 2H), 3.70-3.90 (m, 3H), 4.20-4.35 (m, 1 H), 4.75-4.90 (m, 2H), 5.17 (s, 2H), 6.71-6.74 (m, 1 H), 6.86 (s, 1 H), 7.28-7.47 (m, 11 H), 7.76-7.78 (m, 1 H).
MS m/z 547 [M+H]+
Preparation 12
4-(benzyloxy)-2-(((3S,4S)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4- yl)oxy)benzamide
Figure imgf000076_0001
The title compound was prepared according to the method described for Preparation 9 using 4-(benzyloxy)-2-(((3S,4S)-3-fluoropiperidin-4-yl)oxy)benzamide hydrochloride (Preparation 17).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .60-1.75 (m, 1 H), 1.95-2.05 (m, 1 H), 3.30-3.95 (m, 4.5H), 4.10-4.25 (m, 1.5H), 4.90-5.00 (m, 2H), 5.17 (s, 2H), 6.68-6.74 (m, 1 H), 6.86 (s, 1 H), 7.29-7.47 (m, 11 H), 7.76-7.78 (m, 1 H).
MS m/z 547 [M+H]+ Preparation 13
6-chloro-2-(((3S,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)pipehdin-4- yl)oxy)nicotinamide
Figure imgf000076_0002
The title compound was prepared according to the method described for Preparation 9 using 6-chloro-2-(((3S,4R)-3-fluoropiperidin-4-yl)oxy)nicotinamide hydrochloride (Preparation 19).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .77-1.88 (m, 1 H), 1.98-2.08 (m, 1 H), 2.95-3.05 (m, 0.5H), 3.20-3.40 (m, 1 H), 3.57-3.84 (m, 2.5H), 4.00-4.05 (m, 0.5H), 4.30-4.40 (m, 1 H), 4.55-4.60 (m, 0.5H), 5.00-5.20 (m, 1 H), 5.40-5.50 (m, 1 H), 7.26-7.42 (m, 6H), 7.86 (br s, 1 H), 8.22-8.33 (m, 1 H).
MS m/z 476 [M+H]+ Preparation 14
4-(benzyloxy)-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzamide hydrochloride
Figure imgf000077_0001
To a solution of tert-butyl (3R,4S)-4-(5-(benzyloxy)-2-carbamoylphenoxy)-3- fluoropiperidine-1-carboxylate (Preparation 20, 900 mg, 2.02 mmol) in dioxane (3 mL) was added 4M HCI in dioxane (10 mL) at 0°C. The reaction was stirred at room temperature for 2 hours before concentrating in vacuo. The solid residue was triturated with ether and used directly in the next step (695 mg, 99%).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .97-2.14 (m, 2H), 3.10-3.69 (m, 4H), 4.82-4.99 (br m, 2H), 5.17 (s, 2H), 6.77-6.79 (m, 1 H), 6.90 (s, 1 H), 7.35-7.52 (m, 6H), 7.85-7.87 (m, 1 H), 8.83-8.85 (br m, 1 H), 9.67-9.69 (m, 1 H).
MS m/z 345 [M+H]+
Preparation 15
4-(benzyloxy)-2-(((3S,4R)-3-fluoropiperidin-4-yl)oxy)benzamide hydrochloride
Figure imgf000077_0002
The title compound was prepared according to the method described for Preparation 14 using tert-butyl (3S,4R)-4-(5-(benzyloxy)-2-carbamoylphenoxy)-3-fluoropiperidine-1- carboxylate (Preparation 300C).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .97-2.14 (m, 2H), 3.10-3.70 (m, 6H), 5.00-5.31 (m, 2H), 6.77-6.79 (m, 1 H), 6.90 (s, 1 H), 7.34-7.52 (m, 7H), 7.85-7.87 (m, 1 H), 8.86 (br m, 1 H). MS m/z 345 [M+H]+
Preparation 16
4-(benzyloxy)-2-(((3R,4R)-3-fluoropiperidin-4-yl)oxy)benzamide hydrochloride
Figure imgf000078_0001
The title compound was prepared according to the method described for Preparation 14 using tert-butyl (3R,4R)-4-(5-(benzyloxy)-2-carbamoylphenoxy)-3-fluoropiperidine-1- carboxylate (Preparation 21 ).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .94-2.00 (m, 1 H), 2.14-2.32 (m, 1 H), 3.00-3.40 (m, 3H), 3.50-3.60 (m, 1 H), 4.97-5.00 (m, 1 H), 5.12-5.16 (m, 3H), 6.72-6.75 (m, 1 H), 6.88 (s, 1 H), 7.32-7.47 (m, 7H), 7.63-7.65 (m, 1 H).
