WO2017064068A1

WO2017064068A1 - New trpa1 antagonists

Info

Publication number: WO2017064068A1
Application number: PCT/EP2016/074352
Authority: WO
Inventors: Jose Aiguade Bosch; Stephen Connolly; Paul Robert Eastwood; Richard Spurring Roberts; Sara Sevilla Gomez; Juan Francisco Caturla Javaloyes
Original assignee: Almirall SA
Current assignee: Almirall SA
Priority date: 2015-10-14
Filing date: 2016-10-11
Publication date: 2017-04-20
Anticipated expiration: 2018-04-14

Abstract

The present invention relates to bicyclic heterocyclic derivatives of Forrmula (I), to the process for preparing such compounds and to their use in the treatment of a pathological condition or disease susceptible to amelioration by TRPA1 channel inhibition or antagonism.

Description

New TRPA1 antagonists

FIELD OF THE INVENTION

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.

BACKGROUND OF THE INVENTION

TRPA1 is a non-cation selective channel that belongs to the Transient Receptor Potential (TRP) superfamily. TRPA1 was first identified from cultured lung fibroblasts (Jaquemar et a/., 1999), and further studies indicated that TRPA1 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 a/., 2013). Moreover, TRPA1 has been identified in the small intestine, colon, pancreas, skeletal muscle, heart, brain, and T and B-lymphocytes (Stokes et a/., 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.

TRPA1 is not only sensitive to electrophiles, but is also activated by oxidizing agents. Reactive oxygen species (ROS) are released by cells in response to tissue damage and can cause lipid peroxidation. 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.

Another mechanism of TRPA1 activation is modulation by G protein-coupled receptors (GPCRs) through second-messenger signalling cascades. 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. In mammals 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 trigemional neurons (TG), and project to a variety of peripheral targets, including skin, airways, and gastrointestinal (Gl) tract.

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. Among these, Mas-related GPCR from human (MrgprXI ) and mice (MrgprA3, MrgprCH ), receptors of chloroquine (A3, X1 ) and BAM8-22 (C1 1 , X1 ) (Wilson 201 1 ), TSLP-evoked scratching (Wilson et al., Cell 2013), dry skin-evoked chronic itch (Wilson et al. 2013), haptens-induced inflammation and itch in contact dermatitis (Liu et al., 2013), IL-13-induced itch in atopic dermatitis by IL-13 (Oh et al. 2013), IL-31 -induced Th cell-dependent itch (Cevikbas et al., 2013), and PGE2, bradykinin, PAR-2 ligands, etc. Overall, these studies suggest that TRPA1 would be key in the non-histaminergic itch.

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. 2007, Koivisto 2012). Disease models of diabetes strongly implicate TRPA1 in the inflammatory pain states associated with this metabolic disorder. Diabetic neuropathy affects more than 80% of all diabetes patients and can cause severe pain, tingling and numbing sensations, and disability. TRPA1 is a promising target for the treatment of this chronic diabetic neuropathy associated with peripheral demyelination and the degeneration of nerve fibres.

In cancer research, there is an increasing appreciation of the role that chronic inflammation plays in tumorigenesis and of the presence of inflammation in the tumour microenvironment (Lorusso et al. , 2008; reviewed in Bautista et al. 2013). Neurogenic components of inflammation may contribute to pain and other debilitating

consequences of cancer. 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).

Some anaesthetics, such as isoflurane or lidocaine, also activate TRPA1 , suggesting a possible role for TRPA1 antagonists in post-surgical pain.

A number of studies suggest that 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.

There is growing evidence, generated using TRPA1 blockers and also

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).

Several publications implicate 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. In preclinical models TRPA1 agonists induced cough. Thus, cough can be attenuated by TRPA1 inhibitors. 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.

Allergen-challenged 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.

In addition, cigarette smoke extract (CSE) or aldehydes increased Ca²⁺ 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 ei a/., 2013).

Several lines of evidence identify TRPA1 as a potential drug target for bladder disorders. 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

(Andrade et al., 201 1 ; Meotti et al. , 2013) in rats, which can be attenuated by TRPA1 antagonists. TRPA1 antagonists could show potential for the treatment of bladder instability, urinary incontinence and cystitis. 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.

In view of these physiological effects, 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

(WO2013103155), amino ketones (WO2012050512 and Bioorg. Med. Chem. Lett. 2012, 22, 5485), decalins (WO 201 1043954), oximes (WO2009089082,

WO2009089083 and Bioorg. Med. Chem. Lett. 2010, 20, 276), prolines and aminoacid derivatives (WO2010141805, EP2520566, WO2013108857 and WO2014049047), pyrimidinedione /xanthines based compouds (WO2007073505, WO2009002933, WO20091 18596, WO2009144548, WO2009158719, WO2010004390,

WO2010036821 , WO2010075353, WO2010109287, WO2010109328,

WO2010109329, WO2010109334, WO2010125469, WO2010132838,

WO2010138879, WO201 1 1 14184, WO201 1 132017, WO2012176105,

WO2012085662, WO2013023102 and Med. Chem. Comm. 2012, 3, 187), thioureas (WO2007073505, WO2009147079 and Bioorg. Med. Chem. Lett 2012, 22, 797), and various other structures (such as in WO2007098252 and WO2012152940).

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.

Thus, there is a need for new TRPA1 antagonists or inhibitors being suitable for the treatment of the above-mentioned diseases.

SUMMARY OF THE INVENTION

Thus the present invention provides new compounds that possess TRPA1 antagonistic activity. Accordingly, there is provided a byciclic heterocyclic derivative which is a compound of Formula (I), or a pharmaceutically acceptable salt, or a solvate, or a N- oxide, or a a tautomer, or a a stereoisomer, or an isotopically-labeled derivative thereof,

Formula (I) wherein:

• G¹ is selected from the group consisting of a C atom and a N atom;

• G² , G³, G⁴ and G⁵ are each independently selected from the group consisting of a N atom, a N(R^b) group, a C(R^b) group and a C(R^C) group;

• n is an integer selected from 0 to 1 ;

• G⁶, G⁷ and G⁸ are each independently selected from the group consisting of a N atom and a C(R^b) group;

• G⁹ and G¹⁰ are each independently selected from the group consisting of a N atom and a N(R^b) group;

• represents a single or a double bond;

• L is selected from the group consisting of a direct bond, a -CH2- group, an oxygen atom, a sulphur atom and a N(R^b) group;

• m is an integer selected from 0 to 1 ;

• R^a is selected from the group consisting of a halogen atom, a cyano group, a linear or branched C1-4 haloalkyl group, a linear or branched C1-4 alkyl group, a linear or branched C1-4 alkoxy group and a linear or branched C1-4 haloalkoxy group;

• R^b is selected from the group consisting of a hydrogen atom and a linear or branched C1-4 alkyl group, and

• R^c is selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-4 alkyl group, a linear or branched C1-4 alkoxy group, an oxo group, a linear or branched C1-4 haloalkyl group, an amino group, a hydroxyl group, a C1-4 monoalkylamino group, a C1-4 dialkylamino group, a monocyclic C3-7 cycloalkyl group, a monocyclic 3- to 7-membered heterocyclyl group containing at least one heteroatom selected from O, S and N, and a benzyl group.

The invention further provides synthetic processes and intermediates described herein, which are useful for preparing compounds of the invention.

The invention is also directed to a compound 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 compound of the invention and a pharmaceutically-acceptable diluent or carrier. The invention also provides a compound 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 compound 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 compound of the invention. The invention further provides a method of treatment comprising administering a therapeutically effective amount of a combination of a compound of the invention together with one or more other therapeutic agents.

The invention also provides a combination product comprising (i) a compound of the invention as described herein; and (ii) one or more additional active substances.

DETAILED DESCRIPTION OF THE INVENTION

When describing the compounds, compositions, combinations and methods of the invention, the following terms have the following meanings, unless otherwise indicated. As used herein the term 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.

As used herein, the term 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.

As used herein, the term C1-4 haloalkyl is a linear or branched alkyl group, which is substituted by one or more, preferably 1 , 2 or 3 halogen atoms. Examples of haloalkyl groups include CCI3, CFs and CHF2.

As used herein, the term 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.

As used herein, the term monocyclic C3-7 cycloalkyl radical embraces saturated monocyclic ring having from 3 to 7 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

As used herein, the term monocyclic 3- to 7-membered heterocyclyl radical embraces typically a non-aromatic, monocyclic, saturated or unsaturated C3-7 carbocyclic ring system in which one or more, for example 1 , 2 or 3 of the carbon atoms are replaced preferably by a heteroatom selected from N, O and S. Representative examples include aziridinyl, azetidinyl, piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl, morpholinyl thiomorpholinyl, pyrazolinyl and pirazolidinyl.

As used herein, the term halogen atom embraces chlorine, fluorine, bromine or iodine atoms typically a fluorine, chlorine or bromine atom. The term halo when used as a prefix has the same meaning.

As used herein, the term C1-4 monoalkylamino is represented by the formula -NH(Ci-4 alkyl) where C1-4 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 (iert-butyl)amino group.

The term C1-4 dialkylamino as used herein is represented by the formula - N(Ci-4 alkyl)2 where C1-4 alkyl is a described above. Representative examples include dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group and di(ferf- butyl)amino group.

As used herein, some of the 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. The term "therapeutically effective amount" refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.

The term "treatment" as used herein refers to the treatment of a disease or medical condition in a human patient which includes:

(a) preventing the disease or medical condition from occurring, i.e., prophylactic treatment of a patient;

(b) ameliorating the disease or medical condition, i.e., causing regression of the disease or medical condition in a patient;

(c) suppressing the disease or medical condition, i.e., slowing the development of the disease or medical condition in a patient; or

(d) alleviating the symptoms of the disease or medical condition in a patient.

The phrase "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. Such 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. The term "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.

The term "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.

By the term "respiratory disorder", it is meant 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.

The term "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). The term "gastrointestinal inflammatory disorders" as used herein includes, but is not limited to, disorders such as inflammatory bowel disease, ulcerative colitis and Crohn's disease.

The term "urinary tract disorders" as used herein includes, but is not limited to, disorders such as urinary incontinence, bladder instability and cystitis.

The term "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. Particularly preferred are salts derived from formic, fumaric, hydrobromic, hydrochloric, hydrofluoric, acetic, sulfuric, methanesulfonic, xinafoic, tartaric, maleic, succinic and napadisilic acids.

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, A/J^-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.

Other preferred salts according to the invention are quaternary ammonium compounds wherein an equivalent of an anion (X^") is associated with the positive charge of the N atom. 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. 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.

As used herein, an /V-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent.

As used herein, the term 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. When the solvent is water, the term hydrate is used instead of solvate. The invention also includes isotopically-labeled 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. 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 sulfur, such as ³⁵S.

Isotopically-labeled 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-labeled reagent in place of the non-labeled reagent otherwise employed.

Preferred isotopically-labeled compounds include deuterated derivatives of the compounds of the invention. As used herein, the term deuterated derivative embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium. Deuterium (D or ²H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.

As used herein the term stereoisomer means a compound that has the same molecular formula and sequence of bonded atoms (constitution), but differs in the three-dimensional orientations of their atoms in the space. The compounds of the invention may contain one or more chiral centers. Accordingly, the invention includes racemic mixtures, enantiomers, diastereomers 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.

As used herein, the term 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.

Typically in the compounds of the present invention: • G⁴ is a CH group;

• G⁶ and G⁸ are each independently selected from the group consisting of a N atom and a CH group;

• L is selected from a direct bond and an oxygen atom;

· R^a is selected from the group consisting of a halogen atom, a cyano group and a linear or branched C1-4 haloalkyl group; and

• R^c is selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-4 alkyl group, a linear or branched C1-4 alkoxy group, an oxo group, an amino group, a hydroxyl group, a C1-4 monoalkylamino group, a C1-4 dialkylamino group, a monocyclic C3-7 cycloalkyl group, a monocyclic 3- to 7-membered heterocyclyl group containing at least one heteroatom selected from O, S and N, and a benzyl group.

In a preferred embodiment of the invention, G¹ is a N atom, G² is a C(R^C) group, G³ is N atom, n represents 0, and G⁵ is a C(R^C) group; preferably G² is a CH group a C- benzyl group or a C-cyclopropyl group and G⁵ is a C(CH3) group or a C(CN) group; more preferably G² is a CH group and G⁵ is a C(CH3) group.

In another preferred embodiment, G¹ is a N atom, G² is a N atom, G³ is a CH group, n represents 0, and G⁵ is a C(R^b) group; preferably G⁵ is C(CH3) group.

In another preferred embodiment, G¹ is a C atom, G² is a N atom, G³ is a N atom, n represents 0, and G⁵ is N(R^b) group; preferably G⁵ is a N(CH3) group.

In another preferred embodiment, G¹ is a C atom, G² is a C(R^b) group, G³ is a N atom, n represents 0, and G⁵ is a N(R^b) group; preferably G² is a C(CH3) group or a CH group, and G⁵ is a N(CH3) group.

In another preferred embodiment, G¹ is a C atom, G² is a N(R^b) group, G³ is a N atom, n represents 0 and G⁵ is a C(R^b) group; preferably G² is a N(CH3) group and G⁵ is a C(CH3) group.

In another preferred embodiment, G¹ is a C atom, G² is a N atom, G³ is a C(R^b) group, n represents 0 and G⁵ is a N(R^b) group; preferably G³ is a CH group and G⁵ is a N(CH₃) group. In another preferred embodiment, G¹ is a C atom, G² is a N(R^b) group, G³ is a

C(R^C) group, n represents 0 and G⁵ is a N(R^b) group; preferably G² is N(CH3) group, G³ is a C(O) group and G⁵ is a N(CH₃) group. In another preferred embodiment G¹ is a C atom, G² is a C(R^C) group, G³ is a N atom, n represents 1 , G⁴ is a CH group and G⁵ is a C(R^C) group; preferably G² is a CH group and G⁵ is a C(CI) group.

In another preferred embodiment G¹ is a C atom, G² is a N atom, G³ is a C(R^C) group, n represents 1 , G⁴ is a CH group and G⁵ is a C(R^C) group; preferably G³ is a C(OCH₃) group and G⁵ is a C(CH₃) group.

In another preferred embodiment G¹ is a C atom, G² is a N(R^b) group, G³ is a C(R^C) group, n represents 1 , G⁴ is a CH group and G⁵ is a C(R^C) group; preferably G² is a NH or a N(CH₃) group, G³ is a C(O) group and G⁵ is a C(CH₃) group.

In a more preferred embodiment of the present invention, n represents 0 and the bicydic heterocyclic derivative of Formula (I) is represented by Formula (la) to Formula (Ig)

In another more preferred embodiment of the present invention, n represents 1 and the bicydic heterocyclic derivative of Formula (I) is represented by Formula (Ih) to Formula (Ij)

In another preferred embodiment of the present invention:

• G⁹ and G¹⁰ are each independently selected from the group consisting of a N atom, a NH group and a N(CH3) group; preferably G⁹ and G¹⁰ are each independently selected from the group consisting of a N atom and a NH group; more preferably G⁹ is a N atom and G¹⁰ is a NH group or G⁹ is a NH group and G¹⁰ is a N atom;

• G⁶ is a N atom;

• G⁷ is a CH group; and

• G⁸ is a N atom.

Still in another embodiment:

• G⁹ and G¹⁰ are each independently selected from the group consisting of a N atom and a NH group; preferably G⁹ is a N atom and G¹⁰ is a NH group or G⁹ is a NH group and G¹⁰ is a N atom;

• G⁶ is a CH group;

• G⁷ is selected from the group consisting of a N atom, a CH group and a C(CH3) group; and

• G⁸ is selected from the group consisting of a N atom and a CH group. Still in another embodiment:

• G⁶ is a N atom;

• G⁷ is selected from the group consisting of a N atom and a CH group; and • G⁸ is a CH group.

In another preferred embodiment of the present invention:

• R^a is selected from the group consisting of a halogen atom, a cyano group and a C1-2 haloalkyl group; preferably R^a is selected from the group consisting of a CI atom, a Br atom, a cyano group, and a CF3 group.

In another preferred embodiment:

• R^b is selected from the group consisting of a hydrogen atom and a C1-2 alkyl group.

In another preferred embodiment: · R^c is selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a C1-2 alkyl group, a C1-2 alkoxy group, an oxo group, an amino group, a hydroxyl group, a C1-2 monoalkylamino group, a C1-2 dialkylamino group, a monocyclic C3-6 cycloalkyl group, a monocyclic 6-membered heterocyclyl group containing at least one heteroatom selected from O, S and N, and a benzyl group; preferably R^c is selected from the group consisting of a hydrogen atom, a CI atom, a cyano group, a methyl group, an ethyl group, a methoxy group, an oxo group, a methylamino group, a dimethylamino group, a cyclopropyl group, a morpholinyl group and a benzyl group.

In a more preferred embodiment of the present invention, the bicyclic heterocyclic derivative according to Formula (I) is represented by Formula (la)' to Formula (Ig)'

wherein:

L is an oxygen atom;

m is an integer selected from 0 to 1 , preferably m is 1 ;

R^a is selected from the group consisting of a CI atom, a Br atom, and a CF3 group, preferably R^a is a CI atom;

R^b is selected from the group consisting of a hydrogen atom and a methyl group, preferably is a methyl group;

R^c is selected from the group consisting of a hydrogen atom, a methyl group, cyclopropyl group, a benzyl group, and an oxo group.

In another more preferred embodiment of the present invention, the bicyclic heterocyclic derivative according to Formula (I) is represented by Formula (Ih)' to Formula (lj)'

wherein:

• L is an oxygen atom;

• m is an integer selected from 0 to 1 , preferably m is 1 ;

• R^a is selected from the group consisting of a CI atom, a Br atom, and a CF3 group, preferably R^a is a CI atom;

• R^b is selected from the group consisting of a hydrogen atom and a methyl group; and

• R^c is selected from the group consisting of a hydrogen atom, a CI atom, a methyl group, a methoxy group, and an oxo group.

