WO2017060488A1 - Nouveaux antagonistes de trpa1 - Google Patents

Nouveaux antagonistes de trpa1 Download PDF

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Publication number
WO2017060488A1
WO2017060488A1 PCT/EP2016/074094 EP2016074094W WO2017060488A1 WO 2017060488 A1 WO2017060488 A1 WO 2017060488A1 EP 2016074094 W EP2016074094 W EP 2016074094W WO 2017060488 A1 WO2017060488 A1 WO 2017060488A1
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methyl
group
oxadiazol
chlorophenyl
preparation
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PCT/EP2016/074094
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English (en)
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Jose Aiguade Bosch
Stephen Connolly
Paul Robert Eastwood
Elena Gomez Castillo
Immaculada Montserrat Moreno Mollo
Richard Spurring Roberts
Sara Sevilla Gomez
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Almirall, S.A.
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Publication of WO2017060488A1 publication Critical patent/WO2017060488A1/fr

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to novel compounds having TRPA1 activity.
  • This invention also relates to pharmaceutical compositions containing them, processes for their preparation and their use in the treatment of several disorders.
  • TRPA1 is a non-cation selective channel that belongs to the Transient Receptor Potential (TRP) superfamily.
  • TRP Transient Receptor Potential
  • TRPA1 was first identified from cultured lung fibroblasts (Jaquemar ef a/., 1999), and further studies indicated that TRPAI was highly expressed in sensory neurons of the dorsal root, trigeminal and nodose ganglia. In sensory neurons, TRPA1 expression is most prevalent in small diameter neurons where it colocalizes with markers of peptidergic nociceptors such as TRPV1 , calcitonin gene-related peptide (CGRP) and substance P (Kaneko et al., 2013). Moreover, TRPA1 has been identified in the small intestine, colon, pancreas, skeletal muscle, heart, brain, and T and B-lymphocytes (Stokes et al., 2006).
  • TRPA1 is activated by a variety of noxious stimuli, including cold temperatures and pungent natural compounds (e.g., mustard, cinnamon and garlic). TRPA1 is also activated by environmental irritants, including isocyanates and heavy metals produced during the manufacturing of polymers, fertilizers and pesticides. Vehicle exhaust, burning vegetation and electrophilic tear gases used as incapacitating agents, are potent activators of TRPA1 . TRPA1 antagonists or inhibitors could also have applications in defence against such agents.
  • noxious stimuli including cold temperatures and pungent natural compounds (e.g., mustard, cinnamon and garlic).
  • TRPA1 is also activated by environmental irritants, including isocyanates and heavy metals produced during the manufacturing of polymers, fertilizers and pesticides. Vehicle exhaust, burning vegetation and electrophilic tear gases used as incapacitating agents, are potent activators of TRPA1 . TRPA1 antagonists or inhibitors could also have applications in defence against such agents.
  • TRPA1 is not only sensitive to electrophiles, but is also activated by oxidizing agents.
  • Reactive oxygen species ROS
  • ROS Reactive oxygen species
  • Reactive carbonyl species like 4- hydroxynonenal (4-HNE) and 4-oxononenal (4-ONE), resulting from lipid peroxidation act directly on TRPA1 .
  • ROS generated during inflammation excites airway sensory nerve fibres, and this response is largely reduced in TRPA1 -deficient mice.
  • TRPA1 activation is modulation by G protein-coupled receptors (GPCRs) through second-messenger signalling cascades.
  • GPCRs G protein-coupled receptors
  • Prostaglandin PGE2 and bradykinin (BK) are indirect activators of TRPA1 (Bessac, 2008).
  • TRPA1 has emerged as a key regulator of neuropeptide release and neurogenic inflammation.
  • TRPA1 is expressed in a subset of C-fibres that express TrkA and TRPV1 .
  • These afferent nerves have cell bodies in nodose, dorsal root ganglia (DRG) and trigeminal neurons (TG), and project to a variety of peripheral targets, including skin, airways, and gastrointestinal (Gl) tract.
  • DDG dorsal root ganglia
  • TG trigeminal neurons
  • TRP channels are present in both neuronal and non-neuronal cells in the skin where they are thought to play a key role in itch, regulation of barrier function, keratinocyte differentiation, hair growth, inflammation, and wound healing (reviewed in Moran et al., 201 1 ).
  • TRPA1 is an essential component of the pathways that promote histamine- independent itch and may act as a downstream transduction channel onto which multiple pathways converge.
  • TRPA1 role as a pain sensor is well-established.
  • a gain-of-function point mutation in TRPA1 was identified as the cause of Familial Episodic Pain Syndrome, a rare human pain disorder characterized by severe upper body pain triggered by fasting and physical stress (Kremeyer et al., 2010). Taming these hyperactive TRP channels by antagonists may prove clinically beneficial.
  • TRPA1 is required for the hypersensitivity that occurs in inflammatory pain models (Bautista et al. 2013, Julius 2013). TRPA1 expression is increased by inflammatory mediators such as nerve growth factor (NGF) and following nerve injury or inflammation. Activation of TRPA1 has been shown to cause pain and neurogenic inflammation. Intrathecal TRPA1 antisense oligonucleotides administration suppressed inflammation and nerve injury-induced cold allodynia. TRPA1 gene knock-out studies showed impaired sensory function to noxious cold, chemical and mechanical stimuli, suggesting that TRPA1 represents an important target for development of therapeutics for inflammatory and neuropathic pain conditions (Obata et al. 2003, McNamara et al. 2007, Petrus et al.
  • TRPA1 is a promising target for the treatment of this chronic diabetic neuropathy associated with peripheral demyelination and the degeneration of nerve fibres.
  • TRPA1 may have a role in the pathogenesis of cancer and other inflammatory diseases. TRPA1 antagonists have been reported to revert oxaliplatin-induced neuropathic pain (Nativi, 2005).
  • TRPAI antagonists in post-surgical pain.
  • TRPA1 is implicated in migraine (Edelmayer et al., 2012), and dental pain (Haas et al., 201 1 ), as a result from neurogenic inflammation.
  • the activation of trigeminal TG neurons through nasal application of TRPA1 activators causes a CGRP-dependent increase in meningeal blood flow, that has been clinically shown to correlate with migraine headache.
  • TRPA1 could be considered a target for such conditions.
  • TRPA1 -/- mice to support a role for TRPA1 in the pathogenesis of different airway diseases including chronic cough, asthma, and COPD (Nassini et al., 2012b).
  • TRPA1 in the generation of irritant-induced cough reflexes.
  • Inhalation of a variety of TRPA1 agonists (acrolein, cinnamaldehyde, allyl isothiocyanate, crotonaldehyde) has been shown to produce a dose-dependent robust cough response in conscious guinea pigs and in humans (Andre et al., 2009; Birrell et al. , 2009).
  • Stimulating TRPA1 channels has been demonstrated to activate vagal bronchopulmonary C-fibres in the guinea pig and rodent lung.
  • TRPA1 agonists induced cough.
  • cough can be attenuated by TRPA1 inhibitors.
  • TRPA1 channels Antagonism of TRPA1 channels is expected to inhibit afferent nerve activation induced by cough stimulants, and represents an option for anti-tussive drugs development (Grace et al., 2012 and 2013). Moreover, patients treated with angiotensin-converting enzyme (ACE) inhibitors for hypertension have chronic cough as a side effect as result of heightened bradykinin levels. TRPA1 antagonists could represent an option to treat such side effects and chronic cough conditions.
  • ACE angiotensin-converting enzyme
  • TRPA1 -/- mice show little sign of lung inflammation, near- normal airway resistance, reduced eosinophil infiltration in the bronchi, and decreased production of proinflammatory cytokines and neuropeptides release in the airways, compared to TRPA1 +/+mice (Caceres et al., 2009). These studies point to TRPA1 as a promising target for the development of drugs aimed at treating the asthmatic response, allergen-induced airways inflammation, mucus production and airways hyper-reactivity.
  • CSE cigarette smoke extract
  • aldehydes increased Ca 2+ influx in
  • TRPA1 transfected cells and promoted neuropeptide release from isolated guinea pig airway tissue. Instillation of CSE into the trachea of wild-type mice and TRPA1 -/- mice only induced plasma protein extravasation in the wild type mice (Andree et al., 2008). These data suggest that targeting TRPA1 may have therapeutic potential in diseases caused by cigarette smoke such as COPD.
  • TRPA1 has been reported to have a critical role in mediating gastrointestinal (Gl) hypersensitivity to mechanical stimuli and serves as an important mediator of neuropeptide release triggered by inflammatory agents.
  • TRPA1 expression is elevated in the inflamed mouse gut (Yang et al., 2008; Izzo et al., 2012).
  • Experimental colitis induced by dinitrobenzene sulphonic acid (DNBS) was attenuated after both pharmacological blockade and genetic inactivation of TRPA1 (Engel et al., 201 1 ), pointing at potential of the target in Gl inflammatory conditions such as inflammatory bowel disease, Crohn's disease and ulcerative colitis, and colicky pain of Gl origin (Blackshaw et al., 2013).
  • TRPA1 is highly expressed in sensory neurons innervating bladder, urothelium, sub-urothelial space, muscle layers and around blood vessels (Streng et al. , 2008). Similar to TRPM8, TRPA1 is up-regulated in bladder mucosa in patients with bladder outlet obstruction (Du et al., 2008). TRPA1 agonists increased the micturition frequency models of cyclophosphamide-induced cystitis and spinal cord injury
  • TRPA1 antagonists could show potential for the treatment of bladder instability, urinary incontinence and cystitis.