Preparation 17
4-(benzyloxy)-2-(((3S,4S)-3-fluoropiperidin-4-yl)oxy)benzamide hydrochloride
Figure imgf000078_0002
The title compound was prepared according to the method described for Preparation 14 using tert-butyl (3S,4S)-4-(5-(benzyloxy)-2-carbamoylphenoxy)-3-fluoropiperidine-1- carboxylate (Preparation 23) and taken on directly to the next step.
Preparation 18
2-(((3S,4R)-3-fluoropiperidin-4-yl)oxy)-4-morpholinobenzamide hydrochloride
Figure imgf000079_0001
The title compound was prepared according to the method described for Preparation 14 using tert-butyl (3S,4R)-4-(2-carbamoyl-5-morpholinophenoxy)-3-fluoropiperidine-1- carboxylate (Preparation 19) and taken on directly to the next step.
Preparation 19
6-chloro-2-(((3S,4R)-3-fluoropiperidin-4-yl)oxy)nicotinamide hydrochloride
Figure imgf000079_0002
The title compound was prepared according to the method described for Preparation 14 using tert-butyl (3S,4R)-4-((3-carbamoyl-6-chloropyridin-2-yl)oxy)-3-fluoropiperidine- 1-carboxylate (Preparation 24) and taken on directly to the next step.
Preparation 20
tert-butyl (3R,4S)-4-(5-(benzyloxy)-2-carbamoylphenoxy)-3-fluoropiperidine-1- carboxylate
Figure imgf000079_0003
To a solution of tert-butyl (3R,4S)-4-(5-(benzyloxy)-2-cyanophenoxy)-3-fluoropiperidine- 1-carboxylate (Preparation 26, 1.7 g, 3.99 mmol) in tert-butanol (20 ml_) was added powdered KOH (335 mg, 5.99 mmol) and the reaction was heated to 80°C for 16 hours. The reaction was cooled, diluted with EtOAc, washed with water, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 20% EtOAc in hexanes to afford the title compound (900 mg, 51 %).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1.40 (s, 9H), 1 .62-1.78 (m, 1 H), 1.86-1.90 (m, 1 H), 2.85-3.30 (br m, 2H), 3.90-4.05 (m, 1 H), 4.15-4.30 (m, 1 H), 4.87-5.05 (m, 2H), 5.15 (s, 2H), 6.60-6.61 (m, 1 H), 6.88 (s, 1 H), 7.32-7.47 (m, 7H), 7.88-7.90 (m, 1 H).
MS m/z 445 [M+H]+
Preparation 21
tert-butyl (3S,4R)-4-(5-(benzyloxy)-2-carbamoylphenoxy)-3-fluoropiperidine-1- carboxylate
Figure imgf000080_0001
The title compound was prepared according to the method described for Preparation 20 using tert-butyl (3S,4R)-4-(5-(benzyloxy)-2-cyanophenoxy)-3-fluoropiperidine-1- carboxylate (Preparation 27).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1.40 (s, 9H), 1 .62-1.80 (m, 1 H), 1.87-1.90 (m, 1 H), 2.85-3.30 (br m, 2H), 3.90-4.08 (m, 1 H), 4.15-4.30 (m, 1 H), 4.85-5.10 (m, 2H), 5.15 (s, 2H), 6.75-6.77 (m, 1 H), 6.88 (s, 1 H), 7.33-7.47 (m, 7H), 7.87-7.90 (m, 1 H).
MS m/z 445 [M+H]+ Preparation 22
tert-butyl (3R,4R)-4-(5-(benzyloxy)-2-carbamoylphenoxy)-3-fluoropiperidine-1- carboxylate
Figure imgf000081_0001
The title compound was prepared according to the method described for Preparation 20 using tert-butyl (3R,4R)-4-(5-(benzyloxy)-2-cyanophenoxy)-3-fluoropiperidine-1- carboxylate (Preparation 28).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1.40 (s, 9H), 1 .61 -1.66 (m, 1 H), 1.90-2.04 (m, 2H), 3.20-3.35 (m, 1 H), 3.58-3.61 (m, 1 H), 3.92-4.01 (m, 1 H), 4.82-4.90 (m, 2H), 5.16 (s, 2H), 6.71-6.73 (m, 1 H), 6.84 (s, 1 H), 7.32-7.47 (m, 6H), 7.76-7.78 (m, 1 H).