Particular individual compounds of the invention include:

• 3-{[6-(4-Chlorophenyl)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one

• 3-{[6-(4-Chlorophenyl)-5-methyl-1 H-imidazo[4,5-b]pyridin-2-yl]methyl}-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one

• 3-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one

• 3-{[6-(3-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one

• 7-Chloro-3-{[6-(4-chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one

• 3-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5,7- dimethylimidazo[5,1 -f][1 ,2,4]triazin-4(3H)-one

• 3-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-7-ethyl-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one • 7-Benzyl-3-{[6-(4-chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylimidazo[5,1-f|[1 ,2,4]triazin-4(3H)-one

• 3-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-7-cyclopropyl-5- methylimidazo[5,1-f|[1 ,2,4]triazin-4(3H)-one

• 3-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5-methyl-7- morpholin-4-ylimidazo[5,1-f|[1 ,2,4]tnazin-4(3H)-one

• 3-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5-methyl-7- (methylamino)imidazo[5,1 -f|[1 ,2,4]tnazin-4(3H)-one

• 3-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-7- (dimethylamino)-5-methylimidazo[5,1 -f][1 ,2,4]triazin-4(3H)-one

• 5-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-1 ,3-dimethyl-

1.5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

• 6-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-1 ,3-dimethyl-

1.6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

• 5-Chloro-3-{[6-(4-chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2- yl]methyl}pyrido[3,4-d]pyrimidin-4(3H)-one

• 6-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-1-methyl-1 ,6- dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one

• 1-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-7-methyl-1 ,7- dihydro-6H-purin-6-one

• 3-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-4-oxo-3,4- dihydroimidazo[5,1-f][1 ,2,4]triazine-5-carbonitrile

• 3-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylpyrazolo[5,1 -f][1 ,2,4]triazin-4(3H)-one

• 3-{[6-(3-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylpyrazolo[5,1 -f][1 ,2,4]triazin-4(3H)-one

• 1-{[6-(3-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-7,9-dimethyl- 7,9-dihydro-1 H-purine-6,8-dione

• 3-{[6-(3-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-7-methoxy-5- methylpyrido[2,3-d]pyrimidin-4(3H)-one

• 3-{[6-(3-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

• 3-{[6-(3-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5,8- dimethylpyrido[2,3-d]pynmidine-4,7(3H,8H)-dione

• 1-Methyl-6-[(5-phenoxy-1 H-imidazo[4,5-b]pyrazin-2-yl)methyl]-1 ,6-dihydro-7H- [1 ,2,3]tnazolo[4,5-d]pyrimidin-7-one • 1-Methyl-6-({6-[4-(trifluoromethyl)phenoxy]-1 H-imidazo[4,5-b]pyrazin-2- yl}methyl)-1 ,6-dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one

• 6-{[5-(3-Bromophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-1-methyl-1 ,6- dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one

• 1-Methyl-6-({5-[3-(trifluoromethyl)phenoxy]-1 H-imidazo[4,5-b]pyrazin-2- yl}methyl)-1 ,6-dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one

• 3-({2-[(1 -Methyl-7-oxo-1 ,7-dihydro-6H-[1 ,2,3]triazolo[4,5-d]pyrimidin-6- yl)methyl]-1 H-imidazo[4,5-b]pyrazin-5-yl}oxy)benzonitrile

• 4-({2-[(1 -Methyl-7-oxo-1 ,7-dihydro-6H-[1 ,2,3]triazolo[4,5-d]pyrimidin-6- yl)methyl]-1 H-imidazo[4,5-b]pyrazin-5-yl}oxy)benzonitrile

• 3-{[5-(4-Chlorophenoxy)-3H-imidazo[4,5-b]pyridin-2-yl]methyl}-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one

• 3-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-c]pyridin-2-yl]methyl}-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one

• 6-{[2-(4-Chlorophenoxy)-9H-purin-8-yl]methyl}-1 ,3-dimethyl-1 ,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one

• 3-{[6-(4-Chlorophenoxy)-1-methyl-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one

• 3-{[5-(4-Chlorophenoxy)-1-methyl-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one

• 6-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyridin-2-yl]methyl}-1 , 3-d im ethyl- 1 ,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

• 6-{[6-(4-Chlorophenoxy)-1 H-benzimidazol-2-yl]methyl}-1 ,3-dimethyl-1 ,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

• 6-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-1-methyl-1 ,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a steroisomer, or an isotopically-labeled derivative thereof

Of particular interest are the compounds:

• 3-{[6-(3-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one • 7-Benzyl-3-{[6-(4-chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one

• 3-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-7-cyclopropyl-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one

1.5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

1.6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

• 1-Methyl-6-[(5-phenoxy-1 H-imidazo[4,5-b]pyrazin-2-yl)methyl]-1 ,6-dihydro-7H- [1 ,2,3]tnazolo[4,5-d]pyrimidin-7-one

• 1-Methyl-6-({5-[3-(trifluoromethyl)phenoxy]-1 H-imidazo[4,5-b]pyrazin-2- yl}methyl)-1 ,6-dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a steroisomer, or an isotopically-labeled derivative thereof. GENERAL SYNTHETIC PROCEDURES

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.

Additionally, as will be apparent to those skilled in the art, conventional 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.

Processes for preparing compounds of the invention are provided as further embodiments of the invention and are illustrated by the procedures below.

Specific synthetic processes not covered by Schemes 1 - 5 are described in detail in the Experimental section.

Intermediates of the general formula (6) wherein G¹ to G⁵ and n are as defined in Claim 1 , and where the heterobicyclic group is also defined as a group A, may be prepared following the synthetic routes depicted in Scheme 1 .

HCONH₂

G² NH₂

(4)

Scheme 1

Compounds of general formula (6) may be prepared from compounds of formula (2) wherein R¹¹ represents a hydrogen atom, an alkyl group such as methyl, ethyl, propyl, iert-butyl group or a benzyl group, and a formamide equivalent such as formamide or formamidine and salts thereof. In one instance, wherein R¹¹ is a hydrogen atom or an alkyl group such as methyl, ethyl, propyl, iert-butyl group 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}. In another instance, wherein R¹¹ is an alkyl group such as methyl, ethyl, propyl, iert-butyl group 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). In another instance, the 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). In another instance, the reaction is carried out by mixing a compound of formula (3) with an ortho- formate of formula (5) wherein R¹² 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.

In the specific case where G¹ is a nitrogen atom and G² to G⁵ and n are as defined in Claim 1 , intermediates of formulas (2) and (3) may be prepared following the synthetic routes depicted in Scheme 2.

G -Q₂ N aminating reagent ^¾² ^ " ΝΗ₂

(7) (2)

O O

[G1^{G A}NH₂ ^b3Se , [Gl^{G A}NH₂

3 M . .. r.3

G-¾2 aminating reagent ^¾² ^"ΝΗ2 (7) (3)

Scheme 2

Intermediates of formula (2), wherein wherein R¹¹ is a an alkyl group such as methyl, ethyl, propyl, iert-butyl group 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 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.

In a similar fashion, Intermediates of formula [3] may be prepared from intermediates of formula (7) 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. Bicyclic heterocycles of general formula (8} wherein G¹ to G⁵ and n are as defined in Claim 1 and independently of their attachment to other groups through the amide nitrogen may be further modified to compounds such as (9], (10) or (1 1 ) following the synthetic routes depicted in Scheme 3.

(8) ( (10)

(1 1 )

Scheme 3

In some instances, compounds containing a bicyclic heterocycle of formula (9) wherein one or more of the groups G² to G⁵ is a carbon atom substituted with a W³ group, wherein W³ is a halogen atom such as chlorine, bromine or iodine may be synthesized from a compound containing a bicyclic heterocycle of formula (8) wherein one or more of the groups G² to G⁵ is a CH group. The reaction may be carried out by mixing a compound of formula (8) with a halogenating reagent such as copper(ll) bromide, /V-chlorosuccinimide, /V-bromosuccinimide, /V-iodoosuccinimide, bromine or iodine, in a solvent such as acetonitrile, chloroform or dimethylformamide at a temperature from 0 °C to 100 °C.

Compounds containing a bicyclic heterocycle of formula (10) wherein R¹³ and R¹⁴ are independently selected from a group containing a hydrogen atom or an alkyl group such as methyl, ethyl or isopropyl, wherein the NR¹³R¹⁴ group together represents a cyclic amine such as azetidine, pyrrolidine, piperidine or morpholine may be synthesized from a compound containing a bicyclic heterocycle of formula (9) wherein W³ represents a halogen atom such as chlorine, bromine or iodine. The reaction may be carried out by mixing a compound of formula {9} with an amine of general formula NHR¹³R¹⁴, 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. Compounds containing a bicyclic heterocycle of formula (1 1 ) wherein R¹⁵ represents an alkyl group such as methyl, ethyl, isopropyl, cyclopropyl group, or a benzyl group, may be synthesized from a compound containing a bicyclic heterocycle of formula (9) wherein W³ represents a halogen atom such as chlorine, bromine or iodine. The halogenated derivative (9} is treated with an organometallic reagent of general formula M¹-R¹⁵ wherein M¹ is selected from lithium or salts or complexes of magnesium, zinc, copper, tin or boron. The reaction is carried out by treating the halogenated derivative according to standard literature methods known to those skilled in the art of carbon-carbon cross-coupling reactions. In one instance the reaction can be carried out by treating the halogenated derivative with a potassium trifluoroborate reagent in the presence of a transition metal catalyst such as palladium(ll) acetate, in the presence of a phosphine such as di(1-adamantyl)-n-butylphosphine and a base such as caesium carbonate, in a solvent such as water, toluene or mixtures thereof at a temperature from 50 °C to 150 °C under an inert atmosphere such as argon. Intermediates of general formula (6), wherein G¹ to G⁵ and n are defined in Claim 1 , and where the heterobicyclic group is also defined as a group A may be modified to intermediates such as (13) or (14) following the synthetic routes depicted in Scheme 4.

(^β) (13) (14) Scheme 4

Compounds of general formula (13) wherein A is as hereinbefore defined and R¹⁰ represents an alkyl group such as methyl, ethyl, propyl, iert-butyl group, or a benzyl group may be prepared from heterobicyclic compounds of formula {6} and an alkylating agent of formula (12) wherein W¹ 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 (12) 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 (14) wherein A is as hereinbefore defined may be prepared from compounds of formula (13) wherein R¹⁰ is as hereinbefore defined by hydrolysis according to standard literature methods known to those skilled in the art of ester hydrolysis. In one example, 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. Another example is through the use of 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 (1}, wherein G¹ to G⁵, L, R^a, n and m are as defined in Claim 1 , and wherein the heterobicyclic group defined by G¹ to G⁵ can also be defined as group A, may be synthesized following the synthetic routes depicted in Scheme 5.

Scheme 5

Intermediates of formula (16), wherein G⁶ to G¹⁰ are as defined in Claim 1 , W¹ represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate and W² represents a halogen atom such as chlorine, bromine or iodine may be synthesized from a compound of formula (15) and a compound of formula (20), wherein W³ represents either a OH group and hence (20) is a carboxylic acid, a chlorine atom and hence (20) is an acyl chloride or a half-stoichiometric oxygen atom and hence (20) is an anhydride. The reaction is carried out by mixing a compound of formula (15) and a compound of formula (20) with a dehydrating agent such as phosphorous oxychloride, either neat or in a solvent such as toluene, at a temperature from 50 °C to 150 °C.

Intermediates of formula (17), wherein G⁶ to G¹⁰ are as defined in Claim 1 , W² represents a halogen atom such as chlorine, bromine or iodine and A represents the heterobicyclic ring as defined by G¹ to G⁵ in Claim 1 , may be synthesized from a compound of formula (16) wherein W¹ is as hereinbefore defined, and a compound of formula (6). The reaction is carried out by mixing a compound of formula (16) with a compound of formula (6) in the presence of a base such as caesium carbonate, in a solvent such as dimethylformamide, at a temperature from room temperature to 50 °C to give a compound of formula (17).

Intermediates of formula (17), may also be synthesized from a compound of formula (15) wherein G⁶ to G¹⁰ and W² are as hereinbefore defined and a compound of formula (14), wherein A is as hereinbefore defined. The reaction is carried out by first mixing a compound of formula (14) with an acyl activating reagent known to those skilled in the art of peptide coupling. In one instance, the activating reagent is carbonyl diimidazole in a solvent such as butyronitrile at room temperature. The mixture is then subsequently treated with a compound of formula (15) at a temperature from 50 °C to 200 °C to give a compound of formula (17). Alternatively, a compound of formula (15) is treated with a compound of formula (14) and wherein the acyl activating agent is phosphorous oxychloride, either neat or in a solvent such as toluene, at a temperature from 50 °C to 200 °C to give a compound of formula (17).

Intermediates of formula (18), wherein G⁶ to G¹⁰, R^a, L and m are as defined in Claim 1 , may be be synthesized from a compound of formula (15), wherein W² represents a halogen such as chlorine, bromine or iodine and a compound of formula (21 ) wherein M² is lithium or salts or complexes of magnesium, zinc, copper, tin or boron when either L is a -CH2- group or a direct bond, or alternatively M² is a hydrogen atom in the case where L is an oxygen atom, a sulphur atom or a NH group. In the first instance where L is a -CH2- group or a direct bond, the reaction is carried out by treating the halogenated derivative (15) with the organometallic reagent (21 ) according to standard literature methods known to those skilled in the art of carbon-carbon cross- coupling reactions. In one instance the reaction can be carried out by treating the halogenated derivative (15) with a boronic acid (21 ) in the presence of a transition metal catalyst such as [1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), in the presence of a base such as caesium carbonate, in a solvent such as dioxane, water or mixtures thereof at a temperature from room temperature to 150 °C under an inert atmosphere such as argon. In the instance where L is an oxygen atom, a sulphur atom or a NH group, the reaction may be carried out by treating the halogenated derivative (15) with a compound of formula (21 ) wherein M² is a hydrogen atom in the presence or absence of a catalyst such as copper(l) iodide and in the presence or absence of a ligand such as Ν,Ν-dimethylglycine and in the presence or absence of a base such as caesium carbonate either neat or in a solvent such as dioxane at a temperature from room temperature to 150 °C under an inert atmosphere such as nitrogen.

Intermediates of formula (19), wherein G⁶ to G¹⁰, R^a, L and m are as defined in Claim 1 , and W¹ represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate may be synthesized from a compound of formula (18), and a compound of formula (20), and wherein W¹ is as hereinbefore defined and wherein W³ represents either a OH group and hence (20) is a carboxylic acid, a chlorine atom and hence (20) is an acyl chloride or a half-stoichiometric oxygen atom and hence (20) is an anhydride. The reaction is carried out by mixing a compound of formula (18) and a compound of formula (20) in a dehydrating agent such as phosphorous oxychloride, either neat or in a solvent such as toluene, at a temperature from 50 °C to 150 °C.

Compounds of formula (1}, wherein G⁶ to G¹⁰, R^a, L and m are as defined in Claim 1 , and A represents the heterobicyclic ring as defined by G¹ to G⁵ in Claim 1 may be be synthesized from a compound of formula (17), wherein W² represents a halogen such as chlorine, bromine or iodine and a compound of formula (21 ) wherein M² is lithium or salts or complexes of magnesium, zinc, copper, tin or boron when either L is a -CH2- group or a direct bond, or alternatively M² is a hydrogen atom in the case where L is an oxygen atom, a sulphur atom or a NH group. In the first instance, where L is a -CH2- group or a direct bond, the reaction is carried out by treating the halogenated derivative (17) with the organometallic reagent (21 ) according to standard literature methods known to those skilled in the art of carbon-carbon cross-coupling reactions. In one instance the reaction can be carried out by treating the halogenated derivative (17) with a boronic acid (21 ) in the presence of a transition metal catalyst such as [1 ,1 '-tetrakis(triphenylphosphine)palladium(0), in the presence of a base such as sodium carbonate, in a solvent such as dioxane, water or mixtures thereof at a temperature from room temperature to 150 °C under an inert atmosphere such as nitrogen. In the instance where L is an oxygen atom, a sulphur atom or a NH group, the reaction may be carried out by treating the halogenated derivative (17) with a compound of formula (21 ) wherein M² is a hydrogen atom in the presence or absence of a catalyst such as copper(l) iodide and in the presence or absence of a ligand such as Ν,Ν-dimethylglycine and in the presence or absence of a base such as caesium carbonate either neat or in a solvent such as dioxane at a temperature from room temperature to 150 °C under an inert atmosphere such as nitrogen.

Compounds of formula £1} may also be synthesized from a compound of formula (18) wherein G⁶ to G¹⁰, R^a, L and m are as hereinbefore defined and a compound of formula (14), wherein A is as hereinbefore defined. The reaction is carried out by first mixing a compound of formula (14) with an acyl activating reagent known to those skilled in the art of peptide coupling. In one instance, the acyl activating reagent is carbonyl diimidazole in a solvent such as butyronitrile at room temperature. The mixture is then subsequently treated with a compound of formula (18) at a temperature from 50 °C to 200 °C to give a compound of formula (1}. Alternatively, a compound of formula (18) is treated with a compound of formula (14) and wherein the acyl activating agent is phosphorous oxychloride, either neat or in a solvent such as toluene, at a temperature from 50 °C to 200 °C to give a compound of formula £1}.

Compounds of formula £1} may also be synthesized from a compound of formula (19) wherein G⁶ to G¹⁰, R^a, L and m are as hereinbefore defined and wherein W¹ represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate and a compound of formula £6], wherein A is hereinbefore defined. The reaction is carried out by mixing a compound of formula (19) with a compound of formula £6] in the presence of a base such as caesium carbonate, in a solvent such as dimethylformamide, at a temperature from room temperature to 50 °C to give a compound of formula (1 ).

PREPARATION EXAMPLES

The syntheses of the compounds of the invention are illustrated by the following Examples (1 to 37) including Preparations (1 to 92) which do not limit the scope of the invention in any way. General

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 μιη) 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. Purifications in reverse phase were also made in a Biotage SP1® automated purification system equipped with a C18 column and using a gradient of, unless otherwise stated, water-acetonitrile/MeOH (1 :1 ) (0.1 % v/v ammonium formate both phases) from 0% to 100% acetonitrile/MeOH (1 :1 ) in 80 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 freeze dried.

Gas chromatography was performed using a Thermo Trace Ultra gas chromatograph, coupled to a DSQ mass detector. Injections were performed on a split/splitless injector and a HP-1 MS was the capillary column. Mass spectra were obtained by electron impact ionisation at 70 eV. Preparative HPLC-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 μΜ) column for methods A, B and C and a Symmetry C18 (2.1 x 100 mm, 3.5 μΜ) 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. Method Run time 0% B 0 to 95% B 95% B

A 5 min 0.2 min 3 min 0.8 min

B 9 min 0.5 min 6.5 min 1 min

C 15 min 0 min 10.5 min 1 .5 min

D 30 min 0 min 20 min 4 min

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 microliters. 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 HPLC.

The UPLC 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.

Preparative HPLC was carried out on an Agilent 1200 Series (AE-0010) with diode array detection and peak collection. Specific details are mentioned in the experimental section.

¹ H Nuclear Magnetic Resonance Spectra were recorded on a Varian Mercury plus operating at a frequency of 400MHz, Varian Gemini-2000 spectrometer operating at a frequency of 300MHz or a Varian VNMRS operating at 600MHz and equipped with a cold probe for the 1 H spectra. Samples were dissolved in the specified deuterated solvent. Tetramethylsilane was used as a reference.

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% ³⁵CI to 24% ³⁷CI and 49% ⁷⁹Br to 51 % ⁸¹ Br)

Standard synthetic methods are described the first time they are used. Compounds synthesized with similar methods are refered to only by their starting materials, without full experimental detail. Slight modifications to the general experiemental methods used are permitted in these cases. Specific synthetic transformations already described in the literature are referred to only by their bibliographical reference. Other specific methods are also described in full.

PREPARATIONS

PREPARATION 1

1 ,3-Dimethyl-1 ,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

A suspension of 5-amino-1 ,3-dimethyl-1 H-pyrazole-4-carboxamide (0.800 g, 5.2 mmol) in triethylorthoformate (20 mL) was stirred and heated to 150 °C in a sealed tube. After 2 h at 150 °C and subsequent cooling to room temperature, a precipitate had formed. The precipitate was collected by filtration, was washed with diethyl ether and dried in a stream of air to give 0.63 g (3.84 mmol, 74% yield) of the title compound as a white solid. Purity 100%.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 12.02 (1 H, br s), 8.00 (1 H, s), 3.80 (3H, s), 2.41 (3H, s).