  • TRPA1 antagonists could show potential for the treatment of bladder instability, urinary incontinence and cystitis.
  • TRPA1 antagonists could show potential for the treatment of bladder instability, urinary incontinence and cystitis.
  • TRPA1 Several properties of TRPA1 make it an attractive drug target to treat inflammatory disorders; its ability to be activated by a large variety of endogenous and exogenous inflammatory compounds makes it an ideal detector of inflammatory cues, both in acute and in chronic conditions. Its peripheral expression of TRPA1 allows systemic, but also selective targeting of drugs by inhalation, ingestion, or topical application.
  • TRPA1 modulators of varied chemical structures have been recently disclosed for the treatment or prevention of chronic and acute inflammatory diseases and other pathological conditions, diseases and disorders known to be susceptible to amelioration by inhibition or antagonism of TRPA1 .
  • TRPA1 modulators of varied chemical structures have been recently disclosed for the treatment or prevention of chronic and acute inflammatory diseases and other pathological conditions, diseases and disorders known to be susceptible to amelioration by inhibition or antagonism of TRPA1 .
  • Several structural families of antagonists are observed. These include alcohols
  • Compounds having the capacity to selectively antagonise TRPA1 are in active development by several companies. Examples of these compounds are GRC-17536 and HX-100.
  • TRPA1 antagonists or inhibitors being suitable for the treatment of the above-mentioned diseases.
  • bicyclic heterocycle derivative for use in the treatment of the human or animal body, which bicyclic heterocycle derivative is a compound of Formula (I), or a pharmaceutically acceptable salt, or a solvate, or a N- oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof:
  • G 1 is selected from the group consisting of a C atom and a N atom
  • ⁇ G 2 , G 3 ,G 4 and G 5 are each independently selected from the group consisting of a C(R a ) group, a N(R b ) group and N atom;
  • G 6 is an N atom
  • G 7 is a C atom
  • G 8 is a N atom
  • G 9 is O atom
  • R a is selected from the group consisting of a H atom, a linear or branched C1-4 alkyl group, a halogen atom, a linear or branched Ci-4 alkoxy group, a linear or branched C1-4 haloalkyl group, a linear or branched C1-4 haloalkoxy group, an oxo group, a C3-7 cycloalkyl group, a cyano group, an amino group, a C1-4 monoalkylamino group, a Ci-4 dialkylamino group and a hydroxyl group;
  • R b is selected from the group consisting of a H atom and a linear or branched C1-4 alkyl group;
  • ⁇ L represents a linear or branched C2- 4 alkylene group unsubstituted or
  • R' and R" each independently represent a hydrogen atom, a linear or branched C1-C4 alkyl group or a linear or branched C1-C4 haloalkyl group;
  • Q is selected from the group consisting of a monocyclic or bicyclic C6-i4 aryl group and a monocyclic or bicyclic 5- to 14-membered heteroaryl group containing at least one heteroatom selected from N, O and S; wherein the aryl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 alkoxy group, a linear or branched C1-4 haloalkyl group, a linear or branched C1-4 haloalkoxy group, a linear or branched C1-4 thioalkyl group, a linear or branched C1-4 halothioalkyl group and a cyano group;
  • n 0 or 1 ;
  • bicyclic heterocycle derivative is other than:
  • the present invention also provides a bicyclic heterocycle derivative, which bicyclic heterocycle derivative is a compound of Formula (I), or a pharmaceutically acceptable salt, or a solvate, or a /V-oxide, or a tautomer, or a stereoisomer, or an isotopically- labelled derivative thereof :
  • G 1 is selected from the group consisting of a C atom and a N atom
  • ⁇ G 2 , G 3 ,G 4 and G 5 are each independently selected from the group consisting of a C(R a ) group, a N(R b ) group and N atom;
  • G 6 is an N atom
  • G 7 is a C atom
  • G 8 is a N atom
  • G 9 is O atom
  • R a is selected from the group consisting of a H atom, a linear or branched C1-4 alkyl group, a halogen atom, a linear or branched Ci-4 alkoxy group, a linear or branched C1-4 haloalkyl group, a linear or branched C1-4 haloalkoxy group, an oxo group, a C3-7 cycloalkyl group, a cyano group, an amino group, a C1-4 monoalkylamino group, a Ci-4 dialkylamino group and a hydroxyl group;
  • R b is selected from the group consisting of a H atom and a linear or branched C1-4 alkyl group;
  • ⁇ L represents a linear or branched C2- 4 alkylene group unsubstituted or
  • R' and R" each independently represent a hydrogen atom, a linear or branched C1-C4 alkyl group or a linear or branched C1-C4 haloalkyl group;
  • Q is selected from the group consisting of a monocyclic or bicyclic C6-i4 aryl group and a monocyclic or bicyclic 5- to 14-membered heteroaryl group containing at least one heteroatom selected from N, O and S; wherein the aryl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 alkoxy group, a linear or branched C1-4 haloalkyl group, a linear or branched C1-4 haloalkoxy group, a linear or branched C1-4 thioalkyl group, a linear or branched C1-4 halothioalkyl group and a cyano group;
  • n 0 or 1 ;
  • bicyclic heterocycle derivative is other than:
  • the invention further provides synthetic processes and intermediates described herein, which are useful for preparing said bicyclic heterocycle derivatives.
  • the invention is also directed to a bicyclic heterocycle derivative of the invention as described herein for use in the treatment of the human or animal body by therapy.
  • the invention also provides a pharmaceutical composition comprising a bicyclic heterocycle derivative of the invention and a pharmaceutically-acceptable diluent or carrier.
  • the invention also provides a bicyclic heterocycle derivative of the invention for use in the treatment of a disease or condition susceptible to amelioration by TRPA1 antagonists or inhibitors, in a mammal, in particular wherein the pathological condition or disease is selected from acute and/or chronic pruritus, acute and/or chronic pain, inflammatory dermatological diseases, respiratory disorders, gastrointestinal inflammatory disorders and urinary tract disorders.
  • the invention also provides the use of a bicyclic heterocycle derivative of the invention in the manufacture of a formulation or medicament for treating a disease or condition susceptible to amelioration by TRPA1 antagonists or inhibitors, in particular wherein the condition or disease is as described above.
  • the invention also provides a method of treating a disease or condition as described above; comprising such method administering to the mammal, a therapeutically effective amount of a bicyclic heterocycle derivative of the invention.
  • the invention further provides a method of treatment comprising administering a therapeutically effective amount of a combination of a bicyclic heterocycle derivative of the invention together with one or more other therapeutic agents.
  • the invention also provides a combination product comprising (i) a bicyclic heterocycle derivative of the invention as described herein; and (ii) one or more additional active substances.
  • C1-4 alkyl embraces unsubstituted or substituted, linear or branched radicals having 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, / ' -propyl, n-butyl, sec-butyl or i-butyl.
  • C2-4 alkylene embraces divalent alkyl moieties typically having from 2 to 4 carbon atoms.
  • C2-3 alkylene embraces divalent alkyl moieties typically having from 2 to 3 carbon atoms.
  • Examples of C2-4 alkylene radicals include ethylene, propylene and butylene radicals.
  • a said alkylene group is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different.
  • C1-4 alkoxy (or alkyloxy) embraces unsubstituted or substituted, linear or branched oxy-containing radicals each having alkyl portions of 1 to 4 carbon atoms. Examples of C1-4 alkoxy radicals include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy and t-butoxy.
  • C1-4 thioalkyl embraces radicals containing a linear or branched alkyl radicals of 1 to 4 carbon atoms attached to a divalent -S- radical. Examples include methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, sec- butylthio and t-butylthio.
  • Ci-4 haloalkyl is a linear or branched alkyl group, which is substituted by one or more, preferably 1 , 2 or 3 halogen atoms.
  • haloalkyl groups include CCI3, CFs and CHF2.
  • Ci-4 haloalkoxy is typically a C1-4 alkoxy group substituted by one or more halogen atoms. Typically, it is substituted by 1 , 2 or 3 halogen atoms. Examples of haloalkoxy groups include -OCF3 and -OCCI3.
  • Ci-4 halothioalkyl is typically a C1-4 thioalkyl group substituted by one or more halogen atoms. Typically, it is substituted by 1 , 2 or 3 halogen atoms. Examples of halothioalkyl groups include -SCF3 and -SCCI3.
  • C3-7 cycloalkyl embraces saturated carbocyclic radicals monocyclic or polycyclic ring having from 3 to 7 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • C3-7 cycloalkylene embraces divalent cycloalkyl moieties typically having from 3 to 7 carbon atoms.
  • Examples of C3-7 cycloalkylene radicals include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and cycloheptylene radicals.
  • Ce-14 aryl radical embraces typically a Ce-14, more preferably Ce- ⁇ monocyclic or bicyclic aryl radical such as phenyl, naphthyl, anthranyl and phenanthryl. Phenyl is preferred.
  • a said Ce-14 aryl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different.
  • monocyclic or bicyclic 5- to 14-membered heteroaryl radical embraces typically a 5- to 14- membered ring system, comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N, preferably S and N.
  • a 5- to 14-membered heteroaryl radical may be a single ring or two fused rings wherein at least one ring contains a heteroatom.
  • Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, benzo[b]thienyl, benzothiazolyl, indolyl, indazolyl, purinyl, quinolinyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl, cinnolinyl, triazolyl, indolizinyl, indolinyl, isoindolinyl, isoindolyl, imidazolidinyl, pteridinyl, thiant
  • the term 5- to 7-membered N-containing heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated C5-7 carbocyclic ring system in which one or more, for example 1 or 2 of the carbon atoms preferably 1 carbon atom is replaced by a N atom.
  • the term 5- to 6-membered N- containing heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated C5-6 carbocyclic ring system in which one or more, for example 1 or 2 of the carbon atoms preferably 1 carbon atom is replaced by a N atom.
  • Examples include piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl, pyrazolinyl, pirazolidinyl, pyrazolyl, tetrazolyl, imidazolidinyl and hexahidroazepenyl.
  • the 5- to 7-membered N-containing heterocyclyl might be fused to a phenyl ring group.
  • fused bicyclic examples include indolinyl, isoindolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzotetrahydro[b]azepenyl, benzotetrahydro[c]azepenyl and benzotetrahydro[d]azepenyl.
  • the term 4- to 6-membered N-containing heterocyclylene embraces divalent typically a non-aromatic, saturated or unsaturated C4-6 carbocyclic ring system, in which one or more, for example 1 , 2 or 3 of the carbon atoms preferably 1 carbon atom is replaced by a N atom.
  • the term 4- to 5-membered N- containing heterocyclylene embraces divalent typically a non-aromatic, saturated or unsaturated C4-5 carbocyclic ring system, in which one or more, for example 1 or 2 of the carbon atoms preferably 1 carbon atom is replaced by a N atom. Examples include azetidinylene, pyrrolidylene, piperidylene, pyrrolinylene, piperazinylene and pyrrolylene.
  • halogen atom embraces chlorine, fluorine, bromine or iodine atoms typically a fluorine, chlorine or bromine atom.
  • halo when used as a prefix has the same meaning.
  • Ci-4 rmonoalkylamino is represented by the formula -NH(Ci-4 alkyl) where Ci-4 alkyl is as described above.
  • Representative examples include methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, and (ieri-butyl)amino group.
  • C1-4 dialkylamino as used herein is represented by the formula - N(Ci-4 alkyl)2 where C1-4 alkyl is as described above.
  • Representative examples include dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group and d ⁇ tert- butyl)amino group.
  • atoms, radicals, moieties, chains and cycles present in the general structures of the invention are "unsubstituted or substituted". This means that these atoms, radicals, moieties, chains and cycles can be either unsubstituted or substituted in any position by one or more, for example 1 , 2, 3 or 4, substituents, whereby the hydrogen atoms bound to the unsubstituted atoms, radicals, moieties, chains and cycles are replaced by chemically acceptable atoms, radicals, moieties, chains and cycles.
  • therapeutically effective amount refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
  • treatment refers to the treatment of a disease or medical condition in a human patient which includes:
  • pathological condition or disease susceptible to amelioration by inhibition or antagonism of TRPA1 includes all disease states and/or conditions that are acknowledged now, or that are found in the future, to be associated with an increased TRPA1 activity.
  • disease states include, but are not limited to, acute and/or chronic pruritus, acute and/or chronic pain, inflammatory dermatological diseases, respiratory disorders, gastrointestinal inflammatory disorders and urinary tract disorders.
  • the term "pruritus” is used herein in the broadest sense and refers to all types of itching and stinging sensations localized and generalized, acute intermittent and persistent.
  • the pruritus may be dermatologic, idiopathic, allergic, metabolic, infectious, drug-induced, due to liver, kidney disease or cancer.
  • pain is used herein in the broadest sense and refers to all types of pain, including acute and chronic pain, such as nociceptive pain, e.g. somatic pain and visceral pain; inflammatory pain; dysfunctional pain; idiopathic pain; neuropathic pain, e.g. centrally generated pain and peripherally generated pain; migraine and cancer pain.
  • nociceptive pain e.g. somatic pain and visceral pain
  • inflammatory pain e.g. somatic pain and visceral pain
  • dysfunctional pain e.g. somatic pain and visceral pain
  • idiopathic pain e.g. centrally generated pain and peripherally generated pain
  • migraine and cancer pain e.g. centrally generated pain and peripherally generated pain.
  • inflammatory dermatological disease includes the following dermatological diseases as non-limiting examples of such dermatological diseases: acne vulgaris, actinic keratosis, eczema, atopic dermatitis, insect bite inflammation, drug-induced skin reactions, psoriasis, rosacea and seborrheic dermatitis.
  • respiratory disorder any condition or disease related to respiration or the respiratory system and includes, but is not limited to, airway inflammation, asthma, emphysema, bronchitis, COPD, sinusitis, rhinitis, cough, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, bronchiectasis, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), inflammatory respiratory diseases conditions poorly responder to corticosteroids (i.e. severe COPD and asthma), sensory hyper-reactivity, multiple chemical sensitivity and aid in smoking cessation therapy.
  • airway inflammation asthma, emphysema, bronchitis, COPD, sinusitis, rhinitis, cough, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, bronchiectasis, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), inflammatory respiratory diseases conditions poorly responder to cortico
  • cough refers to both acute and/or chronic cough and includes interstitial lung disease cough, post-viral cough, gastroesophageal reflux disease (GERD)-related cough, cough variant asthma, COPD cough, lung cancer cough, upper airways cough syndrome (UACS), post nasal drip cough, idiopathic cough and cough associated with other respiratory diseases such as idiopathic pulmonary fibrosis (IPF).
  • GFD gastroesophageal reflux disease
  • COPD COPD cough
  • UACS upper airways cough syndrome
  • IPF idiopathic cough and cough associated with other respiratory diseases such as idiopathic pulmonary fibrosis
  • gastrointestinal inflammatory disorders includes, but is not limited to, disorders such as inflammatory bowel disease, ulcerative colitis and Crohn's disease.
  • urinary tract disorders includes, but is not limited to, disorders such as urinary incontinence, bladder instability and cystitis.
  • pharmaceutically-acceptable salt refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal.
  • Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids.
  • Salts derived from pharmaceutically-acceptable acids include acetic, benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, hydrofluoric, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, xinafoic (1 -hydroxy-2-naphthoic acid), napadisilic (1 ,5-naphthalenedisulfonic acid), triphenyl acetic and the like.
  • salts derived from formic, fumaric, hydrobromic, hydrochloric, hydrofluoric, acetic, sulfuric, methanesulfonic, xinafoic, tartaric, maleic, succinic and napadisilic acids are particularly preferred.
  • Salts derived from pharmaceutically-acceptable inorganic bases include aluminium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Particularly preferred are calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of ammonia, primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as ammonia, arginine, betaine, caffeine, choline, /V,/V-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, /V-ethylmorpholine, /V-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • X " may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
  • mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate
  • organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
  • X " is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably X " is chloride, bromide, trifluoroacetate or methanesulphonate.
  • an /V-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent.
  • solvate means a compound which further includes a stoichiometric or non-stoichiometric amount of solvent such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, or the like, bound by non-covalent intermolecular forces.
  • solvent such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, or the like
  • hydrate is used instead of solvate.
  • the invention also includes isotopically-labelled compounds of the invention, wherein one or more atoms is replaced by an atom 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 sulfur, such as 35 S.
  • Isotopically-labelled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labelled reagent in place of the non-labelled reagent otherwise employed.
  • Preferred isotopically-labelled compounds include deuterated derivatives of the compounds of the invention.
  • deuterated derivative embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium.
  • Deuterium (D or 2 H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.
  • stereoisomer means a compound that have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three- dimensional orientations of their atoms in space.
  • the compounds of the invention may contain one or more chiral centers. Accordingly, the invention includes racemic mixtures, enantiomers, and mixtures enriched in one or more stereoisomer.
  • the scope of the invention as described and claimed encompasses the racemic forms of the compounds as well as the individual enantiomers, diastereomers, and stereoisomer-enriched mixtures.
  • tautomer means two or more forms or isomers of an organic compound that readily could be interconverted into each other via a common chemical reaction called tautomerization. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond.
  • the concept of tautomerizations is called tautomerism. Because of the rapid interconversion, tautomers are generally considered to be the same chemical compound. In solutions in which tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH.
  • G 4 represents a C-H group or a N atom
  • G 5 represents a C(R a ) group or a N(R b ) group.
  • G 2 is a N atom and n is 0, G 1 is C atom, G 3 is a N atom and G 5 is a N(R b ) group or G 1 is C atom, G 3 is a N(R b ) group and G 5 is a C(R a ) group or G 1 is a N atom, G 3 is a C(R a ) group and G 5 is a C(R a ) group or G 1 is C atom, G 3 is a C(R a ) group and G 5 is a N(R b ) group; and preferably wherein G 2 is a N atom and n is 0, G 1 is C atom, G 3 is a N atom and G 5 is a N-Me group or G 1 is a N atom, G 3 is a C-H group and G 5 is a C-Me group or G 1 is C atom, G 3 is a C-H group and G 5 a N atom, G 3 is
  • G 3 is a C(R a ) group
  • G 4 is a N atom or a C-H group
  • G 5 is a C(R a ) group
  • G 2 is a N atom
  • G 1 is C atom and n is 1
  • G 3 is a C-NH2 group
  • G 4 is a N atom and G 5 is a C-Me group
  • G 3 is a C(R a ) group
  • G 4 is a C-H group and G 5 is a C-Me group
  • R a is a chlorine atom or a methoxy group.