Preparation 23
tert-butyl (3S,4S)-4-(5-(benzyloxy)-2-carbamoylphenoxy)-3-fluoropiperidine-1- carboxylate
Figure imgf000081_0002
The title compound was prepared according to the method described for Preparation 20 using tert-butyl (3S,4S)-4-(5-(benzyloxy)-2-cyanophenoxy)-3-fluoropiperidine-1- carboxylate (Preparation 29).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1.41 (s, 9H), 1 .60-1.75 (m, 1 H), 1.95-1.98 (m, 2H), 3.10-3.20 (m, 1 H), 3.58-3.61 (m, 1 H), 3.88-3.92 (m, 1 H), 4.70-4.90 (m, 2H), 5.17 (s, 2H), 6.71-6.73 (m, 1 H), 6.85 (s, 1 H), 7.32-7.47 (m, 7H), 7.76-7.78 (m, 1 H).
MS m/z 445 [M+H]+
Preparation 24 tert-butyl (3S,4R)-4-(2-carbamoyl-5-morpholinophenoxy)-3-fluoropiperidine-1 - carboxylate
Figure imgf000082_0001
To a solution of 2-hydroxy-4-morpholinobenzamide (WO2002020500, 100 mg, 0.45 mmol) and tert-butyl (3S,4S)-3-fluoro-4-(tosyloxy)piperidine-1-carboxylate (JOC (2013),
78 (17), 8892-8897, 174 mg, 0.50 mmol) in anhydrous DMF (2 ml_) was added cesium carbonate (440 mg, 1.35 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction was quenched by the addition of water and extracted into EtOAc.
The organic layer was collected, washed with water, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 5% MeOH in EtOAc followed by trituration with ether to afford the title compound as a white solid (50 mg, 26%).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1.40 (s, 9H), 1 .65-1.70 (m, 1 H), 1.90-2.00 (m, 2H), 3.22-3.25 (m, 4H), 3.72-3.74 (m, 4H), 3.90-4.05 (m, 1 H), 4.20-4.30 (m, 1 H), 4.90-5.06 (m, 3H), 6.62-6.65 (m, 2H), 7.29 (br s, 1 H), 7.39 (br s, 1 H), 7.79-7.81 (m, 1 H).
MS m/z 424 [M+H]+
Preparation 25
tert-butyl (3S,4R)-4-((3-carbamoyl-6-chloropyridin-2-yl)oxy)-3-fluoropiperidine-1- carboxylate
Figure imgf000082_0002
To a solution of tert-butyl-(3S,4R)-3-fluoro-4-hydroxypiperidine (JOC (2013), 78 (17), 8892-8897, 343 mg, 1.57 mmol) in dioxane (10 ml_) was added KOtBu (263 mg, 2.35 mmol) and the reaction was stirred at room temperature for 30 minutes. 2,6- dichloronicotinamide (300 mg, 1.57 mmol) was added and the reaction stirred at room temperature for 16 hours. The reaction was quenched by the addition of water and extracted into EtOAc. The organic layer was collected, washed with water, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 20% EtOAc in hexanes to afford the title compound as a white solid (450 mg, 77%).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1.40 (s, 9H), 1 .80-1.90 (m, 1 H), 1.95-2.00 (m, 1 H), 3.02-3.45 (m, 1 H), 3.90-4.20 (m, 2H), 4.96 (br m, 1 H), 5.08 (br m, 1 H), 5.33-5.42 (m, 1 H), 7.25-7.27 (d, 1 H), 7.42 (br s, 1 H), 7.85 (br s, 1 H), 8.21 -8.23 (d, 1 H).
MS m/z 374 [M+H]+ Preparation 26
tert-butyl (3R,4S)-4-(5-(benzyloxy)-2-cvanophenoxy)-3-fluoropiperidine-1-carboxylate
Figure imgf000083_0001
To a solution of 4-(benzyloxy)-2-fluorobenzonitrile (WO2006016548, 1 g, 4.4 mmol) in DMF (20 ml_) was added tert-butyl-(3R,4S)-3-fluoro-4-hydroxypiperidine (JOC (2013), 78 (17), 8892-8897, 1 g, 4.84 mmol) and cesium carbonate (2.86 g, 8.802 mmol). The reaction was heated to 100°C for 16 hours before cooling and diluting with EtOAc. The solution was washed with water, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 10% EtOAc in hexanes to afford the title compound as a yellow gum (1.7 g, 90%).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1.40 (s, 9H), 1 .70-1.90 (m, 2H), 2.95-3.40 (m, 2H), 3.80-3.90 (m, 1 H), 4.00-4.15 (m, 1 H), 4.86-5.00 (m, 2H), 5.19 (s, 2H), 6.77-6.79 (m, 1 H), 6.99 (s, 1 H), 7.34-7.47 (m, 5H), 7.65-7.67 (m, 1 H).