UPLC/MS (3 min) retention time 0.66 min.

LRMS: m/z 165 (M+1 ).

PREPARATION 2

1 -Methyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one A mixture of methyl 4-amino-1 -methyl-1 /-/-pyrazole-5-carboxylate (0.40 g, 2.1 mmol), formimidamide acetic acid salt (0.24 g, 2.3 mmol) and diisopropylethylamine (1 .82 ml, 10.5 mmol) in n-butanol (2 mL) was stirred at 1 10 °C. After 1 h at 1 10 °C and subsequent cooling to room temperature, a precipitate had formed. The precipitate was collected by filtration, was washed with diethyl ether and dried at 35 °C in vacuo to give 0.31 g (1 .96 mmol, 94% yield) of the title compound as a white solid. Purity 98%. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.94 (s, 1 H), 7.83 (s, 1 H), 4.16 (s, 3H).

UPLC/MS (3 min) retention time 0.57 min.

LRMS: m/z 151 (M+1 ).

PREPARATION 3 1 ,3-Dimethyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

Synthesized from methyl 4-amino-1 ,3-dimethyl-1 /-/-pyrazole-5-carboxylate and formimidamide following the method of PREPARATION 2: Yield 88%. Purity 100%.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 12.19 (1 H, br s), 7.80 (1 H, s), 4.1 1 (3H, s), 2.34 (3H, s). UPLC/MS (3 min) retention time 0.71 min. LRMS: m/z 165 (M+1 ). PREPARATION 4

Ethyl 1 -amino-4-methyl-1 H-imidazole-5-carboxylate

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 susbsequently the mixture was evaporated to dryness. The resultant solid was treated with dichloromethane and the mixture was filtered and the filter cake was washed with further portions of dichloromethane. The combined filtrate and washings were evaporated to give a solid which was purified by flash chromatography (methanol-dichloromethane gradient, 0: 100 rising to 5:95) to give 1 .75 g (10.3 mmol, 53% yield) of the title compound as a white solid. Purity 100%.

¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.59 (s, 1 H), 5.33 (br s, 2H), 4.37 (q, 2H, J = 7.4 Hz), 2.46 (s, 3H), 1 .40 (t, 3H, J = 7.4 Hz).

UPLC/MS (3 min) retention time 0.56 min.

LRMS: m/z 170 (M+1 ). PREPARATION 5

5-Methylimidazo[5,1 -f][1 ,2,4]triazin-4(3H)-one

A solution of the title compound of PREPARATION 4 (1 .73 g, 10.2 mmol) in formamide (6 mL) was stirred and heated to 180 °C in a sealed tube. After 3.5 h at 180 °C, the mixture was cooled to room temperature. The mixture was diluted with ethyl acetate and the solid that formed was triturated with several portions of ethyl acetate, collected by filtration and dried in a stream of air to give 1 .31 g (8.7 mmol, 85% yield) of the title compound as a white solid. Purity 95%.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (s, 1 H), 8.26 (s, 1 H), 7.78 (s, 1 H), 2.44 (s, 3H).

UPLC/MS (3 min) retention time 0.51 min. LRMS: m/z 151 (M+1 ). PREPARATION 6

Ethyl 2,4-dimethyl-1 H-imidazole-5-carboxylate Thionyl chloride (20 mL) was added to a stirred suspension of 2,4-dimethyl-1 H- imidazole-5-carboxylic acid (5.0 g, 35.7 mmol) in ethanol (75 mL) and the mixture was stirred and heated to reflux. Further thionyl chloride (15 mL) was added in three portions over 3 days. Subsequently the mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and 1 M aqueous sodium hydroxide solution. The organic layer was washed with brine, dried and evaporated to give 3.40 g (20.2 mmol, 57% yield) of the title compound as a white solid. Purity 98%.

¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 9.65 (br s, 1 H), 4.33 (q, 2H, J = 7.0 Hz), 2.45 (s, 3H), 2.42 (s, 3H), 1 .37 (t, 3H, J = 7.0 Hz).

UPLC/MS (3 min) retention time 0.53 min. LRMS: m/z 169 (M+1 ).

PREPARATION 7

Ethyl 1 -amino-2,4-dimethyl-1 H-imidazole-5-carboxylate Synthesized from the title compound of PREPARATION 6 and O- (diphenylphosphoryl)hydroxylamine following the method of PREPARATION 4. Yield: 87%. Purity 98%.

¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 5.21 (br s, 2H), 4.33 (q, 2H, J = 7.0 Hz), 2.42 (s, 3H), 2.41 (s, 3H), 1 .39 (t, 3H, J = 7.0 Hz).

UPLC/MS (3 min) retention time 0.51 min.

LRMS: m/z 184 (M+1 ). PREPARATION 8

5,7-Dimethylimidazo[5,1 -f][1 ,2,4]triazin-4(3H)-one Synthesized from the title compound of PREPARATION 7 and formamide following the method of PREPARATION 5. Yield: 76%. Purity 98%.

¹ H NMR (300 MHz, DMSO-d6) δ ppm 1 1 .35 (br s, 1 H), 7.77 (s, 1 H), 2.43 (s, 3H), 2.42 (s, 3H).

UPLC/MS (3 min) retention time 0.38 min. LRMS: m/z 165 (M+1 ). PREPARATION 9

7-Bromo-5-methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one

N-Bromosuccinimide (0.25 g, 1 .40 mmol) was added to a stirred suspension of the title compound of PREPARATION 5 (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) δ ppm 1 1 .81 (s, 1 H), 7.88 (s, 1 H), 2.44 (s, 3H).

UPLC/MS (3 min) retention time 0.81 min.

LRMS: m/z 229, 231 (M+1 , 1 *Br).

PREPARATION 10 5-Methyl-7-(dimethylamino)imidazo[5,1 -f][1 ,2,4]triazin-4(3H)-one

The title compound of PREPARATION 9 (37 mg, 0.16 mmol) was combined with dimethylamine (2M in tetrahydrofuran, 2 ml, 4 mmol) and caesium fluoride (8 mg, 0.05 mmol). The mixture was heated at 140 °C under microwave irradiation for 3 h. The mixture was evaporated under reduced pressure. The residue was purified by flash chromatography (methanol-dichloromethane gradient, 0: 100 rising to 10:90) to give 31 mg (0.16 mmol, 98% yield) of the title compound as a pale brown solid. Purity 96%.

UPLC/MS (3 min) retention time 0.57 min.

LRMS: m/z 194 (M+1 ). PREPARATION 1 1

(Azidomethyl)benzene

Sodium azide (1 .73 g, 26.6 mmol) was added to a solution of benzyl bromide (2.10 mL, 17.7 mmol) in dry dimethylformamide (42 mL) under an atmosphere of nitrogen and the mixture was stirred at room temperature overnight. Subsequently, the mixture was diluted with water and extracted with pentane. The organic layer was washed with water, brine, dried, and evaporated to give 2.32 g (17.4 mmol, 99% yield) of the title compound as an oil. Purity 95%.

¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.40 (m, 5H), 4.40 (s, 2H). UPLC/MS (3 min) retention time 1 .63 min. LRMS: m/z No ionization. PREPARATION 12

5-Amino-1 -benzyl-1 H-1 ,2,3-triazole-4-carboxamide

Cyanoacetamide (1 .47 g, 17.5 mmol) and the title compound of PREPARATION 1 1 (2.32 g, 17.4 mmol) were added sequentially to a solution of sodium ethoxide (6.5 mL of a 21 % solution in ethanol) in absolute ethanol (10 mL) and the mixture was stirred and heated to reflux. After 3.5 h, the reaction mixture was cooled to room temperature and the resulting precipitate was filtered and washed with ethanol and water and dried in vacuo to give 2.81 g (12.9 mmol, 74% yield) of the title compound as a white solid. Purity 99%. ¹ H NMR (300 MHz, DMSO-d6) δ ppm 7.43 (br s, 1 H), 7.19-7.37 (m, 5H), 7.07 (br s, 1 H), 6.38 (s, 2H), 5.41 (s, 2H).

UPLC/MS (3 min) retention time 1 .04 min.

LRMS: m/z 218 (M+1 ). PREPARATION 13

4-Amino-5-(aminocarbonyl)-3-benzyl-1 -methyl-1 H-1 ,2,3-triazol-3-ium bromide

A stirred suspension of the title compound of PREPARATION 14 (1 .50 g, 6.91 mmol) and methyl toluene-p-sulphonate (1 .52 mL, 10.1 mmol) in dimethylsulphoxide (0.75 mL) was placed in an oil bath preheated to 150 °C. After 5 min, the almost homogenous melt was cooled causing solidification to occur. Ethanol (15 mL) was added and the mixture was cooled to 0 °C. The precipitate was filtered off, washed with a little cold ethanol (5 mL) and dried to give 1 .29 g (3.19 mmol, 46% yield) of the title compound as a yellow solid. Purity 95%.

UPLC/MS (3 min) retention time 0.68 min. LRMS: m/z 232 (cation M).

PREPARATION 14

4-Amino-1 -methyl-1 H-1 ,2,3-triazole-5-carboxamide

10% Palladium on carbon (0.34 g) was added to a stirred suspension of the title compound of PREPARATION 13 (1 .28 g, 3.15 mmol) in absolute ethanol (50 mL). The mixture was evacuated and hydrogen was introduced via a balloon and stirring was continued at room temperature under an atmosphere of hydrogen for 48 h. The mixture was then filtered through Celite and the filtercake was washed with ethanol. The combined filtrate and washings were evaporated and the sticky solid was triturated with diethylether and dried to give 0.830 g (2.64 mmol, 84% yield) of the title compound as a white solid. Purity 100%.

UPLC/MS (3 min) retention time 0.30 min. LRMS: m/z 142 (M+1 ). PREPARATION 15

1 -Methyl-1 H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one Synthesized from the title compound of PREPARATION 14 and formamide following the method of PREPARATION 5. Yield: 66%. Purity 95%.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 12.66 (br. s, 1 H), 8.08 (s, J = 2.4 Hz, 1 H), 4.33 (s, J = 2.1 Hz, 3H). UPLC/MS (3 min) retention time 0.44 min.

LRMS: m/z 152 (M+1 ).

PREPARATION 16

7-Methyl-1 ,7-dihydro-6H-purin-6-one

Synthesized from ethyl 4-amino-1 -methyl-1 H-imidazole-5-carboxylate and formamide following the method of PREPARATION 5. Yield: 85%. Purity 98%.

¹ H NMR (300 MHz, DMSO-d6) δ ppm 8.40 (s, 1 H), 8.10 (s, 1 H), 7.92 (s, 1 H), 3.95 (s, 3H).

UPLC/MS (3 min) retention time 0.36 min. LRMS: m/z 151 (M+1 ). PREPARATION 17

1 -Amino-4-cyano-1 H-imidazole-5-carboxamide

Synthesized from 4-cyano-1 H-imidazole-5-carboxamide and O- (diphenylphosphoryl)hydroxylamine following the procedure of PREPARATION 4. Yield: 62%. Purity 97%. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (s, 1 H), 8.06 (s, 1 H), 7.92 (s, 1 H), 6.71 (s, 2H).

UPLC/MS (5 min) retention time 0.32 min.

LRMS: m/z 152 (M+1 ).

PREPARATION 18 4-0x0-3, 4-dihydroimidazo[5,1 -f][1 , 2, 4]triazine-5-carbonitrile

Synthesized from the title compound of PREPARATION 17 and formamide following the method of PREPARATION 5. Yield: 53%. Purity 100%. UPLC/MS (5 min) retention time 0.57 min. LRMS: m/z 162 (M+1 ). PREPARATION 19

Methyl 1 -amino-4-methyl-1 H-pyrazole-5-carboxylate Synthesized from methyl 4-methyl-1 H-pyrazole-5-carboxylate and O- (diphenylphosphoryl)hydroxylamine following the procedure of PREPARATION 4. Yield: 49%. Purity 100%.

¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.15 (s, 1 H), 6.19 (br s, 2H), 3.93 (s, 3H), 2.24 (s, 3H). UPLC/MS (3 min) retention time 0.85 min.

LRMS: m/z 156 (M+1 ).

PREPARATION 20

5-Methylpyrazolo[5,1 -f][1 ,2,4]triazin-4(3H)-one

Synthesized from the title compound of PREPARATION 19 and formamide following the method of PREPARATION 5. Yield: 52%. Purity 98%.

¹ H NMR (300 MHz, DMSO-d6) δ ppm 12.2 (br s, 1 H), 7.95 (s, 1 H), 7.60 (s, 1 H), 2.33 (s, 3H).

UPLC/MS (3 min) retention time 0.67 min. LRMS: m/z 151 (M+1 ). PREPARATION 21

5-Bromopyrido[3,4-d]pyrimidin-4(3H)-one

Synthesized from 3-amino-5-bromoisonicotinic acid and formamide following the method of PREPARATION 5. Yield: 71 %. Purity 92%.

UPLC/MS (3 min) retention time 0.81 min. LRMS: m/z 226, 228 (M+1 , 1 *Br).

PREPARATION 22 6-Chloro-N-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%.

¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.40 (s, 1 H), 6.38 (s, 1 H), 2.98 (d, 3H, J = 5.1 Hz).

UPLC/MS (3 min) retention time 0.74 min. LRMS: m/z 144 (M+1 , 1 *CI). PREPARATION 23

6-Methoxy-N-methylpyrimidin-4-amine

The title compound of PREPARATION 22 (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%. ¹ H NMR (300 MHz, DMSO-d6) δ ppm 8.10 (s, 1 H), 7.00 (s, 1 H), 5.62 (s, 1 H), 3.80 (s, 3H), 3.10 (s, 3H)

UPLC/MS (3 min) retention time 0.45 min. LRMS: m/z 140 (M+1 ).

PREPARATION 24 6-(Methylamino)pyrimidin-4(3H)-one hydrochloride hydrate The title compound of PREPARATION 23 (7.80 g, 56 mmol) was suspended in 1 10 ml concentrated hydrochloric acid and the mixture was stirred at 60 °C for 2 days. The mixture was then evaporated under reduced pressure to give 10.0 g (56 mmol, 99% yield) of the title compound as a white solid. Purity 100%. UPLC/MS (3 min) retention time 0.32 min.

LRMS: m/z 126 (M+1 ).

PREPARATION 25

6-(Methylamino)-5-nitropyrimidin-4(3H)-one

The title compound of PREPARATION 24 (4.0 g, 32.0 mmol) was suspended in 9.6 ml concentrated sulphuric acid. 3.2 ml concentrated nitric acid was added drop-wise with stirring. The mixture was stirred for 20 min and then poured over ice. The solution was neutralized with ammonium hydroxide solution forming a yellow precipitate. The solid was collected by filtration and was dried in vacuo to give 1 .19 g (7.0 mmol, 22% yield) of the title product as a yellow solid. Purity 98%. ¹ H NMR (300 MHz, DMSO-d6) δ ppm 9.42 (br s, 1 H), 8.04 (s, 1 H), 3.00 (d, 3H, J = 4.7 Hz).

HPLC/MS (5 min) retention time 0.50 min.

LRMS: m/z 171 (M+1 ).

PREPARATION 26 5-Amino-6-(methylamino)pyrimidin-4(3H)-one

The title compound of PREPARATION 25 (1 .18 g, 6.9 mmol) was dissolved in 35 ml methanol. Raney nickel (1 .1 g) was added and the mixture was agitated at room temperature under a hydrogen atmosphere (14 psi) for 2 d. A further 1 g Raney nickel was added and the mixture agitated overnight under a hydrogen atmosphere (14 psi). The mixture was filtered and the filtrate evaporated under reduced pressure to give 0.59 g (4.2 mmol, 60% yield) of the title compound as a pale grey solid. Purity 100%.

¹ H NMR (300 MHz, DMSO-d6) δ ppm 7.53 (s, 1 H), 5.66 (m, 1 H), 3.70 (br s, 2H), 2.84 (d, 3H, J = 4.7 Hz).

UPLC/MS (3 min) retention time 0.20 min. LRMS: m/z 141 (M+1 ).

PREPARATION 27

9-Methyl-7,9-dihydro-1 H-purine-6,8-dione

The title compound of PREPARATION 26 (0.59 g, 4.2 mmol) and urea (0.49 g, 9.7 mmol) were fused together at 175 °C for 10 min. The mixture was allowed to cool, water was added and the mixture was stirred for 15 min. The mixture was filtered, the solid was washed with water and dried in vacuo at 45 °C to give 0.40 g (2.4 mmol, 58% yield) of the title compound as a pale brown solid. Purity 100%.

¹ H NMR (300 MHz, DMSO-d6) δ ppm 12.42 (br s, 1 H), 1 1 .20 (br s, 1 H), 7.97 (s, 1 H), 3.20 (s, 3H).

UPLC/MS (3 min) retention time 0.30 min.

LRMS: m/z 167 (M+1 ).

PREPARATION 28

2-Chloro-6-methoxy-4-methylnicotinonitrile 6-Chloro-2-methoxy-4-methylnicotinonitrile

2,6-Dichloro-4-methylnicotinonitrile (3.70 g, 19.8 mmol) was suspended in 30 ml methanol. Sodium methoxide solution (25% in methanol, 4.3 ml, 18.8 mmol) was added carefully with stirring and the mixture was stirred for 90 min. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give 3.43 g (18.8 mmol, 100% yield) of an approx 1 : 1 mixture of the title compounds as white solid. Used directly without further purification. Combined purity 96%.

Isomer 1 : ¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 6.61 (s, 1 H), 3.99 (s, 3H), 2.50 (s, 3H).

UPLC/MS (3 min) retention time 1 .48 min.

LRMS: m/z no ionization

Isomer 2: ¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 6.61 (s, 1 H), 3.99 (s, 3H), 2.50 (s, 3H). UPLC/MS (3 min) retention time 1 .50 min. LRMS: m/z no ionization PREPARATION 29

2-[(Diphenylmethylene)amino]-6-methoxy-4-methylnicotinonitrile 6-[(Diphenylmethylene)amino]-2-methoxy-4-methylnicotinonitrile

A mixture of the title compounds of PREPARATION 28 (1 .59 g, 8.7 mmol) was dissolved in 30 ml toluene. Benzophenone imine (1 .89 g, 10.4 mmol) and caesium carbonate (3.97 g, 12.2 mmol) were added and the mixture was submitted to three vacuum-argon cycles. Palladium(ll) acetate (0.04 g, 0.18 mmol) and 2,2'- bis(diphenylphosphino)-1 , 1 '-binaphthalene (0.16 g, 0.26 mmol) were added, the reaction vessel was sealed and the mixture was stirred at 100 °C for 4 h. The mixture was allowed to cool and was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give 3.45 g of a crude mixture of the title compounds as white solid. Used directly without further purification. Combined purity 83%.