  • G 2 is a N(R b ) group
  • G 1 is C atom and n is
  • G 3 is a C(R a ) group or a N atom and G 5 is a N(R b ) group or a C(R a ) group
  • G 2 is a N-Me group
  • G 1 is C atom and n is
  • G 5 is a N-Me group or G 3 is a N atom and G 5 is a C(R a ) group, wherein R a is a H atom or a methyl group.
  • G 2 is a N(R b ) group
  • G 1 is C atom and n is 1
  • G 3 is a C(R a ) group
  • G 4 is a C-H group
  • G 5 is a C(R a ) group
  • G 2 is a N-H group or a N-Me group
  • G 1 is C atom and n is 1
  • G 4 is a C-H group and G 5 is a C-Me group.
  • G 2 is a C(R a ) group
  • G 1 is a C atom and n is 1
  • G 3 is a N atom or a C(R a ) group
  • G 4 and G 5 are C(R a ) groups; preferably wherein G 2 is a C-H group, G 3 and G 4 are C-H groups and G 5 is a C-Me group; or G 2 is a C-H group or a C-OMe group, G 3 is a N atom, G 4 is a C-H group and G 5 is a C-Me group.
  • a compound of Formula (I) is represented by compounds from Formula (la) to Formula (Ig):
  • R a is selected from the group consisting of a H atom, a linear or branched Ci-3 alkyl group, a halogen atom, a linear or branched Ci-2 alkoxy group, an oxo group, a cyano group, an amino group, a Ci-2 rmonoalkylamino group and a hydroxyl group.
  • R a is selected from the group consisting of a H atom, a linear or branched C1-2 alkyl group, a chlorine atom, a methoxy group, an oxo group, a cyano group, an amino group, a methylamino group and a hydroxyl group.
  • R b is selected from the group consisting of a H atom and a linear or branched C1-3 alkyl group.
  • R b is a H atom and a linear or branched C1-2 alkyl group.
  • R' and R" each independently represent a hydrogen atom, a linear or branched C1-2 alkyl group or a linear or branched C1-2 haloalkyl group.
  • Q is selected from the group consisting of a monocyclic or bicyclic Ce-14 aryl group and a monocyclic or bicyclic 5- to 14-membered heteroaryl group containing at least one heteroatom selected from N and S of formula (iv), (v), (vi) or (vii);
  • aryl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-3 alkyl group, a linear or branched C1-2 alkoxy group, a linear or branched C1-2 haloalkyl group, a linear or branched C1-2 haloalkoxy group, a linear or branched C1-2 thioalkyl group and a linear or branched C1-2 halothioalkyl group;
  • Q is selected from the group consisting of a phenyl group, a naphthyl group, a quinolyl group or a thienyl group; wherein the phenyl, naphthyl group, quinolyl group and thienyl groups are unsubstituted or substituted by one or more substituents selected from a chlorine atom, a bromide atom, a -CF3 group, a -OCF3 group, a -SCF3 group and an isopropyl group;
  • a compound of Formula (I) is represented by compounds from Formula (Ip) to Formula (Iv):
  • R a is selected from the group consisting of a H atom, a linear or branched C1-2 alkyl group or an oxo group;
  • R b is independently selected from the group consisting of a H atom or a linear or branched C1-2 alkyl group;
  • L represents an ethylene group substituted by a hydroxyl group
  • Q is selected from the group consisting of a phenyl group, a naphthyl group, a quinolinyl group and a thienyl group; wherein the phenyl, naphthyl, quinolinyl and thienyl groups are unsubstituted or substituted by one or more substituents selected from a chlorine atom, a bromine atom, a -CF3 group, a -OCF3 group, a -SCF3 group and an isopropyl group.
  • Particular individual compounds of the invention include:
  • the compounds of the invention can be prepared using the methods and procedures described herein, or using similar methods and procedures. It will be appreciated that where typical or preferred process conditions are given (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • the choice of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and de-protection, are well known in the art. For example, numerous protecting groups, and their introduction and removal are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
  • Compounds of general formula (6) may be prepared from compounds of formula (2) wherein R 11 represents a hydrogen atom, an alkyl group such as methyl, ethyl, propyl, ie f-butyl or a benzyl group, and a formamide equivalent such as formamide or formamidine and salts thereof.
  • R 11 represents a hydrogen atom, an alkyl group such as methyl, ethyl, propyl, ie f-butyl or a benzyl group
  • the reaction is carried out by mixing a compound of formula (2) with formamide in the presence or absence of an acid such as acetic acid at a temperature from 50°C to 200 °C to give a compound of formula (6).
  • R 11 is an alkyl group such as methyl, ethyl, propyl, ie/f-butyl or a benzyl group
  • the reaction is carried out by mixing a compound of formula (2) with formamidine acetic acid salt in the presence or absence of an acid such as acetic acid, in a solvent such as n-butanol at a temperature from 50 °C to 150 °C to give a compound of formula (6).
  • Compounds of general formula (6) may also be prepared from compounds of formula (3).
  • reaction is carried out by mixing a compound of formula (3) with formamide in the presence or absence of an acid such as acetic acid at a temperature from 50°C to 200 °C to give a compound of formula (6).
  • reaction is carried out by mixing a compound of formula (3) with an ortho- formate of formula (5) wherein R 12 represents an alkyl group such as methyl or ethyl, in the presence or absence of a solvent such as acetic anhydride at a temperature from 50 °C to 200 °C.
  • Compounds of general formula (6) may also be prepared from compounds of formula (4) and formic acid, in the presence or absence of an acid such as sulphuric acid at a temperature from 50 °C to 200 °C.
  • Intermediates of formula (8), wherein wherein R 11 is a an alkyl group such as methyl, ethyl, propyl, ie f-butyl or a benzyl group may be prepared from intermediates of formula (7) in the presence of a base such as lithium hexamethyldisilazide and an aminating agent such as 0-(diphenylphosphoryl)hydroxylamine, in a solvent such as tetrahydrofuran, dimethylformamide or mixtures thereof at a temperature from -78 °C to room temperature under an inert atmosphere such as nitrogen or argon.
  • a base such as lithium hexamethyldisilazide and an aminating agent such as 0-(diphenylphosphoryl)hydroxylamine
  • intermediates of formula (10) may be prepared from intermediates of formula (9) in the presence of a base such as lithium hexamethyldisilazide and an aminating agent such as O- (diphenylphosphoryl)hydroxylamine, in a solvent such as tetrahydrofuran, dimethylformamide or mixtures thereof at a temperature from -78 °C to room temperature under an inert atmosphere such as nitrogen or argon.
  • a base such as lithium hexamethyldisilazide and an aminating agent such as O- (diphenylphosphoryl)hydroxylamine
  • Bicyclic heterocycles of general formula (1 1 ) wherein G 1 to G 5 and n are as defined in Claim 1 and independent of their attachment to other groups through the amide nitrogen may be further modified to compounds such as (12) or (14) following the synthetic routes depicted in Scheme 3.
  • compounds containing a bicyclic heterocycle of formula (12) wherein one or more of the groups G 2 to G 5 is a carbon atom substituted with a W 3 group, wherein W 3 is a halogen atom such as fluorine, chlorine, bromine or iodine may be synthesized from a compound containing a bicyclic heterocycle of formula (1 1 ) wherein one or more of the groups G 2 to G 5 is a CH group.
  • the reaction may be carried out by mixing a compound of formula (1 1 ) with a halogenating reagent such as 1 - (chloromethyl)-4-fluoro-1 ,4- diazabicyclo[2.2.2]octane-1 ,4-diium tetrafluoroborate, copper(ll) bromide, /V-chlorosuccinimide, /V-bromosuccinimide, /V-iodosuccinimide, bromine or iodine, in a solvent such as acetonitrile, chloroform or dimethylformamide at a temperature from 0 °C to 100 °C.
  • a halogenating reagent such as 1 - (chloromethyl)-4-fluoro-1 ,4- diazabicyclo[2.2.2]octane-1 ,4-diium tetrafluoroborate, copper(ll) bromide, /V-chlorosuccinimide
  • compounds containing a bicyclic heterocycle of formula (12) wherein W 3 is a halogen atom such as bromine or iodine, prepared as described above may be used as substrates in metal catalysed cross coupling reactions with a suitable partner such as an alkyl and/or aryl boronate, a boronic acid or a trifluoroborate salt for introduction of aryl and alkyl groups on the bicyclic heterocycle (12).
  • a suitable partner such as an alkyl and/or aryl boronate, a boronic acid or a trifluoroborate salt for introduction of aryl and alkyl groups on the bicyclic heterocycle (12).
  • Compounds containing a bicyclic heterocycle of formula (14) wherein R 13 and R 14 are independently selected from a group containing a hydrogen atom or an alkyl group such as methyl, ethyl or isopropyl, may be synthesized from a compound containing a bicyclic heterocycle of formula (12) wherein W 3 represents a halogen atom such as chlorine, bromine or iodine.
  • the reaction may be carried out by mixing a compound of formula (12) with an amine of formula (13), in the presence or absence of a base such as diisopropylethylamine of potassium carbonate, in a solvent such as tetrahydrofuran, dimethylformamide or mixtures thereof at a temperature from 50 °C to 150 °C.