MS m/z 427 [M+H]+ Preparation 27
tert-butyl (3S,4R)-4-(5-(benzyloxy)-2-cvanophenoxy)-3-fluoropiperidine-1-carboxylate
Figure imgf000084_0001
The title compound was prepared according to the method described for Preparation 26 using tert-butyl-(3S,4R)-3-fluoro-4-hydroxypiperidine (JOC (2013), 78 (17), 8892- 8897) and 4-(benzyloxy)-2-fluorobenzonitrile (WO2006016548).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1.40 (s, 9H), 1 .81 -1.82 (m, 2H), 2.95-3.40 (m, 2H), 3.80-3.90 (m, 1 H), 4.00-4.15 (m, 1 H), 4.86-4.96 (m, 2H), 5.19 (s, 2H), 6.77-6.79 (m, 1 H), 6.99 (s, 1 H), 7.34-7.47 (m, 5H), 7.65-7.67 (m, 1 H).
MS m/z 427 [M+H]+
Preparation 28
tert-butyl (3R,4R)-4-(5-(benzyloxy)-2-cvanophenoxy)-3-fluoropipehdine-1-carboxylate
Figure imgf000084_0002
The title compound was prepared according to the method described for Preparation 26 using tert-butyl-(3R,4R)-3-fluoro-4-hydroxypiperidine (JOC (2013), 78 (17), 8892- 8897) and 4-(benzyloxy)-2-fluorobenzonitrile (WO2006016548).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .40-1.42 (m, 10H), 1.57-1.61 (m, 1 H), 1.98-2.00 (m, 1 H), 3.31-3.48 (m, 2H), 3.76-3.85 (m, 1 H), 4.60-4.72 (m, 1 H), 4.90-5.00 (m, 1 H), 5.20 (s, 2H), 6.77-6.80 (m, 1 H), 7.03 (s, 1 H), 7.33-7.47 (m, 5H), 7.65-7.67 (m, 1 H).
Preparation 29
tert-butyl (3S,4S)-4-(5-(benzyloxy)-2-cvanophenoxy)-3-fluoropipehdine-1-carboxylate
Figure imgf000085_0001
The title compound was prepared according to the method described for Preparation 26 using tert-butyl-(3S,4S)-3-fluoro-4-hydroxypiperidine (JOC (2013), 78 (17), 8892- 8897) and 4-(benzyloxy)-2-fluorobenzonitrile (WO2006016548).
1 H NMR (400 MHz, DMSO-d6):6 ppm 1 .40-1.42 (m, 10H), 1.57-1.61 (m, 1 H), 1.90-2.05 (m, 1 H), 3.40-3.55 (m, 2H), 3.70-3.90 (m, 1 H), 4.60-4.80 (m, 1 H), 4.80-5.00 (m, 1 H), 5.20 (s, 2H), 6.77-6.80 (m, 1 H), 7.03-7.04 (m, 1 H), 7.33-7.47 (m, 5H), 7.65-7.67 (m, 1 H).
Preparation 30
1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl methanesulfonate
Figure imgf000085_0002
To a solution of 1-(4-hydroxypiperidin-1-yl)-2-(4-(trifluoromethoxy)phenyl)ethan-1-one (Preparation 31 , 3.1 g, 10.2 mmol) in DCM (30 mL) was added triethylamine (3.2 mL, 22.5 mmol) followed by methanesulfonyl chloride at 0°C. The reaction was stirred at room temperature for 4.5 hours before being washed with saturated aqueous NaHCC solution (30 mL), water (30 mL) and brine (30 mL). The organic layer was dried over sodium sulphate and concentrated in vacuo to afford the title compound that was used directly in the next step.
Preparation 31
1-(4-hvdroxypiperidin-1-yl)-2-(4-(trifluoromethoxy)phenyl)ethan-1-one
Figure imgf000086_0001
To a solution of 4-hydroxypiperidine (14.4 g, 143 mmol) in DCM (200 mL) at 0°C was added triethylamine (20 mL, 143 mmol) followed by 2-(4-(trifluoromethoxy)phenyl)acetyl chloride (17.0 g, 71.3 mmol) dropwise. The reaction was stirred at room temperature for 3 hours before being quenched by the addition of water (200 mL). The organic layer was collected, washed with 2M HCI (aq) (200 mL), saturated aqueous NaHCC>3 solution (200 mL) and brine (200 mL). The organic layer was dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 10% MeOH in DCM to afford the title compound as an amber oil (7.35 g, 34%).