UPLC/MS (3 min) retention time 1 .94 and 1 .96 min. LRMS: m/z 328 (M+1 ). PREPARATION 30 2-Amino-6-methoxy-4-methylnicotinonitrile 6-Amino-2-methoxy-4-methylnicotinonitrile

The crude mixture of the title compounds of PREPARATION 29 (3.45 g) was dissolved in 25 ml tetrahydrofuran. Dilute hydrochloric acid (2M, 3 ml, 6 mmol) was added and the mixture was stirred for 90 min. The mixture was neutralized with 4% sodium bicarbonate solution and the organic solvent was evaporated under reduced pressure. The mixture was extracted with ethyl acetate, the organic layer was washed consecutively with water and brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue was stirred in dichloromethane and the suspension was filtered. The solid was dried in vacuo to give 0.84 g of a mixture of the title compounds. The filtrate was evaporated and purified using the Isolera

(methanol-dichloromethane gradient, 0: 100 rising to 2:98) to give a further 0.33 g product. Total yield 1 .17 g (7.2 mmol, 83% yield over two steps) as an approx 1 : 1 mixture of regioisomers. Combined purity 100%.

UPLC/MS (3 min) retention time 1 .02 and 1 .18 min.

LRMS: m/z 164 (M+1 ). PREPARATION 31

2-Amino-6-methoxy-4-methylnicotinamide

6- Amino-2-methoxy-4-methylnicotinamide

A mixture of the mixture of title compounds of PREPARATION 30 (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. Major isomer: 2- amino-6-methoxy-4-methylnicotinamide:

¹ H NMR (300 MHz, DMSO-d6) δ ppm 7.45 (br s, 1 H), 7.40 (br s, 1 H), 5.91 (br s, 2H), 5.83 (s, 1 H), 3.72 (s, 3H), 2.20 (s, 3H).

UPLC/MS (3 min) retention time 0.53 min.

LRMS: m/z 182 (M+1 ). PREPARATION 32

7- Methoxy-5-methylpyrido[2,3-d]pyrimidin-4(3H)-one

Synthesized from the title compound of PREPARATION 31 and triethylorthoformate following the method of PREPARATION 1 . Yield: 61 %. Purity 100%.

¹ H NMR (300 MHz, DMSO-d6) δ ppm 12.3 (br s, 1 H), 8.17 (s, 1 H), 6.70 (s, 1 H), 3.90 (s, 3H), 2.65 (s, 3H).

UPLC/MS (3 min) retention time 0.92 min.

LRMS: m/z 192 (M+1 ).

PREPARATION 33 2-Amino-1 ,4-dimethyl-6-oxo-1 ,6-dihydropyridine-3-carbonitrile

N-methyl-3-oxobutanamide (400 mg, 2.43 mmol) and malonitrile (160 mg, 2.43 mmol) were suspended in 10 mL of ethanol. Five drops of piperidine were added and 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%.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.40 (s, 2H), 5.58 (s, 1 H), 3.28 (s, 3H), 2.10 (s, 3H).

UPLC/MS (3 min) retention time 0.76 min. LRMS: m/z 164 (M+1 ). PREPARATION 34

5,8-Dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione The title compound of PREPARATION 33 (73 mg, 0.44 mmol) was suspended in 0.75 ml formic acid. 2 drops of concentrated sulphuric acid were added and the mixture was stirred at 100 °C for 12 days. The mixture was allowed to cool and was diluted with water forming a precipitate. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organics were washed twice with water, twice with brine, dried over anhydrous magnesium sulphate, filtered and evaporated to give 38 mg (0.19 mmol, 42% yield) of the title compound as a white solid. Purity 95%.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.24 (1 H, s), 6.23 (1 H, s), 3.52 (3H, s), 2.50 (3H, s). UPLC/MS (3 min) retention time 0.72 min. LRMS: m/z 192 (M+1 ). PREPARATION 35

2-Amino-6-chloro-4-methylnicotinonitrile

6-Amino-2-chloro-4-methylnicotinonitrile A suspension of 2,6-dichloro-4-methylnicotinonitrile (1 .39 g, 7.43 mmol) in concentrated aqueous ammonia solution (40 mL) was stirred and heated to 50 °C in a pressure vessel. After 48 h, the mixture was cooled in an ice bath and the resultant precipitate was filtered, washed with water and dried to give 1 .15 g (6.88 mmol, 93% yield) of the title compounds, in a 2: 1 mixture, as a white solid. Combined purity 99%

Major isomer: UPLC/MS (3 min) retention time 0.99 min.

LRMS: m/z 168 (M+1 , 1 *CI).

Minor isomer: U PLC/MS (3 min) retention time 1 .13 min. LRMS: m/z 168 (M+1 , 1 *CI). PREPARATION 36

2-Amino-6-chloro-4-methylnicotinamide

6- Amino-2-chloro-4-methylnicotinamide

A mixture of the 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%.

Major isomer: ¹ H NMR (300 MHz, DMSO-d6) δ ppm 7.71 (br s, 1 H), 7.43 (br s, 1 H), 6.34 (br s, 2H), 6.21 (s, 1 H), 2.12 (s, 3H).

UPLC/MS (3 min) retention time 0.32 min.

LRMS: m/z 186 (M+1 , 1 *CI).

Minor isomer: ¹ H NMR (300 MHz, DMSO-d6) δ ppm 7.78 (br s, 1 H), 7.61 (br s, 1 H), 6.50 (s, 1 H), 6.15 (br s, 2H), 2.20 (s, 3H). UPLC/MS (3 min) retention time 0.71 min.

LRMS: m/z 186 (M+1 , 1 *CI).

PREPARATION 37

7- Chloro-5-methylpyrido[2,3-d]pyrimidin-4(3H)-one Synthesized from the mixture of title compounds of PREPARATION 36 and triethylorthoformate following the method of PREPARATION 1 . Yield: 35%. Purity 98%.

¹ H NMR (300 MHz, DMSO-d6) δ ppm 8.28 (s, 1 H), 7.45 (s, 1 H), 2.76 (s, 3H). UPLC/MS (3 min) retention time 0.88 min. LRMS: m/z 196 (M+1 , 1 *CI). PREPARATION 38 tert-Butyl (1 ,3-dimethyl-4-oxo-1 ,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5- yl)acetate Tert-butyl 2-bromoacetate (2.20 mL, 14.9 mmol) was added dropwise to a suspension of the title compound of PREPARATION 1 (2.20 g, 13.4 mmol) and potassium carbonate (3.70 g, 26.8 mmol) in dimethylformamide (34 mL) and the mixture was stirred at room temperature. After 2 h, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate and evaporated to give 3.73 g (13.4 mmol, 100% yield) of the title compound as a yellow oil. Purity 95%.

¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.81 (s, 1 H), 4.57 (s, 2H), 3.91 (s, 3H), 2.57 (s, 3H), 1 .48 (s, 9H).

UPLC/MS (3 min) retention time 1 .90 min. LRMS: m/z 279 (M+1 ).

PREPARATION 39

(1 ,3-Dimethyl-4-oxo-1 ,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)acetic acid hydrochloride salt

A solution of the title compound of PREPARATION 38 (3.73 g, 13.4 mmol) and hydrochloric acid (4M in dioxane, 174 mL) was stirred at room temperature. After 24 h, the reaction mixture was concentrated in vacuo and the residue was triturated with diethyl ether resulting in the formation of a precipitate which was filtered and dried to give 3.10 g (12.0 mmol, 89% yield) of the title compound as a hydrochloride salt as a white solid. Purity 100%. ¹ H NMR (300 MHz, DMSO-d6) δ ppm 13.18 (br s, 1 H), 8.32 (s, 1 H), 4.68 (s, 2H), 3.83 (s, 3H), 2.42 (s, 3H).

UPLC/MS (3 min) retention time 0.63 min.

LRMS: m/z 223 (M+1 ). PREPARATION 40 tert-Butyl (1 ,3-dimethyl-7-oxo-1 ,7-dihydro-6H-pyrazolo[4,3-d]pyrimidin-6- yl)acetate

Synthesized from the title compound of PREPARATION 3 and tert-butyl bromoacetate following the method of PREPARATION 38. Yield: 99%. Purity 100%. ¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.71 (s, 1 H), 4.61 (s, 2H), 4.24 (s, 3H), 2.50 (s, 3H), 1 .50 (s, 9H).

UPLC/MS (3 min) retention time 1 .29 min.

LRMS: m/z 279 (M+1 ).

PREPARATION 41 (1 ,3-Dimethyl-7-oxo-1 ,7-dihydro-6H-pyrazolo[4,3-d]pyrimidin-6-yl)acetic acid hydrochloride salt

Synthesized as a hydrochloride salt from the title compound of PREPARATION 40 following the method of PREPARATION 39. Yield: 90%. Purity 100%.

¹ H NMR (300 MHz, DMSO-d6) δ ppm 8.12 (s, 1 H), 4.74 (s, 2H), 4.12 (s, 3H), 2.36 (s, 3H).

UPLC/MS (3 min) retention time 0.66 min. LRMS: m/z 223 (M+1 ). PREPARATION 42 tert-Butyl (1 -methyl-7-oxo-1 ,7-dihydro-6H-[1 ,2,3]triazolo[4,5-d]pyrimidin-6- yl)acetate

Synthesized from the title compound of PREPARATION 15 and tert-butyl bromoacetate following the method of PREPARATION 38. Yield: 85%. Purity 98%. ¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.95 (s, 1 H), 4.65 (s, 2H), 4.47 (s, 3H), 1 .51 (s, 9H).

UPLC/MS (3 min) retention time 1 .15 min.

LRMS: m/z 266 (M+1 ). PREPARATION 43

(1 -Methyl-7-oxo-1 ,7-dihydro-6H-[1 ,2,3]triazolo[4,5-d]pyrimidin-6-yl)acetic acid hydrochloride salt

Synthesized as hydrochloride sat from the title compound of PREPARATION 42 following the method of PREPARATION 39. Yield: 90%. Purity 95%. ¹ H NMR (300 MHz, DMSO-d6) δ ppm 8.40 (s, 1 H), 4.80 (s, 2H), 4.35 (s, 3H).

UPLC/MS (3 min) retention time 0.32 min.

LRMS: m/z 210 (M+1 ).

PREPARATION 44 tert-Butyl (5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)acetate Synthesized from the title compound of PREPARATION 5 and tert-butyl bromoacetate following the method of PREPARATION 38. Yield: 98%. Purity 100%.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.97 (s, 1 H), 7.34 (s, 1 H), 4.46 (s, 2H), 2.62 (s, 3H), 1 .49 (s, 9 H)

UPLC/MS (3 min) retention time 1 .28 min. LRMS: m/z 265 (M+1 ).

PREPARATION 45

(5-Methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)acetic acid hydrochloride salt

Synthesized as a hydrochloride salt from the title compound of PREPARATION 44 following the method of PREPARATION 39. Yield: 92%. Purity 100%. ¹ H NMR (300 MHz, DMSO-d6) δ ppm 8.82 (s, 1 H), 8.22 (s, 1 H), 4.61 (s, 2H), 2.52 (s, 3H). UPLC/MS (3 min) retention time 0.47 min. LRMS: m/z 209 (M+1 ). PREPARATION 46 tert-Butyl (5,7-dimethyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)acetate Synthesized from the title compound of PREPARATION 8 and tert-butyl bromoacetate following the method of PREPARATION 38. Yield: 90%. Purity 95%.

¹ H NMR (400 MHz, CHLOROFORM-d) 7.32 (s, 1 H), 4.47 (s, 2H), 2.60 (s, 3H), 2.57 (s, 3H), 1 .50 (s, 9 H)

UPLC/MS (3 min) retention time 1 .21 min. LRMS: m/z 279 (M+1 ). PREPARATION 47

(5,7-Dimethyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)acetic acid hydrochloride salt

Synthesized as a hydrochloride salt from the title compound of PREPARATION 46 following the method of PREPARATION 39. Yield: 90%. Purity 100%.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.21 (s, 1 H), 4.60 (s, 2H), 2.55 (s, 3H), 2.50 (s, 3H)

UPLC/MS (3 min) retention time 0.38 min.

LRMS: m/z 223 (M+1 ). PREPARATION 48 tert-Butyl (7-ethyl-5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)acetate

The title compound of PREPARATION 62 (106 mg, 0.31 mmol), potassium ethyltrifluoroborate (105 mg, 0.78 mmol), palladium(ll) acetate (10 mg, 0.04 mmol) and cesium carbonate (305 mg, 0.94 mmol) were suspended in a mixture of toluene (5 mL) and water (0.5 mL) in a Shlenck tube. The mixture was submitted to three vacuum- argon cycles. Di(1 -adamantyl)-n-butylphosphine (25 mg, 0.07 mmol) was added and the mixture was submitted to a further three vacuum-argon cycles. The reaction vessel was sealed and the contents were stirred at 100 °C overnight. The mixture was allowed to cool and was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated to give a solid. Purification using the Isolera (ethyl acetate-hexane gradient, 0: 100 rising to 60:40) gave 37 mg (0.124 mmol, 40% yield) of the title compound as a yellow laquer. Purity 98%.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.30 (s, 1 H), 4.45 (s, 2H), 2.95 (q, J = 7.6 Hz, 2H), 2.60 (s, 3H), 1 .49 (s, 9H), 1 .35 (t, J = 7.6 Hz, 3H). UPLC/MS (3 min) retention time 1 .41 min.

LRMS: m/z 293 (M+1 ).

PREPARATION 49

(7-Ethyl-5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)acetic acid hydrochloride salt Synthesized as a hydrochloride salt from the title compound of PREPARATION 48 following the method of PREPARATION 39. Yield: 100%. Purity 95%.

UPLC/MS (3 min) retention time 0.55 min.

LRMS: m/z 237 (M+1 ).

PREPARATION 50 tert-Butyl (7-cyclopropyl-5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)- yl)acetate

Synthesized from the title compound of PREPARATION 62 and potassium cyclopropyltrifluoroborate following the method of PREPARATION 48. Yield: 68%. Purity 100%. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.30 (s, 1 H), 4.44 (s, 2H), 2.55 (s, 3H), 2.35 (ddd, J = 8.5, 5.1 , 3.4 Hz, 1 H), 1 .49 (s, 9H), 1 .13 - 1 .22 (m, 2H), 1 .01 - 1 .12 (m, 2H),

UPLC/MS (3 min) retention time 1 .47 min. LRMS: m/z 305 (M+1 ). PREPARATION 51

(7-Cyclopropyl-5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)acetic acid hydrochloride salt

Synthesized as a hydrochloride salt from the title compound of PREPARATION 50 following the method of PREPARATION 39. Yield: 90%. Purity 95%.

UPLC/MS (3 min) retention time 0.70 min.

LRMS: m/z 249 (M+1 ).

PREPARATION 52 tert-Butyl (5-methyl-7-morpholin-4-yl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)- yl)acetate

The title compound of PREPARATION 62 (24 mg, 0.070 mmol) was dissolved in 1 ml dimethylformamide. Morpholine (0.15 ml, 1 .7 mmol) was added and the mixture was heated under microwave irradiation at 120 °C for 1 h, and then at 130 °C for 2 h. The mixture was allowed to cool and was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated to give a solid. Purification using the Isolera (ethyl acetate-hexane gradient, 0: 100 rising to 100:0) gave 14 mg (0.040 mmol, 57% yield) of the title compound as a colourless laquer. Purity 90%.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.21 (s, 1 H), 4.42 (s, 2H), 3.84 (dd, J = 5.6, 3.8 Hz, 4H), 3.77 - 3.64 (m, 4H), 2.60 (s, 3H), 1 .48 (s, 9H).

UPLC/MS (3 min) retention time 1 .39 min.

LRMS: m/z 350 (M+1 ). PREPARATION 53

(5-Methyl-7-morpholin-4-yl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)acetic acid hydrochloride salt

Synthesized as a hydrochloride salt in crude form from the title compound of PREPARATION 52 following the method of PREPARATION 39. Purity 91 %. UPLC/MS (3 min) retention time 0.69 min. LRMS: m/z 294 (M+1 ). PREPARATION 54 tert-Butyl [5-methyl-7-(methylamino)-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)- yl] acetate Synthesized from the title compound of PREPARATION 62 and methylamine (2M in tetrahydrofuran) following the method of PREPARATION 52. Yield: 51 %. Purity 100%.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.26 (s, 1 H), 4.59 (s, 1 H), 4.37 (s, 2H), 3.1 1 (d, J = 5.2 Hz, 3H), 2.54 (s, 3H), 1 .48 (s, 9H).

UPLC/MS (3 min) retention time 1 .05 min. LRMS: m/z 294 (M+1 ).

PREPARATION 55

[5-Methyl-7-(methylamino)-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl]acetic acid hydrochloride salt

Synthesized as a hydrochloride salt in crude form from the title compound of PREPARATION 54 following the method of PREPARATION 39. Purity 90%.

UPLC/MS (3 min) retention time 0.42 min.

LRMS: m/z 238 (M+1 ).

PREPARATION 56 tert-Butyl [7-(dimethylamino)-5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)- yl] acetate

Synthesized from the title compound of PREPARATION 10 and tert-butyl bromoacetate following the method of PREPARATION 38. Yield: 80%. Purity 100%.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.10 (s, 1 H), 4.38 (s, 2H), 3.13 (s, 6H), 2.53 (s, 3H), 1 .48 (s, 9H) UPLC/MS (3 min) retention time 1 .26 min.

LRMS: m/z 308 (M+1 ).

PREPARATION 57 [7-(Dimethylamino)-5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl]acetic acid hydrochloride salt

Synthesized as a hydrochloride salt from the title compound of PREPARATION 56 following the method of PREPARATION 39. Yield: 100%. Purity 95%. UPLC/MS (3 min) retention time 0.55 min.

LRMS: m/z 252 (M+1 ).

PREPARATION 58 tert-Butyl (7-benzyl-5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)acetate

Synthesized from the title compound of PREPARATION 62 and potassium benzyltrifluoroborate following the method of PREPARATION 48. Yield: 27%. Purity 100%.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.1 1 - 7.37 (m, 6H), 4.44 (s, 2H), 4.29 (s, 2H), 2.60 (s, 3H), 1 .49 (s, 9H).

UPLC/MS (3 min) retention time 1 .67 min. LRMS: m/z 355 (M+1 ).

PREPARATION 59

(7-Benzyl-5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)acetic acid hydrochloride salt

Synthesized as a hydrochloride salt from the title compound of PREPARATION 58 following the method of PREPARATION 39. Yield: 80%. Purity 98%.

UPLC/MS (3 min) retention time 1 .09 min.

LRMS: m/z 299 (M+1 ).

PREPARATION 60 tert-Butyl (5-methyl-4-oxopyrazolo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)acetate Synthesized from the title compound of PREPARATION 20 and tert-butyl bromoacetate following the method of PREPARATION 38. Yield: 97%. Purity 98%. ¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.59 (s, 1 H), 7.54 (s, 1 H), 4.53 (s, 2H), 2.47 (s, 3H), 1 .51 (s, 9H).

HPLC/MS (5 min) retention time 2.62 min.

LRMS: m/z 265 (M+1 ). PREPARATION 61

(5-Methyl-4-oxopyrazolo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)acetic acid hydrochloride salt

Synthesized as a hydrochloride salt from the title compound of PREPARATION 60 following the method of PREPARATION 39. Yield: 88%. Purity 95%.