  • a base such as diisopropylethylamine of potassium carbonate
  • a solvent such as tetrahydrofuran, dimethylformamide or mixtures thereof at a temperature from 50 °C to 150 °C.
  • Compounds of general formula (16) wherein A is as hereinbefore defined and R 11 represents an alkyl group such as methyl, ethyl, propyl, ie f-butyl or a benzyl group may be prepared from bicyclic compounds of formula (6) and an alkylating agent of formula (15) wherein W 1 represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate.
  • the reaction is carried out by mixing a compound of formula (6) and compound of formula (15) in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide at a temperature from room temperature to 80 °C.
  • Compounds of general formula (17), wherein A is as hereinbefore defined may be prepared from compounds of formula (16), wherein R 11 is as hereinbefore defined by hydrolysis according to standard literature methods known to those skilled in the art of ester hydrolysis.
  • this may be through the use of a base such as sodium hydroxide in a solvent such as water, methanol, ethanol or tetrahydrofuran, or mixtures thereof, at a temperature from room temperature to 50 °C.
  • a base such as sodium hydroxide in a solvent such as water, methanol, ethanol or tetrahydrofuran, or mixtures thereof, at a temperature from room temperature to 50 °C.
  • an acid such as hydrochloric acid or trifluoroacetic acid in water, dichloromethane, chloroform or dioxane or a mixture thereof at a temperature from room temperature to 50 °C.
  • Compounds of general formula (19), wherein A is as hereinbefore defined, may be prepared from bicyclic compounds of formula (6) and an alkylating agent of formula (18) wherein W 1 represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate.
  • the reaction is carried out by mixing a compound of formula (6) and compound of formula (18) in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide at a temperature from room temperature to 80 °C.
  • the reaction is carried out by mixing a compound of formula (20) and a compound of formula (22) in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide at a temperature from room temperature to 80 °C.
  • a base such as potassium carbonate
  • a solvent such as dimethylformamide
  • Route C Compounds of general formula (23) may also be prepared via a range of routes referred to as Route C.
  • An example of Route C is, but not limited to, the case wherein G 6 and G 8 represent a nitrogen atom, G 7 represents a carbon atom and G 9 represents a sulphur atom and hence the heteroaromatic ring defined by G 6 to G 9 is a thiadiazole.
  • Compounds of general formula (27) wherein L and Q are defined according to Claim 1 may be prepared from compounds of formula (26) according to standard literature methods known to those skilled in the art of formation of amides. In one instance, this may involve first treating a compound of formula (26) with a peptide coupling reagent such as dicyclohexylcarbodiimide (DCC) or 1 -ethyl-3-(3- dimethylaminopropyl)-carbodiimide (EDC), in the presence or absence of a catalyst such as 1 -hydroxybenzotriazole (HOBt) and then treating the mixture with ammonia to give a compound of formula (27).
  • a peptide coupling reagent such as dicyclohexylcarbodiimide (DCC) or 1 -ethyl-3-(3- dimethylaminopropyl)-carbodiimide (EDC)
  • DCC dicyclohexylcarbodiimide
  • EDC 1 -
  • Compounds of general formula (28), wherein L and Q are as hereinbefore defined, may be prepared from compounds of formula (27) and chlorocarbonylsulfenyl chloride.
  • the reaction is carried out by mixing a compound of formula (27) and chlorocarbonylsulfenyl chloride in a solvent such as toluene at a temperature from 50 °C to the boiling point of the solvent to give a compound of formula (28).
  • Compounds of general formula (30), a subset of general formula (23), wherein L and Q are as hereinbefore defined and R 11 is an alkyl group such as methyl, ethyl, propyl, ie f-butyl or a benzyl group, may be prepared from compounds of formula (28) and a compound of formula (29) wherein R 11 is hereinbefore defined.
  • the reaction is carried out by mixing a compound of formula (28) and a compound of formula (29) in a solvent such as tetrahydrofuran at a temperature from 100 °C to 180 °C in a sealed vessel under microwave irradiation to give a compound of formula (30).
  • Compounds of general formula (24) wherein G 1 to G 5 , L and Q are as defined in Claim 1 may be prepared from compounds of formula (21 ) and an alkylating agent of formula (22) wherein W 1 represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate.
  • the reaction is carried out by mixing a compound of formula (21 ) and a compound of formula (22) in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide at a temperature from room temperature to 80 °C.
  • Route B is, but not limited to the case where G 6 , G 7 and G 9 represent a nitrogen atom and G 8 represents a C-H group and hence the heteroaromatic ring defined by G 6 to G 9 is a 1 ,2,4-triazole.
  • Compounds of general formula (24) may be prepared from compounds of formula (23) and a reducing agent according to standard literature methods known to those skilled in the art of reduction of esters to alcohols.
  • the reaction is carried out by mixing a compound of formula (23) and a reducing agent such as sodium borohydride in a solvent such as ethanol at a temperature from 0 °C to 50 °C to give a compound of formula (24).
  • Route D Compounds of general formula (24) may also be prepared via range of routes referred to as Route D.
  • An example of Route D is, but not limited to, the case wherein G 6 and G 9 represent a nitrogen atom, G 7 represents a carbon atom and G 8 represents an oxygen atom and hence the heteroaromatic ring defined by G 6 to G 9 is a 1 ,2,4- oxadiazole.
  • Example route D is, but not limited to, the case wherein G 6 and G 9 represent a nitrogen atom, G 7 represents a carbon atom and G 8 represents an oxygen atom and hence the heteroaromatic ring defined by G 6 to G 9 is a 1 ,2,4- oxadiazole.
  • Compounds of general formula (31 ) wherein L and Q are defined according to Claim 1 may be prepared from compounds of formula (26) and dihydroxyethanimidamide according to standard literature methods known to those skilled in the art of formation of amides. In one instance, this may involve first converting a compound of formula (26) to an acid chloride with an activating agent such as thionyl chloride or phosphorous oxychloride and then reacting the acid chloride with dihydroxyethanimidamide in the presence of a base such as diisopropylehtylamine in a solvent such as tetrahydrofuran to give a compound of formula (31 ).
  • an activating agent such as thionyl chloride or phosphorous oxychloride
  • a base such as diisopropylehtylamine
  • solvent such as tetrahydrofuran
  • Compounds of general formula (32), a subset of general formula (24), wherein L and Q are as hereinbefore defined may be prepared from compounds of formula (31 ) by condensation.
  • a compound of formula (31 ) is treated with a base such as sodium acetate in a solvent such as ethanol at a temperature from room temperature to the boiling point of the solvent to give a compound of formula (32).
  • Route D is, but not limited to the case wherein G 6 and G 8 represent a nitrogen atom, G 7 represents a carbon atom and G 9 represents an oxygen atom and hence the heteroaromatic ring defined by G 6 to G 9 is a 1 ,2,4-oxadiazole.
  • L is also defined as a 4- to 6-membered N-containing heterocyclylene group, or that when Q represents a phenyl group, L together with Q, as defined in Claim 1 form a 5- to 7-membered N-containing heterocyclyl fused to the phenyl group;
  • Compounds of general formula (35) wherein W 3 represents a halogen atom such as chlorine, bromine or iodine and PG represents a suitable alcohol protecting group selected from an ester group such as acetate or benzoate, or an acetal such as tetrahydropyranyl, may be prepared from compounds of formula (33) and compound of formula (34).
  • the reaction is carried out by treating a compound of formula (33) with a compound of formula (34) in the presence of a base such as sodium bicarbonate in a solvent such as toluene at a temperature from 40 °C to the boiling point of the solvent to give a compound of formula (35).
  • Compounds of general formula (25) wherein G 6 to G 9 , L and Q are as defined in Claim 1 , and W 1 represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate may be prepared from compounds of formula (24).
  • W 1 represents a halogen atom
  • a compound of formula (24) is treated with a halogenating reagent such as thionyl chloride or phosphorus oxychloride in a solvent such as chloroform or toluene, at a temperature from 50 °C to the boiling point of the solvent to give a compound of formula (25).
  • Route E Compounds of general formula (25) wherein may also be prepared via range of routes referred to as Route E.
  • An example of Route E is, but not limited to, the case wherein G 6 and G 8 represent a nitrogen atom, G 7 represents a carbon atom and G 9 represents an oxygen atom and hence the heteroaromatic ring defined by G 6 to G 9 is a 1 ,2,4-oxadiazole.
  • Compounds of general formula (40) wherein L and Q are as defined in Claim 1 may be prepared from compounds of formula (39) and hydroxylamine or salts thereof.
  • the reaction is carried out by treating a compound of formula (39) with hydroxylamine hydrochloride, in the presence of a base such as sodium bicarbonate, in a solvent such as methanol or ethanol, at a temperature from room temperature to the boiling point of the solvent to give a compound of formula (40).
  • Compounds of general formula (42), a subset of general formula (25), wherein L and Q are as hereinbefore defined and wherein W 1 represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate may be prepared from compounds of formula (40) and a compound of formula (41 ), wherein W 2 represents either a halogen such as chlorine and hence (41 ) is an acyl chloride or a half-stoichiometric oxygen atom and hence (41 ) is an anhydride.