1 H NMR (400 MHz, CDCI3):5 ppm 1 .30-1.40 (m, 1 H), 1.42-1.50 (m, 1 H), 1.70-1.85 (m, 2H), 3.20-3.30 (m, 2H), 3.70 (s, 3H), 3.90-4.10 (m, 2H), 7.10-7.30 (m, 4H).
Preparation 32
Cis-3-(benzyloxy)cvclobutyl methanesulfonate
Figure imgf000086_0002
To a solution of cis-3-(benzyloxy)cyclobutan-1 -ol (Preparation 35, 60 mg, 0.34 mmol) in DCM (3 mL) was added triethylamine (51 mg, 0.506 mmol) followed by mesyl chloride (46 mg, 0.41 mmol) at -30°C. The reaction was stirred at this temperature for 3 hours. The reaction was diluted with DCM and washed with saturated aqueous NaHCOs solution, brine, dried over sodium sulphate and concentrated in vacuo. The residue was used directly in the next step.
Preparation 33
Trans-3-(benzyloxy)cvclobutyl methanesulfonate
Figure imgf000087_0001
The title compound was prepared according to the method described for Preparation 32 using trans-3-(benzyloxy)cyclobutan-1-ol (Preparation 34) and taken directly on to the next step.
Preparation 34
Tran -3-(benzyloxy)cyclobutan- 1 -ol
Figure imgf000087_0002
To a suspension of cis-3-(benzyloxy)cyclobutan-1-ol (600 mg, 3.37 mmol) in toluene (10 mL) was added para-nitrobenzoic acid (563 mg, 3.37 mmol) and triphenylphosphine (883 mg, 3.37 mmol). The reaction was cooled to between 5-10°C and treated with DIAD (0.66 mL, 3.37 mmol) drop-wise. The reaction was stirred at room temperature for 14 hours before diluting with water and extracting into EtOAc. The organic layer was collected, washed with water, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 6% EtOAc in hexanes. The residue was dissolved in THF (5 mL) and treated with NaOH (147 mg, 3.67 mmol). The reaction was stirred at room temperature for 2 hours before extracting into DCM. The organic layer was collected, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 15% EtOAc in hexanes to afford the title compound as a yellow gum (300 mg, 92%).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .98-2.04 (m, 2H), 2.14-2.20 (m, 2H), 4.1 1-4.16 (m, 1 H), 4.24-4.29 (m, 1 H), 4.33 (s, 2H), 4.96-5.01 (m, 1 H), 7.25-7.35 (m, 5H).
Preparation 35
Cis-3-(benzyloxy)cvclobutan-1-ol
Figure imgf000088_0001
To a solution of 3-(benzyloxy)cyclobutan-1-one (300 mg, 1.71 mmol) in EtOH (5 mL) at 0°C was added sodium borohydride (65 mg, 1.71 mmol) and the reaction was stirred at this temperature for 3 hours. The reaction was quenched by the addition of cold water and extracted into EtOAc. The organic layer was collected, washed with water, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 10% EtOAc in hexanes to afford the title compound as a pale yellow oil (300 mg, 99%).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .69-1.76 (m, 2H), 2.49-2.55 (m, 2H), 3.49-3.72 (m, 2H), 4.33 (s, 2H), 4.97-5.01 (m, 1 H), 7.25-7.35 (m, 5H).
Preparation 36
2-(dibenzylamino)- -methylpropyl methanesulfonate
Figure imgf000088_0002
The title compound was prepared according to the method described for Preparation 32 using 2-(dibenzylamino)-2-methylpropan-1-ol (Preparation 37) and taken on directly to the next step.
Preparation 37
2-(dibenzylamino)-2-methylpropan-1-ol
Figure imgf000088_0003
To a solution of 2-amino-2-methylpropan-1-ol (500 mg, 5.6 mmol) in acetone:water (4: 1 , 10 mL) was added potassium carbonate (1.55 g, 1 1.2 mmol) followed by benzyl bromide (1.33 ml_, 11.2 mmol) and the reaction was heated to reflux for 40 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was partitioned between DCM and water, the organic layer was collected, washed with water, brine, dried over sodium carbonate and concentrated in vacuo, the residue was purified using silica gel column chromatography eluting with 2-5% MeOH in DCM to afford the title compound as a white solid (1.3 g, 86%).
1 H NMR (400 MHz, DMSO-d6):5 ppm 1 .02 (s, 6H), 3.35 (s, 2H), 3.74 (s, 4H), 7.06-7.09 (m, 2H), 7.15-7.19 (m, 4H), 7.25-7.27 (m, 4H). Biological Activity
Isolated TRK Enzyme assays use the HTRF KinEASE-TK kit (Cisbio Cat# 62TK0PEJ) with recombinant His-tagged cytoplasmic domains of TRKA receptor sourced from Invitrogen (see table below). This activity-assay measures the phosphorylation of tyrosine residues within a substrate from the HTRF kit which has been validated by Cisbio for a variety of tyrosine kinases including the TRK receptors.