¹ H NMR (300 MHz, DMSO-d6) δ ppm 8.24 (s, 1 H), 7.73 (s, 1 H), 4.64 (s, 2H), 2.36 (s, 3H).

HPLC/MS (5 min) retention time 1 .55 min. LRMS: m/z 209 (M+1 ). PREPARATION 62 tert-Butyl (7-bromo-5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)acetate Synthesized from the title compound of PREPARATION 9 and tert-butyl bromoacetate following the method of PREPARATION 38. Yield: 100%. Purity 100%.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.42 (s, 1 H), 4.47 (s, 2H), 2.61 (s, 3H), 1 .49 (s, 9H) .

UPLC/MS (3 min) retention time 1 .47 min. LRMS: m/z 343, 345 (M+1 , 1 *Br). PREPARATION 63

(7-Chloro-5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)acetic acid hydrochloride salt

Synthesized as a hydrochloride salt in crude form from the title compound of PREPARATION 62 following the method of PREPARATION 39. Purity 80%.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.18 (s, 1 H), 4.57 (s, 2H), 2.45 (s, 3H) UPLC/MS (3 min) retention time 0.74 min. LRMS: m/z 243 (M+1 , 1 *CI). PREPARATION 64 tert-Butyl (7-methyl-6-oxo-6,7-dihydro-1 H-purin-1 -yl)acetate Synthesized from the title compound of PREPARATION 16 and tert-butyl bromoacetate following the method of PREPARATION 38. Yield: 96%. Purity 96%.

UPLC/MS (3 min) retention time 1 .02 min.

LRMS: m/z 265 (M+1 ).

PREPARATION 65 (7-Methyl-6-oxo-6,7-dihydro-1 H-purin-1 -yl)acetic acid hydrochloride salt

Synthesized as a hydrochloride salt form from the title compound of PREPARATION 64 following the method of PREPARATION 39. Yield: 88%. Purity 99%.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.25 (s, 1 H), 8.22 (s, 1 H), 4.71 (s, 2H), 3.94 (s, 3H). UPLC/MS (3 min) retention time 0.39 min. LRMS: m/z 209 (M+1 ). PREPARATION 66 tert-Butyl (7-methoxy-5-methyl-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl)acetate

Synthesized from the title compound of PREPARATION 32 and tert-butyl bromoacetate following the method of PREPARATION 38. Yield: 92%. Purity 93%.

UPLC/MS (3 min) retention time 1 .52 min.

LRMS: m/z 306 (M+1 ).

PREPARATION 67

(7-Methoxy-5-methyl-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl)acetic acid Synthesized from the title compound of PREPARATION 66 following the method of PREPARATION 39. Yield: 100%. Purity 92%. ¹ H NMR (300 MHz, DMSO-d6) δ ppm 8.48 (s, 1 H), 6.79 (s, 1 H), 4.66 (s, 2H), 3.92 (s, 3H), 2.67 (s, 3H).

UPLC/MS (3 min) retention time 0.90 min.

LRMS: m/z 250 (M+1 ). PREPARATION 68 tert-Butyl (5-bromo-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)acetate

Synthesized from the title compound of PREPARATION 21 and tert-butyl bromoacetate following the method of PREPARATION 38. Yield: 37%. Purity 92%.

¹ H NMR (300 MHz, DMSO-d6) δ ppm 9.00 (s, 1 H), 8.81 (s, 1 H), 8.54 (s, 1 H), 4.68 (s, 2H), 1 .40 (s, 9H).

UPLC/MS (3 min) retention time 1 .47 min.

LRMS: m/z 340, 342 (M+1 , 1 *Br).

PREPARATION 69

(5-Bromo-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)acetic acid Synthesized from the title compound of PREPARATION 68 following the method of PREPARATION 39. Yield: 86%. Purity 95%.

¹ H NMR (300 MHz, DMSO-d6) δ ppm 9.00 (s, 1 H), 8.80 (s, 1 H), 8.55 (s, 1 H), 4.70 (s, 2H).

UPLC/MS (3 min) retention time 0.72 min. LRMS: m/z 284, 286 (M+1 , 1 *Br). PREPARATION 70 tert-Butyl (9-methyl-6,8-dioxo-6,7,8,9-tetrahydro-1 H-purin-1 -yl)acetate

Synthesized from the title compound of PREPARATION 27 and tert-butyl bromoacetate following the method of PREPARATION 38. Yield: 40%. Purity 99%. ¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.90 (br s, 1 H), 7.82 (s, 1 H), 4.63 (s, 2H), 3.40 (s, 3H), 1 .47 (s, 9H). UPLC/MS (3 min) retention time 0.98 min. LRMS: m/z 281 (M+1 ). PREPARATION 71 tert-Butyl (7,9-dimethyl-6,8-dioxo-6,7,8,9-tetrahydro-1 H-purin-1 -yl)acetate The title compound of PREPARATION 70 (180 mg, 0.64 mmol) was dissolved in 4 ml dimethylformamide and the solution was cooled to 0°C in an ice-bath. Sodium hydride (60% suspension in oil, 41 mg, 1 .0 mmol) was added and the mixture was stirred for 30 min. Methyl iodide (42 μΙ, 0.67 mmol) was added and the mixture was stirred overnight, warming to room temperature. The mixture was partitioned between ethyl acetate and water. The organics were washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated to give 190 mg (0.64 mmol, 100% yield) of the title compound as a yellow oil. Purity 96%.

¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.80 (s, 1 H), 4.60 (s, 2H), 3.63 (s, 3H), 3.40 (s, 3H), 1 .50 (s, 9H). UPLC/MS (3 min) retention time 1 .1 1 min.

LRMS: m/z 295 (M+1 ).

PREPARATION 72

(7,9-Dimethyl-6,8-dioxo-6,7,8,9-tetrahydro-1 H-purin-1 -yl)acetic acid

Synthesized from the title compound of PREPARATION 71 following the method of PREPARATION 39. Yield: 99%. Purity 99%.

¹ H NMR (300 MHz, DMSO-d6) δ ppm 8.31 (s, 1 H), 4.72 (s, 2H), 3.57 (s, 3H), 3.45 (s, 3H).

UPLC/MS (3 min) retention time 0.50 min. LRMS: m/z 239 (M+1 ). PREPARATION 73

5-Bromopyrazine-2,3-diamine

3,5-Dibromopyrazin-2-amine (10.0 g, 39.5 mmol) was suspended in 200 ml concentrated (32%) aqueous ammonia and the mixture was stirred at 130 °C in a pressure tube for 5 days. The mixture was allowed to cool, forming a precipitate. The solid was collected by filtration, washed with water and dried in vacuo to give 5.10 g (27.0 mmol, 68% yield) of the title compound as a pale brown solid. Purity 100%.

¹ H NMR (300 MHz, DMSO-d6) δ ppm 7.20 (s, 1 H), 6.40 (br s, 2H), 6.05 (br s, 2H). UPLC/MS (3 min) retention time 0.69 min.

LRMS: m/z 189, 191 (M+1 , 1 *Br).

PREPARATION 74

3-[(6-Bromo-1 H-imidazo[4,5-b]pyrazin-2-yl)methyl]-5-methylimidazo[5,1 - f][1,2,4]triazin-4(3H)-one The title compound of PREPARATION 45 (240 mg, 1 .2 mmol) and 1 , 1 '- carbonyldiimidazole (240 mg, 1 .5 mmol) were dissolved in 3 ml butyronitrile and the mixture was stirred in a sealed microwave tube for 15 min at room temperature affording a thick white suspension. The title compound of PREPARATION 73 (220 mg, 1 .2 mmol) was added and the reaction was heated 180 °C under microwave irradiation for 2 h. The mixture was allowed to cool and was evaporated under reduced pressure. The residue was purified by flash chromatography (methanol-dichloromethane gradient, 0: 100 rising to 10:90) to give 240 mg (0.66 mmol, 58% yield) of the title compound as a white solid. Purity 97%.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.54 (s, 1 H), 8.44 (s, 1 H), 8.27 (s, 1 H), 5.40 (s, 2H), 2.50 (s, 3H).

UPLC/MS (3 min) retention time 0.98 min.

LRMS: m/z 361 , 363 (M+1 , 1 *Br).

PREPARATION 75

6-(4-Chlorophenyl)-5-methylpyridine-2,3-diamine 5-Bromo-6-methylpyridine-2,3-diamine (50 mg, 0.25 mmol), 4-chlorophenylboronic acid (45 mg, 0.29 mmol), and cesium carbonate (240 mg, 0.74 mmol) were suspended in dioxane/water (4: 1 ; v/v) (1 .25 ml) and this mixture was degassed (3 x vacuum- nitrogen cycles). [1 , 1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (1 : 1 ) dichloromethane complex was added and the mixture degassed again (3 x vacuum- nitrogen cycles). The resulting reaction mixture was stirred at 1 10 °C for 16 h. Then, the mixture was allowed to cool and it was worked-up adding chloroform and washing with water and brine. The organic phase was dried and evaporated under reduced pressure to afford a residue of 93 mg. This crude material was purified by flash chromatography (methanol-dichloromethane gradient, 0: 100 rising to 10:90) to give 46 mg (0.20 mmol, 80% yield) of the title compound as a solid. Purity 95%.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.35 (d, 2H, J = 8.3 Hz), 7.20 (d, 2H, J = 8.3 Hz), 6.78 (s, 1 H), 4.30 (br.s, 2H), 3.23 (br.s, 2H), 2.28 (s, 3H)

UPLC/MS (3 min) retention time 1 .08 min.

LRMS: m/z 234 (M+1 , 1 *CI). PREPARATION 76

5-(4-Chlorophenoxy)pyrazine-2,3-diamine

The title compound of PREPARATION 73 (1 .1 g, 5.65 mmol) was dissolved in 16 ml dioxane in a Schlenk tube under nitrogen atmosphere. 4-Chlorophenol (1 .45 g, 1 1 .3 mmol), copper(l) iodide (0.22 g, 1 .16 mmol), Ν,Ν-dimethyl glycine hydrochloride (0.48 g, 3.44 mmol) and caesium carbonate (5.5 g, 16.9 mmol) were added sequentially. The mixture was subjected to three vacuum-nitrogen cycles, the tube was sealed and the mixture was stirred at 1 15 °C for 2 days. The mixture was allowed to cool and was diluted with dichloromethane. The mixture was filtered through a plug of Celite and was washed throught with more dichloromethane. The combined organics were washed with water, twice with 2N sodium hydroxide solution, once with brine and were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give 0.78 g (3.3 mmol, 58% yield) of the title compound as a dark brown oil. Purity 95%.

¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.30 (d, 2H, J = 9.0 Hz), 7.28 (s, 1 H), 6.98 (d, 2H, J = 9.0 Hz), 4.39 (br s, 2H), 3.71 (br s, 2H).

UPLC/MS (3 min) retention time 1 .27 min.

LRMS: m/z 237 (M+1 , 1 *CI).

PREPARATION 77

5-(3-Chlorophenoxy)pyrazine-2,3-diamine Synthesized from the title compound of PREPARATION 73 and 3-chlorophenol following the method of PREPARATION 76. Yield: 28%. Purity 95%.

¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.00-7.40 (m, 5H), 4.40 (br s, 2H), 4.10 (br s, 2H). UPLC/MS (3 min) retention time 1 .26 min. LRMS: m/z 237 (M+1 , 1 *CI). PREPARATION 78 5-Phenoxypyrazine-2,3-diamine

Synthesized from the title compound of PREPARATION 73 and phenol following the method of PREPARATION 76. Yield: 31 %. Purity 100%.

¹ H NMR (300 MHz, DMSO-d6) δ ppm 7.00-7.40 (m, 6H).

UPLC/MS (3 min) retention time 0.94 min.

LRMS: m/z 203 (M+1 ).

PREPARATION 79 5-(3-Bromophenoxy)pyrazine-2,3-diamine

Synthesized from the title compound of PREPARATION 73 and 3-bromophenol following the method of PREPARATION 76. Yield: 20%. Purity 88%.

¹ H NMR (300 MHz, DMSO-d6) δ ppm 7.00-7.40 (m, 5H).

UPLC/MS (3 min) retention time 1 .29 min. LRMS: m/z 281 , 283 (M+1 , 1 *Br).

PREPARATION 80

5-[3-(Trifluoromethyl)phenoxy]pyrazine-2,3-diamine

Synthesized from the title compound of PREPARATION 73 and 3- (trifluoromethyl)phenol following the method of PREPARATION 76. Yield: 49%. Purity 100%. ¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.35 (br s, 2H), 7.18-7.48 (m, 4H), 6.77 (br s, 2H), 6.69 (s, 1 H).

UPLC/MS (3 min) retention time 1 .35 min.

LRMS: m/z 271 (M+1 ). PREPARATION 81

3- [(5,6-Diaminopyrazin-2-yl)oxy]benzonitrile

Synthesized from the title compound of PREPARATION 73 and 3-hydroxybenzonitrile following the method of PREPARATION 76. Yield: 19%. Purity 100%.

UPLC/MS (3 min) retention time 0.94 min. LRMS: m/z 228 (M+1 ).

PREPARATION 82

4- [(5,6-Diaminopyrazin-2-yl)oxy]benzonitrile

Synthesized from the title compound of PREPARATION 73 and 4-hydroxybenzonitrile following the method of PREPARATION 76. Yield: 27%. Purity 95%. ¹ H NMR (300 MHz, DMSO-d6) δ ppm 7.79 (d, 2H, J = 9.0 Hz), 7.09 (d, 2H, J = 9.0 Hz), 7.06 (s, 1 H), 6.60 (br s, 2H).

UPLC/MS (3 min) retention time 0.92 min.

LRMS: m/z 228 (M+1 ).

PREPARATION 83 5-Chloro-3-nitro-6-[4-(trifluoromethyl)phenoxy]pyrazin-2 -amine

Sodium hydride (60% dispersion in mineral oil, 0.02 g, 0.50 mmol) was added to a stirred solution of 4-(trifluoromethyl)phenol (0.08 g, 0.49 mmol) in dimethylformamide (0.8 mL). After 5 min, the mixture was cooled (ice-bath) and 5,6-dichloro-3- nitropyrazin-2-amine (synthesized according to the method described in Hartman et al, J. Med. Chem., 1984, 27(12), 1634-9, 0.10 g, 0.48 mmol) was added and the mixture was warmed to room temperature. After 2h, the reaction mixture was diluted with water and the precipitate was filtered, washed with water and dried to give 0.12 g (0.36 mmol, 75% yield) of the title compound as a yellow solid. Purity 98%. ¹ H NMR (300 MHz, DMSO-d6) δ ppm 7.89 (d, 2H, J = 8.6 Hz), 7.58 (d, 2H, J = 8.6 Hz).

UPLC/MS (3 min) retention time 1 .74 min.

LRMS: m/z 333 (M-1 , 1 *CI).

PREPARATION 84 5-[4-(Trifluoromethyl)phenoxy]pyrazine-2,3-diamine

A solution of the title compound of PREPARATION 83 (0.120 g, 0.36 mmol) in ethanol (30 mL) was subjected to hydrogenation using the H-Cube apparatus (10% Pd/C cartridge, 5 bar hydrogen pressure, 35 °C, flow 1 mL/min) under continuous flow conditions. After 24 h, the solvent was evaporated in vacuo to give 0.083 g (0.31 mmol, 86% yield) of the title compound as a brown solid. Purity 90%.

¹ H NMR (300 MHz, DMSO-d6) δ ppm 7.69 (d, 2H, J = 8.6 Hz), 7.15 (d, 2H, J = 8.6 Hz), 7.08 (s, 1 H).

UPLC/MS (3 min) retention time 1 .38 min.

LRMS: m/z 271 (M+1 ). PREPARATION 85

2-(Chloromethyl)-5-(4-chlorophenoxy)-1 H-imidazo[4,5-b]pyrazine

The title compound of PREPARATION 76 (85 mg, 0.42 mmol) and chloroacetyl chloride (48 mg, 0.42 mmol) were dissolved in phosphorus oxychloride (3.6 ml) and the mixture was stirred at 90 °C for 2 h. The mixture was allowed to cool and was evaporated under reduced pressure. The residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic phase were washed with brine, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give 96 mg of the crude title compound. Used as such without further purifications. Purity 83%. ¹ H NMR (400 MHz, METHANOL-d4) δ ppm 8.28 (s, 1 H), 7.42 (d, 2H, J=8.99 Hz), 7.21 (d, 2H, J=8.99 Hz)

UPLC/MS (3 min) retention time 1 .51 min. LRMS: m/z 295 (M+1 , 2xCI). PREPARATION 86

6-(4-Chlorophenoxy)pyridine-3,4-diamine

Synthesized in crude form from 6-bromopyridine-3,4-diamine and 4-chlorophenol following the method of PREPARATION 76. Purity 75%. UPLC/MS (3 min) retention time 0.85 min.

LRMS: m/z 236 (M+1 , 1 *CI).

PREPARATION 87

2-(4-Chlorophenoxy)pyrimidine-4,5-diamine

A neat mixture of 2-chloropyrimidine-4,5-diamine (200 mg, 1 .38 mmol) and 4- chlorophenol (500 mg, 3.89 mmol) was stirred at 90 °C for 5 h. The mixture was allowed to cool and was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organics were washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated to give 34 mg (0.14 mmol, 10% yield) of the title compound. Purity 99%. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.66 (s, 1 H), 7.34 (d, 2H, J=8.80 Hz), 7.1 1 (d, 2H, J=8.80 Hz), 5.06 (br.s, 2H), 2.87 (br.s, 2H)

UPLC/MS (3 min) retention time 0.87 min.

LRMS: m/z 237 (M+1 , 1 *CI).

PREPARATION 88 5-(4-Chlorophenoxy)-3-nitropyridin-2-amine

Synthesized in crude form from 5-bromo-3-nitropyridin-2-amine and 4-chlorophenol following the method of PREPARATION 76. Purity 66%.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.29 (d, 1 H, J=2.74 Hz), 8.10 (d, 1 H, J=2.74 Hz), 7.33 (d, 2H, J=8.99 Hz), 6.93 (s, 2H, J=8.99 Hz) UPLC/MS (3 min) retention time 1 .71 min.

LRMS: m/z 266 (M+1 , 1 *CI).

PREPARATION 89 5-(4-Chlorophenoxy)pyridine-2,3-diamine

To a solution of the crude title compound of PREPARATION 88 (50 mg) in methanol, in a schlenk tube under nitrogen, was added a small amount of Ni-Raney slurry and afterwards hydrazine monohydrate (40 μΙ, 0.82 mmol) was added dropwise at room temperature. The reaction mixture was stirred at this temperature for 1 h. The mixture was filtered though a pad of Celite® and the filtrate evaporated under reduced pressure to give 64 mg of the crude title compound. Used as such without further purification. Purity 77%.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.48 (d, 1 H, J=2.54 Hz), 7.25 (d, 2H, J=8.99 Hz), 6.89 (d, 2H, J=8.99 Hz), 6.66 (d, 1 H, J=2.54 Hz), 4.1 1 (br.s, 2H), 3.43 (br.s, 2H)

UPLC/MS (3 min) retention time 1 .03 min.

LRMS: m/z 236 (M+1 , 1 *CI).