  • the reaction is carried out by treating a compound of formula (40) with a compound of formula (41 ) in a solvent such as toluene at a temperature from 50 °C to the boiling point of the solvent to give a compound of formula (42).
  • a solvent such as toluene
  • Another example of Route E is, but not limited to, the case wherein G 6 represents an oxygen atom, G 7 represents a carbon atom and G 8 and G 9 represent a nitrogen atom and hence the heteroaromatic ring defined by G 6 to G 9 is a 1 ,3,4-oxadiazole.
  • Compounds of general formula (43) wherein L and Q are as defined in Claim 1 may be prepared from compounds of formula (26) and hydrazine, or its hydrate, or salts thereof.
  • the reaction may be carried out by treating a compound of formula (26) with hydrazine monohydrate in a sealed vessel at a temperature from 100 °C to 180 °C under microwave irradiation to give a compound of formula (43).
  • the reaction is carried out by treating a compound of formula (43) with a compound of formula (41 ) in the presence of a base such as triethylamine, in a solvent such as dichloromethane at a temperature from 0 °C to 50 °C to give a compound of formula (44).
  • a base such as triethylamine
  • a further example of Route E is, but not limited to, the case wherein G 6 represents a nitrogen atom, G 7 represents a carbon atom, G 8 represent a C-H group and G 9 represents an oxygen atom and hence the heteroaromatic ring defined by G 6 to G 9 is an oxazole.
  • Compounds of general formula (47) wherein L and Q are as defined in Claim 1 may be prepared from compounds of formula (46) by a Strecker-type reaction followed by hydrolysis.
  • the reaction may be carried out by first treating a compound of formula (46) with a cyanide source such as sodium cyanide and an ammonia source such as ammonium chloride in a solvent such as ethanol at a temperature from 0 °C to 50 °C, followed by treatment with an acid such as hydrochloric acid at a temperature from 50 °C to 100 °C to give a compound of formula (47).
  • a cyanide source such as sodium cyanide and an ammonia source such as ammonium chloride in a solvent such as ethanol
  • an acid such as hydrochloric acid
  • Compounds of general formula (48) wherein L and Q are as hereinbefore defined may be prepared from compounds of formula (47) and a reducing agent according to standard literature methods known to those skilled in the art of reduction of carboxylic acids to alcohols.
  • the reaction is carried out by mixing a compound of formula (47) and a reducing agent such as borane-dimethylsulfide complex in a solvent such as tetrahydrofuran at a temperature from 0 °C to 50 °C to give a compound of formula (48).
  • the reaction may be carried out by treating a compound of formula (48) with a compound of formula (41 ) in the presence of a base such as triethylamine, in a solvent such as dichloromethane at a temperature from -78 °C to room temperature to give a compound of formula (49).
  • a base such as triethylamine
  • a solvent such as dichloromethane
  • Compounds of general formula (50) wherein L, Q and W 1 are as hereinbefore defined may be prepared from compounds of formula (49) and an oxidizing agent according to standard literature methods known to those skilled in the art of oxidation alcohols to aldehydes.
  • reaction is carried out by mixing a compound of formula (49) and an oxidizing agent such as the Dess-Martin periodinane in a solvent such as dichloromethane at a temperature from 0 °C to 50 °C to give a compound of formula (50).
  • an oxidizing agent such as the Dess-Martin periodinane
  • a solvent such as dichloromethane
  • Compounds of general formula (51 ), a subset of general formula (25), wherein L, Q and W 1 are as hereinbefore defined may be prepared from compounds of formula (50) by dehydration.
  • the reaction is carried out by mixing a compound of formula (50) and a dehydration agent such as phosphorous oxychloride at a temperature from 50 °C to 100 °C to give a compound of formula (51 ).
  • Compounds of formula (1_) may be prepared from compounds of formula (6) wherein A refers to the heterobicyclic group defined by G 1 to G 5 and n of Claim 1 and compounds of formula (25) wherein G 6 to G 9 , L and Q are as defined in Claim 1 and W 1 represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate.
  • the reaction may be carried out by treating a compound of formula (6) with a compound of formula (25) in the presence of a base such as potassium carbonate, in a solvent such as dimethylformamide, at a temperature from room temperature to 50 °C to give a compound of formula (1).
  • Compounds of general formula may also be prepared from either a compound of formula (16), wherein R 11 is an alkyl group such as methyl, ethyl, propyl, ieri-butyl or a benzyl group, or from a compound of formula (17) via a range of routes to construct the heterocycle defined by G 6 to G 9 , referred to as Route F.
  • Route F is, but not limited to, the case wherein G 6 and G 8 represent a nitrogen atom, G 7 represents a carbon atom and G 9 represents an oxygen atom and hence the heteroaromatic ring defined by G 6 to G 9 is a 1 ,2,4-oxadiazole.
  • compounds of general formula (53) may also be prepared from compounds of formula (17) and a compound of formula (40).
  • the reaction may be carried out by treating a compound of formula (17) with a compound of formula (40) in the presence of a peptide coupling reagent such as /V-(3-dimethylaminopropyl)-/V- ethylcarbodiimide hydrochloride in a solvent such as dichloroethane, dimethylformamide or mixtures thereof at temperatures from room temperature to 120 °C to give a compound of formula (53).
  • a peptide coupling reagent such as /V-(3-dimethylaminopropyl)-/V- ethylcarbodiimide hydrochloride
  • a solvent such as dichloroethane, dimethylformamide or mixtures thereof
  • Route F is, but not limited to, the case wherein the heteroaromatic ring defined by G 6 to G 9 is a 1 ,2,4-oxadiazole and L is defined as a - CH 2 CH(OH)- group.
  • Compounds of formula (55) wherein Q is as defined in Claim 1 may be prepared from compounds of formula (54).
  • the reaction is carried out by treating a compound of formula (54) with acetonitrile in the presence of a base such as lithium hexamethyldisilazide, in a solvent such as tetrahydrofuran, at a temperature from -78 °C to room temperature, under an inert atmosphere such as argon to give a compound of formula (55).
  • a base such as lithium hexamethyldisilazide
  • solvent such as tetrahydrofuran
  • Compounds of general formula (56) wherein Q is as hereinbefore defined may be prepared from compounds of formula (55) and hydroxylamine or salts thereof.
  • the reaction is carried out by treating a compound of formula (55) with hydroxylamine hydrochloride, in the presence of a base such as potassium carbonate, in a solvent such as methanol or ethanol, at a temperature from room temperature to the boiling point of the solvent to give a compound of formula (56).
  • Compounds of general formula (57), a subset of general formula (1_), wherein Q and A are as hereinbefore defined may be prepared from compounds of formula (16) wherein R 11 is an alkyl group such as methyl, ethyl, propyl, ie f-butyl or benzyl and a compound of formula (56).
  • the reaction may be carried out by treating a compound of formula (16) with a compound of formula (56) in the presence of a base such as potassium carbonate, in a solvent such as toluene, at a temperature from 50 °C to the boiling point of the solvent to give a compound of formula (57).
  • a further example of Route F is, but not limited to, the case wherein the heteroaromatic ring defined by G 6 to G 9 is a 1 ,2,4-oxadiazole and L is defined as a - CONH- group.
  • Compounds of general formula (59), wherein A is as hereinbefore defined and R 11 is an alkyl group such as methyl, ethyl, propyl, ie f-butyl or a benzyl group may be prepared from compounds of formula (17) and a compound of formula (58).
  • the reaction may be carried out by treating a compound of formula (17) with a compound of formula (58) in the presence of a peptide coupling reagent such as N-(3- dimethylaminopropyl)-/V-ethylcarbodiimide hydrochloride in a solvent such as dichloroethane, dimethylformamide or mixtures thereof at temperatures from room temperature to 120 °C to give a compound of formula (59).
  • a peptide coupling reagent such as N-(3- dimethylaminopropyl)-/V-ethylcarbodiimide hydrochloride
  • a solvent such as dichloroethane, dimethylformamide
  • Compounds of general formula (59) may also be prepared from compounds of formula (6) and a compound of formula (60) wherein A and R 11 are hereinbefore defined, and W 3 represents a halogen atom such as chlorine, bromine or iodine.
  • the reaction may be carried out by treating a compound of formula (6) with a compound of formula (60) in the presence of a base such as potassium carbonate, in a solvent such as dimethylformamide, at a temperature from room temperature to 50 °C to give a compound of formula (59).
  • the reaction is carried out by first hydrolysing a compound of formula (59) according to standard methods of ester hydrolysis, for example with lithium hydroxide monohydrate in water, and then treating the resulting carboxylic acid with an amine of formula (61 ) in the presence of a peptide coupling reagent such as /V-ethyl-/V'-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1 -hydroxybenzotriazole hydrate in a solvent such as dichloromethane to give a compound of formula (62).
  • a peptide coupling reagent such as /V-ethyl-/V'-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1 -hydroxybenzotriazole hydrate in a solvent such as dichloromethane
  • Route G is, but not limited to, the case wherein G 6 represents a nitrogen atom, G 7 represents a NH group, G 8 represents a carbonyl group and G 9 represents an oxygen atom and hence the heteroaromatic ring defined by G 6 to G 9 is a 1 ,3,4-oxadiazolone.