Assay details:
Figure imgf000089_0001
0.5mM stock solutions of test compounds are prepared and serially diluted in 100% DMSO. A standard curve using the compound of Example 135 disclosed in WO2005/116035 of 150uM is also prepared on each test plate. High percentage effect (HPE) is defined by 150uM (using the compound of Example 135 as disclosed in WO2005/116035) and 0% effect (ZPE) is defined by 100% DMSO. Greiner low volume black plates containing 0.2ul of serially diluted compound, standard and HPE/ZPE are created using the Bravo nanolitre dispenser.
1X enzyme buffer is prepared from 5X Enzymatic Buffer from the Cisbio KinEASE TK kit using MilliQ water. The buffer is then supplemented with 10mM MgCI and 2mM DTT (both from Sigma). In the case of TRKB, the buffer is also supplemented with 125nM Supplement Enzymatic Buffer (SEB) from the Cisbio kit.
2X FAC of enzyme and 2X FAC ATP diluted in 1X complete enzyme buffer is incubated at room temperature for 20minutes to preactivate the enzyme. Following this preactivation step, 5ul/well of enzyme + ATP mix is added using a Multidrop Micro to the assay plate, spotted with 0.2ul 100% DMSO compound. This is left for 20mins at room temperature before adding 5ul of 2uM TK-substrate-Biotin (from the Cisbio kit) diluted in 1X enzyme buffer (1 uM FAC) using the Multidrop Micro. The reaction is incubated at room temperature for the optimized assay reaction time (see table). The reaction is stopped by adding 10ul/well HTRF Detection Buffer containing 0.25uM Streptavidin- XL665 (0.125uM FAC) and 1 :200 TK Antibody-Cryptate using a Multidrop.
After the Detection Reagent addition, plates are covered and incubated at room temperature for 60 minutes. HTRF signal is read using an Envision reader, measured as a ratio of emissions at two different wavelengths, 620nm and 665nm. Any compound that inhibits the action of the TRK kinase will have a lower fluorescence ratio value 665/620nM than compounds which do not inhibit theTRK kinase. Test compound data are expressed as percentage inhibition defined by HPE and ZPE values for each plate. Percentage inhibition in the presence of test compound is plotted against compound concentration on a log scale to determine an IC50 from the resultant sigmoid curve. Cell Based Assays were carried out using Cell lines from DiscoveRx utilising their PathHunter technology and reagents in an antagonist assay:
Figure imgf000090_0001
The assays are based upon DiscoveRx's proprietary Enzyme Fragment Complementation (EFC) technology. In the case of the TRK cell lines, the enzyme acceptor (EA) protein is fused to a SH2 protein and the TRK receptor of interest has been tagged with a Prolink tag. Upon neurotrophin binding, the TRKA receptor becomes phosphorylated, and the tagged SH2 protein binds. This results in functional complementation and restored β- Galactosidase activity which is can be measured using the luminescent Galacton Star substrate within the PathHunter reagent kits.
Generally, small molecule inhibitors bind to the kinase domain so are not competing with the neurotrophin (agonist) which binds to an extracellular site. This means that the IC50 is a good measure of affinity and should be unaffected by concentration neurotrophin stimulant.
Cryopreserved PathHunter cells are used from either in-house produced batches or bulk batches bought directly from DiscoveRx. Cryopreserved cells are resuscitated, spun l OOOrpm for 4min to remove freezing media, and resuspended in MEM + 0.5% horse serum (both Invitrogen) to 5e5cells/ml. The cells are then plated using a Multidrop into Greiner white tissue culture treated plates at 20ul/well and incubated for 24h at 37°C, 5% CO2, high humidity. On the day of the assay, the cell plates are allowed to cool to room temperature for 30min prior to the assay.
4mM stock solutions of test compounds are prepared and serially diluted in 100% DMSO. A standard curve using the compound of Example 135, WO2005/116035 at a top concentration of 150uM is also prepared on each test plate. High percentage effect (HPE) is defined by 150uM of the compound of Example 135, WO2005/116035 and 0% effect (ZPE) is defined by 100% DMSO. Plates containing 1 ul of serially diluted compound, standard and HPE/ZPE are diluted 1/66 in assay buffer (PBS minus Ca2+, minus Mg2+ with 0.05% pluronic F127) using a Wellmate. Using a Platemate Plus, 5ul of 1/66 diluted test compounds is then transferred to the cell plate and allowed to reach equilibrium by incubating for 30min at room temperature before addition of agonist stimulus: 10ul/well of 2nM (0.571 nM FAC) of the cognate neurotrophin (Peprotech) diluted in agonist buffer (HBSS with 0.25% BSA). Final assay concentration of the test compounds is 8.66μΜ, (the compound of Example 135, WO2005/116035 FAC is 0.325uM). The plates are left at room temperature for a further 2hours before addition of 10ul of the DiscoveRx PathHunter detection reagent (made up by adding 1 part Galacton Star, 5 parts Emerald II and 19 parts Cell Assay Buffer as per the manufacturer's instructions).