PREPARATION 90 [5-(4-Chlorophenoxy)-2-nitrophenyl]amine

To a mixture of 5-fluoro-2-nitroaniline (31 1 mg, 2 mmol), and 4-chlorophenol (266 mg, 2.07 mmol) in dimethylformamide (6.3 ml) was added potassium carbonate (719 mg, 5.2 mmol) and the resulting mixture was heated to 100 °C overnight. Then, the mixture was allowed to cool and partitioned between ethyl acetate/hexane 1/1 and water. The organics were washed with water, brine, dried over anhydrous sodium sulphate, filtered and evaporated to give 390 mg (1 .37 mmol, 69% yield) of the title compound. Purity 93%.

UPLC/MS (3 min) retention time 1 .83 min. LRMS: m/z 263 (M-1 , 1 *CI). PREPARATION 91

4-(4-Chlorophenoxy)benzene-1 ,2-diamine

Synthesized from the title compound of PREPARATION 90 following the method of PREPARATION 89. Yield: 91 %. Purity 95%.

UPLC/MS (3 min) retention time 1 .30 min. LRMS: m/z 235 (M+1 , 1 *CI). PREPARATION 92

6-(4-Chlorophenoxy)pyridine-2,3-diamine

Synthesized from 6-bromopyridine-2,3-diamine and 4-chlorophenol following the method of PREPARATION 76. Yield: 20%. Purity 98%.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.28 (d, 2H, J=8.99 Hz), 6.93 - 7.02 (m, 3H), 6.16 (d, 1 H, J=7.82 Hz), 4.30 (br.s, 2H), 3.10 (br.s, 2H)

UPLC/MS (3 min) retention time 1 .32 min.

LRMS: m/z 236 (M+1 , 1 *CI). EXAMPLES

EXAMPLE 1

3-{[6-(4-Chlorophenyl)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylimidazo[5,1 -f][1 ,2,4]triazin-4(3H)-one

The title compound of PREPARATION 74 (40 mg, 0.1 1 mmol), (4-chlorophenyl)boronic acid (52 mg, 0.33 mmol) and sodium carbonate (47 mg, 0.44 mmol) were suspended in 2 ml dioxane and 1 ml water in a Schlenk flask. The mixture was degassed by submitting it to three vacuum-nitrogen cycles was degassed. Tetrakis(triphenylphosphine)palladium (13 mg, 0.01 mmol) was added and the mixture as submitted to a further vacuum-nitrogen cycle. The resulting mixture was stirred overnight at 95 °C. The mixture was allowed to cool and was diluted with dichloromethane. The mixture was washed with water and then with saturated sodium bicarbonate solution. The organic phase was evaporated under reduced pressure. The residue was purified by flash chromatography (methanol-dichloromethane gradient, 0: 100 rising to 5:95) to give 17 mg (0.04 mmol, 39% yield) of the title compound as a white solid. Purity 99%.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.99 (s, 1 H), 8.41 (s, 1 H), 8.25 (s, 1 H), 8.15 (d, 2H, J = 8.8 Hz), 7.58 (d, 2H, J = 8.8 Hz), 5.75 (s, 1 H), 5.38 (s, 2H), 2.47 (s, 3H)

UPLC/MS (3 min) retention time 1 .47 min. LRMS: m/z 393 (M+1 , 1 *CI).

EXAMPLE 2

3-{[6-(4-Chlorophenyl)-5-methyl-1 H-imidazo[4,5-b]pyridin-2-yl]methyl}-5- methylimidazo[5,1 -f][1 ,2,4]triazin-4(3H)-one Synthesized from the title compound of PREPARATION 45 and the title compound of PREPARATION 75 following the method of PREPARATION 74. Yield: 40%. Purity 95%.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.97 (s, 1 H), 7.78 (s, 1 H), 7.70 (s, 2H), 7.42 (d, 2H, J = 8.4 Hz), 7.26 (d, 2H, J = 8.4 Hz), 5.30 (s, 2H), 2.62 (s, 3H), 2.52 (s, 3H)

UPLC/MS (3 min) retention time 1 .51 min. LRMS: m/z 406 (M+1 , 1 *CI). EXAMPLE 3

3-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylimidazo[5,1 -f][1 ,2,4]triazin-4(3H)-one

Method A

The title compound of PREPARATION 45 (22 mg, 0.1 1 mmol) and the title compound of PREPARATION 76 (26 mg, 0.1 1 mmol) were suspended in phosphorus oxychloride (1 .4 ml) and the mixture stirred at 90 °C for 5 h. The mixture was allowed to cool and was evaporated under reduced pressure. The residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (methanol-dichloromethane gradient, 0: 100 rising to 5:95) to give 33 mg (0.08 mmol, 74% yield) of the title compound as a solid. Purity 100%.

Method B

The title compound of PREPARATION 5 (14 mg, 0.09 mmol) was dissolved in 0.5 ml dry dimethylformamide. Caesium carbonate (82 mg, 0.25 mmol) was added and the suspension was stirred at room temperature for 15 min. A solution of the crude title compound of PREPARATION 85 (26 mg) dissolved in 0. 5ml dry dimethylformamide was added and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted three times with ethyl acetate. The combined organics were washed with water, brine, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residue was partially purified by flash chromatography (methanol-dichloromethane gradient, 0: 100 rising to 10:90). The crude compound obtained was triturated with a mixture of dichloromethane-diethyl ether to give 3 mg (0.007 mmol, 8% yield) of the title compound. Purity 99%.

¹ H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (s, 1 H), 8.29 (br s, 1 H), 8.21 (s, 1 H), 7.47 (d, 2H, J = 8.6 Hz), 7.24 (d, 2H, J = 8.6 Hz), 5.31 (s, 2H), 2.45 (s, 3H). HPLC/MS (5 min) retention time 2.32 min.

LRMS: m/z 409 (M+1 , 1 *CI).

EXAMPLE 4

3-{[6-(3-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylimidazo[5,1 -f][1 ,2,4]triazin-4(3H)-one Synthesized from the title compound of PREPARATION 45 and the title compound of PREPARATION 77 following method A of EXAMPLE 3. Yield: 37%. Purity 99%.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (s, 1 H), 8.27 (s, 1 H), 8.20 (s, 1 H), 7.44 (t, 1 H, J=8.01 Hz), 7.34 (s, 1 H), 7.26 - 7.31 (m, 1 H), 7.14 - 7.20 (m, 1 H), 5.75 (s, 1 H), 5.31 (s, 2H), 2.45 (s, 3H) UPLC/MS (3 min) retention time 1 .48 min.

LRMS: m/z 409 (M+1 , 1 *CI).

EXAMPLE 5

7-Chloro-3-{[6-(4-chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylimidazo[5,1 -f][1 ,2,4]triazin-4(3H)-one Synthesized from the crude title compound of PREPARATION 63 and the title compound of PREPARATION 76 following method A of EXAMPLE 3. Yield: 69%. Purity 94%.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (s, 1 H), 8.31 (s, 1 H), 7.50 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 5.38 (s, 2H), 2.48 (s, 3H). UPLC/MS (3 min) retention time 1 .62 min. LRMS: m/z 443 (M+1 , 2*CI). EXAMPLE 6

3-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5,7- dimethylimidazo[5,1 -f][1 ,2,4]triazin-4(3H)-one

Synthesized from the title compound of PREPARATION 47 and the title compound of PREPARATION 76 following method A of EXAMPLE 3. Yield: 50%. Purity 99%.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (s, 1 H), 8.17 (s, 1 H), 7.45 (d, 1 H, J=8.60 Hz), 7.22 (d, 1 H, d, J=8.60 Hz), 5.29 (s, 2H), 2.50 (s, 3H), 2.41 (s, 3H) UPLC/MS (3 min) retention time 1 .43 min.

LRMS: m/z 423 (M+1 , 1 *CI).

EXAMPLE 7

3-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-7-ethyl-5- methylimidazo[5,1 -f][1 ,2,4]triazin-4(3H)-one

Synthesized from the title compound of PREPARATION 49 and the title compound of PREPARATION 76 following method A of EXAMPLE 3. Yield: 72%. Purity 93%.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (s, 1 H), 8.22 (s, 1 H), 7.50 (d, J = 8.9 Hz, 2H), 7.27 (d, J = 8.9 Hz, 2H), 7.06 (s, 1 H), 5.34 (s, 2H ), 2.92 (q, J = 7.6 Hz, 2H), 2.46 (s, 3H), 1 .31 (t, J = 7.6 Hz, 3H).

UPLC/MS (3 min) retention time 1 .59 min.

LRMS: m/z 437 (M+1 , 1 *CI).

EXAMPLE 8

7-Benzyl-3-{[6-(4-chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylimidazo[5,1 -f][1 ,2,4]triazin-4(3H)-one

Synthesized from the title compound of PREPARATION 59 and the title compound of PREPARATION 76 method A of EXAMPLE 3. Yield: 82%. Purity 98%. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (s, 1H), 8.24 (s, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.38 - 7.22 (m, 8H), 5.34 (s, 2H), 4.30 (s, 2H), 2.46 (s, 3H).

UPLC/MS (3 min) retention time 1.77 min.

LRMS: m/z499 (M+1, 1*CI). EXAMPLE 9

3-{[6-(4-Chlorophenoxy)-1H-imidazo[4,5-b]pyrazin-2-yl]methyl}-7-cyclopropyl-5- methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one

Synthesized from the title compound of PREPARATION 51 and the title compound of PREPARATION 76 method A of EXAMPLE 3. Yield: 67%. Purity 98%. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (s, 1H), 8.22 (s, 1H), 7.50 (d, J = 8.9 Hz, 2H), 7.27 (d, J = 8.9 Hz, 2H), 5.34 (s, 2H), 2.41 (s, 3H), 2.38 (dd, J = 8.3, 4.9 Hz, 1H), 1.10 (ddt, J = 11.3, 5.8, 3.0 Hz, 2H), 1.04 (dt, J = 5.0, 2.7 Hz, 2H).

UPLC/MS (3 min) retention time 1.63 min.

LRMS: m/z449 (M+1, 1*CI). EXAMPLE 10

3-{[6-(4-Chlorophenoxy)-1H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5-methyl-7- morpholin-4-ylimidazo[5,1-f][1,2,4]triazin-4(3H)-one

Synthesized from the title compound of PREPARATION 53 and the title compound of PREPARATION 76 following method A of EXAMPLE 3. Yield: 55% over two steps. Purity 95%.

¹H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (s, 1H), 8.02 (s, 1H), 7.50 (d, J = 8.9 Hz, 2H), 7.25 (d, J = 8.9 Hz, 2H), 5.27 (s, 2H), 3.85 - 3.66 (m, 4H), 3.61 - 3.47 (m, 4H), 2.41 (s, 3H).

UPLC/MS (3 min) retention time 1.56 min. LRMS: m/z 494 (M+1 , 1 *CI). EXAMPLE 11

3-{[6-(4-Chlorophenoxy)-1H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5-methyl-7- (methylamino)imidazo[5,1-f][1,2,4]triazin-4(3H)-one Synthesized from the title compound of PREPARATION 55 and the title compound of PREPARATION 76 method A of EXAMPLE 3. Yield: 65%. Purity 92%.

¹H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (s, 1 H), 7.95 (s, 1 H), 7.63 - 7.42 (m, 2H), 7.28 (d, J = 7.8 Hz, 2H), 6.70 (s, 1 H), 5.24 (s, 2H), 2.92 (d, J = 4.7 Hz, 3H), 2.37 (s, 3H).

UPLC/MS (3 min) retention time 1.30 min. LRMS: m/z 436 (M+1 , 1 *CI). EXAMPLE 12

3-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-7- (dimethylamino)-5-methylimidazo[5,1 -f][1 ,2,4]triazin-4(3H)-one

Synthesized from the title compound of PREPARATION 57 and the title compound of PREPARATION 76 following method A of EXAMPLE 3. Yield: 63%. Purity 100%. H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (s, 1 H), 7.91 (s, 1 H), 7.45 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 5.20 (s, 2H), 3.04 (s, 6H), 2.33 (s, 3H). UPLC/MS (3 min) retention time 1.47 min.

LRMS: m/z 452 (M+1 , 1 xCI).

EXAMPLE 13

5-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-1 ,3-dimethyl-1 ,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Synthesized from the title compound of PREPARATION 39 and the title compound of PREPARATION 76 following method A of EXAMPLE 3. Yield: 81 %. Purity 97%.

¹H NMR (400 MHz, DMSO-d6) δ ppm 8.49 (s, 1 H), 8.27 (s, 1 H), 7.46 (d, J = 8.9 Hz, 2H), 7.23 (d, J = 8.9 Hz, 2H), 5.42 (s, 2H), 3.85 (s, 3H), 2.39 (s, 3H)

UPLC/MS (3 min) retention time 1.52 min. LRMS: m/z 423 (M+1 , 1 xCI). EXAMPLE 14

6-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-1 ,3-dimethyl-1 ,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

Synthesized from the title compound of PREPARATION 41 and the title compound of PREPARATION 76 following method A of EXAMPLE 3. Yield: 85%. Purity 95%.

¹H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (s, 2H), 7.46 (d, 2H, J = 8.8 Hz), 7.23 (br.d, 2H, J = 8.8 Hz), 5.47 (s, 2H), 4.08 (s, 3H), 2.38 (s, 3H)

UPLC/MS (3 min) retention time 1.54 min.

LRMS: m/z 423 (M+1 , 1 CI). EXAMPLE 15

5-Chloro-3-{[6-(4-chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2- yl]methyl}pyrido[3,4-d]pyrimidin-4(3H)-one

Synthesized from the title compound of PREPARATION 69 and the title compound of PREPARATION 76 following method A of EXAMPLE 3. Yield: 30%. Purity 95%. ¹H NMR (300 MHz, DMSO-d6) δ ppm 9.03 (s, 1 H), 8.70 (m, 2H), 8.29 (br s, 1 H), 7.63 (s, 1 H), 7.46 (d, 2H, J = 8.7 Hz), 7.24 (d, 2H, J = 8.7 Hz), 5.47 (s, 2H).

UPLC/MS (3 min) retention time 1.60 min.

LRMS: m/z 440 (M+1 , 2*CI).

EXAMPLE 16 6-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-1 -methyl-1 ,6- dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one

Synthesized from the title compound of PREPARATION 43 and the title compound of PREPARATION 76 following method A of EXAMPLE 3. Yield: 60%. Purity 98%.

¹H NMR (300 MHz, DMSO-d6) δ ppm 8.59 (s, 1 H), 8.54 (br s, 1 H), 8.30 (s, 1 H), 7.47 (d, 2H, J = 8.7 Hz), 7.24 (d, 2H, J = 8.7 Hz), 5.54 (s, 2H), 4.35 (s, 3H).

UPLC/MS (3 min) retention time 1.42 min.

LRMS: m/z 410 (M+1 , 1 <CI). EXAMPLE 17

1 -{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-7-methyl-1 ,7- dihydro-6H-purin-6-one

Synthesized from the title compound of PREPARATION 65 and the title compound of PREPARATION 76 following method A of EXAMPLE 3. Yield: 40%. Purity 99%.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.37 (br.s, 1 H), 8.27 (s, 1 H), 7.86 (s, 1 H), 7.32 - 7.42 (m, 2H), 7.13 (d, 2H, J=8.99 Hz), 5.44 (s, 2H), 4.1 1 (s, 3H)

UPLC/MS (3 min) retention time 1 .35 min.

LRMS: m/z 409 (M+1 , 1 *CI). EXAMPLE 18

3-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-4-oxo-3,4- dihydroimidazo[5,1 -f][1 ,2,4]triazine-5-carbonitrile

Synthesized from the title compound of PREPARATION 18 and the crude title compound of PREPARATION 85 following method B of EXAMPLE 3. Yield: 7%. Purity 86%.

¹ H NMR (400 MHz, METHANOL-d4) δ ppm , 8.30 (s, 1 H), 8.23 (s, 1 H), 7.41 (d, J = 8.9 Hz, 2H), 7.19 (d, J = 8.9 Hz, 2H), 5.50 (s, 1 H), 5.47 (s, 2H)

UPLC/MS (3 min) retention time 1 .51 min.

LRMS: m/z 420 (M+1 , 1 *CI). EXAMPLE 19

3-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylpyrazolo[5,1 -f][1 ,2,4]triazin-4(3H)-one

Synthesized from the title compound of PREPARATION 61 and the title compound of PREPARATION 76 following method A of EXAMPLE 3. Yield: 60%. Purity 98%. ¹ H NMR (300 MHz, DMSO-d6) δ ppm 13.60 (br s, 1 H), 8.38 (s, 1 H), 8.29 (s, 1 H), 7.74 (s, 1 H), 7.46 (d, 2H, J = 8.6 Hz), 7.24 (d, 2H, J = 8.6 Hz), 5.38 (s, 2H), 2.34 (s, 3H).

UPLC/MS (3 min) retention time 1 .57 min. LRMS: m/z 409 (M+1 , 1 *CI). EXAMPLE 20

3-{[6-(3-Chlorophenoxy)-1H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylpyrazolo[5,1-f][1,2,4]triazin-4(3H)-one Synthesized from the title compound of PREPARATION 61 and the title compound of PREPARATION 77 following method A of EXAMPLE 3. Yield: 60%. Purity 99%.

¹H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (s, 1 H), 8.33 (br s, 1 H), 7.74 (s, 1 H), 7.15- 7.47 (m, 4H), 5.39 (s, 2H), 2.34 (s, 3H).

HPLC/MS (5 min) retention time 2.55 min. LRMS: m/z 409 (M+1 , 1 xCI).

EXAMPLE 21

1-{[6-(3-Chlorophenoxy)-1H-imidazo[4,5-b]pyrazin-2-yl]methyl}-7,9-dimethyl-7,9- dihydro-1 H-purine-6,8-dione

Synthesized from the title compound of PREPARATION 72 and the title compound of PREPARATION 76 following method A of EXAMPLE 3. Yield: 37%. Purity 98%.

¹H NMR (300 MHz, DMSO-d6) δ ppm 13.62 (br s, 1 H), 8.50 (s, 1 H), 8.29 (s, 1 H), 7.17- 7.47 (m, 4H), 5.46 (s, 2H), 3.42 (S, 3H), 3.30 (s, 3H).

HPLC/MS (5 min) retention time 2.23 min.

LRMS: m/z 439 (M+1 , 1 *CI). EXAMPLE 22

3-{[6-(3-Chlorophenoxy)-1H-imidazo[4,5-b]pyrazin-2-yl]methyl}-7-methoxy-5- methylpyrido[2,3-d]pyrimidin-4(3H)-one

Synthesized from the title compound of PREPARATION 67 and the title compound of PREPARATION 76 following method A of EXAMPLE 3. Yield: 41 %. Purity 99%. ¹H NMR (300 MHz, DMSO-d6) δ ppm 8.67 (s, 1 H), 8.27 (m, 1 H), 7.17-7.47 (m, 4H), 6.81 (s, 1 H), 5.42 (s, 2H), 3.96 (s, 3H), 2.66 (s, 3H).

HPLC/MS (5 min) retention time 2.80 min. LRMS: m/z 450 (M+1 , 1 *CI).