  • Compounds of general formula (63) wherein A is as hereinbefore defined may be prepared from compounds of formula (17) according to standard literature methods known to those skilled in the art of formation of amides. In one instance, this may involve treating a compound of formula (17) with semicarbazide in the presence of a peptide coupling reagent such as (benzotriazol-l -yloxy)tris(dimethylamino) phosphonium hexa-fluorophosphate, in the presence of a base such as triethylamine in a solvent such as dichloromethane to give a compound of formula (63).
  • a peptide coupling reagent such as (benzotriazol-l -yloxy)tris(dimethylamino) phosphonium hexa-fluorophosphate
  • Compounds of general formula (64), a subset of general formula (52), wherein A is as hereinbefore defined may be prepared from compounds of formula (63) by cyclization. In one instance, this may involve treating a compound of formula (63) with a dehydrating agent such as trimethylsilyl tnfluoromethanesulfonate in the presence of a base such as triethylamine, in solvent such as dioxane in a sealed vessel at a temperature from 100 °C to 180 °C to give a compound of formula (64).
  • a dehydrating agent such as trimethylsilyl tnfluoromethanesulfonate
  • solvent such as dioxane
  • Compounds of general formula (1_) may additionally be prepared from compounds of formula (52) and an alkylating agent of formula (22) wherein W 1 represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para- toluenesulphonate or methylsulfonate.
  • the reaction is carried out by mixing a compound of formula (52) and a compound of formula (22) in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide at a temperature from room temperature to 80 °C.
  • Route H Compounds of general formula may further be prepared from compounds of formula (19) via a range of routes to construct the heterocycle defined by G 6 to G 9 , referred to as Route H.
  • An example of Route H is, but not limited to, the case wherein G 6 and G 8 represent a nitrogen atom, G 7 represents a carbon atom and G 9 represents a NH group and hence the heteroaromatic ring defined by G 6 to G 9 is a 1 ,2,4-triazole.
  • Compounds of general formula (65), a subset of general formula (1_), wherein L, Q and A are hereinbefore defined may be prepared from compounds of formula (19) and a compound of formula (43).
  • the reaction may be carried out by treating a compound of formula (19) with a compound of formula (43) in the presence of a base such as 4-dimethylaminopyridine, in a solvent such as ethanol, in a sealed vessel at a temperature from 100 °C to 180 °C to give a compound of formula (65).
  • a further example of Route H is, but not limited to, the case wherein the heteroaromatic ring defined by G 6 to G 9 is a 1 ,2,4-oxadiazole and L is also defined as a 4- to 6-membered N-containing heterocyclylene group, or that when Q represents a phenyl group, L together with Q, as defined in Claim 1 form a 5- to 7-membered N- containing heterocyclyl fused to the phenyl group.
  • Compounds of general formula (66) wherein A is as hereinbefore defined and W 3 represents a halogen atom such as chlorine, bromine or iodine may be prepared from compounds of formula (19) and compound of formula (34).
  • the reaction is carried out by treating a compound of formula (19) with a compound of formula (34) in the presence of a base such as sodium bicarbonate in a solvent such as toluene at a temperature from 40 °C to the boiling point of the solvent to give a compound of formula (66).
  • Compounds of general formula (67), a subset of general formula (1 ), wherein Q is defined according to Claim 1 may be prepared from compounds of formula (66) wherein W 3 is as hereinbefore defined and an amine of formula (36).
  • the reaction is carried out by treating a compound of formula (66) with a compound of formula (36) in a solvent such as ethanol at a temperature from 40 °C to the boiling point of the solvent to give a compound of formula (67).
  • Reagents, starting materials, and solvents were purchased from commercial suppliers and used as received. Commercial intermediates are referred to in the experimental section by their lUPAC name. Ether refers to diethyl ether, unless otherwise specified. Concentration or evaporation refer to evaporation under vacuum using a Buchi rotatory evaporator.
  • Reaction products were purified, when necessary, by flash chromatography on silica gel (40-63 ⁇ ) with the solvent system indicated. Purifications in reverse phase were made in a Biotage Isolera® automated purification system equipped with a C18 column and using a gradient, unless otherwise stated, of water-acetonitrile/MeOH (1 :1 ) (0.1 % v/v ammonium formate both phases) from 0% to 100% acetonitrile/MeOH (1 :1 ) in 40 column volumes.
  • the conditions "formic acid buffer” refer to the use of 0.1 % v/v formic acid in both phases.
  • the appropriate fractions were collected and the solvents evaporated under reduced pressure and/or liofilized.
  • Preparative H PLC-MS were performed on a Waters instrument equipped with a 2767 injector/collector, a 2525 binary gradient pump, a 2996 PDA detector, a 515 pump as a make-up pump and a ZQ4000 Mass spectrometer detector.
  • the chromatographic separations were obtained using a Waters 2795 system equipped with a Symmetry C18 (2.1 x 50 mm, 3.5 ⁇ ) column for methods A, B and C and a Symmetry C18 (2.1 x 100 mm, 3.5 ⁇ ) for method D.
  • the mobile phases were (B): formic acid (0.4 ml), ammonia (0.1 ml), methanol (500 ml) and acetonitrile (500 ml) and (A): formic acid (0.5 ml), ammonia (0.125 ml) and water (1000 ml) (A), the gradients are specified in the following table for each method used.
  • the flow rate was 0.8 ml/min for method A and 0.4 ml/min for method B, C and D.
  • the injection volume was 5 microliter.
  • a Waters 2996 diode array was used as a UV detector.
  • Chromatograms were processed at 210 nM or 254 nM. Mass spectra of the chromatograms were acquired using positive and negative electrospray ionization in a Micromass ZMD or in a Waters ZQ detectors coupled to the H PLC.
  • Chromatographic separations were also obtained using a Waters 2795 system equipped with a Symmetry C18 (2.1 x 50 mm, 3.5 ⁇ ) column for methods E.
  • the mobile phases were (B): formic acid (0.7 ml) and acetonitrile (1000 ml) and (A): formic acid (1 ml) and water (1000 ml) (A), the gradients specified as follows:
  • the U PLC chromatographic separations were obtained using a Waters Acquity UPLC system coupled to a SQD mass spectrometer detector.
  • the system was equipped with an ACQUITY UPLC BEH C-18 (2.1 x50mm, 1 .7 mm) column.
  • the mobile phase was formic acid (0.4 ml), ammonia (0.1 ml), methanol (500 ml) and acetonitrile (500 ml) (B) and formic acid (0.5 ml), ammonia (0.125 ml) and water (1000 ml) (A).
  • a gradient between 0 to 95% of B was used.
  • the run time was 3 or 5 minutes.
  • the injection volume was 0.5 microliter. Chromatograms were processed at 210 nM or 254 nM. Mass spectra of the chromatograms were acquired using positive and negative electrospray ionization.
  • Mass Spectra (m/z) were recorded on a Micromass ZMD or in a Waters ZQ mass spectrometer using ESI ionization.
  • "CI” or “Br” after the mass ion refers to the presence of those halogens based on the standard isotope mass pattern (76% 35 CI to 24% 37 CI and 49% 79 Br to 51 % 81 Br) Standard synthetic methods are described the first time they are used.
  • Lithium hexamethyldisilazide (1 M in tetrahydrofuran, 21 .4 ml, 21 .4 mmol) was added dropwise over 15 min to a stirred, cooled (-10 °C) suspension of ethyl 4-methyl-1 H- imidazole-5-carboxylate (3.00 g, 19.5 mmol) in dry dimethylformamide (200 ml) under an atmosphere of argon. After stirring for a further 10 min, O- (diphenylphosphoryl)hydroxylamine (5.45 g, 23.4 mmol) was added and the mixture was warmed to room temperature. After 6 h, water was added until a clear homogeneous solution formed and subsequently the mixture was evaporated to dryness.
  • N-Bromosuccinimide (0.25 g, 1 .40 mmol) was added to a stirred suspension of the title compound of PREPARATION 6 (0.20 g, 1 .33 mmol) in dimethylformamide (8 ml). After 6 h, further N-bromosuccinimide (0.25 g, 1 .40 mmol) was added and stirring was continued at room temperature. After 7.5 h, the mixture was diluted with 4% aqueous sodium hydrogen carbonate solution and the solid that formed was filtered, washed with water and dried to give 0.178 g (0.78 mmol, 58% yield) of the title compound as a white solid. Purity 98%. 1 H NMR (400 MHz, DMSO-d6) ⁇ ppm 1 1 .81 (s, 1 H), 7.88 (s, 1 H), 2.44 (s, 3H).
  • N-methyl-3-oxobutanamide 400 mg, 2.43 mmol
  • malonitrile 160 mg, 2.43 mmol
  • 10 ml of ethanol 5 drops
  • piperidine 5 drops
  • the mixture was stirred and heated at 80°C overnight.
  • the mixture was then cooled to room temperature and was concentrated in vacuo.
  • the residue was purified by flash chromatography using the Isolera purification system (ethyl acetate-hexane gradient, 0: 100 rising to 100:0) to give 95 mg (0.58 mmol, 24% yield) of the title compound as a yellow solid. Purity 100%.
  • 6-Chloro-W-methylpyrimidin-4-amine 4,6-Dichloropyrimidine (10 g, 67 mmol) was dissolved in 100 ml isopropanol and the solution was cooled to 0 °C, reprecipitating.
  • Methylamine solution (33% w/w, 17 ml, 140 mmol) was added slowly with stirring and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure. The residue was resuspended in water, stirred for 15 min and then filtered. The solid was dried under reduced pressure. The filtrate was extracted three times with ethyl acetate. The combined organics were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The solid obtained was combined with the first precipitate to give 8.50 g (59 mmol, 88% yield) of the title compound as a white solid. Purity 87%.