After reagent addition, plates are covered and incubated at room temperature for 60 minutes. Luminescence signal is read using an Envision. Test compound data are expressed as percentage inhibition defined by HPE and ZPE values for each plate. Percentage inhibition in the presence of test compound is plotted against compound concentration on a log scale to determine an IC50 from the resultant sigmoid curve.
Below are TrkA IC50 data generated using the PV3144 TrkA enzyme assay. Where more than one reading was taken, the arithmetic mean is presented.
Example TRKA IC50 (nM)
1 9.1
2 14.1
3 13.8
4 12.3
5 144.3
6 77.1
7 1 19.8
8 17
9 7.3
10 23.1
1 1 21 .8
12 27
13 10.8
14 9.9
15 4.9
16 9.4
17 16.5
18 1 15
19 146.1 All publications cited in this application are each herein incorporated by reference in their entirety.
Although the invention has been described above with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention.
Accordingly, the invention is limited only by the following claims.

Claims

Figure imgf000094_0001
Wherein
Q1 is N or CR1 ,
Q2 is N or CR2,
R1 , R2, R4 and R5 are each independently H, F, CN, OH, NH2, Ci-3 alkyl optionally substituted by one or more F, or C1-3 alkoxy optionally substituted by one or more F, R3 is H, F, CI, CN, Ci-4 alkyl optionally substituted by one or more F, Ci-4 alkoxy optionally substituted by one or more F , or C3- cycloalkyloxy optionally substituted by one or more F, or C1-4 alkylthio optionally substituted by one or more F,
With the proviso that at least 2 of R1 , R2, R3, R4 and R5 are H,
R6 and R7 can be attached at any point on the piperidine ring and are independently H, F, CN, OH, NH2, C1-3 alkyl optionally substituted by one or more F, or C1-3 alkoxy optionally substituted by one or more F,
or R6 and R7 can be taken together, with the atoms to which they are attached, to form a 5- to 7-membered cycloalkane ring,
R8 is CONR101 R102,
each of X1 , X2 and X3 is independently CR101 or N, R101 and R102 are each independently selected from H and Ci-3 alkyl, Z is CH2, CH(CH3), NH or O,
A is (C1-4 alkoxy optionally substituted by NH2, OH, CONH2, S02CH3 or CN), (C1-4 alkylamino optionally substituted by NH2, OH, CONH2, S02CH3 or CN), or (C3-6 cycloalkyoxy optionally substituted by NH2, OH, CONH2, S02CH3 or CN),
Or
A is a phenyl or a 5- or 6-membered saturated or unsaturated heterocyclic ring containing 1 , 2 or 3 hetero-atoms selected from S, N and O,
each of which is optionally fused to a further 5- or 6-membered saturated or unsaturated heterocyclic ring containing 1 , 2 or 3 hetero-atoms selected from S, N and O, and which phenyl or heterocyclic ring or fused ring system is optionally substituted by 1 , 2 or 3 substituents independently selected from =0, C02R9, CN and Co-6 alkyl optionally substituted by 1 or 2 substituents independently selected from OH, NH2, S02CH3, Ci-4 alkoxy, CON(R103)(R104) and a group selected from
Figure imgf000095_0001
where X4 is selected from NR101 , O and S02,
X5 is H, OH or F,
R9 is H or Ci-6 alkyl,
R101 and R102 are each independently selected from H and Ci-3 alkyl,
R103 and R104 are each independently selected from H, (C1-6 alkyl optionally substituted by OH, C1-6 alkoxy or by one or more F), and (C3- cycloalkyl optionally substituted by OH, C1-6 alkoxy or by one or more F), Or a pharmaceutically acceptable salt thereof.