EXAMPLE 23

3-{[6-(3-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione Trichloromethylsilane (0.04 mL, 0.32 mmol) was added to a stirred suspension of the title compound of EXAMPLE 22 (0.030 g, 0.07 mmol) and sodium iodide (0.050 g, 0.33 mmol) in acetonitrile (1 .5 mL) and the mixture was stirred and heated to 70 °C in a sealed tube. After 60 min, the mixture was cooled and evaporated and the residue was treated with water. Saturated aqueous sodium thiosulphate solution was added dropwise to the stirred mixture until no further colour change was observed. After stirring for a further 60 min, the solid was filtered, washed with water and dried and then purified by flash chromatography (methanol-dichloromethane gradient, 0: 100 rising to 10:90) to give 0.014 g (0.03 mmol, 48% yield) of the title compound as a white solid. Purity 97%. ¹ H NMR (300 MHz, DMSO-d6) δ ppm 13.62 (br s, 1 H), 12.27 (s, 1 H), 8.62 (s, 1 H), 8.29 (s, 1 H), 7.17-7.47 (m, 4H), 6.18 (s, 1 H), 5.37 (s, 2H), 2.45 (s, 3H).

HPLC/MS (5 min) retention time 2.28 min.

LRMS: m/z 436 (M+1 , 1 *CI).

EXAMPLE 24 3-{[6-(3-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5,8- dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

Synthesized from the title compound of PREPARATION 34 and the crude title compound of PREPARATION 85 method B of EXAMPLE 3. Yield: 4% over two steps. Purity 99%. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.37 (s, 1 H), 8.32 (s, 1 H), 7.35 (m, 1 H), 7.23 (s, 1 H), 7.21 (s, 1 H), 7.06 - 7.13 (m, 1 H), 6.43 (s, 1 H), 5.36 (s, 2H), 3.68 (s, 3H), 2.65 (s, 3H)

UPLC/MS (3 min) retention time 1 .52 min. LRMS: m/z 450 (M+1 , 1 *CI). EXAMPLE 25

1 -Methyl-6-[(5-phenoxy-1 H-imidazo[4,5-b]pyrazin-2-yl)methyl]-1 ,6-dihydro-7H- [1 ,2,3]triazolo[4,5-d]pyrimidin-7-one

Synthesized from the title compound of PREPARATION 43 and the title compound of PREPARATION 78 following method A of EXAMPLE 3. Yield: 75%. Purity 96%.

¹ H NMR (300 MHz, DMSO-d6) δ ppm 8.56 (s, 1 H), 8.24 (s, 1 H), 7.41 (m, 2H), 7.19 (m, 3H), 5.50 (s, 2H), 4.33 (s, 3H).

HPLC/MS (5 min) retention time 1 .81 min.

LRMS: m/z 376 (M+1 ). EXAMPLE 26

1 -Methyl-6-({6-[4-(trifluoromethyl)phenoxy]-1 H-imidazo[4,5-b]pyrazin-2- yl}methyl)-1 ,6-dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one

Synthesized from the title compound of PREPARATION 43 and the title compound of PREPARATION 84 following method A of EXAMPLE 3. Yield: 34%. Purity 100%. ¹ H NMR (300 MHz, DMSO-d6) δ ppm 8.58 (s, 1 H), 8.36 (s, 1 H), 7.78 (d, 2H, J = 8.6 Hz), 7.40 (d, 2H, J = 8.6 Hz), 5.54 (s, 2H), 4.34 (s, 3H).

UPLC/MS (3 min) retention time 1 .49 min.

LRMS: m/z 444 (M+1 ).

EXAMPLE 27 6-{[5-(3-Bromophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-1 -methyl-1 ,6- dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one

Synthesized from the title compound of PREPARATION 43 and the title compound of PREPARATION 79 method A of EXAMPLE 3. Yield: 62%. Purity 97%.

¹ H NMR (300 MHz, DMSO-d6) δ ppm 13.61 (br s, 1 H), 8.57 (s, 1 H), 8.29 (s, 1 H), 7.20- 7.46 (m, 4H), 5.52 (s, 2H), 4.33 (s, 3H).

HPLC/MS (5 min) retention time 2.26 min.

LRMS: m/z 454, 456 (M+1 , 1 *Br). EXAMPLE 28

1 -Methyl-6-({5-[3-(trifluoromethyl)phenoxy]-1 H-imidazo[4,5-b]pyrazin-2- yl}methyl)-1 ,6-dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one

Synthesized from the title compound of PREPARATION 43 and the title compound of PREPARATION 80 following method A of EXAMPLE 3. Yield: 48%. Purity 99%.

¹ H NMR (300 MHz, DMSO-d6) δ ppm 13.61 (br s, 1 H), 8.57 (s, 1 H), 8.34 (s, 1 H), 7.52- 7.68 (m, 4H), 5.52 (s, 2H), 4.34 (s, 3H).

HPLC/MS (5 min) retention time 2.35 min.

LRMS: m/z 444 (M+1 ). EXAMPLE 29

3-({2-[(1 -Methyl-7-oxo-1 ,7-dihydro-6H-[1 ,2,3]triazolo[4,5-d]pyrimidin-6-yl)methyl]- 1 H-imidazo[4,5-b]pyrazin-5-yl}oxy)benzonitrile

Synthesized from the title compound of PREPARATION 43 and the title compound of PREPARATION 81 following method A of EXAMPLE 3. Yield: 27%. Purity 98%. ¹ H NMR (300 MHz, DMSO-d6) δ ppm 13.65 (br s, 1 H), 8.58 (s, 1 H), 8.34 (s, 1 H), 7.59- 7.79 (m, 4H), 5.53 (s, 2H), 4.34 (s, 3H).

HPLC/MS (5 min) retention time 1 .70 min.

LRMS: m/z 401 (M+1 ).

EXAMPLE 30 4-({2-[(1 -Methyl-7-oxo-1 ,7-dihydro-6H-[1 ,2,3]triazolo[4,5-d]pyrimidin-6-yl)methyl]- 1 H-imidazo[4,5-b]pyrazin-5-yl}oxy)benzonitrile

Synthesized from the title compound of PREPARATION 43 and the title compound of PREPARATION 82 method A of EXAMPLE 3. Yield: 35%. Purity 99%.

¹ H NMR (300 MHz, DMSO-d6) δ ppm 13.70 (br s, 1 H), 8.59 (s, 1 H), 8.36 (s, 1 H), 7.90 (d, 2H, J = 8.6 Hz), 7.39 (d, 2H, J = 8.6 Hz), 5.55 (s, 2H), 4.35 (s, 3H).

HPLC/MS (5 min) retention time 1 .67 min.

LRMS: m/z 401 (M+1 ). EXAMPLE 31

3-{[5-(4-Chlorophenoxy)-3H-imidazo[4,5-b]pyridin-2-yl]methyl}-5- methylimidazo[5,1 -f][1 ,2,4]triazin-4(3H)-one

Synthesized from the title compound of PREPARATION 45 and the title compound of PREPARATION 92 following method A of EXAMPLE 3. Yield: 10%. Purity 88%.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.99 (s, 1 H), 7.97 (br. s, 1 H), 7.69 (s, 1 H), 7.35 (d, 2H, J=8.99 Hz), 7.10 (d, 2H, J=8.99 Hz), 6.93 (d, 1 H, J=8.99 Hz), 5.18 (s, 2H), 2.65 (s, 3H)

UPLC/MS (3 min) retention time 1 .52 min. LRMS: m/z 408 (M+1 , 1 *CI). EXAMPLE 32

3-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-c]pyridin-2-yl]methyl}-5- methylimidazo[5,1 -f][1 ,2,4]triazin-4(3H)-one

Synthesized from the title compound of PREPARATION 45 and the crude title compound of PREPARATION 86 following method A of EXAMPLE 3. Yield: 7%. Purity 89%.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.81 (br.s, 1 H), 8.66 (s, 1 H), 8.00 (s, 1 H), 7.71 (s, 1 H), 7.33 (d, 2H, J=8.99 Hz), 7.03 (d, 2H, J=8.99 Hz), 6.93 (s, 1 H), 5.25 (s, 2H), 2.63 (s, 3H) UPLC/MS (3 min) retention time 1 .41 min.

LRMS: m/z 408 (M+1 , 1 *CI).

EXAMPLE 33

6-{[2-(4-Chlorophenoxy)-9H-purin-8-yl]methyl}-1 ,3-dimethyl-1 ,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one Synthesized from the title compound of PREPARATION 41 and the title compound of PREPARATION 87 following method A of EXAMPLE 3. Yield: 1 1 %. Purity 87%. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.87 (br.s, 1 H), 8.87 (s, 1 H), 8.02 (s, 1 H), 7.38 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H), 5.36 (s, 2H), 4.25 (s, 3H), 2.47 (s, 3H)

UPLC/MS (3 min) retention time 1 .42 min. LRMS: m/z 423 (M+1 , 1 *CI).

EXAMPLE 34.1 and EXAMPLE 34.2

3-{[6-(4-Chlorophenoxy)-1 -methyl-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylimidazo[5,1 -f][1 ,2,4]triazin-4(3H)-one

3-{[5-(4-Chlorophenoxy)-1 -methyl-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylimidazo[5,1 -f][1 ,2,4]triazin-4(3H)-one

Sodium hydride (60% dispersion in mineral oil, 0.006 g, 0.15 mmol) was added to a cooled (ice-bath), stirred solution of the title compound of EXAMPLE 3 (0.050 g, 0.12 mmol) in dry dimethylformamide (0.7 mL). After 30 min, methyl iodide (0.009 mL, 0.14 mmmol) was added and stirring was continued at 0 °C. After 4 h, the mixture was diluted with water and extracted with ethyl acetate and the organic layer was washed with brine, dried and evaporated to give a residue that was purified by flash chromatography (methanol-dichloromethane gradient, 0: 100 rising to 5:95) to give a mixture of the title compounds as a white solid. Isomers unassigned.

Major isomer: 9 mg (0.021 mmol, 17% yield). Purity 95%. ¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.23 (s, 1 H), 7.97 (s, 1 H), 7.84 (s, 1 H), 7.34 (d, 2H, J = 8.9 Hz), 7.13 (d, 2H, J = 8.9 Hz), 5.27 (s, 2H), 4.08 (s, 3H), 2.60 (s, 3H).

HPLC/MS (5 min) retention time 2.60 min.

LRMS: m/z 423 (M+1 , 1 *CI). Minor isomer: 6 mg (0.014 mmol, 12% yield). Purity 98%.

¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.33 (s, 1 H), 7.99 (s, 1 H), 7.90 (s, 1 H), 7.38 (d, 2H, J = 8.9 Hz), 7.12 (d, 2H, J = 8.9 Hz), 5.29 (s, 2H), 3.89 (s, 3H), 2.61 (s, 3H).

HPLC/MS (5 min) retention time 2.59 min. LRMS: m/z 423 (M+1 , 1 *CI). EXAMPLE 35

6-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyridin-2-yl]methyl}-1 ,3-dimethyl-1 ,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one Synthesized from the title compound of PREPARATION 41 and the title compound of PREPARATION 89 following method A of EXAMPLE 3. Yield: 37%. Purity 86%.

¹ H NMR (400 MHz, METHANOL-d4) δ ppm 8.39 (d, 1 H, J = 2.5 Hz), 8.28 (s, 1 H), 7.82 (d, 1 H, J = 2.5 Hz), 7.42 (d, 2H, J = 8.9 Hz), 7.09 (d, 2H, J = 8.9 Hz), 5.64 (s, 2H), 4.18 (s, 3H), 2.47 (s, 3H) UPLC/MS (3 min) retention time 1 .53 min.

LRMS: m/z 422 (M+1 , 1 *CI).

EXAMPLE 36

6-{[6-(4-Chlorophenoxy)-1 H-benzimidazol-2-yl]methyl}-1 ,3-dimethyl-1 ,6-dihydro- 7H-pyrazolo[4,3-d]pyrimidin-7-one Synthesized from the title compound of PREPARATION 41 and the title compound of PREPARATION 91 following method A of EXAMPLE 3. Yield: 7%. Purity 92%.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.09 (s, 1 H), 7.55 (s, 1 H), 7.25 (m, 3H), 6.99 (dd, J = 8.8, 2.3 Hz, 1 H), 6.89 (d, J = 8.8 Hz, 2H), 5.38 (s, 2H), 4.27 (s, 3H), 2.47 (s, 3H) UPLC/MS (3 min) retention time 1 .68 min. LRMS: m/z 421 (M+1 , 1 *CI). EXAMPLE 37

6-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-1 -methyl-1 ,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one Synthesized from the title compound of PREPARATION 2 and the title compound of PREPARATION 85 following method B of EXAMPLE 3. Yield: 8%. Purity 87%.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.35 (1 H, br. s.), 8.07 (1 H, s), 7.91 (1 H, s), 7.34 - 7.41 (2H, m), 7.12 (2H, d, J=8.6 Hz), 5.40 (2H, s), 4.33 (3H, s). UPLC/MS (3 min) retention time 1 .48 min. LRMS: m/z 409 (M+1 , 1 *CI). PHARMACOLOGICAL ACTIVITY

Calcium flux assay for the determination of TRPA1 activity CHO cells containing a tetracycline-inducible human TRPA1 expression system suspended in Ham^'s F12 containing 10% fetal bovine serum (FBS) and 1 μg ml tetracycline were plated into 384-well plates at a density of 15000 cells/well, 24 h before the assay. On the day of the assay, cells were washed 4x with Hank's balanced salt solution (HBSS). Cells were then loaded by adding 20 μΙ of dye solution (FLIPR Calcium 5 Express Kit, Molecular Devices) for 1 h at room temperature in the presence of 250 μΜ sulfinpyrazone. Test compounds were solved in DMSO 100% and prepared at 10 concentrations with 3 fold serial dilutions using the same solvent. Compound dose response curves were further dilute 100 times in assay buffer (HBSS containing 20 mM HEPES pH=7.4). 5 μΙ of compound plate content were added by the FLIPR Tetra from Molecular Devices into assay plates and fluorescence (Ex: 485 nm; Em: 525 nm) recorded during 15 minutes to assess agonist activity. After this incubation period, 5 μΙ of AITC were added by the FLIPR into the plates to reach a concentration of 1 μΜ (approximately AITC EC80) and fluorescence intensity recorded for 3 extra minutes to assess compound inhibition. Peak and base line were taken for the calculation of the ratio (Peak/Base Line). Percentage activation or inhibition for each compound was calculated by normalizing compound ratios to maximal and minimal ratios obtained for 100 μΜ and 1 μΜ of AITC, for agonist and antagonist mode respectively, as total response and vehicle (0.1 % DMSO) for basal response.

In the following table, IC50 values are represented by letters according to the value:

A: < 100 nM

B: 100 - 1000 nM

C: > 1000 nM Example FLIPR assay ICso (nM)

1 B

2 B

3 A

4 A

5 B

6 B

7 B

8 A

9 A

10 B

1 1 B

12 B

13 B

14 A

15 A

16 A

17 B

18 C

19 A

20 A

21 A

22 B

23 B

24 A

25 B 26 C

27 A

28 B

29 B

30 C

31 B

32 B

33 C

34.1 C

34.2 C

35 B

36 B

37 B

COMBINATIONS

The compounds of the invention may also be combined with other active compounds in the treatment of diseases indicated above. For example the compounds of the present invention can be combined with active substances which are known to be useful in the treatment of these diseases.

Examples of such active substances are: a. Corticoids and glucocorticoids, such as beclomethasone, betamethasone, betamethasone dipropionate, budesonide, dexamethasone, fluticasone furoate, fluticasone propionate, hydrocortisone, methylprednisolone, mometasone furoate, prednicarbate, prednisolone or prednisone; b. Calcineurin inhibitors, such as cyclosporine A, tacrolimus, pimecrolimus or voclosporin; c. Kappa opioid agonists, such as nalfurafine, nalbuphine, asimadoline or CR- d. Neurokinin receptor 1 antagonists, such as aprepitant, fosaprepitant, rolapitant, orvepitant, tradipitant or serlopitant; e. Dihydropteroate synthase inhibitors, such as dapsone or sulfadoxine; f. Histamine 1 (H1 ) receptor antagonists, such as azelastine, ebastine,

desloratadine, promethazine, mizolastine or cetirizine; g. Antiinflammatory agents, such as anti-IL31 , Phosphodiesterase IV inhibitors NSAIDs, JAK inhibitors or Syk inhibitors; h. Analgesics, such as paracetamol or opioids; i. Leukotriene receptor antagonists, such as 5-lipoxygenase inhibitors, 5- lipoxygenase activating protein inhibitors; j. Dihydrofolate reductase inhibitors, such as methotrexate or pralatrexate; k. Dihydroorotate dehydrogenase (DHODH) inhibitors such as leflunomide, teriflunomide or ASLAN-003 or LAS186323;

I. Purine antagonists, such as azathioprine, mercaptopurine or tioguanine; m. Antimalarials, such as hydroxichloroquine, chloroquine or quinacrine; n. Inosine-monophosphate dehydrogenase (IMPDH) inhibitors, such as

mycophenolate mophetyl, ribavirin or mizoribine; o. Fumaric acid esters, such as dimethyl fumarate; p. Vitamine D3 derivatives such as calcipotriol, calcitriol or tacalcitol; q. Retinoids, such as tazarotene, alitretinoin, acitretin or isotretinoin; r. Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) monoclonal antibodies, such as infliximab, adalimumab, certolizumab pegol or golimumab; s. Soluble Tumor necrosis factor-alpha (TNF-alpha) receptors such as

etanercept or CC-1 1050; t. Anti-lnterleukin 6 Receptor (IL-6R) antibody, such as tocilizumab, sarilumab, SA-237 or ALX-0061 ; u. Anti-lnterleukin 12 Receptor (IL-12R) / Interleukin 23 Receptor (IL-23R) antibody, such as ustekinumab; v. Anti-lnterleukin 17 Receptor (IL-17R) antibody, such as brodalumab; w. Anti-CD20 (B lymphocyte protein) antibody, such as rituximab, ofatumumab, obinutuzumab, ocrelizumab, ublituximab, veltuzumab, ocaratuzumab; x. Anti-lnterleukin 5 (IL-5) antibody, such as mepolizumab; y. Anti-lnterleukin 5 Receptor (IL-5R) antibody, such as benralizumab; z. Anti-lnterleukin 13 (IL-13) antibody, such as lebrikizumab or tralokinumab; aa. Anti-lnterleukin 4 Receptor (IL-4R) / Interleukin 13 Receptor (IL-13R)

antibody, such as dupilumab; bb. Anti-lnterleukin 17 (IL-17) antibody, such as secukinumab, ixekizumab or bimekizumab; cc. Anti-lnterleukin 1 Receptor (IL-1 R) antibody dd. Anti-lnmunoglobuline E (IgE) antibody, such as omalizumab or quilizumab; ee. Anti-B-cell activating factor (BAFF), such as belimumab or atacicept; ff. Anti-CD19 (B lymphocyte protein) monoclonal antibody, such as

blinatumomab, MEDI-551 or MOR-208; gg. Cysteinyl leukotriene (CysLT) receptor antagonists, such as montelukast, zafirlukast, tipelukast, masilukast; hh. Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitors, such as OC-459, AZD-1981 , ADC-3680, ARRY-502 or setipripant; ii. Topical anti-septics, such as triclosan, chlorhexidine, crystal violet 0.3% or sodium hypochlorite water-baths.