  • the title compound of PREPARATION 24 (8.5 g, 59 mmol) was dissolved in 100 ml methanol. Sodium methoxide (19.8 g, 370 mmol) was added in several portions over a 4 day period while the mixture was stirred at reflux. The mixture was allowed to cool and was evaporated under reduced pressure. The solid residue was resuspended in dichloromethane and was stirred for 1 h. The solution was filtered and the filtrate was evaporated under reduced pressure to give 7.80 g (56 mmol, 95% yield) of the title compound as a white solid. Purity 100%.
  • 6-Amino-2-methoxy-4-methylnicotinamide A mixture of the mixture of title compounds of PREPARATION 32 (710 mg, 4.35 mmol) was dissolved in 5 ml concentrated sulphuric acid and the mixture was agitated for 80 h at 40 °C. The mixture was poured onto ice and neutralized with solid sodium bicarbonate. The aqueous was extracted several times with chloroform and with dichloromethane, also forming a solid interface. The organic layer was filtered, dried over anhydrous sodium sulphate, refiltered and evaporated to give 530 mg (2.91 mmol, 67% yield) of an approx 3:1 mixture of the title compounds.
  • PREPARATION 36 2-Amino-6-chloro-4-methylnicotinamide 6-Amino-2-chloro-4-methylnicotinamide A mixture of the title compounds of PREPARATION 35 (1 .43 g, 8.53 mmol) in concentrated sulphuric acid (14 ml) was stirred and heated to 40 °C. After 96 h, the mixture was cooled, poured onto ice/water and neutralized with solid sodium hydrogen carbonate. The precipitate was filtered, washed with water and dried to give 1 .10 g (5.93 mmol, 70%) of the title compounds, in a 2: 1 mixture, as a white solid. Combined purity 96%.
  • Guanidine hydrochloride (1 .92 g, 20.1 mmol) was added to a suspension of the title compound of PREPARATION 38 (3.08 g, 20.1 mmol) and triethylamine (5.60 ml, 40.2 mmol) in ethanol (70 ml) and dimethylformamide (20 ml) and the mixture was stirred and heated to reflux. After 9 d, the mixture was cooled to room temperature and the precipitate was filtered and washed with ethanol.
  • hydrochloride salt Synthesized from the title compound of PREPARATION 44 following the method of PREPARATION 48. Yield: 100%. Purity 92%.
  • 3-(4-Chlorophenyl)propionic acid (0.50 g, 2.71 mmol) was dissolved in 2.5 ml dimethylformamide.
  • 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.78 g, 4.06 mmol) and 1 -hydroxybenzotriazole hydrate (0.55 g, 4.06 mmol) were added and the mixture was stirred at room temperature.
  • Ammonium hydroxide (32% solution in water, 1 .0 ml, 8.13 mmol) was added and the mixture was stirred overnight at 50°C. The mixture was allowed to cool and was partitioned between ethyl acetate and water.
  • This preparation was immediately dissolved in 1 ml tetrahydrofuran and ⁇ /,/V-diisopropyethylamine (765 ⁇ , 4.41 mmol) was added. The solution was cooled to 0 °C in an ice bath and 3-(4- chlorophenyl)propanoyl chloride (550 mg, 2.71 mmol) in 0.5 ml of tetrahydrofuran was added drop-wise. The mixture was stirred at 0 °C for 2 h. The mixture was partitioned between ethyl ether and saturated ammonium chloride solution. The aqueous phase was extracted with ethyl ether.
  • Methyl iodide (2.80 ml, 5.52 mmol) was added dropwise to a suspension of the title compound of PREPARATION 89 (1 .00 g, 5.51 mmol) and silver(l) oxide (1 .28 g, 5.52 mmol) in acetonitrile (10 ml) and the mixture was stirred at room temperature. After 24 h, further methyl iodide (1.40 ml, 2.76 mmol) was added and stirring was continued.
  • Lithium diisopropylamide (2M in tetrahydrofuran, 2.25 ml, 4.5 mmol) was diluted with 5 ml anhydrous tetrahydrofuran and cooled to -78 °C under argon atmosphere.
  • Acetonitrile (0.22 ml, 4.2 mmol) diluted with 8 ml anhydrous tetrahydrofuran was added drop-wise and with the mixture was then stirred for 15 min.
  • 4- (Trifluoromethyl)benzaldehyde 500 mg, 2.87 mmol
  • 8 ml anhydrous tetrahydrofuran was added. The mixture was stirred at -78 °C for 30 min and was then allowed to warm to room temperature.
  • PREPARATION 124 (1 Z)-3-(3,4-Dichlorophenyl)-yV',3-dihydroxypropanimidamide Synthesized from the title compound of PREPARATION 123 and hydroxylamine hydrochloride following the method of PREPARATION 114. Yield: 54%. Purity 95%.

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Abstract

La présente invention concerne des composés de formule (I), le procédé de préparation de tels composés et leur utilisation pour le traitement d'un état pathologique ou d'une maladie susceptible d'être amélioré par une activité antagoniste ou une inhibition des canaux TRPA1.
PCT/EP2016/074094 2015-10-09 2016-10-07 Nouveaux antagonistes de trpa1 WO2017060488A1 (fr)

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WO2018162607A1 (fr) * 2017-03-07 2018-09-13 F. Hoffmann-La Roche Ag Oxadiazole en tant qu'inhibiteurs de canaux potentiels de récepteur transitoire
WO2019182925A1 (fr) * 2018-03-19 2019-09-26 Genentech, Inc. Inhibiteurs de canal à potentiel de récepteur transitoire à base d'oxadiazole
CN111150847A (zh) * 2020-01-19 2020-05-15 广州浚远康生物科技有限公司 Trpa1的抑制剂在制备治疗炎症药物中的应用
WO2021074196A1 (fr) * 2019-10-15 2021-04-22 Boehringer Ingelheim International Gmbh Thiénopyrimidones en tant qu'inhibiteurs de trpa1
WO2021074198A1 (fr) * 2019-10-15 2021-04-22 Boehringer Ingelheim International Gmbh Nouveaux tétrazoles
WO2021074197A1 (fr) * 2019-10-15 2021-04-22 Boehringer Ingelheim International Gmbh Thiénopyrimidones en tant qu'inhibiteurs de trpa1
CN113272285A (zh) * 2018-09-21 2021-08-17 爱思开生物制药株式会社 含噁二唑的化合物、和含有其的药物组合物
WO2022002782A1 (fr) 2020-06-29 2022-01-06 Boehringer Ingelheim International Gmbh Dérivés de tétrazole utiles en tant qu'inhibiteurs de trpa1
WO2022002780A1 (fr) 2020-06-29 2022-01-06 Boehringer Ingelheim International Gmbh Dérivés de tétrazole utiles en tant qu'inhibiteurs de trpa1
WO2022058946A1 (fr) 2020-09-18 2022-03-24 Université Grenoble Alpes Inhibition du canal trpa1 astrocytaire comme nouvelle cible therapeutique neuroprotectrice dans les phases prodromales de la maladie d'alzheimer
WO2022079091A1 (fr) 2020-10-14 2022-04-21 Boehringer Ingelheim International Gmbh Dérivés de tétrazole en tant qu'inhibiteurs de trpa1
WO2022079092A1 (fr) 2020-10-14 2022-04-21 Boehringer Ingelheim International Gmbh Dérivés de tétrazole en tant qu'inhibiteurs de trpa1
US11332459B2 (en) 2017-10-19 2022-05-17 Teijin Pharma Limited Benzimidazole derivatives and their uses
WO2022219012A1 (fr) 2021-04-14 2022-10-20 Boehringer Ingelheim International Gmbh Dérivés de 3h,4h,5h,6h,7h-pyrimido[4,5-b][1,4]oxazine-4,6-dione en tant qu'inhibiteurs de trpa1
WO2022219015A1 (fr) 2021-04-14 2022-10-20 Boehringer Ingelheim International Gmbh Dérivés d'imidazo[4,5-d]pyridazinonyle utilisés en tant qu'inhibiteurs de trpa1
WO2022219013A1 (fr) 2021-04-14 2022-10-20 Boehringer Ingelheim International Gmbh Dérivés d'uracile utiles en tant qu'inhibiteurs de trpa1
WO2022219014A1 (fr) 2021-04-14 2022-10-20 Boehringer Ingelheim International Gmbh Dérivés 3h, 4h-thiéno [2,3-d] pyrimidin-4-one en tant qu'inhibiteurs de trpa1
IT202100015098A1 (it) 2021-06-09 2022-12-09 Flonext S R L Composto antagonista del canale trpa1 per uso in patologie degenerative della retina
WO2023150592A3 (fr) * 2022-02-03 2023-08-31 D.E. Shaw Research, Llc Composés d'uracile n3-substitués utilisés en tant qu'inhibiteurs de trpa1
WO2023215775A1 (fr) * 2022-05-04 2023-11-09 D. E. Shaw Research, Llc Composés de pyridone en tant qu'inhibiteurs de trpa1
RU2812890C2 (ru) * 2017-09-13 2024-02-05 Ванда Фармасьютиклз Инк. Усовершенствованное лечение атопического дерматита традипитантом

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