2. A compound or salt according to claim 1 wherein one of X1 , X2 and X3 is CR101 or N, and the others are CR101.
3. A compound or salt according to claim 1 or 2 wherein X1 is CH or N.
4. A compound or salt according to claim 1 , 2 or 3 wherein X2 and X3 are CH.
5. A compound or salt according to claim 1 , 2, 3 or 4 wherein X1 is CH.
6. A compound or salt according to claim 1 , 2, 3, 4, or 5 wherein Z is CH2.
7. A compound or salt according to claim 1 , 2, 3, 4, 5 or 6 wherein R8 is CONH2.
8. A compound or salt according to claim 1 , 2, 3, 4, 5, 6 or 7 wherein Q1 is CH or N and Q2 is CH or N.
9. A compound or salt according to claim 1 , 2, 3, 4, 5, 6, 7, or 8 wherein R7 is F, H or
CH3.
10. A compound or salt according to claim 1 , 2, 3, 4, 5, 6, 7, 8 or 9 which has the substructure
Figure imgf000096_0001
la 11 . A compound or salt according to claim 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 wherein R3 is OCF3, CF3, C(CH3)3, SCF3, CH(CH3)2 or cyclopropyloxy.
12. A compound or salt according to claim 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 wherein A is an imidazolyl, morpholinyl, pyrrolidinyl, thiazolyl, pyridyl, phenyl, or pyrazolyl group optionally substituted by 1 or 2 substituents independently selected from C02R9 and C0- alkyl optionally substituted by 1 or 2 substituents independently selected from OH, NH2 SO2CH3, Ci-4 alkoxy, CON(R103)(R104) and a group selected from
Figure imgf000097_0001
13. A compound according to claim 1 selected from :
2-(((3R,4S)-3-fluoro-1 -(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4-(2- hydroxy-2-methylpropoxy)benzamide;
2-(((3S,4R)-3-fluoro-1 -(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4-(2- hydroxyethoxy)benzamide;
2-(((3S,4R)-3-fluoro-1 -(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4- methoxybenzamide;
2-(((3S,4R)-3-fluoro-1 -(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4-(2- hydroxy-2-methylpropoxy)benzamide;
4-(2-hydroxyethoxy)-2-((1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4- yl)oxy)benzamide;
4-(2-amino-2-oxoethoxy)-2-((1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4- yl)oxy)benzamide;
2-(((3R,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4-(2- hydroxy-2-methylpropoxy)benzamide;
2-(((3S,4S)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4-(2- hydroxy-2-methylpropoxy)benzamide;
4-(cyanomethoxy)-2-(((3S,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin 4-yl)oxy)benzamide; 2-(((3S,4R)-3-fluoro-1 -(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4-(((R)-1- hydroxypropan-2-yl)oxy)benzamide;
2-(((3S,4R)-3-fluoro-1 -(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4-(((S)-1- hydroxypropan-2-yl)oxy)benzamide;
2-(((3S,4R)-3-fluoro-1 -(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4- ((methylsulfonyl)methoxy)benzamide;
2-(((3S,4R)-3-fluoro-1 -(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4-((1- hydroxy-2-methylpropan-2-yl)oxy)benzamide;
Trans-2-(((3S,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4- (3-hydroxycyclobutoxy)benzamide;
Cis-2-(((3S,4R)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4-(3- hydroxycyclobutoxy)benzamide;
2-(((3S,4R)-3-fluoro-1 -(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4- morpholinobenzamide;
2-(((3S,4R)-3-fluoro-1 -(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-6- morpholinonicotinamide;
2-(((3S,4R)-3-fluoro-1 -(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-6-((2- hydroxy-2-methylpropyl)amino)nicotinamide;
4-(2-amino-2-methylpropoxy)-2-(((3S,4R)-3-fluoro-1-(2-(4-
(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)benzamide,
or a pharmaceutically acceptable salt thereof.
14. 2-(((3R,4S)-3-fluoro-1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)oxy)-4-(2- hydroxy-2-methylpropoxy)benzamide or a pharmaceutically acceptable salt thereof.
15: A pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of the preceding claims 1 to 14, and a pharmaceutically acceptable carrier.
16. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 14, for use as a medicament.
17. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 14 for use in the treatment of a disease for which a Trk receptor antagonist is indicated.
18. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 14 for use in the treatment of pain or cancer.
19. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or composition thereof, as defined in any one of claims 1 to 14, for the manufacture of a medicament to treat a disease for which a Trk receptor antagonist is indicated
20. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or composition thereof, as defined in any one of claims 1 to 14, for the manufacture of a medicament to treat pain or cancer.
21 . A method of treatment of a mammal, to treat a disease for which a Trk receptor antagonist is indicated, comprising treating said mammal with an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 14.
22. A method of treatment of pain or cancer in a mammal, comprising treating said mammal with an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 14.
23. A compound or salt according to any one of claims 1 to 14 for use in a medical treatment in combination with a further drug substance.
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