Accordingly, another embodiment of the invention is a combination product comprising (i) at least a compound of formula (I) as defined previously, and (ii) one or more active ingredients as described above, for simultaneous, separate or sequential use in the treatment of the human or animal body. The combinations of the invention may be used in the treatment of disorders which are susceptible to amelioration by TRPA1 inhibition or antagonism. Thus, the present application encompasses methods of treatment of these disorders, as well as the use of the combinations of the invention in the manufacture of a medicament for the treatment of these disorders.

The amount of each active which is required to achieve a therapeutic effect will, of course, vary with the particular active, the route of administration, the subject under treatment, and the particular disease or disorder being treated. However, an effective dosage is typically in the range of 0.01 -3000 mg, more preferably 0.5-1000 mg of active ingredient or the equivalent amount of a pharmaceutically acceptable salt thereof per day.

The active ingredients may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity. Preferably, the active ingredients are administered once or twice a day, most preferably once a day.

The active compounds in the combination product may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route.

PHARMACEUTICAL COMPOSITIONS

Pharmaceutical compositions according to the present invention comprise the compounds of the invention in association with a pharmaceutically acceptable diluent or carrier.

As used herein, the term pharmaceutical composition refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts, solvates, /V-oxides, tautomers, stereoisomers, or isotopically-labeled derivatives thereof, with other chemical components, such as

physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.

As used herein, a physiologically/pharmaceutically acceptable diluent or carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. A pharmaceutically acceptable excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound.

The invention further provides pharmaceutical compositions comprising the compounds of the invention in association with a pharmaceutically acceptable diluent or carrier together with one or more other therapeutic agents such as the previously described for use in the treatment of a pathological condition or disease susceptible to amelioration by TRPA1 antagonists or inhibitors, 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 is also directed to pharmaceutical compositions of the invention for use in the treatment of a pathological disease or disorder susceptible to

amelioration by TRPA1 antagonists or inhibitors, in particular wherein the pathological disease or disorder is as described above.

The invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by TRPA1 receptor antagonists in particular wherein the pathological condition or disease is as described above, comprising administering a therapeutically effective amount of a pharmaceutical composition of the invention.

The present invention also provides pharmaceutical compositions which comprise, as an active ingredient, at least a compound of formula (I) or a

pharmaceutically acceptable salt, solvate, /V-oxide, stereoisomer, tautomer or isotopically-labeled derivative thereof in association with a pharmaceutically acceptable excipient such as a carrier or diluent. The active ingredient may comprise 0.001 % to 99% by weight, preferably 0.01 % to 90% by weight, of the composition depending upon the nature of the formulation and whether further dilution is to be made prior to application. Preferably the compositions are made up in a form suitable for oral, oral mucosa, inhaled, topical, nasal mucosa, rectal/intravaginal, percutaneous, parenteral, ocular or aural administration. More preferably the compositions are made up in a form suitable for oral administration.

Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington: The Science and Practice of Pharmacy, 21 st Edition,

Lippincott Williams & Wilkins, Philadelphia, Pa., 2001 .

The pharmaceutically acceptable excipients which are admixed with the active compound or a pharmaceutically acceptable salts, solvates, /V-oxides, tautomers, stereoisomers, or isotopically-labeled derivatives thereof, to form the compositions of this invention are well-known per se and the actual excipients used depend inter alia on the intended method of administering the compositions. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additional suitable carriers for formulations of the compounds of the present invention can be found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001.

i) Oral Administration The compounds of the invention may be administered orally (peroral administration; per os (latin)). Oral administration involve swallowing, so that the compound is absorbed from the gut and delivered to the liver via the portal circulation (hepatic first pass metabolism) and finally enters the gastrointestinal (Gl) tract.

Compositions for oral administration may take the form of tablets, retard tablets, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, dry powder inhalation, or liquid preparations, such as mixtures, solutions, elixirs, syrups or suspensions, all containing the compound of the invention; such preparations may be made by methods well-known in the art. The active ingredient may also be presented as a bolus, electuary or paste. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, talc, gelatine, acacia, stearic acid, starch, lactose and sucrose.

A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.

Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.

For tablet dosage forms, depending on dose, the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% 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, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% 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, pregelatinized 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 include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% 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 are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet. Other conventional ingredients include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80 wt% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% 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 tabletting. The final formulation may include one or more layers and may be coated or uncoated; or encapsulated. The formulation of tablets is discussed in detail in "Pharmaceutical Dosage

Forms: Tablets, Vol. 1 ", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., 1980.

Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatine capsule. Where the composition is in the form of a soft gelatine capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatine capsule.

Solid formulations for oral administration 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 are described in U.S. Patent No.

6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can 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 disclosures of these references are incorporated herein by reference in their entireties.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include 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. The solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in association with, for example, sucrose to form a syrup. The suspensions may comprise an insoluble active compound of the invention or a pharmaceutically acceptable salt thereof in association with water, together with a suspending agent or flavouring agent. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

ii) Oral mucosa administration The compounds of the invention can also be administered via the oral mucosa administration. Within the oral mucosa cavity, delivery of drugs is classified into three categories: (a) sublingual delivery, which is systemic delivery of drugs through the mucosal membranes lining the floor of the mouth, (b) buccal delivery, which is drug administration through the mucosal membranes lining the cheeks (buccal mucosa), and (c) local delivery, which is drug delivery into the oral cavity.

Pharmaceutical products to be administered via the oral mucosa can be designed using mucoadhesive, quick dissolve tablets and solid lozenge formulations, which are formulated with one or more mucoadhesive (bioadhesive) polymers (such as hydroxy propyl cellulose, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, hydroxy propyl methyl cellulose, hydroxy ethyl cellulose, polyvinyl alcohol,

polyisobutylene or polyisoprene); and oral mucosal permeation enhancers (such as butanol, butyric acid, propranolol, sodium lauryl sulphate and others)

iii) Inhaled administration

The compounds of the invention can also be administered by inhalation, typically in the form of a dry powder from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer, or nebulizer, with or without the use of a suitable propellant. For intranasal use, the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin.

iv) Nasal mucosa administration

The compounds of the invention may also be administered via the nasal mucosa.

Typical compositions for nasal mucosa administration are typically applied by a metering, atomizing spray pump and are in the form of a solution or suspension in an inert vehicle such as water optionally in combination with conventional excipients such as buffers, anti-microbials, tonicity modifying agents and viscosity modifying agents.

v) Parenteral administration The compounds of the invention may also 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 non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

vi) Topical administration

The compounds 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, fibers, 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, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis,

phonophoresis, sonophoresis and microneedle or needle-free injection.

vii) Rectal/lntravaqinal administration

Compounds 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 alternatives may be used as appropriate. Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. viii) Ocular and aural administration.

Compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized 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 nonbiodegradable (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. ix) Other Technologies

Compounds 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.

The pharmaceutical formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.

The following preparations forms are cited as formulation examples:

Formulation Example 1 (Oral suspension)

Methyl paraben 0,1 g

Granulated sugar 25 g

Sorbitol (70% solution) 1 1 g

Veegum K 1 ,0 g

Flavoring 0,02 g

Dye 0,5 mg

Distilled water q.s. to 100 ml

Formulation Example 2 (Hard gelatine capsule for oral administration)

Modifications, which do not affect, alter, change or modify the essential aspects of the compounds, combinations or pharmaceutical compositions described, are included within the scope of the present invention.

Claims

1. A bicyclic heterocyclic derivative which is a compound of Formula (I) or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a steroisomer, or an isotopically-labeled derivative thereof,

Formula (I)

• G¹ is selected from the group consisting of a C atom and a N atom;

• n is an integer selected from 0 to 1 ;

• represents a single or a double bond;

• m is an integer selected from 0 to 1 ;

• R^b is selected from the group consisting of a hydrogen atom and a linear or branched C1-4 alkyl group, and • R^c is selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-4 alkyl group, a linear or branched C1-4 alkoxy group, an oxo group, a linear or branched C1-4 haloalkyl group, an amino group, a hydroxyl group, a C1-4 monoalkylamino group, a C1-4 dialkylamino group, a monocyclic C3-7 cycloalkyl group, a monocyclic 3- to 7-membered heterocyclyl group containing at least one heteroatom selected from O, S and N, and a benzyl group.

2. A bicyclic heterocylic derivative according to claim 1 wherein:

• G⁴ is a CH group;

· G⁶ and G⁸ are each independently selected from the group consisting of a N atom and a CH group;

• L is selected from a direct bond and an oxygen atom;

• R^a is selected from the group consisting of a halogen atom, a cyano group and a linear or branched C1-4 haloalkyl group; and

· R^c is selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-4 alkyl group, a linear or branched C1-4 alkoxy group, an oxo group, an amino group, a hydroxyl group, a C1-4 monoalkylamino group, a C1-4 dialkylamino group, a monocyclic C3-7 cycloalkyl group, a monocyclic 3- to 7-membered heterocyclyl group containing at least one heteroatom selected from O, S and N, and a benzyl group.

3. A bicyclic heterocyclic derivative according to claims 1 or 2, wherein n represents 0 and the compound of Formula (I) is represented by Formula (la) to Formula (Ig)

4. A bicyclic heterocyclic derivative according to claims 1 or 2, wherein n represents 1 and the compound of Formula (I) is represented by Formula (Ih) to Formula (Ij)

5. A bicyclic heterocyclic derivative according to claims 1 to 4 wherein:

• G⁹ and G¹⁰ are each independently selected from the group consisting of a N atom, a NH group and a N(CH3) group; preferably G⁹ and G¹⁰ are each independently selected from the group consisting of a N atom and a NH group; more preferably G⁹ is a N atom and G¹⁰ is a NH group or G⁹ is a NH group and G¹⁰ is a N atom; • G⁶ is a N atom;

• G⁷ is a CH group; and

• G⁸ is a N atom.

6. A bicyclic heterocyclic derivative according to claims 1 to 4 wherein: · G⁹ and G¹⁰ are each independently selected from the group consisting of a N atom and a NH group; preferably G⁹ is a N atom and G¹⁰ is a NH group or G⁹ is a NH group and G¹⁰ is a N atom;

• G⁶ is a CH group;

• G⁸ is selected from the group consisting of a N atom and a CH group.

7. A bicyclic heterocyclic derivative according to claims 1 to 4 wherein:

• G⁶ is a N atom;

• G⁷ is selected from the group consisting of a N atom and a CH group; and

• G⁸ is a CH group.

8. A bicyclic heterocyclic derivative according to claims 1 to 7 wherein: · R^a is selected from the group consisting of a halogen atom, a cyano group and a Ci-2 haloalkyl group; preferably R^a is selected from the group consisting of a CI atom, a Br atom, a cyano group, and a CF3 group.

9. A bicyclic heterocyclic derivative according to claims 1 to 7 wherein:

10. A bicyclic heterocyclic derivative according to claims 1 to 7 wherein:

• R^c is selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a C1-2 alkyl group, a C1-2 alkoxy group, an oxo group, an amino group, a hydroxyl group, a C1-2 monoalkylamino group, a C1-2 dialkylamino group, a monocyclic C3-6 cycloalkyl group, a monocyclic 6-membered heterocyclyl group containing at least one heteroatom selected from O, S and N, and a benzyl group; preferably R^c is selected from the group consisting of a hydrogen atom, a CI atom, a cyano group, a methyl group, an ethyl group, a methoxy group, an oxo group, a methylamino group, a dimethylamino group, a cyclopropyl group, a morpholinyl group and a benzyl group.

11. A bicyclic heterocyclic derivative according to claims 1 to 3 and 5 to 10, wherein the compound of Formula (I) is represented by Formula (la)' to Formula (lg)'

• L is an oxygen atom;

• m is an integer selected from 0 to 1 , preferably m is 1 ;

• R^b is selected from the group consisting of a hydrogen atom and a methyl group, preferably is a methyl group;

• R^c is selected from the group consisting of a hydrogen atom, a methyl group, cyclopropyl group, a benzyl group, and an oxo group.

12. A bicyclic heterocyclic derivative according to claims 1 to 2 and 4 to 10, wherein th compound of Formula (I) is represented by Formula (lh)' to Formula (lj)'

wherein:

L is an oxygen atom;

m is an integer selected from 0 to 1 , preferably m is 1 ;

R^b is selected from the group consisting of a hydrogen atom and a methyl group; and

R^c is selected from the group consisting of a hydrogen atom, a CI atom, a methyl group, a methoxy group, and an oxo group.

13. A bicyclic heterocyclic derivative according to claims 1 to 12, wherein the compound of Formula (I) is one of:

· 3-{[6-(3-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one

• 3-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5,7- dimethylimidazo[5,1 -f][1 ,2,4]triazin-4(3H)-one • 3-{[6-(4-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-7-ethyl-5- methylimidazo[5,1-f|[1 ,2,4]triazin-4(3H)-one

• 7-Benzyl-3-{[6-(4-chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5- methylimidazo[5,1-f|[1 ,2,4]triazin-4(3H)-one

1.5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

1.6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

• 3-{[6-(3-Chlorophenoxy)-1 H-imidazo[4,5-b]pyrazin-2-yl]methyl}-5,8- dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione • 1-Methyl-6-[(5-phenoxy-1 H-imidazo[4,5-b]pyrazin-2-yl)methyl]-1 ,6-dihydro-7H- [1 ,2,3]triazolo[4,5-d]pyrimidin-7-one

• 1-Methyl-6-({6-[4-(trifluoromethyl)phenoxy]-1 H-imidazo[4,5-b]pyrazin-2- yl}methyl)-1 ,6-dihydro-7H-[1 ,2,3]triazolo[4,5-d]pyrimidin-7-one

and a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a steroisomer, or an isotopically-labeled derivative thereof.

14. A bicyclic heterocyclic derivative according to claims 1 to 13, for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibition or antagonism of TRPA1.

15. A bicyclic heterocyclic derivative according to claims 1 to 13 for use according to claim 14, wherein the treatment is of a pathological condition or disease selected from acute and/or chronic pruritus, acute and/or chronic pain, inflammatory dermatological diseases, respiratory disorders, gastrointestinal inflammatory disorders and urinary tract disorders.

16. A pharmaceutical composition comprising a bicyclic heterocyclic derivative according to claims 1 to 13, in association with a pharmaceutically acceptable diluent or carrier.

17. Use of a bicyclic heterocyclic derivative according to claims 1 to 13, for the manufacture of a medicament for the treatment of a pathological condition or disease as defined in claim 14 or 15.

18. A method for treating a subject afflicted with a pathological condition or disease as defined in claim 14 or 15, which comprises administering to said subject a

therapeutically effective amount of a bicyclic heterocyclic derivative according to claims 1 to 13, or a pharmaceutical composition as defined in claim 16.

19. A combination product comprising (i) at least a bicyclic heterocyclic derivative according to claims 1 to 13, and (ii) one or more active ingredients selected from: a Corticoids and glucocorticoids, such as beclomethasone,

betamethasone, betamethasone dipropionate, budesonide, dexamethasone, fluticasone furoate, fluticasone propionate,

hydrocortisone, methylprednisolone, mometasone furoate, prednicarbate, prednisolone or prednisone;

b Calcineurin inhibitors, such as cyclosporine A, tacrolimus, pimecrolimus or voclosporin;

c Kappa opioid agonists, such as nalfurafine, nalbuphine, asimadoline or CR-845;

d Neurokinin receptor 1 antagonists, such as aprepitant, fosaprepitant, rolapitant, orvepitant, tradipitant or serlopitant;

e Dihydropteroate synthase inhibitors, such as dapsone or sulfadoxine; f. Histamine 1 (H 1 ) receptor antagonists, such as azelastine, ebastine, desloratadine, promethazine, mizolastine or cetirizine;

9 Antiinflammatory agents (such as anti-IL31 , Phosphodiesterase IV

inhibitors NSAIDs, JAK inhibitors or Syk inhibitors);

h Analgesics (such as paracetamol or opioids); i. Leukotriene receptor antagonists (such as 5-lipoxygenase inhibitors, 5- lipoxygenase activating protein inhibitors)

j. Dihydrofolate reductase inhibitors, such as methotrexate or pralatrexate; k. Dihydroorotate dehydrogenase (DHODH) inhibitors such as leflunomide, teriflunomide or ASLAN-003 or LAS186323;

I. Purine antagonists, such as azathioprine, mercaptopurine or tioguanine; m. Antimalarials, such as hydroxichloroquine, chloroquine or quinacrine; n. Inosine-monophosphate dehydrogenase (IMPDH) inhibitors, such as mycophenolate mophetyl, ribavirin or mizoribine;

o. Fumaric acid esters, such as dimethyl fumarate;

p. Vitamine D3 derivatives such as calcipotriol, calcitriol or tacalcitol;

q. Retinoids, such as tazarotene, alitretinoin, acitretin or isotretinoin;

r. Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) monoclonal

antibodies, such as infliximab, adalimumab, certolizumab pegol or golimumab;

s. Soluble Tumor necrosis factor-alpha (TNF-alpha) receptors such as etanercept or CC-1 1050;

t. Anti-lnterleukin 6 Receptor (IL-6R) antibody, such as tocilizumab,

sarilumab, SA-237 or ALX-0061 ;

u. Anti-lnterleukin 12 Receptor (IL-12R) / Interleukin 23 Receptor (IL-23R) antibody, such as ustekinumab;

v. Anti-lnterleukin 17 Receptor (IL-17R) antibody, such as brodalumab; w. Anti-CD20 (B lymphocyte protein) antibody, such as rituximab,

ofatumumab, obinutuzumab, ocrelizumab, ublituximab, veltuzumab, ocaratuzumab;

x. Anti-lnterleukin 5 (IL-5) antibody, such as mepolizumab;

y. Anti-lnterleukin 5 Receptor (IL-5R) antibody, such as benralizumab; z. Anti-lnterleukin 13 (IL-13) antibody, such as lebrikizumab or

tralokinumab;

aa. Anti-lnterleukin 4 Receptor (IL-4R) / Interleukin 13 Receptor (IL-13R) antibody, such as dupilumab;

bb. Anti-lnterleukin 17 (IL-17) antibody, such as secukinumab, ixekizumab or bimekizumab;

cc. Anti-lnterleukin 1 Receptor (IL-1 R) antibody

dd. Anti-lnmunoglobuline E (IgE) antibody, such as omalizumab or

quilizumab; ee. Anti-B-cell activating factor (BAFF), such as belimumab or atacicept; ff. Anti-CD19 (B lymphocyte protein) monoclonal antibody, such as

blinatumomab, MEDI-551 or MOR-208;

gg. Cysteinyl leukotriene (CysLT) receptor antagonists, such as montelukast, zafirlukast, tipelukast, masilukast;

hh. Chemoattractant receptor homologous molecule expressed on TH2 cells

(CRTH2) inhibitors, such as OC-459, AZD-1981 , ADC-3680, ARRY-502 or setipripant;

ii. Topical anti-septics, such as triclosan, chlorhexidine, crystal violet 0.3% or sodium hypochlorite water-baths. for simultaneous, separate or sequential use in the treatment of the human or animal body.